Alzheimer's: Unraveling the Mystery )NTRODUCTION
h.EVER HAVE ) LOVED MY HUSBAND OF YEARS MORE THAN ) DO TODAY4HOUGH HE MAY NOT KNOW )M HIS WIFE HE DOES KNOW THAT MY PRESENCE MEANS HIS FAVORITE FOODS AND DRINKS ARE NEAR AT HAND) WONDER WHY ) CAN SIT DAILY BY HIS SIDE AS ) PLAY TAPES RELATE BITS AND PIECES OF NEWS HOLD HIS HAND TELL HIM ) LOVE HIM 9ET ) AM CONTENT WHEN ) AM WITH HIM THOUGH ) GRIEVE FOR THE LOSS OF HIS SMILE THE SOUND OF MY NAME ON HIS LIPSv
HIS EXCERPT FROM ,ESSONS ,EARNED 3HARED STUDYING !$ SO THAT THEY CAN lND WAYS TO MANAGE %XPERIENCES IN #OPING BY PARTICIPANTS TREAT AND ONE DAY PREVENT THIS TERRIBLE DISEASE OF THE $UKE 5NIVERSITY !LZHEIMER 3UPPORT 'ROUPS GIVES A GLIMPSE INTO !$ ! '2/7).' .!4)/.!, 02/",%- WHAT A PERSON WITH !LZHEIMERS DISEASE !$ AND 4 &OR MANY OLDER ADULTS AND THEIR FAMILIES !$ A FAMILY CAREGIVER MIGHT EXPERIENCE AS THE DISEASE STANDS IN THE WAY OF THE h'OLDEN 9EARSv )T ALSO PROGRESSES 4HE GRADUAL SLIPPING AWAY OF MIND PRESENTS A MAJOR PROBLEM FOR OUR HEALTH CARE SYSTEM AND MEMORY IS FRIGHTENING AND FRUSTRATING BOTH AND SOCIETY AS A WHOLE !$ IS THE MOST COMMON FOR THE PERSON WITH THE DISEASE AND FOR FAMILY AND CAUSE OF DEMENTIA AMONG OLDER PEOPLE 2ECENT FRIENDS AND CAN ELICIT STRONG FEELINGS OF LOVE GRIEF ESTIMATES OF HOW MANY PEOPLE IN THE 5NITED 3TATES ANGER AND EXHAUSTION CURRENTLY HAVE !$ DIFFER WITH NUMBERS RANGING !$ IS AN IRREVERSIBLE PROGRESSIVE BRAIN DISEASE FROM MILLION TO MILLION DEPENDING ON HOW THAT SLOWLY DESTROYS MEMORY AND THINKING SKILLS !$ IS MEASURED "UT SCIENTISTS AGREE THAT UNLESS EVENTUALLY EVEN THE ABILITY TO CARRY OUT THE SIMPLEST THE DISEASE CAN BE EFFECTIVELY TREATED OR PREVENTED TASKS )N MOST PEOPLE WITH !$ SYMPTOMS lRST THE NUMBERS WILL INCREASE SIGNIlCANTLY IF CURRENT APPEAR AFTER AGE !$ IS CAUSED BY A DISEASE THAT POPULATION TRENDS CONTINUE AFFECTS THE BRAIN )N THE ABSENCE OF DISEASE THE /UR AGING SOCIETY MAKES !$ AN ESPECIALLY CRITI HUMAN BRAIN OFTEN CAN FUNCTION WELL INTO THE CAL ISSUE ! #ENSUS "UREAU REPORT ON AGING TH DECADE OF LIFE IN THE 5NITED 3TATES NOTES THAT THE POPULATION .OT SO LONG AGO WE WERE NOT ABLE TO DO AGE AND OLDER IS EXPECTED TO DOUBLE IN SIZE TO MUCH FOR PEOPLE WITH !$ 4ODAY THAT SITUATION ABOUT MILLION PEOPLE WITHIN THE NEXT YEARS IS CHANGING 4HOUSANDS OF SCIENTISTS VOLUNTARY -OREOVER THE AND OLDER AGE GROUP IS NOW THE ORGANIZATIONS AND HEALTH CARE PROFESSIONALS ARE FASTEST GROWING SEGMENT OF THE POPULATION 4HIS IS ALL THE MORE IMPORTANT FOR A NEURODEGENERATIVE
3EE THE GLOSSARY ON PAGE FOR DElNITIONS OF BOLDFACED TERMS
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY DISEASE LIKE !$ BECAUSE THE NUMBER OF PEOPLE BEGINS MANY YEARS PERHAPS EVEN DECADES WITH THE DISEASE DOUBLES FOR EVERY YEAR AGE BEFORE SYMPTOMS EMERGE $ISCOVERING WAYS TO INTERVAL BEYOND AGE IDENTIFY !$ IN THE EARLIEST STAGES AND HALT OR SLOW !$ NOT ONLY AFFECTS THE PEOPLE WITH THE DISEASE ITS PROGRESS WILL BENElT INDIVIDUALS FAMILIES AND OF COURSE 4HE NUMBER OF !$ CAREGIVERSAND THE .ATION AS A WHOLE THEIR NEEDSCAN BE EXPECTED TO RISE RAPIDLY AS THE POPULATION AGES AND AS THE NUMBER OF PEOPLE !"/54 4()3 "//+ WITH !$ GROWS $URING THEIR YEARS OF !$ CARE 4HINKING ABOUT !$ LEADS TO QUESTIONS SUCH AS GIVING SPOUSES RELATIVES AND FRIENDS EXPERIENCE 7HAT CAUSES IT 7HAT CAN BE DONE TO CURE IT OR GREAT EMOTIONAL PHYSICAL AND lNANCIAL CHALLENGES PREVENT IT 7ILL ) GET IT 3CIENTISTS ASK THE SAME !S THE DISEASE RUNS ITS COURSE AND THE ABILITIES OF TYPES OF QUESTIONS AND THIS BOOK DESCRIBES THEIR PEOPLE WITH !$ STEADILY DECLINE FAMILY MEMBERS SEARCH FOR ANSWERS )T IS WRITTEN FOR PEOPLE WITH FACE DIFlCULT AND OFTEN COSTLY DECISIONS ABOUT THE !$ THEIR FAMILY MEMBERS AND FRIENDS CAREGIVERS LONG TERM CARE OF THEIR LOVED ONES AND OTHERS INTERESTED IN !$ 4HE GROWING NUMBER OF PEOPLE WITH !$ AND 4HIS BOOK HAS FOUR SECTIONS THE COSTS ASSOCIATED WITH THE DISEASE ALSO PUT A N 0ART GIVES READERS SOME BASICS ABOUT THE HEAVY ECONOMIC BURDEN ON SOCIETY 4HE NATIONAL HEALTHY BRAIN )LLUSTRATIONS AND TEXT SHOW WHAT A DIRECT AND INDIRECT COSTS OF CARING FOR PEOPLE WITH HEALTHY BRAIN LOOKS LIKE AND HOW IT WORKS !$ ARE ESTIMATED TO BE MORE THAN BILLION A N 0ART FOCUSES ON WHAT HAPPENS IN THE BRAIN YEAR ! STUDY PROVIDED AN EQUALLY SOBERING DURING !$ PICTURE OF THE IMPACT OF !$ )T IS ESTIMATED THAT IF CURRENT !$ TRENDS CONTINUE TOTAL &EDERAL -EDICARE SPENDING TO TREAT BENElCIARIES WITH THE 6ISIT THE .ATIONAL )NSTITUTE ON !GING DISEASE WILL INCREASE FROM BILLION IN TO .)! !LZHEIMERS $ISEASE %DUCATION BILLION IN AND 2EFERRAL !$%!2 #ENTER WEBSITE &OR THESE REASONS !$ IS AN URGENT RESEARCH AT WWWNIANIHGOV!LZHEIMERS!$VIDEO PRIORITY 7E NEED TO lND WAYS TO MANAGE AND TREAT TO VIEW AN ANIMATION THAT HELPS THIS PART !$ BECAUSE OF ITS BROAD REACHING AND DEVASTATING OF THE BOOK COME ALIVE IMPACT 7E NOW KNOW THAT THE DISEASE PROCESS
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY )NTRODUCTION
N 0ART TALKS ABOUT CURRENT RESEARCH AND THE ! BOOK LIKE THIS IS POSSIBLE ONLY BECAUSE OF ADVANCES THAT ARE BRINGING US CLOSER TO WAYS OF THE MAJOR PROGRESS THAT SCIENTISTS THROUGHOUT THE MANAGING AND EVENTUALLY DEFEATING !$ WORLD HAVE MADE .OT LONG AGO WE KNEW VERY N 0ART FOCUSES ON ISSUES IMPORTANT TO !$ LITTLE ABOUT !$ OTHER THAN SOME FACTS ABOUT ITS CAREGIVERS AND FAMILIES INCLUDING CURRENT RESEARCH MAJOR CHARACTERISTICS 4ODAY WE ARE BEGINNING THAT IS lNDING WAYS TO IMPROVE CAREGIVER SUPPORT TO UNDERSTAND MORE ABOUT WHAT !$ IS AND WHO GETS IT HOW AND WHY IT DEVELOPS AND WHAT COURSE 4HE END OF THE BOOK INCLUDES A LIST OF PUBLICA IT FOLLOWS 7E ARE LEARNING ABOUT THE COMPLEX TIONS AND RESOURCES THAT PEOPLE WITH !$ FAMILY INTERFACE BETWEEN !$ AND NORMAL AGE RELATED MEMBERS AND CAREGIVERS MAY lND USEFUL AS THEY CHANGES IN THE BRAIN 7E ALSO ARE GETTING MUCH LIVE DAY TO DAY WITH THE DISEASE
4HEN AND .OW 4HE &AST 0ACE OF $EVELOPMENTS IN !$ 2ESEARCH
S SHOWN IN THIS TIMELINE WE HAVE LEARNED A LOT SINCE $R !LZHEIMER PRESENTED THE CASE OF HIS PATIENT !UGUSTE $ ! 4HE PACE OF RESEARCH CONTINUES TO ACCELERATE AS NEW lNDINGS OPEN MORE AND MORE DOORS TO DISCOVERY / /S N $R !LOIS !LZHEIMER A 'ERMAN NEUROLOGIST AND N 3CIENTISTS DISCOVER A LINK BETWEEN DEMENTIA AND PSYCHIATRIST DESCRIBES THE CASE OF A YEAR OLD THE NUMBER OF PLAQUES PRESENT IN THE BRAIN !$ IS WOMAN !UGUSTE $ WHO HAD BEEN ADMITTED TO RECOGNIZED AS A DISTINCT DISEASE NOT A NORMAL PART A HOSPITAL YEARS EARLIER WITH A CLUSTER OF UNUSUAL OF AGING SYMPTOMS INCLUDING PROBLEMS WITH COMPREHENSION AND MEMORY AN INABILITY TO SPEAK DISORIENTATION /S BEHAVIORAL PROBLEMS AND HALLUCINATIONS !FTER HER N 3CIENTISTS lND THAT LEVELS OF ACETYLCHOLINE A DEATH $R !LZHEIMER EXAMINED HER BRAIN TISSUE AND NEUROTRANSMITTER IMPORTANT IN MEMORY FORMATION DESCRIBED TWO OF THE HALLMARKS OF !$NUMEROUS FALLS SHARPLY IN PEOPLE WITH !$ 4HIS DISCOVERY IS GLOBS OF STICKY PROTEINS IN THE SPACES BETWEEN ONE OF THE lRST TO LINK !$ WITH BIOCHEMICAL CHANGES NEURONS BETA AMYLOID PLAQUES AND A TANGLED IN THE BRAIN BUNDLE OF lBRILS WITHIN NEURONS NEUROlBRILLARY N h!LZHEIMERS DISEASEv BECOMES A COMMON TERM AS TANGLES RECOGNITION OF !$ AS A MAJOR PUBLIC HEALTH PROBLEM GROWS /S n /S N .)! IS ESTABLISHED N "ELIEF PERSISTS THAT hSENILE DEMENTIAv IS A NORMAL PART OF AGING /S N $IAGNOSTIC CRITERIA FOR !$ ARE ESTABLISHED /S N 'ENETIC LINKS TO EARLY ONSET !$ BEGIN TO SURFACE N 3CIENTISTS STUDY THE BIOLOGICAL STRUCTURE OF PLAQUES N #ONGRESS MANDATES .)! AS LEAD &EDERAL AGENCY AND TANGLES FOR !$ RESEARCH
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY BETTER AT DIAGNOSING IT EARLY AND ACCURATELY -OST FUNCTION IN HEALTHY OLDER PEOPLE AND IDENTIlED IMPORTANT WE NOW HAVE SOME PROMISING LEADS ON WAYS WE MIGHT LESSEN NORMAL AGE RELATED DECLINES POSSIBLE TREATMENTS 3TUDIES ALSO ARE BEGINNING IN MENTAL FUNCTION -OST IMPORTANTLY THIS ACCU TO FOCUS ON PREVENTIVE STRATEGIES BY EXAMINING MULATED RESEARCH HAS INCREASED OUR APPRECIATION LIFESTYLE FACTORS THAT MIGHT INmUENCE A PERSONS FOR JUST HOW COMPLEX !$ IS )T IS NOW CLEAR THAT RISK OF DEVELOPING !$ MANY SCIENTIlC AND CLINICAL DISCIPLINES NEED TO 3INCE THE S RESEARCH SUPPORTED BY WORK TOGETHER TO UNTANGLE THE GENETIC BIOLOGICAL .)! AND OTHER ORGANIZATIONS HAS DEEPENED AND ENVIRONMENTAL FACTORS THAT OVER MANY OUR UNDERSTANDING OF THIS DEVASTATING DISEASE YEARS SET A PERSON ON A COURSE THAT ULTIMATELY )T ALSO HAS EXPANDED OUR KNOWLEDGE OF BRAIN RESULTS IN !$
N 3CIENTISTS START TO UNRAVEL THE BIOLOGICAL PATHWAYS ///S THAT LEAD TO THE DEVELOPMENT OF BETA AMYLOID N 4HE &$! APPROVES OTHER !$ DRUGS INCLUDING PLAQUES IN THE BRAIN RIVASTIGMINE %XELON GALANTAMINE 2AZADYNE N !BNORMAL TAU PROTEIN IN TANGLES IS IDENTIlED DONEPEZIL !RICEPT AND MEMANTINE .AMENDA TO TREAT SYMPTOMS OF !$ /S N %ARLY WORK ON AN !$ VACCINE BEGINS N 4HE 53 &OOD AND $RUG !DMINISTRATION &$! N -ANY NEW !$ CLINICAL TRIALS INITIATIVES AND APPROVES TACRINE #OGNEX THE lRST DRUG USED TO STUDIES ARE LAUNCHED LOOKING AT A BROAD ARRAY OF TREAT !$ 4HIS DRUG HAS SINCE BEEN REPLACED BY TRANSLATIONAL TREATMENT AND PREVENTION ISSUES OTHER MEDICATIONS N .EW TRANSGENIC MOUSE MODELS INCLUDING ONE N 'ENETIC MUTATIONS LINKED TO EARLY ONSET AND THAT DEVELOPS BOTH PLAQUES AND TANGLES ARE LATE ONSET !$ ARE DISCOVERED DEVELOPED N 4HE FIRST TRANSGENIC MOUSE MODEL OF !$ IS N 0ITTSBURGH #OMPOUND " 0I" IS DEVELOPED ALLOWING CREATED RESEARCHERS TO hSEEv BETA AMYLOID PLAQUES IN THE N !DDITIONAL DIAGNOSTIC CRITERIA ARE DEVELOPED FOR !$ BRAINS OF LIVING PEOPLE N #HARACTERISTICS OF MILD COGNITIVE IMPAIRMENT ARE N 4HE GROWING SOPHISTICATION OF NEUROIMAGING DESCRIBED AND DElNED TECHNIQUES GENETICS MEMORY AND COGNITIVE N .)! LAUNCHES THE !LZHEIMERS $ISEASE %DUCATION TESTS STRUCTURED INTERVIEWS AND OTHER TECHNOLOGIES AND 2EFERRAL #ENTER !$ #OOPERATIVE 3TUDY AND IMPROVE OUR ABILITY TO IDENTIFY PEOPLE AT HIGH OTHER INITIATIVES TO CONDUCT AND SUPPORT !$ TREATMENT RISK OF !$ AND PREVENTION CLINICAL TRIALS
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY O UNDERSTAND !$ IT IS IMPORTANT TO 4HE "RAINS KNOW A BIT ABOUT THE BRAIN 4HIS PART OF 6ITAL 3TATISTICS 5NRAVELING THE -YSTERY GIVES AN INSIDE VIEW OF THE NORMAL BRAIN HOW IT WORKS AND WHAT HAPPENS DURING AGING 4 !$5,4 7%)'(4 4HE BRAIN IS A REMARKABLE ORGAN 3EEMINGLY ABOUT POUNDS WITHOUT EFFORT IT ALLOWS US TO CARRY OUT EVERY ! $ 5 , 4 3 ) : % ELEMENT OF OUR DAILY LIVES )T MANAGES MANY BODY A MEDIUM CAULImOWER
FUNCTIONS SUCH AS BREATHING BLOOD CIRCULATION . 5 - " % 2 / & . % 5 2 / . 3 AND DIGESTION WITHOUT OUR KNOWLEDGE OR ABOUT BILLION DIRECTION )T ALSO DIRECTS ALL THE FUNCTIONS WE CARRY OUT CONSCIOUSLY 7E CAN SPEAK HEAR SEE MOVE .5-"%2 /& 39.!03%3 REMEMBER FEEL EMOTIONS AND MAKE DECISIONS THE GAPS BETWEEN NEURONS BECAUSE OF THE COMPLICATED MIX OF CHEMICAL AND ABOUT TRILLION ELECTRICAL PROCESSES THAT TAKE PLACE IN OUR BRAINS .5-"%2 /& #!0),,!2)%3 4HE BRAIN IS MADE OF NERVE CELLS AND SEVERAL TINY BLOOD VESSELS OTHER CELL TYPES .ERVE CELLS ALSO ARE CALLED ABOUT BILLION NEURONS 4HE NEURONS OF ALL ANIMALS FUNCTION IN BASICALLY THE SAME WAY EVEN THOUGH ANIMALS CAN BE VERY DIFFERENT FROM EACH OTHER .EURONS SURVIVE THE BRAIN IS ONLY ABOUT PERCENT OF THE BODYS AND FUNCTION WITH THE HELP AND SUPPORT OF GLIAL WEIGHT IT RECEIVES PERCENT OF THE BODYS BLOOD CELLS THE OTHER MAIN TYPE OF CELL IN THE BRAIN 'LIAL SUPPLY "ILLIONS OF TINY BLOOD VESSELS OR CAPILLARIES CELLS HOLD NEURONS IN PLACE PROVIDE THEM WITH CARRY OXYGEN GLUCOSE THE BRAINS PRINCIPAL SOURCE NUTRIENTS RID THE BRAIN OF DAMAGED CELLS AND OTHER OF ENERGY NUTRIENTS AND HORMONES TO BRAIN CELLS CELLULAR DEBRIS AND PROVIDE INSULATION TO NEURONS SO THEY CAN DO THEIR WORK #APILLARIES ALSO CARRY IN THE BRAIN AND SPINAL CORD )N FACT THE BRAIN AWAY WASTE PRODUCTS HAS MANY MORE GLIAL CELLS THAN NEURONSSOME SCIENTISTS ESTIMATE EVEN TIMES AS MANY !NOTHER ESSENTIAL FEATURE OF THE BRAIN IS ITS "RAIN ENORMOUS NETWORK OF BLOOD VESSELS %VEN THOUGH
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 4HE "ASICS OF THE (EALTHY "RAIN )NSIDE THE (UMAN "RAIN
HE BRAIN HAS MANY PARTS EACH OF WHICH N 4HE OCCIPITAL LOBE WHICH IS AT THE BACK OF THE IS RESPONSIBLE FOR PARTICULAR FUNCTIONS BRAIN IS CONCERNED WITH VISION 4HE FOLLOWING SECTION DESCRIBES A FEW N 4HE TEMPORAL LOBE WHICH RUNS ALONG THE KEY STRUCTURES AND WHAT THEY DO SIDE OF THE BRAIN UNDER THE FRONTAL AND PARI 4 ETAL LOBES DEALS WITH THE SENSES OF SMELL TASTE 4(% -!). 0,!9%23 AND SOUND AND THE FORMATION AND STORAGE OF N 4WO CEREBRAL HEMISPHERES ACCOUNT FOR PER MEMORIES CENT OF THE BRAINS WEIGHT 4HE BILLIONS OF NEURONS N 4HE CEREBELLUM SITS ABOVE THE BRAIN STEM AND IN THE TWO HEMISPHERES ARE CONNECTED BY THICK BENEATH THE OCCIPITAL LOBE )T TAKES UP A LITTLE MORE BUNDLES OF NERVE CELL lBERS CALLED THE CORPUS CAL THAN PERCENT OF THE BRAIN 4HIS PART OF THE LOSUM 3CIENTISTS NOW THINK THAT THE TWO HEMI BRAIN PLAYS ROLES IN BALANCE AND COORDINATION 4HE SPHERES DIFFER NOT SO MUCH IN WHAT THEY DO THE CEREBELLUM HAS TWO HEMISPHERES WHICH RECEIVE hLOGICAL VERSUS ARTISTICv NOTION BUT IN HOW THEY INFORMATION FROM THE EYES EARS AND MUSCLES AND PROCESS INFORMATION 4HE LEFT HEMISPHERE APPEARS TO FOCUS ON DETAILS SUCH AS RECOGNIZING A PARTICULAR FACE IN A CROWD 4HE RIGHT HEMISPHERE FOCUSES ON BROAD BACKGROUND SUCH AS UNDERSTANDING THE RELA &RONT 6IEW OF THE "RAIN TIVE POSITION OF OBJECTS IN A SPACE 4HE CEREBRAL HEMISPHERES HAVE AN OUTER LAYER CALLED THE CEREBRAL CORTEX 4HIS IS WHERE THE BRAIN PROCESSES SENSORY INFORMATION RECEIVED FROM THE OUTSIDE WORLD CONTROLS VOLUNTARY MOVEMENT AND REGULATES COGNITIVE FUNCTIONS SUCH AS THINKING LEARNING SPEAKING REMEMBERING AND MAKING DECISIONS 4HE HEMISPHERES HAVE FOUR LOBES EACH OF WHICH HAS DIFFERENT ROLES N 4HE FRONTAL LOBE WHICH IS IN THE FRONT OF THE BRAIN CONTROLS hEXECUTIVE FUNCTIONv ACTIVITIES LIKE THINKING ORGANIZING PLANNING AND PROBLEM SOLVING AS WELL AS MEMORY ATTENTION AND MOVEMENT N 4HE PARIETAL LOBE WHICH SITS BEHIND THE FRONTAL LOBE DEALS WITH THE PERCEPTION AND INTEGRATION OF STIMULI FROM THE SENSES
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 3IDE 6IEW OF THE "RAIN
4HIS ILLUSTRATION SHOWS A THREE DIMENSIONAL SIDE VIEW OF ONE OF TWO CEREBRAL HEMISPHERES OF THE BRAIN 4O HELP VISUALIZE THIS IMAGINE LOOKING AT THE CUT SIDE OF AN AVOCADO SLICED LONG WAYS IN HALF WITH THE PIT STILL IN THE FRUIT )N THIS ILLUSTRATION THE hPITv IS SEVERAL KEY STRUCTURES THAT LIE DEEP WITHIN THE BRAIN THE HYPOTHALAMUS AMYGDALA AND HIPPOCAMPUS AND THE BRAIN STEM 0!24 4HE "ASICS OF THE (EALTHY "RAIN
JOINTS ABOUT THE BODYS MOVEMENTS AND POSITION N 4HE HIPPOCAMPUS WHICH IS BURIED IN THE /NCE THE CEREBELLUM PROCESSES THAT INFORMATION IT TEMPORAL LOBE IS IMPORTANT FOR LEARNING AND SENDS INSTRUCTIONS TO THE BODY THROUGH THE REST OF SHORT TERM MEMORY 4HIS PART OF THE BRAIN IS THE BRAIN AND SPINAL CORD 4HE CEREBELLUMS WORK THOUGHT TO BE THE SITE WHERE SHORT TERM ALLOWS US TO MOVE SMOOTHLY MAINTAIN OUR BALANCE MEMORIES ARE CONVERTED INTO LONG TERM AND TURN AROUND WITHOUT EVEN THINKING ABOUT IT )T MEMORIES FOR STORAGE IN OTHER BRAIN AREAS ALSO IS INVOLVED WITH MOTOR LEARNING AND REMEM N 4HE THALAMUS LOCATED AT THE TOP OF THE BRAIN BERING HOW TO DO THINGS LIKE DRIVE A CAR OR WRITE STEM RECEIVES SENSORY AND LIMBIC INFORMATION YOUR NAME PROCESSES IT AND THEN SENDS IT TO THE CEREBRAL N 4HE BRAIN STEM SITS AT THE BASE OF THE BRAIN )T CORTEX CONNECTS THE SPINAL CORD WITH THE REST OF THE BRAIN N 4HE HYPOTHALAMUS A STRUCTURE UNDER %VEN THOUGH IT IS THE SMALLEST OF THE THREE MAIN THE THALAMUS MONITORS ACTIVITIES SUCH AS BODY PLAYERS ITS FUNCTIONS ARE CRUCIAL TO SURVIVAL 4HE TEMPERATURE AND FOOD INTAKE )T ISSUES INSTRUCTIONS BRAIN STEM CONTROLS THE FUNCTIONS THAT HAPPEN TO CORRECT ANY IMBALANCES 4HE HYPOTHALAMUS ALSO AUTOMATICALLY TO KEEP US ALIVEOUR HEART RATE CONTROLS THE BODYS INTERNAL CLOCK BLOOD PRESSURE AND BREATHING )T ALSO RELAYS INFORMATION BETWEEN THE BRAIN AND THE SPINAL 4(% "2!). ). !#4)/. CORD WHICH THEN SENDS OUT MESSAGES TO THE 3OPHISTICATED BRAIN IMAGING TECHNIQUES ALLOW MUSCLES SKIN AND OTHER ORGANS 3LEEP AND SCIENTISTS TO MONITOR BRAIN FUNCTION IN LIVING DREAMING ARE ALSO CONTROLLED BY THE BRAIN STEM PEOPLE AND TO SEE HOW VARIOUS PARTS OF THE BRAIN ARE USED FOR DIFFERENT KINDS OF TASKS 4HIS IS /4(%2 #25#)!, 0!243 OPENING UP WORLDS OF KNOWLEDGE ABOUT BRAIN 3EVERAL OTHER ESSENTIAL PARTS OF THE BRAIN LIE DEEP FUNCTION AND HOW IT CHANGES WITH AGE OR DISEASE INSIDE THE CEREBRAL HEMISPHERES IN A NETWORK OF /NE OF THESE IMAGING TECHNIQUES IS CALLED STRUCTURES CALLED THE LIMBIC SYSTEM 4HE LIMBIC POSITRON EMISSION TOMOGRAPHY OR 0%4 SYSTEM LINKS THE BRAIN STEM WITH THE HIGHER SCANNING 3OME 0%4 SCANS MEASURE BLOOD REASONING ELEMENTS OF THE CEREBRAL CORTEX )T PLAYS mOW AND GLUCOSE METABOLISM THROUGHOUT THE A KEY ROLE IN DEVELOPING AND CARRYING OUT INSTINC BRAIN &OR MORE ON METABOLISM SEE PAGE TIVE BEHAVIORS AND EMOTIONS AND ALSO IS IMPOR $URING A 0%4 SCAN A SMALL AMOUNT OF A RADIOAC TANT IN PERCEIVING SMELLS AND LINKING THEM WITH TIVE SUBSTANCE IS ATTACHED TO A COMPOUND SUCH MEMORY EMOTION AND INSTINCTIVE BEHAVIORS 4HE AS GLUCOSE AND INJECTED INTO THE BLOODSTREAM LIMBIC SYSTEM INCLUDES 4HIS TRACER SUBSTANCE EVENTUALLY GOES TO THE BRAIN 7HEN NERVE CELLS IN A REGION OF THE BRAIN BECOME N 4HE AMYGDALA AN ALMOND SHAPED STRUCTURE ACTIVE BLOOD mOW AND GLUCOSE METABOLISM IN INVOLVED IN PROCESSING AND REMEMBERING STRONG THAT REGION INCREASE 7HEN COLORED TO REmECT EMOTIONS SUCH AS FEAR )T IS LOCATED IN THE TEMPORAL METABOLIC ACTIVITY INCREASES USUALLY LOOK RED LOBE JUST IN FRONT OF THE HIPPOCAMPUS AND YELLOW 3HADES OF BLUE AND BLACK INDICATE DECREASED OR NO ACTIVITY WITHIN A BRAIN REGION
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY )N ESSENCE A 0%4 SCAN PRODUCES A hMAPv OF SEROTONIN 4O LEARN ABOUT EXCITING DEVELOPMENTS THE ACTIVE BRAIN USING ONE NEW TRACER SEE 0I" AND 0%4 ON PAGE 3CIENTISTS CAN USE 0%4 SCANS TO SEE WHAT HAP 3OME OF THESE NEUROTRANSMITTERS ARE CHANGED PENS IN THE BRAIN WHEN A PERSON IS ENGAGED IN WITH AGE DISEASE AND DRUG THERAPIES A PHYSICAL OR MENTAL ACTIVITY AT REST OR EVEN WHILE SLEEPING OR DREAMING #ERTAIN TRACERS CAN TRACK THE ACTIVITY OF BRAIN CHEMICALS FOR EXAMPLE NEUROTRANSMITTERS SUCH AS DOPAMINE AND
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 4HE "ASICS OF THE (EALTHY "RAIN
.EURONS AND 4HEIR *OBS
HE HUMAN BRAIN IS MADE UP OF BILLIONS TO SURVIVE AND STAY HEALTHY 4HESE PROCESSES ARE OF NEURONS %ACH HAS A CELL BODY COMMUNICATION METABOLISM AND REPAIR AN AXON AND MANY DENDRITES 4HE CELL BODY CONTAINS A NUCLEUS WHICH #/--5.)#!4)/. CONTROLS MUCH OF THE CELLS ACTIVITIES 4HE CELL 4 )MAGINE THE MANY MILES OF lBER OPTIC CABLES THAT BODY ALSO CONTAINS OTHER STRUCTURES CALLED RUN UNDER OUR STREETS $AY AND NIGHT MILLIONS OF ORGANELLES THAT PERFORM SPECIlC TASKS TELEVISED AND TELEPHONIC MESSAGES mASH AT INCREDIBLE 4HE AXON WHICH IS MUCH NARROWER THAN THE SPEEDS LETTING PEOPLE STRIKE DEALS GIVE INSTRUCTIONS WIDTH OF A HUMAN HAIR EXTENDS OUT FROM THE CELL SHARE A LAUGH OR LEARN SOME NEWS -INIATURIZE IT BODY !XONS TRANSMIT MESSAGES FROM NEURON TO MULTIPLY IT MANY FOLD MAKE IT MUCH MORE COMPLEX NEURON 3OMETIMES SIGNAL TRANSMISSIONSLIKE AND YOU HAVE THE BRAIN .EURONS ARE THE GREAT COM THOSE FROM HEAD TO TOEHAVE TO TRAVEL OVER VERY MUNICATORS ALWAYS IN TOUCH WITH THEIR NEIGHBORS LONG DISTANCES !XONS ARE COVERED WITH AN INSULAT .EURONS COMMUNICATE WITH EACH OTHER THROUGH ING LAYER CALLED MYELIN ALSO CALLED WHITE MATTER THEIR AXONS AND DENDRITES 7HEN A DENDRITE RE BECAUSE OF ITS WHITISH COLOR -YELIN WHICH IS CEIVES AN INCOMING SIGNAL ELECTRICAL OR CHEMICAL MADE BY A PARTICULAR KIND OF GLIAL CELL INCREASES AN hACTION POTENTIAL v OR NERVE IMPULSE CAN BE THE SPEED OF NERVE SIGNAL TRANSMISSIONS THROUGH GENERATED IN THE CELL BODY 4HE ACTION POTENTIAL THE BRAIN TRAVELS TO THE END OF THE AXON AND ONCE THERE THE $ENDRITES ALSO BRANCH OUT FROM THE CELL BODY PASSAGE OF EITHER ELECTRICAL CURRENT OR MORE 4HEY RECEIVE MESSAGES FROM THE AXONS OF OTHER TYPICALLY THE RELEASE OF CHEMICAL MESSENGERS NEURONS %ACH NEURON IS CONNECTED TO THOUSANDS CALLED NEUROTRANSMITTERS CAN BE TRIGGERED 4HE OF OTHER NERVE CELLS THROUGH ITS AXON AND DENDRITES NEUROTRANSMITTERS ARE RELEASED FROM THE AXON 'ROUPS OF NEURONS IN THE BRAIN HAVE SPECIAL TERMINAL AND MOVE ACROSS A TINY GAP OR SYNAPSE JOBS &OR EXAMPLE SOME ARE INVOLVED WITH TO SPECIlC RECEPTOR SITES ON THE RECEIVING OR POST THINKING LEARNING AND MEMORY /THERS ARE SYNAPTIC END OF DENDRITES OF NEARBY NEURONS ! RESPONSIBLE FOR RECEIVING INFORMATION FROM THE TYPICAL NEURON HAS THOUSANDS OF SYNAPTIC CONNEC SENSORY ORGANS SUCH AS THE EYES AND EARS OR THE TIONS MOSTLY ON ITS MANY DENDRITES WITH OTHER SKIN 3TILL OTHERS COMMUNICATE WITH MUSCLES NEURONS #ELL BODIES ALSO HAVE RECEPTOR SITES FOR STIMULATING THEM INTO ACTION NEUROTRANSMITTERS 3EVERAL PROCESSES ALL HAVE TO WORK SMOOTHLY TOGETHER FOR NEURONS AND THE WHOLE ORGANISM
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY .EURONS IN THE "RAIN 0!24 4HE "ASICS OF THE (EALTHY "RAIN
/NCE THE POST SYNAPTIC RECEPTORS ARE ACTIVATED -%4!"/,)3- THEY OPEN CHANNELS THROUGH THE CELL MEMBRANE !LL CELLS BREAK DOWN CHEMICALS AND NUTRIENTS TO INTO THE RECEIVING NERVE CELLS INTERIOR OR START OTHER GENERATE ENERGY AND FORM BUILDING BLOCKS THAT PROCESSES THAT DETERMINE WHAT THE RECEIVING NERVE MAKE NEW CELLULAR MOLECULES SUCH AS PROTEINS CELL WILL DO 3OME NEUROTRANSMITTERS INHIBIT NERVE 4HIS PROCESS IS CALLED METABOLISM 4O MAINTAIN CELL FUNCTION THAT IS THEY MAKE IT LESS LIKELY THAT METABOLISM THE BRAIN NEEDS PLENTY OF BLOOD THE NERVE CELL WILL SEND AN ELECTRICAL SIGNAL DOWN CONSTANTLY CIRCULATING THROUGH ITS BILLIONS OF ITS AXON /THER NEUROTRANSMITTERS STIMULATE NERVE CAPILLARIES TO SUPPLY NEURONS AND OTHER BRAIN CELLS PRIMING THE RECEIVING CELL TO BECOME ACTIVE CELLS WITH OXYGEN AND GLUCOSE 7ITHOUT OXYGEN OR SEND AN ELECTRICAL SIGNAL DOWN THE AXON TO MORE AND GLUCOSE NEURONS WILL QUICKLY DIE NEURONS IN THE PATHWAY ! NEURON RECEIVES SIGNALS FROM MANY OTHER NEURONS SIMULTANEOUSLY AND THE 2%0!)2 SUM OF A NEURONS NEUROTRANSMITTER INPUTS AT ANY .ERVE CELLS ARE FORMED DURING FETAL LIFE AND FOR A ONE INSTANT WILL DETERMINE WHETHER IT SENDS A SIG SHORT TIME AFTER BIRTH 5NLIKE MOST CELLS WHICH NAL DOWN ITS AXON TO ACTIVATE OR INHIBIT THE ACTION HAVE A FAIRLY SHORT LIFESPAN NEURONS IN THE BRAIN OF OTHER NEIGHBORING NEURONS LIVE A LONG TIME 4HESE CELLS CAN LIVE FOR UP TO $URING ANY ONE MOMENT MILLIONS OF THESE SIG YEARS OR LONGER 4O STAY HEALTHY LIVING NEURONS NALS ARE SPEEDING THROUGH PATHWAYS IN THE BRAIN MUST CONSTANTLY MAINTAIN AND REPAIR THEMSELVES ALLOWING THE BRAIN TO RECEIVE AND PROCESS INFORMA )N AN ADULT WHEN NEURONS DIE BECAUSE OF DISEASE TION MAKE ADJUSTMENTS AND SEND OUT INSTRUCTIONS OR INJURY THEY ARE NOT USUALLY REPLACED 2ESEARCH TO VARIOUS PARTS OF THE BODY HOWEVER SHOWS THAT IN A FEW BRAIN REGIONS NEW NEURONS CAN BE GENERATED EVEN IN THE OLD BRAIN 4HE #HANGING "RAIN IN(EALTHY!GING
N THE PAST SEVERAL DECADES INVESTIGATORS HAVE N )N SOME PEOPLE STRUCTURES CALLED PLAQUES AND LEARNED MUCH ABOUT WHAT HAPPENS IN THE TANGLES DEVELOP OUTSIDE OF AND INSIDE NEURONS BRAIN WHEN PEOPLE HAVE A NEURODEGENERATIVE RESPECTIVELY ALTHOUGH IN MUCH SMALLER AMOUNTS DISEASE SUCH AS 0ARKINSONS DISEASE !$ OR THAN IN !$ SEE 4HE (ALLMARKS OF !$ ON PAGE )OTHER DEMENTIAS 4HEIR lNDINGS ALSO HAVE REVEALED FOR MORE INFORMATION ON PLAQUES AND TANGLES MUCH ABOUT WHAT HAPPENS DURING HEALTHY AGING N $AMAGE BY FREE RADICALS INCREASES FREE RADICALS 2ESEARCHERS ARE INVESTIGATING A NUMBER OF CHANGES ARE A KIND OF MOLECULE THAT REACTS EASILY WITH OTHER RELATED TO HEALTHY AGING IN HOPES OF LEARNING MORE MOLECULES SEE 4HE !GING 0ROCESS ON PAGE FOR ABOUT THIS PROCESS SO THEY CAN lLL GAPS IN OUR MORE ON THESE MOLECULES KNOWLEDGE ABOUT THE EARLY STAGES OF !$ N )NmAMMATION INCREASES INmAMMATION IS THE !S A PERSON GETS OLDER CHANGES OCCUR IN ALL PARTS COMPLEX PROCESS THAT OCCURS WHEN THE BODY OF THE BODY INCLUDING THE BRAIN RESPONDS TO AN INJURY DISEASE OR ABNORMAL SITUATION N #ERTAIN PARTS OF THE BRAIN SHRINK ESPECIALLY THE PREFRONTAL CORTEX AN AREA AT THE FRONT OF THE 7HAT EFFECTS DOES AGING HAVE ON MENTAL FRONTAL LOBE AND THE HIPPOCAMPUS "OTH AREAS FUNCTION IN HEALTHY OLDER PEOPLE 3OME PEOPLE ARE IMPORTANT TO LEARNING MEMORY PLANNING AND MAY NOTICE A MODEST DECLINE IN THEIR ABILITY TO OTHER COMPLEX MENTAL ACTIVITIES LEARN NEW THINGS AND RETRIEVE INFORMATION SUCH N #HANGES IN NEURONS AND NEUROTRANSMITTERS AS REMEMBERING NAMES 4HEY MAY PERFORM WORSE AFFECT COMMUNICATION BETWEEN NEURONS )N CERTAIN ON COMPLEX TASKS OF ATTENTION LEARNING AND BRAIN REGIONS COMMUNICATION BETWEEN NEURONS MEMORY THAN WOULD A YOUNGER PERSON (OWEVER CAN BE REDUCED BECAUSE WHITE MATTER MYELIN IF GIVEN ENOUGH TIME TO PERFORM THE TASK THE COVERED AXONS IS DEGRADED OR LOST SCORES OF HEALTHY PEOPLE IN THEIR S AND S ARE N #HANGES IN THE BRAINS BLOOD VESSELS OCCUR OFTEN SIMILAR TO THOSE OF YOUNG ADULTS )N FACT AS "LOOD mOW CAN BE REDUCED BECAUSE ARTERIES NARROW THEY AGE ADULTS OFTEN IMPROVE IN OTHER COGNITIVE AND LESS GROWTH OF NEW CAPILLARIES OCCURS AREAS SUCH AS VOCABULARY AND OTHER FORMS OF VERBAL KNOWLEDGE )T ALSO APPEARS THAT ADDITIONAL BRAIN REGIONS CAN BE ACTIVATED IN OLDER ADULTS DURING COGNITIVE TASKS
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 4HE "ASICS OF THE (EALTHY "RAIN
SUCH AS TAKING A MEMORY TEST 2ESEARCHERS DO NOT AND UNIQUE MIX OF GENETICS ENVIRONMENT AND LIFE FULLY UNDERSTAND WHY THIS HAPPENS BUT ONE IDEA IS EXPERIENCES THE BALANCE MAY TIP IN FAVOR OF A DIS THAT THE BRAIN ENGAGES MECHANISMS TO COMPENSATE EASE PROCESS THAT WILL ULTIMATELY LEAD TO DEMENTIA FOR DIFlCULTIES THAT CERTAIN REGIONS MAY BE HAVING &OR ANOTHER PERSON WITH A DIFFERENT RESERVE AND &OR EXAMPLE THE BRAIN MAY RECRUIT ALTERNATE BRAIN A DIFFERENT MIX OF GENETICS ENVIRONMENT AND LIFE NETWORKS IN ORDER TO PERFORM A TASK 4HESE lND EXPERIENCES THE BALANCE MAY RESULT IN NO APPARENT INGS HAVE LED MANY SCIENTISTS TO BELIEVE THAT MAJOR DECLINE IN COGNITIVE FUNCTION WITH AGE DECLINES IN MENTAL ABILITIES ARE NOT INEVITABLE AS 3CIENTISTS ARE INCREASINGLY INTERESTED IN THE PEOPLE AGE 'ROWING EVIDENCE OF THE ADAPTIVE INmUENCE OF ALL THESE FACTORS ON BRAIN HEALTH AND WHAT SCIENTISTS CALL hPLASTICv CAPABILITIES OF THE STUDIES ARE REVEALING SOME CLUES ABOUT ACTIONS OLDER BRAIN PROVIDE HOPE THAT PEOPLE MAY BE ABLE PEOPLE CAN TAKE THAT MAY HELP PRESERVE HEALTHY TO DO THINGS TO SUSTAIN GOOD BRAIN FUNCTION AS BRAIN AGING &ORTUNATELY THESE ACTIONS ALSO BENElT THEY AGE ! VARIETY OF INTERACTING FACTORS SUCH AS A PERSONS OVERALL HEALTH 4HEY INCLUDE LIFESTYLE OVERALL HEALTH ENVIRONMENT AND GENETICS N #ONTROLLING RISK FACTORS FOR CHRONIC DISEASE ALSO MAY PLAY A ROLE SUCH AS HEART DISEASE AND DIABETES FOR EXAMPLE !NOTHER QUESTION THAT SCIENTISTS ARE ASKING KEEPING BLOOD CHOLESTEROL AND BLOOD PRESSURE AT IS WHY SOME PEOPLE REMAIN COGNITIVELY HEALTHY HEALTHY LEVELS AND MAINTAINING A HEALTHY WEIGHT AS THEY GET OLDER WHILE OTHERS DEVELOP COGNITIVE N %NJOYING REGULAR EXERCISE AND PHYSICAL ACTIVITY IMPAIRMENT OR DEMENTIA 4HE CONCEPT OF N %ATING A HEALTHY DIET THAT INCLUDES PLENTY OF hCOGNITIVE RESERVEv MAY PROVIDE SOME INSIGHTS VEGETABLES AND FRUITS #OGNITIVE RESERVE REFERS TO THE BRAINS ABILITY TO N %NGAGING IN INTELLECTUALLY STIMULATING ACTIVITIES OPERATE EFFECTIVELY EVEN WHEN SOME FUNCTION IS AND MAINTAINING CLOSE SOCIAL TIES WITH FAMILY DISRUPTED )T ALSO REFERS TO THE AMOUNT OF DAMAGE FRIENDS AND COMMUNITY THAT THE BRAIN CAN SUSTAIN BEFORE CHANGES IN COGNITION ARE EVIDENT 0EOPLE VARY IN THE COGNITIVE 6ASCULAR $ISEASE ON PAGE AND ,IFESTYLE RESERVE THEY HAVE AND THIS VARIABILITY MAY BE &ACTORS ON PAGE PROVIDE MORE INFORMATION BECAUSE OF DIFFERENCES IN GENETICS EDUCATION ABOUT THESE ISSUES AND HOW THEY MAY INmUENCE THE OCCUPATION LIFESTYLE LEISURE ACTIVITIES OR OTHER LIFE RISK OF DEVELOPING !$ EXPERIENCES 4HESE FACTORS COULD PROVIDE A CERTAIN AMOUNT OF TOLERANCE AND ABILITY TO ADAPT TO CHANGE AND DAMAGE THAT OCCURS DURING AGING !T SOME POINT DEPENDING ON A PERSONS COGNITIVE RESERVE
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY !#4)6% 3TUDY -AY 0ROVIDE #LUES TO (ELP /LDER !DULTS 3TAY -ENTALLY 3HARP
HE PHRASE hUSE IT OR LOSE ITv MAY MAKE YOU THINK N !FTER YEARS PEOPLE IN EACH GROUP PERFORMED 4OF YOUR MUSCLES BUT SCIENTISTS WHO STUDY BRAIN BETTER ON TESTS IN THEIR RESPECTIVE AREAS OF TRAINING HEALTH IN OLDER PEOPLE HAVE FOUND THAT IT MAY APPLY THAN DID PEOPLE IN THE CONTROL GROUP 4HE REASONING TO COGNITIVE SKILLS AS WELL )N SCIENTISTS FUNDED AND PROCESSING SPEED GROUPS WHO RECEIVED BOOSTER BY .)! AND THE .ATIONAL )NSTITUTE OF .URSING 2ESEARCH TRAINING HAD THE GREATEST BENElT COMPLETED A STUDY OF COGNITIVE TRAINING IN OLDER ADULTS 4HE RESEARCHERS ALSO LOOKED AT THE TRAININGS EFFECTS 4HIS STUDY THE !DVANCED #OGNITIVE 4RAINING FOR )NDE ON PARTICIPANTS EVERYDAY LIVES !FTER YEARS ALL THREE PENDENT AND 6ITAL %LDERLY !#4)6% STUDY WAS THE lRST GROUPS WHO RECIEVED TRAINING REPORTED LESS DIFlCULTY RANDOMIZED CONTROLLED TRIAL TO DEMONSTRATE LONG LASTING THAN THE CONTROL GROUP IN TASKS SUCH AS PREPARING POSITIVE EFFECTS OF BRIEF COGNITIVE TRAINING IN OLDER ADULTS MEALS MANAGING MONEY AND DOING HOUSEWORK 4HE !#4)6% STUDY INCLUDED HEALTHY ADULTS (OWEVER THESE RESULTS WERE STATISTICALLY SIGNIlCANT FOR AGE AND OLDER WHO WERE LIVING INDEPENDENTLY ONLY THE GROUP THAT HAD THE REASONING TRAINING 0ARTICIPANTS WERE RANDOMLY ASSIGNED TO FOUR GROUPS !S THEY GET OLDER MANY PEOPLE WORRY ABOUT THEIR 4HREE GROUPS TOOK PART IN UP TO COMPUTER BASED MENTAL SKILLS GETTING hRUSTYv 4HE !#4)6% STUDY OFFERS TRAINING SESSIONS THAT TARGETED A SPECIlC COGNITIVE HOPE THAT COGNITIVE TRAINING MAY BE USEFUL BECAUSE IT ABILITYMEMORY REASONING AND SPEED OF PROCESSING SHOWED THAT RELATIVELY BRIEF AND TARGETED COGNITIVE IN OTHER WORDS HOW FAST PARTICIPANTS COULD RESPOND EXERCISES CAN PRODUCE LASTING IMPROVEMENTS IN THE TO PROMPTS ON A COMPUTER SCREEN 4HE FOURTH GROUP SKILLS TAUGHT .EXT STEPS FOR RESEARCHERS ARE TO DETER THE CONTROL GROUP RECEIVED NO COGNITIVE TRAINING 3IXTY MINE WAYS TO GENERALIZE THE TRAINING BENElTS BEYOND PERCENT OF THOSE WHO COMPLETED THE INITIAL TRAINING ALSO THE SPECIlC SKILLS TAUGHT IN !#4)6% AND TO lND OUT TOOK PART IN MINUTE hBOOSTERv SESSIONS MONTHS WHETHER COGNITIVE TRAINING PROGRAMS COULD PREVENT LATER 4HESE SESSIONS WERE DESIGNED TO MAINTAIN DELAY OR DIMINISH THE EFFECTS OF !$ IMPROVEMENTS GAINED FROM THE INITIAL TRAINING 4HE INVESTIGATORS TESTED THE PARTICIPANTS AT THE BEGINNING OF THE STUDY AFTER THE INITIAL TRAINING AND BOOSTER SESSIONS AND ONCE A YEAR FOR MORE YEARS 4HEY FOUND THAT THE IMPROVEMENTS FROM THE TRAINING ROUGHLY COUNTER ACTED THE DEGREE OF DECLINE IN COGNITIVE PERFORMANCE THAT WOULD BE EXPECTED OVER A TO YEAR PERIOD AMONG OLDER PEOPLE WITHOUT DEMENTIA N )MMEDIATELY AFTER THE INITIAL TRAINING PERCENT OF THE PROCESSING SPEED GROUP PERCENT OF THE REASONING GROUP AND PERCENT OF THE MEMORY GROUP SHOWED IMPROVEMENT IN THE SKILLS TAUGHT
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 4HE (ALLMARKSOF!$
LZHEIMERS DISEASE DISRUPTS CRITICAL METABOLIC !-9,/)$ 0,!15%3 PROCESSES THAT KEEP NEURONS HEALTHY 4HESE !MYLOID PLAQUES ARE FOUND IN THE SPACES BETWEEN DISRUPTIONS CAUSE NERVE CELLS IN THE BRAIN THE BRAINS NERVE CELLS 4HEY WERE lRST DESCRIBED TO STOP WORKING LOSE CONNECTIONS WITH BY $R !LOIS !LZHEIMER IN 0LAQUES CONSIST OTHER NERVE CELLS AND lNALLY DIE 4HE DESTRUCTION ! OF LARGELY INSOLUBLE DEPOSITS OF AN APPARENTLY TOXIC AND DEATH OF NERVE CELLS CAUSES THE MEMORY FAILURE PROTEIN PEPTIDE OR FRAGMENT CALLED BETA AMYLOID PERSONALITY CHANGES PROBLEMS IN CARRYING OUT 7E NOW KNOW THAT SOME PEOPLE DEVELOP DAILY ACTIVITIES AND OTHER FEATURES OF THE DISEASE SOME PLAQUES IN THEIR BRAIN TISSUE AS THEY AGE 4HE BRAINS OF PEOPLE WITH !$ HAVE AN ABUNDANCE (OWEVER THE !$ BRAIN HAS MANY MORE PLAQUES OF TWO ABNORMAL STRUCTURESAMYLOID PLAQUES IN PARTICULAR BRAIN REGIONS 7E STILL DO NOT KNOW AND NEUROlBRILLARY TANGLESTHAT ARE MADE OF WHETHER AMYLOID PLAQUES THEMSELVES CAUSE !$ OR MISFOLDED PROTEINS SEE 0ROTEIN -ISFOLDING ON WHETHER THEY ARE A BY PRODUCT OF THE !$ PROCESS PAGE FOR MORE INFORMATION 4HIS IS ESPECIALLY 7E DO KNOW THAT GENETIC MUTATIONS CAN INCREASE TRUE IN CERTAIN REGIONS OF THE BRAIN THAT ARE PRODUCTION OF BETA AMYLOID AND CAN CAUSE RARE IMPORTANT IN MEMORY INHERITED FORMS OF !$ SEE 'ENES AND %ARLY 4HE THIRD MAIN FEATURE OF !$ IS THE LOSS OF /NSET !LZHEIMERS $ISEASE ON PAGE FOR CONNECTIONS BETWEEN CELLS 4HIS LEADS TO DIMIN MORE ON INHERITED !$ ISHED CELL FUNCTION AND CELL DEATH
4O VIEW A VIDEO SHOWING WHAT HAPPENS TO THE BRAIN IN !$ GO TO WWWNIANIHGOV !LZHEIMERS!$VIDEO
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 7HAT (APPENS TO THE "RAIN IN !$
&ROM !00 TO "ETA !MYLOID 0LAQUES
MYLOID PRECURSOR PROTEIN !00 THE STARTING THE !00 MOLECULE AT ONE ! POINT FOR AMYLOID PLAQUES IS ONE OF MANY PROTEINS END OF THE BETA AMYLOID ASSOCIATED WITH THE CELL MEMBRANE THE BARRIER THAT PEPTIDE RELEASING S!00β ENCLOSES THE CELL !S IT IS BEING MADE INSIDE THE CELL FROM THE CELL &IGURE !00 BECOMES EMBEDDED IN THE MEMBRANE LIKE A TOOTH 'AMMA SECRETASE THEN PICK STUCK THROUGH THE SKIN OF AN ORANGE &IGURE CUTS THE RESULTING !00 )N A NUMBER OF CELL COM FRAGMENT STILL TETHERED IN &IGURE PARTMENTS INCLUDING THE THE NEURONS MEMBRANE OUTERMOST CELL MEMBRANE AT THE OTHER END OF THE SPECIlC ENZYMES SNIP OR BETA AMYLOID PEPTIDE CLEAVE !00 INTO DISCRETE &OLLOWING THE CLEAVAGES FRAGMENTS )N AND AT EACH END THE BETA SCIENTISTS IDENTIlED AMYLOID PEPTIDE IS &IGURE THE ENZYMES RESPONSIBLE RELEASED INTO THE SPACE FOR CLEAVING !00 4HESE ENZYMES ARE CALLED ALPHA &IGURE OUTSIDE THE NEURON AND SECRETASE BETA SECRETASE AND GAMMA SECRETASE BEGINS TO STICK TO OTHER )N A MAJOR BREAKTHROUGH SCIENTISTS THEN DISCOVERED BETA AMYLOID PEPTIDES &IGURE 4HESE SMALL THAT DEPENDING ON WHICH ENZYME IS INVOLVED AND SOLUBLE AGGREGATES OF TWO THREE FOUR OR EVEN THE SEGMENT OF !00 WHERE THE CLEAVING OCCURS !00 UP TO A DOZEN BETA AMYLOID PEPTIDES ARE CALLED PROCESSING CAN FOLLOW ONE OF TWO PATHWAYS THAT OLIGOMERS 3PECIlC SIZES OF OLIGOMERS MAY HAVE VERY DIFFERENT CONSEQUENCES FOR THE CELL BE RESPONSIBLE FOR REACTING WITH RECEPTORS ON )N THE BENIGN PATHWAY ALPHA SECRETASE CLEAVES THE NEIGHBORING CELLS AND SYNAPSES AFFECTING THEIR !00 MOLECULE WITHIN THE PORTION THAT HAS THE POTENTIAL TO ABILITY TO FUNCTION BECOME BETA AMYLOID 4HIS ELIMINATES THE PRODUCTION OF )T IS LIKELY THAT SOME OLIGOMERS ARE CLEARED FROM THE BETA AMYLOID PEPTIDE AND THE POTENTIAL FOR PLAQUE THE BRAIN 4HOSE THAT CANNOT BE CLEARED CLUMP BUILDUP 4HE CLEAVAGE RELEASES FROM THE NEURON A FRAG TOGETHER WITH MORE BETA AMYLOID PEPTIDES !S THE MENT CALLED S!00α WHICH HAS BENElCIAL PROPERTIES PROCESS CONTINUES OLIGOMERS GROW LARGER BECOMING SUCH AS PROMOTING NEURONAL GROWTH AND SURVIVAL 4HE ENTITIES CALLED PROTOlBRILS AND lBRILS %VENTUALLY OTHER REMAINING !00 FRAGMENT STILL TETHERED IN THE NEURONS PROTEINS AND CELLULAR MATERIAL ARE ADDED AND THESE MEMBRANE IS THEN CLEAVED BY GAMMA SECRETASE AT INCREASINGLY INSOLUBLE ENTITIES COMBINE TO BECOME THE THE END OF THE BETA AMYLOID SEGMENT 4HE SMALLER OF WELL KNOWN PLAQUES THAT ARE CHARACTERISTIC OF !$ THE RESULTING FRAGMENTS ALSO IS RELEASED INTO THE SPACE &OR MANY YEARS SCIENTISTS THOUGHT THAT PLAQUES OUTSIDE THE NEURON WHILE MIGHT CAUSE ALL OF THE DAMAGE TO NEURONS THAT IS SEEN THE LARGER FRAGMENT REMAINS IN !$ (OWEVER THAT CONCEPT HAS EVOLVED GREATLY WITHIN THE NEURON AND IN THE PAST FEW YEARS -ANY SCIENTISTS NOW THINK THAT INTERACTS WITH FACTORS IN THE OLIGOMERS MAY BE A MAJOR CULPRIT -ANY SCIENTISTS NUCLEUS &IGURE ALSO THINK THAT PLAQUES ACTUALLY MAY BE A LATE STAGE )N THE HARMFUL PATHWAY ATTEMPT BY THE BRAIN TO GET THIS HARMFUL BETA AMYLOID BETA SECRETASE lRST CLEAVES AWAY FROM NEURONS &IGURE
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY &ROM !00 TO "ETA !MYLOID 0LAQUE
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 7HAT (APPENS TO THE "RAIN IN !$
(EALTHY AND $ISEASED .EURONS
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY )NSIDE A (EALTHY .EURON .%52/&)"2),,!29 4!.',%3 4HE SECOND HALLMARK OF !$ ALSO DESCRIBED BY $R !LZHEIMER IS NEUROlBRILLARY TANGLES 4ANGLES ARE ABNORMAL COLLECTIONS OF TWISTED PROTEIN THREADS FOUND INSIDE NERVE CELLS 4HE CHIEF COMPONENT OF TANGLES IS A PROTEIN CALLED TAU (EALTHY NEURONS ARE INTERNALLY SUPPORTED IN PART BY STRUCTURES CALLED MICROTUBULES WHICH HELP TRANSPORT NUTRIENTS AND OTHER CELLULAR COMPONENTS SUCH AS NEUROTRANSMITTER CONTAINING VESICLES FROM THE CELL BODY DOWN THE AXON 4A U WHICH USUALLY HAS A CERTAIN NUMBER OF PHOSPHATE MOLECULES ATTACHED TO IT BINDS TO MICROTUBULES AND APPEARS TO STABILIZE THEM )N !$ AN ABNORMALLY LARGE NUMBER OF ADDITIONAL PHOSPHATE MOLECULES ATTACH TO TAU !S A RESULT OF THIS hHYPERPHOSPHORYLATION v TAU DISENGAGES FROM THE MICROTUBULES AND BEGINS TO COME TOGETHER WITH OTHER TAU THREADS 4HESE TAU )NSIDE A $ISEASED .EURON THREADS FORM STRUCTURES CALLED PAIRED HELICAL lLAMENTS WHICH CAN BECOME ENMESHED WITH ONE ANOTHER FORMING TANGLES WITHIN THE CELL 4HE MICROTUBULES CAN DISINTEGRATE IN THE PROCESS COLLAPS ING THE NEURONS INTERNAL TRANSPORT NETWORK 4HIS COLLAPSE DAMAGES THE ABILITY OF NEURONS TO COM MUNICATE WITH EACH OTHER
&ORMATION OF 4AU 4ANGLES
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 7HAT (APPENS TO THE "RAIN IN !$
,/33 /& #/..%#4)/. "%47%%. 4HE !$ PROCESS NOT ONLY INHIBITS COMMUNI #%,,3 !.$ #%,, $%!4( CATION BETWEEN NEURONS BUT CAN ALSO DAMAGE 4HE THIRD MAJOR FEATURE OF !$ IS THE GRADUAL NEURONS TO THE POINT THAT THEY CANNOT FUNCTION LOSS OF CONNECTIONS BETWEEN NEURONS .EURONS PROPERLY AND EVENTUALLY DIE !S NEURONS DIE LIVE TO COMMUNICATE WITH EACH OTHER AND THIS THROUGHOUT THE BRAIN AFFECTED REGIONS BEGIN TO VITAL FUNCTION TAKES PLACE AT THE SYNAPSE 3INCE SHRINK IN A PROCESS CALLED BRAIN ATROPHY "Y THE THE S NEW KNOWLEDGE ABOUT PLAQUES AND lNAL STAGE OF !$ DAMAGE IS WIDESPREAD AND TANGLES HAS PROVIDED IMPORTANT INSIGHTS INTO BRAIN TISSUE HAS SHRUNK SIGNIlCANTLY THEIR POSSIBLE DAMAGE TO SYNAPSES AND ON THE DEVELOPMENT OF !$
,OSS OF #ONNECTION "ETWEEN #ELLS
4HIS ILLUSTRATION SHOWS THE DAMAGE CAUSED BY !$ PLAQUES TANGLES AND THE LOSS OF CONNECTION BETWEEN NEURONS
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 4HE #HANGING "RAIN IN!$ O ONE KNOWS EXACTLY WHAT STARTS SEVERITY OF COGNITIVE PROBLEMS AT DIAGNOSIS THE !$ PROCESS OR WHY SOME OF THE !LTHOUGH THE COURSE OF THE DISEASE IS NOT THE SAME NORMAL CHANGES ASSOCIATED WITH IN EVERY PERSON WITH !$ SYMPTOMS SEEM TO AGING BECOME SO MUCH MORE EXTREME DEVELOP OVER THE SAME GENERAL STAGES AND DESTRUCTIVE IN PEOPLE WITH THE DISEASE 7E . KNOW A LOT HOWEVER ABOUT WHAT HAPPENS IN THE 02%#,).)#!, !$ BRAIN ONCE !$ TAKES HOLD AND ABOUT THE PHYSICAL !$ BEGINS DEEP IN THE BRAIN IN THE ENTORHINAL AND MENTAL CHANGES THAT OCCUR OVER TIME 4HE CORTEX A BRAIN REGION THAT IS NEAR THE HIPPOCAMPUS TIME FROM DIAGNOSIS TO DEATH VARIESAS LITTLE AS AND HAS DIRECT CONNECTIONS TO IT (EALTHY NEURONS OR YEARS IF THE PERSON IS OLDER THAN WHEN IN THIS REGION BEGIN TO WORK LESS EFlCIENTLY LOSE DIAGNOSED TO AS LONG AS OR MORE YEARS IF THE THEIR ABILITY TO COMMUNICATE AND ULTIMATELY DIE PERSON IS YOUNGER 3EVERAL OTHER FACTORS BESIDES 4HIS PROCESS GRADUALLY SPREADS TO THE HIPPOCAM AGE ALSO AFFECT HOW LONG A PERSON WILL LIVE WITH PUS THE BRAIN REGION THAT PLAYS A MAJOR ROLE IN !$ 4HESE FACTORS INCLUDE THE PERSONS SEX LEARNING AND IS INVOLVED IN CONVERTING SHORT TERM THE PRESENCE OF OTHER HEALTH PROBLEMS AND THE MEMORIES TO LONG TERM MEMORIES !FFECTED REGIONS BEGIN TO ATROPHY 6ENTRICLES THE mUID lLLED SPACES INSIDE THE BRAIN BEGIN TO ENLARGE 0RECLINICAL !$ AS THE PROCESS CONTINUES 3CIENTISTS BELIEVE THAT THESE BRAIN CHANGES BEGIN TO YEARS BEFORE ANY CLINICALLY DETECTABLE SIGNS OR SYMPTOMS OF FORGETFUL NESS APPEAR 4HATS WHY THEY ARE INCREASINGLY INTERESTED IN THE VERY EARLY STAGES OF THE DISEASE PROCESS 4HEY HOPE TO LEARN MORE ABOUT WHAT HAPPENS IN THE BRAIN THAT SETS A PERSON ON THE PATH TO DEVELOPING !$ "Y KNOWING MORE ABOUT THE EARLY STAGES THEY ALSO HOPE TO BE ABLE TO
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 7HAT (APPENS TO THE "RAIN IN !$
0I" AND 0%4
MAGINE BEING ABLE TO SEE DEEP INSIDE THE BRAIN TISSUE OF )A LIVING PERSON )F YOU COULD DO THAT YOU COULD lND OUT WHETHER THE !$ PROCESS WAS HAPPENING MANY YEARS BEFORE SYMPTOMS WERE EVIDENT 4HIS KNOWLEDGE COULD HAVE A PROFOUND IMPACT ON IMPROVING EARLY DIAGNOSIS MONITORING DISEASE PROGRESSION AND TRACKING RESPONSE TO TREATMENT 3CIENTISTS HAVE STEPPED CLOSER TO THIS POSSIBILITY WITH THE DEVELOPMENT OF A RADIOLABELED COMPOUND CALLED 0ITTSBURGH #OMPOUND " 0I" 0I" BINDS TO BETA AMYLOID PLAQUES IN THE BRAIN AND IT CAN BE IMAGED USING 0%4 SCANS )NITIAL STUDIES SHOWED THAT PEOPLE WITH !$ TAKE UP MORE 0I" IN THEIR BRAINS THAN DO COGNITIVELY HEALTHY OLDER PEOPLE 3INCE THEN SCIEN TISTS HAVE FOUND HIGH LEVELS OF 0I" IN SOME COGNITIVELY HEALTHY PEOPLE SUGGESTING THAT THE DAMAGE FROM BETA AMYLOID MAY )N THIS 0%4 SCAN THE RED AND YELLOW COLORS ALREADY BE UNDERWAY 4HE NEXT STEP WILL BE TO FOLLOW THESE INDICATE THAT 0I" UPTAKE IS HIGHER IN THE BRAIN COGNITIVELY HEALTHY PEOPLE WHO HAVE HIGH 0I" LEVELS TO SEE OF THE PERSON WITH !$ THAN IN THE COGNITIVELY WHETHER THEY DO IN FACT DEVELOP !$ OVER TIME HEALTHY PERSON
DEVELOP DRUGS OR OTHER TREATMENTS THAT WILL TO A SUBSTANCE THE PRESENCE OF A DISEASE OR THE SLOW OR STOP THE DISEASE PROCESS BEFORE SIGNIlCANT PROGRESSION OVER TIME OF A DISEASE &OR EXAMPLE IMPAIRMENT OCCURS SEE 4HE 3EARCH FOR .EW HIGH BLOOD CHOLESTEROL IS A BIOMARKER FOR RISK OF 4REATMENTS ON PAGE FOR MORE INFORMATION HEART DISEASE 3UCH TOOLS ARE CRITICAL TO HELPING SCIENTISTS DETECT AND UNDERSTAND THE VERY EARLY 6%29 %!2,9 3)'.3 !.$ 39-04/-3 SIGNS AND SYMPTOMS OF !$ !T SOME POINT THE DAMAGE OCCURRING IN THE BRAIN BEGINS TO SHOW ITSELF IN VERY EARLY CLINICAL SIGNS AND -ILD #OGNITIVE )MPAIRMENT SYMPTOMS -UCH RESEARCH IS BEING DONE TO IDENTIFY !S SOME PEOPLE GROW OLDER THEY DEVELOP MEMORY THESE EARLY CHANGES WHICH MAY BE USEFUL IN PROBLEMS GREATER THAN THOSE EXPECTED FOR THEIR AGE PREDICTING DEMENTIA OR !$ !N IMPORTANT PART OF "UT THEY DO NOT EXPERIENCE THE PERSONALITY CHANGES THIS RESEARCH EFFORT IS THE DEVELOPMENT OF INCREAS OR OTHER PROBLEMS THAT ARE CHARACTERISTIC OF !$ INGLY SOPHISTICATED NEUROIMAGING TECHNIQUES SEE 4HESE PEOPLE MAY HAVE A CONDITION CALLED MILD %XCITING .EW $EVELOPMENTS IN !$ $IAGNOSIS COGNITIVE IMPAIRMENT -#) -#) HAS SEVERAL ON PAGE FOR MORE ON NEUROIMAGING AND THE USE SUBTYPES 4HE TYPE MOST ASSOCIATED WITH MEMORY OF BIOMARKERS "IOMARKERS ARE INDICATORS SUCH AS LOSS IS CALLED AMNESTIC -#) 0EOPLE WITH -#) ARE CHANGES IN SENSORY ABILITIES OR SUBSTANCES THAT AP A CRITICALLY IMPORTANT GROUP FOR RESEARCH BECAUSE PEAR IN BODY mUIDS SUCH AS BLOOD CEREBROSPINAL mUID OR URINE "IOMARKERS CAN INDICATE EXPOSURE
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY #HARTING THE #OURSE FROM (EALTHY !GING TO !$
HIS CHART SHOWS CUR !MNESTIC -#) #OGNITIVE RENT THINKING ABOUT THE 4 !$ BRAIN MEMORY PROBLEMS DECLINE EVOLUTION FROM HEALTHY AGING CHANGES START OTHER COGNITIVE ACCELERATES TO !$ 2ESEARCHERS VIEW IT AS DECADES BEFORE FUNCTIONS /+ AFTER !$ A SERIES OF EVENTS THAT OCCUR SYMPTOMS BRAIN COMPENSATES DIAGNOSIS SHOW FOR CHANGES IN THE BRAIN OVER MANY YEARS 4HIS GRADUAL PROCESS WHICH RESULTS FROM THE COMBINATION OF BIOLOGICAL GENETIC ENVIRON .ORMAL AGE RELATED MENTAL AND LIFESTYLE FACTORS MEMORY LOSS EVENTUALLY SETS SOME PEOPLE 4OTAL LOSS OF ON A COURSE TO -#) AND INDEPENDENT POSSIBLY !$ /THER PEOPLE FUNCTION WHOSE GENETIC MAKEUP MAY BE THE SAME OR DIFFERENT AND WHO EXPERIENCE A DIFFERENT "IRTH $EATH COMBINATION OF FACTORS OVER A ,IFE #OURSE LIFETIME CONTINUE ON A COURSE (EALTHY !GING !MNESTIC -#) #LINICALLY $IAGNOSED !$ OF HEALTHY COGNITIVE AGING
A MUCH HIGHER PERCENTAGE OF THEM GO ON TO DE !$ SEE 'ENETIC &ACTORS AT 7ORK IN !$ ON VELOP !$ THAN DO PEOPLE WITHOUT THESE MEMORY PAGE FOR MORE INFORMATION !ND THEY HAVE PROBLEMS !BOUT OF EVERY PEOPLE WHO lT FOUND THAT DIFFERENT BRAIN REGIONS APPEAR TO THE DElNITION OF AMNESTIC -#) GO ON TO DEVELOP BE ACTIVATED DURING CERTAIN MENTAL ACTIVITIES IN !$ WITHIN YEARS )N CONTRAST TO PERCENT OF COGNITIVELY HEALTHY PEOPLE AND THOSE WITH -#) PEOPLE OLDER THAN WHO HAVE NORMAL COGNITION 4HESE CHANGES APPEAR TO BE RELATED TO THE EARLY WILL DEVELOP !$ IN ANY ONE YEAR STAGES OF COGNITIVE IMPAIRMENT (OWEVER RESEARCHERS ARE NOT YET ABLE TO SAY DElNITIVELY WHY SOME PEOPLE WITH AMNESTIC -#) /THER 3IGNS OF %ARLY !$ $EVELOPMENT DO NOT PROGRESS TO !$ NOR CAN THEY SAY WHO !S SCIENTISTS HAVE SHARPENED THEIR FOCUS ON THE WILL OR WILL NOT GO ON TO DEVELOP !$ 4HIS RAISES EARLY STAGES OF !$ THEY HAVE BEGUN TO SEE HINTS OF PRESSING QUESTIONS SUCH AS )N CASES WHEN -#) OTHER CHANGES THAT MAY SIGNAL A DEVELOPING DISEASE PROGRESSES TO !$ WHAT WAS HAPPENING IN THE BRAIN PROCESS &OR EXAMPLE IN THE 2ELIGIOUS /RDERS 3TUDY THAT MADE THAT TRANSITION POSSIBLE #AN -#) BE A LARGE !$ RESEARCH EFFORT THAT INVOLVES OLDER NUNS PREVENTED OR ITS PROGRESS TO !$ DELAYED PRIESTS AND RELIGIOUS BROTHERS INVESTIGATORS HAVE 3CIENTISTS ALSO HAVE FOUND THAT GENETIC FACTORS MAY PLAY A ROLE IN -#) AS THEY DO IN
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 7HAT (APPENS TO THE "RAIN IN !$
EXPLORED WHETHER CHANGES IN OLDER ADULTS ABILITY TO -ILD TO -ODERATE !$ MOVE ABOUT AND USE THEIR BODIES MIGHT BE A SIGN OF EARLY !$ 4HE RESEARCHERS FOUND THAT PARTICIPANTS WITH -#) HAD MORE MOVEMENT DIFlCULTIES THAN THE COGNITIVELY HEALTHY PARTICIPANTS BUT LESS THAN THOSE WITH !$ -OREOVER THOSE WITH -#) WHO HAD LOTS OF TROUBLE MOVING THEIR LEGS AND FEET WERE MORE THAN TWICE AS LIKELY TO DEVELOP !$ AS THOSE WITH GOOD LOWER BODY FUNCTION )T IS NOT YET CLEAR WHY PEOPLE WITH -#) MIGHT HAVE THESE MOTOR FUNCTION PROBLEMS BUT THE SCIENTISTS WHO CONDUCTED THE STUDY SPECULATE THAT THEY MAY BE A SIGN THAT DAMAGE TO BLOOD VESSELS IN THE BRAIN OR DAMAGE FROM !$ IS ACCUMULATING IN AREAS OF THE BRAIN RESPONSIBLE FOR MOTOR FUNCTION )F FURTHER RESEARCH SHOWS THAT SOME PEOPLE WITH -#) DO HAVE MOTOR FUNCTION PROBLEMS IN ADDI -),$ !$ TION TO MEMORY PROBLEMS THE DEGREE OF DIFlCULTY !S !$ SPREADS THROUGH THE BRAIN THE NUMBER OF ESPECIALLY WITH WALKING MAY HELP IDENTIFY THOSE AT PLAQUES AND TANGLES GROWS SHRINKAGE PROGRESSES RISK OF PROGRESSING TO !$ AND MORE AND MORE OF THE CEREBRAL CORTEX IS /THER SCIENTISTS HAVE FOCUSED ON CHANGES IN AFFECTED -EMORY LOSS CONTINUES AND CHANGES SENSORY ABILITIES AS POSSIBLE INDICATORS OF EARLY IN OTHER COGNITIVE ABILITIES BEGIN TO EMERGE 4HE COGNITIVE PROBLEMS &OR EXAMPLE IN ONE STUDY THEY CLINICAL DIAGNOSIS OF !$ IS USUALLY MADE DURING FOUND ASSOCIATIONS BETWEEN A DECLINE IN THE ABILITY THIS STAGE 3IGNS OF MILD !$ CAN INCLUDE TO DETECT ODORS AND COGNITIVE PROBLEMS OR DEMENTIA N -EMORY LOSS 4HESE lNDINGS ARE TENTATIVE BUT THEY ARE N #ONFUSION ABOUT THE LOCATION OF FAMILIAR PLACES PROMISING BECAUSE THEY SUGGEST THAT SOME DAY IT GETTING LOST BEGINS TO OCCUR MAY BE POSSIBLE TO DEVELOP WAYS TO IMPROVE EARLY N 4AKING LONGER THAN BEFORE TO ACCOMPLISH DETECTION OF -#) OR !$ 4HESE TOOLS ALSO WILL HELP NORMAL DAILY TASKS SCIENTISTS ANSWER QUESTIONS ABOUT CAUSES AND VERY N 4ROUBLE HANDLING MONEY AND PAYING BILLS EARLY DEVELOPMENT OF !$ TRACK CHANGES IN BRAIN N 0OOR JUDGMENT LEADING TO BAD DECISIONS AND COGNITIVE FUNCTION OVER TIME AND ULTIMATELY N ,OSS OF SPONTANEITY AND SENSE OF INITIATIVE TRACK A PERSONS RESPONSE TO TREATMENT FOR !$ N -OOD AND PERSONALITY CHANGES INCREASED ANXIETY ANDOR AGGRESSION )N MILD !$ A PERSON MAY SEEM TO BE HEALTHY BUT IS ACTUALLY HAVING MORE AND MORE TROUBLE MAKING SENSE OF THE WORLD AROUND HIM OR HER 4HE REALIZATION THAT SOMETHING IS WRONG OFTEN COMES GRADUALLY TO THE PERSON AND HIS OR HER FAMILY
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY !CCEPTING THESE SIGNS AS SOMETHING OTHER THAN N (ALLUCINATIONS DELUSIONS SUSPICIOUSNESS OR NORMAL AND DECIDING TO GO FOR DIAGNOSTIC TESTS CAN PARANOIA IRRITABILITY BE A BIG HURDLE FOR PEOPLE AND FAMILIES /NCE THIS N ,OSS OF IMPULSE CONTROL SHOWN THROUGH HURDLE IS OVERCOME MANY FAMILIES ARE RELIEVED TO UNDRESSING AT INAPPROPRIATE TIMES OR PLACES KNOW WHAT IS CAUSING THE PROBLEMS 4HEY ALSO CAN OR VULGAR LANGUAGE TAKE COMFORT IN THE FACT THAT DESPITE A DIAGNOSIS N !N INABILITY TO CARRY OUT ACTIVITIES THAT INVOLVE OF -#) OR EARLY !$ A PERSON CAN STILL MAKE MULTIPLE STEPS IN SEQUENCE SUCH AS DRESSING MEANINGFUL CONTRIBUTIONS TO HIS OR HER FAMILY MAKING A POT OF COFFEE OR SETTING THE TABLE AND TO SOCIETY FOR A TIME "EHAVIOR IS THE RESULT OF COMPLEX BRAIN PROCESSES ALL OF WHICH TAKE PLACE IN A FRACTION OF -/$%2!4% !$ A SECOND IN THE HEALTHY BRAIN )N !$ MANY OF "Y THIS STAGE !$ DAMAGE HAS SPREAD TO THE AREAS THOSE PROCESSES ARE DISTURBED AND THESE DISRUPTED OF THE CEREBRAL CORTEX THAT CONTROL LANGUAGE COMMUNICATIONS BETWEEN NEURONS ARE THE BASIS REASONING SENSORY PROCESSING AND CONSCIOUS FOR MANY DISTRESSING OR INAPPROPRIATE BEHAVIORS THOUGHT !FFECTED REGIONS CONTINUE TO SHRINK &OR EXAMPLE A PERSON MAY ANGRILY REFUSE TO TAKE VENTRICLES ENLARGE AND SIGNS AND SYMPTOMS OF THE A BATH OR GET DRESSED BECAUSE HE DOES NOT UNDER DISEASE BECOME MORE PRONOUNCED AND WIDESPREAD STAND WHAT HIS CAREGIVER HAS ASKED HIM TO DO )F "EHAVIORAL PROBLEMS SUCH AS WANDERING AND HE DOES UNDERSTAND HE MAY NOT REMEMBER HOW AGITATION CAN OCCUR -ORE INTENSIVE SUPERVISION TO DO IT 4HE ANGER CAN BE A MASK FOR HIS CONFU AND CARE BECOME NECESSARY WHICH CAN BE SION AND ANXIETY /R A PERSON WITH !$ MAY DIFlCULT FOR MANY SPOUSES AND FAMILIES 4HE CONSTANTLY FOLLOW HER HUSBAND OR CAREGIVER AND SYMPTOMS OF THIS STAGE CAN INCLUDE FRET WHEN THE PERSON IS OUT OF SIGHT 4O A PERSON N )NCREASING MEMORY LOSS AND CONFUSION WHO CANNOT REMEMBER THE PAST OR ANTICIPATE THE N 3HORTENED ATTENTION SPAN FUTURE THE WORLD CAN BE STRANGE AND FRIGHTENING N )NAPPROPRIATE OUTBURSTS OF ANGER 3TICKING CLOSE TO A TRUSTED AND FAMILIAR CAREGIVER N 0ROBLEMS RECOGNIZING FRIENDS AND FAMILY MEMBERS MAY BE THE ONLY THING THAT MAKES SENSE AND N $IFlCULTY WITH LANGUAGE AND PROBLEMS WITH PROVIDES SECURITY READING WRITING AND WORKING WITH NUMBERS N $IFlCULTY ORGANIZING THOUGHTS AND THINKING 3%6%2% !$ LOGICALLY )N THE LAST STAGE OF !$ PLAQUES AND TANGLES ARE N )NABILITY TO LEARN NEW THINGS OR TO COPE WITH WIDESPREAD THROUGHOUT THE BRAIN MOST AREAS OF NEW OR UNEXPECTED SITUATIONS THE BRAIN HAVE SHRUNK FURTHER AND VENTRICLES HAVE N 2ESTLESSNESS AGITATION ANXIETY TEARFULNESS ENLARGED EVEN MORE 0EOPLE WITH !$ CANNOT WANDERINGESPECIALLY IN THE LATE AFTERNOON OR RECOGNIZE FAMILY AND LOVED ONES OR COMMUNICATE AT NIGHT IN ANY WAY 4HEY ARE COMPLETELY DEPENDENT ON N 2EPETITIVE STATEMENTS OR MOVEMENT OCCASIONAL OTHERS FOR CARE /THER SYMPTOMS CAN INCLUDE MUSCLE TWITCHES N 7EIGHT LOSS N 3EIZURES N 3KIN INFECTIONS N $IFlCULTY SWALLOWING
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 7HAT (APPENS TO THE "RAIN IN !$
N 'ROANING MOANING OR GRUNTING !$ 3PREADS 4HROUGH THE "RAIN N )NCREASED SLEEPING N ,ACK OF BLADDER AND BOWEL CONTROL .EAR THE END THE PERSON MAY BE IN BED MUCH OR ALL OF THE TIME 4HE MOST FREQUENT CAUSE OF DEATH FOR PEOPLE WITH !$ IS ASPIRATION PNEUMONIA 4HIS TYPE OF PNEUMONIA DEVELOPS WHEN A PERSON IS NOT ABLE TO SWALLOW PROPERLY AND TAKES FOOD OR LIQUIDS INTO THE LUNGS INSTEAD OF AIR
3EVERE !$
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 4HE "UDDY 0ROGRAM AT .ORTHWESTERN 5NIVERSITY
4HE "UDDY 0ROGRAM AT .ORTHWESTERN 5NIVERSITYHE MEDICAL SCHOOL CURRICULUM 4DEMANDS THAT STUDENTS SPEND ENORMOUS AMOUNTS OF TIME IN THE CLASSROOM AND CLINIC LEARNING THE INFORMATION AND SKILLS NECESSARY FOR A CAREER IN MEDICINE (OW EVER LITTLE OR NO TIME IS SET ASIDE FOR STUDENTS TO BE WITH PATIENTS OUTSIDE THE HOSPITAL OR CLINIC SETTING !S A RESULT IT IS HARD FOR MEDICAL STUDENTS TO GET TO KNOW THE HUMAN SIDE OF THE DISEASES THEY ARE LEARNING ABOUT 4HE "UDDY 0ROGRAM PAIRS MEDICAL STUDENTS AND PEOPLE WITH !$ ! PROGRAM AT .ORTHWESTERN TO SPEND TIME WITHAND LEARN FROMEACH OTHER 5NIVERSITYS #OGNITIVE .EUROLOGY AND !LZHEIMERS $ISEASE #ENTER MUSEUMS EXERCISING TOGETHER OR HANDS ON WAY TO LEARN ABOUT !$ IS ADDING JUST THAT ELEMENT TO ITS EVEN JUST SHARING A COFFEE OR A AND RELATED DEMENTIAS AND IT MEDICAL EDUCATION 4HE "UDDY MEAL 4HE STUDENTS ALSO ARE ABLE HELPS HIM OR HER UNDERSTAND THE 0ROGRAM BEGUN IN TO OBSERVE THEIR BUDDIES CLINICAL DAILY REALITIES AND ISSUES INVOLVED MATCHES lRST YEAR MEDICAL EVALUATIONS AT THE #ENTER /THER IN CARING FOR AND SUPPORTING STUDENTS WITH PEOPLE DIAGNOSED MEDICAL SCHOOLS HAVE STARTED PEOPLE WITH !$ AND THEIR WITH !$ OR ANOTHER FORM OF SIMILAR PROGRAMS FAMILIES )T ALSO INTRODUCES THEM DEMENTIA !BOUT TO 4HE PEOPLE WITH !$ AND TO THE CAREER PATH OF RESEARCH MEDICAL STUDENTS PARTICIPATE THEIR FAMILIES ARE SELECTED FROM AND CLINICAL PRACTICE IN !$ AND EVERY YEAR 4HEY lRST TAKE A .ORTHWESTERNS !LZHEIMERS RELATED DEMENTIAS &OR THE PERSON HOUR ORIENTATION COURSE ON !$ $ISEASE #ENTER AND OTHER WITH !$ PARTICIPATION IN THE FAMILY ISSUES AND COMMUNICATION RELATED PROGRAMS AT THE UNIVERSITY PROGRAM PROVIDES AN OPPORTUNITY SKILLS 4HEN FOR THE NEXT YEAR THEY &AMILIES ARE CONTACTED ABOUT FOR FRIENDSHIP AND SOCIALIZING SPEND AT LEAST HOURS A MONTH PARTICIPATING AND THE PEOPLE AND AN OUTLET FOR SHARING THEIR WITH A PERSON WITH DEMENTIA IN WITH !$ ARE SELECTED BASED ON EXPERIENCES WITH A SYMPATHETIC ADDITION TO MONTHLY MEETINGS THEIR ABILITY TO UNDERSTAND THE LISTENER WITH THE PROGRAM COORDINATORS NATURE OF THE PROGRAM AND THEIR &OR MANY OF THE STUDENTS THE 4OGETHER WITH THE PERSONS WILLINGNESS TO SPEND TIME EVERY PROGRAM IS A TRANSFORMATIVE CAREGIVER AND THE PROGRAMS MONTH WITH THE STUDENT BUDDY EXPERIENCE 4HEY BECOME VERY PROFESSIONAL STAFF STUDENTS AND 4HE PROGRAM HAS CLEAR BEN CLOSE TO THEIR BUDDIES AND FAMILY THEIR hBUDDIESv CHOOSE ACTIVITIES ElTS FOR BOTH THE MEDICAL STUDENT CAREGIVERS DURING THEIR YEAR FOR THEIR VISITS TOGETHER !CTIVITIES AND THE PERSON WITH !$ &OR THE TOGETHER AND CONTINUE THE FRIEND CAN INCLUDE SHOPPING VISITING MEDICAL STUDENT IT PROVIDES A SHIP EVEN AFTER THE YEAR IS OVER
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY CIENTISTS HAVE STUDIED !$ FROM MANY DRUG TREATMENTS &INDINGS FROM CURRENT RESEARCH ANGLES 4HEY HAVE LOOKED AT POPULATIONS ARE POINTING SCIENTISTS IN PROMISING DIRECTIONS FOR TO SEE HOW MANY CASES OF !$ OCCUR THE FUTURE 4HEY ARE ALSO HELPING RESEARCHERS TO EVERY YEAR AND WHETHER THERE MIGHT ASK BETTER QUESTIONS ABOUT THE ISSUES THAT ARE STILL BE LINKS BETWEEN THE DISEASE AND LIFESTYLES OR 3 UNCLEAR GENETIC BACKGROUNDS 4HEY ALSO HAVE CONDUCTED 0ART OF 5NRAVELING THE -YSTERY DESCRIBES WHAT CLINICAL STUDIES WITH HEALTHY OLDER PEOPLE AND SCIENTISTS ARE LEARNING FROM THEIR SEARCH FOR THOSE AT VARIOUS STAGES OF !$ 4HEY HAVE DONE N 4HE CAUSES OF !$ MANY STUDIES WITH LABORATORY ANIMALS 4HEY N .EW TECHNIQUES TO HELP IN DIAGNOSIS HAVE BEGUN TO LOOK AT NEURONAL CIRCUITS AND N .EW TREATMENTS NETWORKS OF CELLS TO LEARN HOW !$ PATHOLOGY DEVELOPS AND SPREADS 4HEY EVEN HAVE EXAMINED 2ESULTS FROM THIS RESEARCH WILL BRING US CLOSER INDIVIDUAL NERVE CELLS TO SEE HOW BETA AMYLOID TO THE DAY WHEN WE WILL BE ABLE TO DELAY THE ONSET TAU AND OTHER MOLECULES AFFECT THE ABILITY OF OF PREVENT OR CURE THE DEVASTATING DISEASE THAT CELLS TO FUNCTION NORMALLY ROBS OUR OLDER RELATIVES AND FRIENDS OF THEIR MOST 4HESE STUDIES HAVE LED TO A FULLER UNDER PRECIOUS POSSESSIONTHEIR MINDS STANDING OF MANY ASPECTS OF THE DISEASE IMPROVED DIAGNOSTIC TESTS NEW WAYS TO MANAGE BEHAVIORAL !NSWERS ASPECTS OF !$ AND A GROWING NUMBER OF POSSIBLE
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 !$ 2ESEARCH "ETTER 1UESTIONS .EW !NSWERS ,OOKING FOR THE #AUSES OF!$
NE OF THE MOST IMPORTANT PARTS OF PERSONS RISK SUCH AS THE AGE AT WHICH THE DISEASE UNRAVELING THE !$ MYSTERY IS BEGINS 3LOW AND CAREFUL DETECTIVE WORK BY SCIENTISTS lNDING OUT WHAT CAUSES THE DISEASE HAS PAID OFF IN DISCOVERIES OF GENETIC LINKS TO THE TWO 7HAT MAKES THE DISEASE PROCESS BEGIN MAIN TYPES OF !$ IN THE lRST PLACE 7HAT MAKES IT WORSE OVER TIME / /NE TYPE IS THE RARE EARLY ONSET !LZHEIMERS 7HY DOES THE NUMBER OF PEOPLE WITH THE DISEASE DISEASE )T USUALLY AFFECTS PEOPLE AGED TO INCREASE WITH AGE 7HY DOES ONE PERSON DEVELOP 3OME CASES OF EARLY ONSET DISEASE ARE INHERITED AND !$ WHILE ANOTHER REMAINS HEALTHY ARE CALLED FAMILIAL !$ &!$ 4HE OTHER IS 3OME DISEASES SUCH AS MEASLES OR PNEUMONIA LATE ONSET !LZHEIMERS DISEASE )T IS BY FAR THE HAVE CLEAR CUT CAUSES 4HEY CAN BE PREVENTED WITH MORE COMMON FORM AND OCCURS IN THOSE AND VACCINES OR CURED WITH ANTIBIOTICS /THERS SUCH AS OLDER 'AINING INSIGHT INTO THE GENETIC FACTORS DIABETES OR ARTHRITIS DEVELOP WHEN GENETIC LIFESTYLE ASSOCIATED WITH BOTH FORMS OF !$ IS IMPORTANT AND ENVIRONMENTAL FACTORS WORK TOGETHER TO START BECAUSE IDENTIFYING GENES THAT EITHER CAUSE THE A DISEASE PROCESS 4HE ROLE THAT ANY OR ALL OF THESE DISEASE OR INmUENCE A PERSONS RISK OF DEVELOPING IT FACTORS PLAY MAY BE DIFFERENT FOR EACH INDIVIDUAL IMPROVES OUR ABILITY TO UNDERSTAND HOW AND WHY !$ lTS INTO THE SECOND GROUP OF DISEASES THE DISEASE STARTS AND PROGRESSES 7E DO NOT YET FULLY UNDERSTAND WHAT CAUSES !$ BUT WE BELIEVE IT DEVELOPS BECAUSE OF A COMPLEX SERIES OF EVENTS THAT TAKE PLACE IN THE BRAIN OVER A LONG PERIOD OF TIME -ANY STUDIES ARE EXPLORING THE FACTORS INVOLVED IN THE CAUSE AND DEVELOP MENT OF !$
'%.%4)# &!#4/23 !4 7/2+ ). !$ 'ENETIC STUDIES OF COMPLEX NEURODEGENERA TIVE DISEASES SUCH AS !$ FOCUS ON TWO MAIN ISSUESWHETHER A GENE MIGHT INmUENCE A PERSONS OVERALL RISK OF DEVELOPING A DISEASE AND WHETHER A GENE MIGHT INmUENCE SOME PARTICULAR ASPECT OF A $.! #HROMOSOMES AND 'ENES 4HE "ODYS !MAZING #ONTROL #ENTER
HE NUCLEUS OF ALMOST 4EVERY HUMAN CELL CONTAINS AN ENCRYPTED hBLUEPRINT v ALONG WITH THE MEANS TO DECIPHER IT 4HIS BLUEPRINT ACCUMULATED OVER EONS OF GENETIC TRIAL AND ERROR CARRIES ALL THE INSTRUCTIONS A CELL NEEDS TO DO ITS JOB 4HE BLUEPRINT IS MADE UP OF $.! WHICH EXISTS AS TWO LONG INTERTWINED THREAD LIKE STRANDS CALLED CHROMOSOMES %ACH CELL HAS CHROMOSOMES IN PAIRS 4HE $.! IN CHROMOSOMES IS MADE UP OF FOUR CHEMICALS OR BASES STRUNG TOGETHER IN VARIOUS SEQUENCE PATTERNS 4HE $.! IN NEARLY ALL CELLS OF AN INDIVIDUAL IS IDENTICAL %ACH CHROMOSOME CONTAINS MANY THOUSANDS OF SEGMENTS CALLED GENES 0EOPLE INHERIT TWO COPIES OF EACH GENE FROM THEIR PARENTS EXCEPT FOR GENES ON THE 8 AND 9 CHROMOSOMES WHICH ARE CONSTRUCTION OPERATION AND REPAIR $.! THAT CAUSES A DISEASE IS CHROMOSOMES THAT AMONG OTHER %VEN THOUGH ALL GENES ARE PRESENT CALLED A MUTATION -UTATIONS FUNCTIONS DETERMINE A PERSONS SEX IN MOST CELLS THE PATTERN IN WHICH ALSO CAN CHANGE THE ACTIVATION %ACH PERSON NORMALLY HAS ONE PAIR THEY ARE ACTIVATED VARIES FROM CELL OF A PARTICULAR GENE /THER MORE OF SEX CHROMOSOMES FEMALES ARE TO CELL AND GIVES EACH CELL TYPE COMMON OR FREQUENT CHANGES IN 88 AND MALES ARE 89 4HE ITS DISTINCTIVE CHARACTER %VEN SLIGHT A GENES SEQUENCE OF BASES DO NOT SEQUENCE OF BASES IN A GENE TELLS ALTERATIONS IN A GENE CAN PRODUCE AUTOMATICALLY CAUSE DISEASE BUT THE CELL HOW TO MAKE SPECIlC AN ABNORMAL PROTEIN WHICH IN TURN THEY CAN INCREASE THE CHANCES THAT PROTEINS 0ROTEINS IN LARGE PART DETER MAY LEAD TO CELL MALFUNCTION AND A PERSON WILL DEVELOP A PARTICULAR MINE THE DIFFERENT KINDS OF CELLS THAT EVENTUALLY TO DISEASE DISEASE 7HEN THIS HAPPENS MAKE UP AN ORGANISM AND DIRECT !NY PERMANENT CHANGE IN THE THE CHANGED GENE IS CALLED A ALMOST EVERY ASPECT OF THE CELLS SEQUENCE OF BASES IN A GENES GENETIC RISK FACTOR
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 !$ 2ESEARCH "ETTER 1UESTIONS .EW !NSWERS
'ENES AND %ARLY /NSET ! $IFFERENT 'ENETIC 3TORY IN !LZHEIMERS $ISEASE ,ATE /NSET !LZHEIMERS $ISEASE )N THE EARLY DAYS OF !$ GENETICS RESEARCH SCIENTISTS 7HILE SOME SCIENTISTS WERE STUDYING THE ROLE OF REALIZED THAT SOME CASES PARTICULARLY OF THE RARE CHROMOSOMES AND IN EARLY ONSET !$ EARLY ONSET !$ RAN IN FAMILIES 4HIS LED THEM TO OTHERS WERE LOOKING ELSEWHERE TO SEE IF THEY COULD EXAMINE $.! SAMPLES FROM THESE FAMILIES TO SEE lND GENETIC CLUES FOR THE LATE ONSET FORM "Y WHETHER THEY HAD SOME GENETIC TRAIT IN COMMON INVESTIGATORS HAD NARROWED THEIR SEARCH TO A REGION #HROMOSOMES AND BECAME THE FOCUS OF OF CHROMOSOME 4HEY FOUND A GENE ON ATTENTION 4HE SCIENTISTS FOUND THAT SOME FAMILIES CHROMOSOME THAT THEY WERE ABLE TO LINK TO HAVE A MUTATION IN SELECTED GENES ON THESE CHROMO LATE ONSET !$ SOMES /N CHROMOSOME THE MUTATION CAUSES AN 4HIS GENE CALLED !0/% PRODUCES A PROTEIN ABNORMAL AMYLOID PRECURSOR PROTEIN TO BE PRODUCED CALLED APOLIPOPROTEIN % !0/% COMES IN SEVERAL SEE PAGE FOR MORE ON !00 /N CHROMOSOME FORMS OR ALLELESε ε AND ε THE MUTATION CAUSES AN ABNORMAL PROTEIN CALLED N 4HE !0/% ε ALLELE IS RELATIVELY RARE AND MAY PRESENILIN TO BE PRODUCED /N CHROMOSOME PROVIDE SOME PROTECTION AGAINST THE DISEASE )F !$ THE MUTATION CAUSES ANOTHER ABNORMAL PROTEIN TO BE DOES OCCUR IN A PERSON WITH THIS ALLELE IT DEVELOPS PRODUCED 4HIS PROTEIN CALLED PRESENILIN IS VERY LATER IN LIFE THAN IN THOSE WITH AN !0/% ε ALLELE SIMILAR TO PRESENILIN %VEN IF ONLY ONE OF THESE N !0/% ε IS THE MOST COMMON ALLELE 2ESEARCH GENES THAT ARE INHERITED FROM A PARENT CONTAINS A ERS THINK IT PLAYS A NEUTRAL ROLE IN !$ MUTATION THE PERSON WILL ALMOST INEVITABLY DEVELOP N !0/% ε OCCURS IN ABOUT PERCENT OF ALL EARLY ONSET !$ 4HIS MEANS THAT IN THESE FAMILIES PEOPLE WHO DEVELOP LATE ONSET !$ AND IS PRESENT CHILDREN HAVE ABOUT A CHANCE OF DEVELOPING IN ABOUT TO PERCENT OF THE POPULATION 0EO THE DISEASE IF ONE OF THEIR PARENTS HAS IT PLE WITH !$ ARE MORE LIKELY TO HAVE AN !0/% ε %ARLY ONSET !$ IS VERY RARE AND MUTATIONS IN ALLELE THAN PEOPLE WHO DO NOT HAVE !$ (OWEVER THESE THREE GENES DO NOT PLAY A ROLE IN THE MORE AT LEAST ONE THIRD OF PEOPLE WITH !$ DO NOT HAVE COMMON LATE ONSET !$ (OWEVER THESE lNDINGS AN !0/% ε ALLELE $OZENS OF STUDIES HAVE CON WERE CRUCIAL BECAUSE THEY SHOWED THAT GENETICS WAS lRMED THAT THE !0/% ε ALLELE INCREASES THE RISK INDEED A FACTOR IN !$ AND THEY HELPED TO IDENTIFY OF DEVELOPING !$ BUT HOW THAT HAPPENS IS NOT SOME KEY CELL PATHWAYS INVOLVED IN THE !$ DISEASE YET UNDERSTOOD 4HESE STUDIES ALSO HAVE HELPED TO PROCESS 4HEY SHOWED THAT MUTATIONS IN !00 CAN EXPLAIN SOME OF THE VARIATION IN THE AGE AT WHICH CAUSE !$ HIGHLIGHTING THE PRESUMED KEY ROLE OF !$ DEVELOPS AS PEOPLE WHO INHERIT ONE OR TWO BETA AMYLOID IN THE DISEASE -UTATIONS IN PRE !0/% ε ALLELES TEND TO DEVELOP !$ AT AN EARLIER SENILIN AND ALSO CAUSE AN INCREASED AMOUNT OF AGE THAN THOSE WHO DO NOT (OWEVER INHERITING THE DAMAGING BETA AMYLOID TO BE MADE IN THE BRAIN AN !0/% ε ALLELE DOES NOT MEAN THAT A PERSON WILL DElNITELY DEVELOP !$ 3OME PEOPLE WITH ONE OR TWO !0/% ε ALLELES NEVER GET THE DISEASE AND OTHERS WHO DO DEVELOP !$ DO NOT HAVE ANY !0/% ε ALLELES
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 4HE (UNT FOR .EW !$ 'ENES
OR SOME TIME SCIENTISTS HAVE )N .)! LAUNCHED THE &SUSPECTED THAT IN ADDITION !LZHEIMERS $ISEASE 'ENETICS TO !0/% ε AS MANY AS HALF A 3TUDY TO IDENTIFY AT LEAST DOZEN OTHER RISK FACTOR GENES EXIST FAMILIES WITH MEMBERS WHO HAVE FOR LATE ONSET !$ BUT THEY HAVE LATE ONSET !$ AS WELL AS MEMBERS BEEN UNABLE TO lND THEM )N WHO DO NOT HAVE THE DISEASE !LL SCIENTISTS UNVEILED THEIR DISCOVERY OF OF THESE FAMILY MEMBERS PROVIDE ONE NEW !$ RISK FACTOR GENE BLOOD SAMPLES AND OTHER CLINICAL 4HIS !$ RISK FACTOR GENE IS DATA FOR THE INITIATIVE 4HE MATERIAL CALLED 3/2, )T IS INVOLVED IN COLLECTED ALLOWS INVESTIGATORS TO RECYCLING !00 FROM THE SURFACE OF CREATE AND MAINTAIN hIMMORTALIZEDv CELLS AND ITS ASSOCIATION WITH !$ CELL LINESCELLS THAT ARE CONTINU WAS IDENTIlED AND CONlRMED IN OUSLY REGENERATED IN THE LABORATORY THREE SEPARATE STUDIES 2ESEARCH 4HESE CELL LINES ARE CRUCIAL FOR THE ERS FOUND THAT WHEN 3/2, IS EXHAUSTIVE $.! ANALYSIS STUDIES EXPRESSED AT LOW LEVELS OR IN A NEEDED TO IDENTIFY RISK FACTOR GENES BE DRAWN FROM EXISTING SAMPLES VARIANT FORM HARMFUL BETA AMYLOID EACH OF WHICH MAY HAVE RELATIVELY OF BLOOD AND TISSUE OTHER GENETIC LEVELS INCREASE PERHAPS BY SMALL EFFECTS ON !$ DEVELOPMENT MATERIAL WILL BE COLLECTED FROM NEW DEmECTING !00 AWAY FROM ITS -ORE THAN NEW CELL LINES PARTICIPANTS NORMAL PATHWAYS AND FORCING IT ARE NOW AVAILABLE FOR RESEARCHERS .EW !$ GENETICS DISCOVERIES INTO CELLULAR COMPARTMENTS THAT TO STUDY RISK FACTOR GENES FOR LATE ARE POSSIBLE LARGELY BECAUSE GENERATE BETA AMYLOID ONSET !$ OF CLOSE COLLABORATION AMONG !S !$ GENETICS RESEARCH HAS ! NEW INITIATIVE THE !LZHEIMERS SCIENTISTS PARTICIPATION OF VOLUNTEER INTENSIlED IT HAS BECOME INCREAS $ISEASE 'ENETICS #ONSORTIUM FAMILIES NEW GENETICS TECH INGLY CLEAR THAT SCIENTISTS NEED WAS LAUNCHED IN TO ACCELER NOLOGIES STATISTICAL AND ANALYTIC MANY DIFFERENT SAMPLES OF GENETIC ATE THE APPLICATION OF GENETICS ADVANCES AND RAPID DATA SHARING MATERIAL IF THEY ARE TO CONTINUE TECHNOLOGIES TO LATE ONSET !$ &OR EXAMPLE THE 3/2, STUDIES MAKING PROGRESS IN IDENTIFYING NEW THROUGH COLLABORATIONS AMONG MOST INVOLVED SCIENTIlC INSTITUTIONS IN RISK FACTOR GENES 'ENETIC MATERIAL OF THE LEADING RESEARCHERS IN !$ .ORTH !MERICA %UROPE AND !SIA IS ALSO ESSENTIAL FOR IDENTIFYING GENETICS 4HE ULTIMATE GOAL OF THIS AND THE PARTICIPATION OF MORE THAN ASSOCIATED ENVIRONMENTAL FACTORS EFFORT IS TO OBTAIN GENETIC MATERIAL PEOPLE WHO DONATED BLOOD AND UNDERSTANDING THE INTERACTIONS FROM PEOPLE WITH !$ AND AND TISSUE FOR GENETIC TYPING !N OF GENES AND THE ENVIRONMENT COGNITIVELY HEALTHY PEOPLE IMPORTANT PART OF .)!S EFFORTS TO 4HESE ADVANCES ULTIMATELY WILL TO COMPREHENSIVELY SCAN THE WHOLE PROMOTE AND ACCELERATE !$ ALLOW INVESTIGATORS TO IDENTIFY PEOPLE GENOME FOR THE REMAINING !$ GENETICS RESEARCH IS TO MAKE AT HIGH RISK OF DEVELOPING !$ AND RISK FACTOR GENES AS WELL AS THOSE BIOLOGICAL SAMPLES AND DATA HELP THEM FOCUS ON NEW PATHWAYS FOR AGE RELATED COGNITIVE DECLINE PUBLICLY AVAILABLE TO APPROVED FOR PREVENTION OR TREATMENT 3OME OF THE GENETIC MATERIAL WILL RESEARCHERS
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 !$ 2ESEARCH "ETTER 1UESTIONS .EW !NSWERS
/4(%2 &!#4/23 !4 7/2+ ). !$ RElNED ANTIBODY APPROACHES ARE NOW BEING TESTED 'ENETICS EXPLAINS SOME OF WHAT MIGHT CAUSE !$ IN CLINICAL TRIALS AND ADDITIONAL RESEARCH ON NEW BUT IT DOES NOT EXPLAIN EVERYTHING 3O RESEARCHERS WAYS OF HARNESSING THE ANTIBODY RESPONSE CONTIN CONTINUE TO INVESTIGATE OTHER POSSIBILITIES THAT MAY UES IN THE LAB EXPLAIN HOW THE !$ PROCESS STARTS AND DEVELOPS !NOTHER IMPORTANT AREA OF RESEARCH IS HOW BETA AMYLOID MAY DISRUPT CELLULAR COMMUNICATION "ETA !MYLOID WELL BEFORE PLAQUES FORM /NE RECENT STUDY 7E NOW KNOW A GREAT DEAL ABOUT HOW BETA DESCRIBED HOW BETA AMYLOID OLIGOMERS TARGET AMYLOID IS FORMED AND THE STEPS BY WHICH SPECIlC SYNAPTIC CONNECTIONS BETWEEN NEURONS BETA AMYLOID FRAGMENTS STICK TOGETHER IN SMALL CAUSING THEM TO DETERIORATE /THER SCIENTISTS ARE AGGREGATES OLIGOMERS AND THEN GRADUALLY FORM STUDYING OTHER POTENTIALLY TOXIC EFFECTS THAT PLAQUES INTO PLAQUES SEE PAGE IN 4HE (ALLMARKS OF HAVE ON NEURONS AND IN CELLULAR COMMUNICATION !$ FOR MORE ON THIS PROCESS !RMED WITH THIS 5NDERSTANDING MORE ABOUT THESE PROCESSES MAY KNOWLEDGE INVESTIGATORS ARE INTENSELY INTERESTED ALLOW SCIENTISTS TO DEVELOP SPECIlC THERAPIES TO IN THE TOXIC EFFECTS THAT BETA AMYLOID OLIGOMERS BLOCK THE TOXIC EFFECTS AND PLAQUES HAVE ON NEURONS 4HIS RESEARCH IS POSSIBLE IN PART BECAUSE SCIENTISTS HAVE BEEN ABLE 4AU TO DEVELOP TRANSGENIC ANIMAL MODELS OF !$ 4AU THE CHIEF COMPONENT OF NEUROlBRILLARY TANGLES 4RANSGENICS ARE ANIMALS THAT HAVE BEEN SPECIALLY SEE PAGE IN 4HE (ALLMARKS OF !$ FOR MORE BRED TO DEVELOP !$ LIKE FEATURES SUCH AS ON TAU IS GENERATING NEW EXCITEMENT AS AN AREA BETA AMYLOID PLAQUES OF STUDY 4HE RECENT FOCUS ON TAU HAS BEEN SPURRED "ETA AMYLOID STUDIES HAVE MOVED FORWARD TO BY THE lNDING THAT A MUTANT FORM OF THE PROTEIN THE POINT THAT SCIENTISTS ARE NOW CARRYING OUT IS RESPONSIBLE FOR ONE FORM OF FRONTOTEMPORAL PRELIMINARY TESTS IN HUMANS OF POTENTIAL THERAPIES DEMENTIA THE THIRD MOST COMMON CAUSE OF LATE LIFE AIMED AT REMOVING BETA AMYLOID HALTING ITS DEMENTIA AFTER !$ AND VASCULAR DEMENTIA 4HIS FORMATION OR BREAKING DOWN EARLY FORMS BEFORE FORM IS KNOWN AS FRONTOTEMPORAL DEMENTIA WITH THEY CAN BECOME HARMFUL PARKINSONISM LINKED TO CHROMOSOME &4$0 &OR EXAMPLE ONE LINE OF RESEARCH BY A PHARMA &INDING THIS MUTANT PROTEIN WAS IMPORTANT CEUTICAL COMPANY STARTED WITH THE OBSERVATION THAT BECAUSE IT SUGGESTED THAT ABNORMALITIES IN THE TAU INJECTING BETA AMYLOID INTO !$ TRANSGENIC MICE PROTEIN ITSELF CAN CAUSE DEMENTIA CAUSED THEM TO FORM ANTIBODIES TO THE BETA .EW TRANSGENIC MOUSE MODELS OF !$ HAVE AMYLOID AND REDUCED THE NUMBER OF AMYLOID HELPED TAU RESEARCH MAKE RAPID PROGRESS &OR PLAQUES IN THE BRAIN 4HIS EXCITING lNDING LED TO EXAMPLE A RECENT MODEL THE hTRIPLE TRANSGENICv OTHER STUDIES AND ULTIMATELY TO CLINICAL TRIALS IN MOUSE FORMS PLAQUES AND TANGLES OVER TIME IN WHICH HUMAN PARTICIPANTS WERE IMMUNIZED WITH BRAIN REGIONS SIMILAR TO THOSE IN HUMAN !$ BETA AMYLOID 4HESE STUDIES HAD TO BE STOPPED !NOTHER RECENT TRANSGENIC MOUSE MODEL WHICH BECAUSE SOME OF THE PARTICIPANTS DEVELOPED CONTAINS ONLY HUMAN TAU FORMS CLUMPS OF HARMFUL SIDE EFFECTS BUT THE INVESTIGATORS DID DAMAGING TAU lLAMENTS ALSO IN A REGION SPECIlC NOT GIVE UP HOPE 2ATHER THEY WENT BACK TO THE FASHION SIMILAR TO !$ IN HUMANS DRAWING BOARD TO RETHINK THEIR STRATEGY -ORE 4HESE STUDIES OF TAU ALSO HAVE SUGGESTED A MECHANISM FOR TAU DAMAGE THAT IS DIFFERENT FROM THAT PREVIOUSLY SUSPECTED 7ITH THESE NEW INSIGHTS
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY SCIENTISTS NOW SPECULATE THAT ONE REASON TAU MAY 0ROTEIN -ISFOLDING DAMAGE AND KILL NEURONS IS BECAUSE IT UPSETS 2ESEARCHERS HAVE FOUND THAT A NUMBER OF DEVASTAT THE NORMAL ACTIVITY OF THE CELL IN ADDITION TO ING NEURODEGENERATIVE DISEASES FOR EXAMPLE !$ FORMING NEUROlBRILLARY TANGLES 0ARKINSONS DISEASE DEMENTIA WITH ,EWY BODIES /THER STUDIES OF MUTANT TAU IN MICE SUGGEST THAT FRONTOTEMPORAL LOBAR DEGENERATION (UNTINGTONS THE ACCUMULATION OF TAU IN TANGLES MAY NOT EVEN BE THE DISEASE AND PRION DISEASES SHARE A KEY CULPRIT IN MEMORY LOSS 2ATHER AS WITH BETA AMYLOID CHARACTERISTICPROTEIN MISFOLDING IT MAY BE THAT AN EARLIER AND MORE SOLUBLE ABNORMAL 7HEN A PROTEIN IS FORMED IT hFOLDSv INTO A FORM OF THE PROTEIN CAUSES THE DAMAGE TO NEURONS UNIQUE THREE DIMENSIONAL SHAPE THAT HELPS IT
2ESEARCHERS %XPLORE .EURODEGENERATIVE h#OUSINSv
EURODEGENERATIVE DISEASES LIKE !$ 0ARKINSONS A COMBINATION OF GENETIC LIFESTYLE AND ENVIRONMENTAL .DISEASE AMYOTROPHIC LATERAL SCLEROSIS !,3 CAUSES AND THEY DEVELOP OVER MANY YEARS AND DEMENTIA WITH ,EWY BODIES SHARE MORE THAN THE 4HIS GRAPHIC SHOWS ONE WAY OF THINKING ABOUT BASIC CHARACTERISTIC OF MISFOLDED PROTEINS 4HEY ALSO HOW THESE DISEASES MAY BE LINKED AS WELL AS WHAT SHARE CLINICAL CHARACTERISTICS &OR EXAMPLE PEOPLE MAKES THEM UNIQUE "Y INVESTIGATING THE UNIQUE WITH !$ HAVE TROUBLE MOVING A CHARACTERISTIC OF CHARACTERISTICS OF THESE DISEASES AS WELL AS THE 0ARKINSONS DISEASE 3LEEP WAKE DISORDERS DELUSIONS CHARACTERISTICS THEY SHARE SCIENTISTS HOPE TO LEARN PSYCHIATRIC DISTURBANCES AND MEMORY LOSS OCCUR IN EVEN MORE THAN THEY WOULD IF THEY FOCUSED ON EACH ALL OF THESE DISEASES 4HESE DISEASES ALSO RESULT FROM DISEASE BY ITSELF
$AMAGING 0ROCESSES ,IFETIME /CCURRING "EFORE .EURODEGENERATIVE )NFLUENCES 3YMPTOMS !PPEAR %ARLY 3YMPTOMS $ISEASES
4REMOR -EMORY LOSS !MYLOID PLAQUES !$0$ %XECUTIVE FUNCTION !$ 4AU TANGLES $," 0$ 'ENES PROBLEMS /THER ABNORMAL -OVEMENT PROBLEMS 0$$ %NVIRONMENT PROTEIN DEPOSITS 6A$ 'AIT AND BALANCE PROBLEMS 3YSTEMIC 2EDUCED OXYGEN FACTORS FLOW TO TISSUES 3LEEP WAKE DISORDERS &4,$ 4OXIC PROCESSES (ALLUCINATIONS !,3 $ELUSIONS 2IGIDITY
!$ !LZHEIMERS DISEASE !$0$ !$ WITH PARKINSONISM !,3 AMYOTROPHIC LATERAL SCLEROSIS $," DEMENTIA WITH ,EWY BODIES &4,$ FRONTOTEMPORAL LOBAR DEGENERATION 6A$ VASCULAR DEMENTIA INCLUDES MULTI INFARCT DEMENTIA 0$ 0ARKINSONS DISEASE 0$$ 0ARKINSONS DISEASE WITH DEMENTIA !DAPTED FROM AN %MORY 5NIVERSITY ILLUSTRATION
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 !$ 2ESEARCH "ETTER 1UESTIONS .EW !NSWERS
PERFORM ITS SPECIlC FUNCTION 4HIS CRUCIAL PROCESS 3CIENTISTS DO NOT KNOW EXACTLY WHY OR HOW CAN GO WRONG FOR VARIOUS REASONS AND MORE THESE PROCESSES OCCUR BUT RESEARCH INTO THE UNIQUE COMMONLY DOES GO WRONG IN AGING CELLS !S A CHARACTERISTICS AND ACTIONS OF VARIOUS MISFOLDED RESULT THE PROTEIN FOLDS INTO AN ABNORMAL SHAPE PROTEINS IS HELPING INVESTIGATORS LEARN MORE ABOUT IT IS MISFOLDED )N !$ THE MISFOLDED PROTEINS ARE THE SIMILARITIES AND DIFFERENCES ACROSS AGE RELATED BETA AMYLOID THE CLEAVED PRODUCT OF !00 SEE NEURODEGENERATIVE DISEASES 4HIS KNOWLEDGE MAY &ROM !00 TO "ETA !MYLOID 0LAQUES ON PAGE SOMEDAY LEAD TO THERAPIES FOR MORE ON THE FORMATION OF BETA AMYLOID AND A CLEAVED PRODUCT OF TAU 4HE !GING 0ROCESS .ORMALLY CELLS REPAIR OR DEGRADE MISFOLDED !NOTHER SET OF INSIGHTS ABOUT THE CAUSE OF !$ PROTEINS BUT IF MANY OF THEM ARE FORMED AS PART COMES FROM THE MOST BASIC OF ALL RISK FACTORS OF AGE RELATED CHANGES THE BODYS REPAIR AND AGING ITSELF !GE RELATED CHANGES SUCH AS INmAM CLEARANCE PROCESS CAN BE OVERWHELMED -ISFOLDED MATION MAY MAKE !$ DAMAGE IN THE BRAIN WORSE PROTEINS CAN BEGIN TO STICK TOGETHER WITH OTHER "ECAUSE CELLS AND COMPOUNDS THAT ARE KNOWN TO BE MISFOLDED PROTEINS TO FORM INSOLUBLE AGGREGATES INVOLVED IN INmAMMATION ARE FOUND IN !$ PLAQUES !S A RESULT THESE AGGREGATES CAN BUILD UP LEADING SOME RESEARCHERS THINK THAT COMPONENTS OF THE TO DISRUPTION OF CELLULAR COMMUNICATION AND INmAMMATORY PROCESS MAY PLAY A ROLE IN !$ METABOLISM AND EVEN TO CELL DEATH 4HESE /THER PLAYERS IN THE AGING PROCESS THAT MAY EFFECTS MAY PREDISPOSE A PERSON TO !$ OR OTHER BE IMPORTANT IN !$ ARE FREE RADICALS WHICH ARE NEURODEGENERATIVE DISEASES OXYGEN OR NITROGEN MOLECULES THAT COMBINE EASILY WITH OTHER MOLECULES SCIENTISTS CALL THEM hHIGHLY REACTIVEv &REE RADICALS ARE GENERATED IN MITOCHONDRIA WHICH ARE STRUCTURES FOUND IN ALL CELLS INCLUDING NEURONS -ITOCHONDRIA ARE THE CELLS POWER PLANT PROVIDING THE ENERGY A CELL NEEDS TO MAINTAIN ITS STRUCTURE DIVIDE AND CARRY
-ITOCHONDRIA AND &REE 2ADICALS !NY GIVEN CELL HAS HUNDREDS OF MITOCHONDRIA 4HIS ILLUSTRATION SHOWS TWOA HEALTHY MITOCHON DRION AND AN OXIDATIVELY STRESSED AND DAMAGED ONE 4HE ARROWS INDICATE THE MOVEMENT OF FREE RADICALS WHICH CAN SPREAD EASILY FROM DAMAGED MITOCHONDRIA TO OTHER PARTS OF THE CELL
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 4HE "RAINS 6ASCULAR 3YSTEM
4HIS IMAGE SHOWS THE COMPLEXITY OF THE HUMAN BRAINS VASCULAR SYSTEM PARTICULARLY LARGE AND SMALL ARTERIES THAT CARRY OXYGEN FROM THE LUNGS TO THE BRAIN !LTHOUGH MANY BLOOD VESSELS ARE VISIBLE HERE THIS IMAGE SHOWS FEWER THAN HALF OF THE TOTAL NUMBER IN THE BRAIN
OUT ITS FUNCTIONS %NERGY FOR THE CELL IS PRODUCED IN AN EFlCIENT METABOLIC PROCESS )N THIS PROCESS FREE RADICALS ARE PRODUCED &REE RADICALS CAN HELP CELLS IN CERTAIN WAYS SUCH AS lGHTING INFECTION (OWEVER BECAUSE THEY ARE VERY ACTIVE AND COMBINE EASILY WITH OTHER MOLECULES FREE RADICALS ALSO CAN DAMAGE THE NEURONS CELL MEMBRANE OR ITS $.! 4HE PRODUCTION OF FREE RADICALS CAN SET OFF A CHAIN REACTION RELEASING EVEN MORE FREE RADICALS THAT CAN FURTHER DAMAGE NEURONS SEE ILLUSTRATION ON 6ASCULAR $ISEASE PAGE 4HIS KIND OF DAMAGE IS CALLED OXIDATIVE &OR SOME TIME NOW HINTS HAVE BEEN EMERGING DAMAGE 4HE BRAINS UNIQUE CHARACTERISTICS INCLUD THAT THE BODYS VAST NETWORK OF SMALL AND LARGE ING ITS HIGH RATE OF METABOLISM AND ITS LONG LIVED BLOOD VESSELSTHE VASCULAR SYSTEMMAY MAKE CELLS MAY MAKE IT ESPECIALLY VULNERABLE TO OXIDA AN IMPORTANT CONTRIBUTION IN THE DEVELOPMENT OF TIVE DAMAGE OVER THE LIFESPAN 4HE DISCOVERY THAT DEMENTIA AND THE CLINICAL SYMPTOMS OF !$ 3OME BETA AMYLOID GENERATES FREE RADICALS IN SOME !$ SCIENTISTS ARE FOCUSING ON WHAT HAPPENS WITH THE PLAQUES IS A POTENTIALLY SIGNIlCANT lNDING IN THE BRAINS BLOOD VESSELS IN AGING AND !$ /THERS ARE QUEST FOR BETTER UNDERSTANDING OF !$ AS WELL AS FOR LOOKING AT THE RELATIONSHIP BETWEEN !$ AND VASCU OTHER NEURODEGENERATIVE DISORDERS AND UNHEALTHY LAR PROBLEMS IN OTHER PARTS OF THE BODY BRAIN AGING 2ESEARCHERS ALSO ARE STUDYING AGE RELATED !$ AND 6ASCULAR 0ROBLEMS IN THE "RAIN CHANGES IN THE WORKING ABILITY OF SYNAPSES IN 4HE BRAIN REQUIRES A CONSTANT AND DEPENDABLE mOW CERTAIN AREAS OF THE BRAIN 4HESE CHANGES MAY OF OXYGEN AND GLUCOSE TO SURVIVE AND mOURISH 4HE REDUCE THE ABILITY OF NEURONS TO COMMUNICATE BRAINS BLOOD VESSELS PROVIDE THE HIGHWAYS TO DELIVER WITH EACH OTHER LEADING TO INCREASED NEURONAL THESE VITAL ELEMENTS TO NEURONS AND GLIAL CELLS VULNERABILITY IN REGIONS OF THE BRAIN IMPORTANT !GING BRINGS CHANGES IN THE BRAINS BLOOD IN !$ !GE RELATED REDUCTIONS IN LEVELS OF VESSELSARTERIES CAN NARROW AND GROWTH OF NEW PARTICULAR GROWTH FACTORS SUCH AS NERVE GROWTH CAPILLARIES SLOWS DOWN )N !$ WHOLE AREAS OF FACTOR AND BRAIN DERIVED NEUROTROPHIC FACTOR NERVOUS TISSUE INCLUDING THE CAPILLARIES THAT SUPPLY ALSO MAY CAUSE IMPORTANT CELL POPULATIONS TO BE COMPROMISED -ANY STUDIES ARE UNDERWAY TO TEASE OUT THE POSSIBLE EFFECTS OF THE AGING PROCESS ON THE DEVELOPMENT OF !$
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 !$ 2ESEARCH "ETTER 1UESTIONS .EW !NSWERS
AND DRAIN IT ALSO ARE LOST "LOOD mOW TO AND FROM STUDIES 4HESE STUDIES HAVE FOUND FOR EXAMPLE VARIOUS PARTS OF THE BRAIN CAN BE AFFECTED AND THE THAT HEART DISEASE AND STROKE MAY CONTRIBUTE TO THE BRAIN MAY BE LESS ABLE TO COMPENSATE FOR DAMAGE DEVELOPMENT OF !$ THE SEVERITY OF !$ OR THE DE THAT ACCUMULATES AS THE DISEASE PROGRESSES VELOPMENT OF OTHER TYPES OF DEMENTIA 3TUDIES ALSO &OR SOME TIME NOW STUDY OF THE BRAINS BLOOD SHOW THAT HIGH BLOOD PRESSURE THAT DEVELOPS DUR VESSEL SYSTEM IN !$ HAS BEEN A PRODUCTIVE LINE OF ING MIDDLE AGE IS CORRELATED WITH COGNITIVE DECLINE INQUIRY /NE IMPORTANT lNDING HAS BEEN THAT THE AND DEMENTIA IN LATER LIFE BRAINS ABILITY TO RID ITSELF OF TOXIC BETA AMYLOID BY !NOTHER FOCUS OF !$ VASCULAR RESEARCH IS THE SENDING IT OUT INTO THE BODYS BLOOD CIRCULATION METABOLIC SYNDROME A CONSTELLATION OF FACTORS THAT IS LESSENED 3OME SCIENTISTS NOW THINK THAT POOR INCREASES THE RISK OF HEART DISEASE STROKE AND TYPE CLEARANCE OF BETA AMYLOID FROM THE BRAIN COM DIABETES -ETABOLIC SYNDROME INCLUDES OBESITY BINED WITH A DIMINISHED ABILITY TO DEVELOP NEW ESPECIALLY AROUND THE WAIST HIGH TRIGLYCERIDE CAPILLARIES AND ABNORMAL AGING OF THE BRAINS BLOOD LEVELS LOW ($, hGOOD CHOLESTEROLv LEVELS HIGH VESSEL SYSTEM CAN LEAD TO CHEMICAL IMBALANCES IN BLOOD PRESSURE AND INSULIN RESISTANCE A CONDITION THE BRAIN AND DAMAGE NEURONS ABILITY TO FUNCTION IN WHICH INSULIN DOES NOT REGULATE BLOOD SUGAR AND COMMUNICATE WITH EACH OTHER 4HESE lNDINGS LEVELS VERY WELL %VIDENCE FROM EPIDEMIOLOGIC ARE EXCITING BECAUSE THEY MAY HELP TO EXPLAIN PART STUDIES NOW SUGGESTS THAT PEOPLE WITH THE META OF WHAT HAPPENS IN THE BRAIN DURING THE DEVELOP BOLIC SYNDROME HAVE INCREASED RISK OF COGNITIVE MENT OF !$ 4HESE lNDINGS ALSO SUGGEST SEVERAL IMPAIRMENT AND ACCELERATED COGNITIVE DECLINE NEW TARGETS FOR POTENTIAL !$ THERAPIES .EARLY ONE IN lVE !MERICANS OLDER THAN AGE HAS TYPE DIABETES AND EPIDEMIOLOGIC STUDIES !$ AND 6ASCULAR 0ROBLEMS IN SUGGEST THAT PEOPLE WITH THIS DISEASE MAY BE /THER 0ARTS OF THE "ODY AT INCREASED RISK OF COGNITIVE PROBLEMS INCLUDING 2ESEARCH ALSO HAS BEGUN TO TEASE OUT SOME -#) AND !$ AS THEY AGE 4HE HIGHER RISK RELATIONSHIPS BETWEEN !$ AND OTHER VASCULAR ASSOCIATED WITH DIABETES MAY BE THE RESULT OF HIGH DISEASES SUCH AS HEART DISEASE STROKE AND TYPE LEVELS OF BLOOD SUGAR OR IT MAY BE DUE TO OTHER DIABETES )T IS IMPORTANT TO SORT OUT THE VARIOUS CONDITIONS ASSOCIATED WITH DIABETES OBESITY HIGH EFFECTS ON THE BRAIN OF THESE DISEASES BECAUSE THEY BLOOD PRESSURE ABNORMAL BLOOD CHOLESTEROL LEVELS ARE MAJOR CAUSES OF ILLNESS AND DEATH IN THE 5NITED PROGRESSIVE ATHEROSCLEROSIS OR TOO MUCH INSULIN 3TATES TODAY IN THE BLOOD 4HESE lNDINGS ABOUT DIABETES -UCH OF THIS EVIDENCE COMES FROM EPIDEMIO HAVE SPURRED RESEARCH ON A NUMBER OF FRONTS LOGIC STUDIES WHICH COMPARE THE LIFESTYLES BE EPIDEMIOLOGIC STUDIES TEST TUBE AND ANIMAL HAVIORS AND CHARACTERISTICS OF GROUPS OF PEOPLE STUDIES AND CLINICAL TRIALS 4HE OBJECTIVE OF THESE SEE $ESCRIBING 3CIENTIlC &INDINGS 4HE 4YPE OF STUDIES IS TO LEARN MORE ABOUT THE RELATIONSHIP 3TUDY -AKES AN )MPORTANT $IFFERENCE ON PAGE BETWEEN DIABETES AND COGNITIVE PROBLEMS AND TO FOR MORE INFORMATION ABOUT EPIDEMIOLOGIC lND OUT IN CLINICAL TRIALS WHETHER TREATING THE DISEASE RIGOROUSLY CAN POSITIVELY AFFECT COGNITIVE HEALTH AND POSSIBLY SLOW OR PREVENT THE DEVELOPMENT OF !$
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY ,IFESTYLE &ACTORS 7E KNOW THAT PHYSICAL ACTIVITY AND A NUTRITIOUS DIET CAN HELP PEOPLE STAY HEALTHY AS THEY GROW OLDER ! HEALTHY DIET AND EXERCISE CAN REDUCE OBESITY LOWER BLOOD CHOLESTEROL AND HIGH BLOOD PRESSURE AND IMPROVE INSULIN ACTION )N ADDITION ASSOCIATION STUDIES SUGGEST THAT PURSUING INTELLECTUALLY STIMULATING ACTIVITIES AND MAINTAINING ACTIVE CONTACTS WITH FRIENDS AND FAMILY MAY CONTRIBUTE TO HEALTHY AGING ! GROWING BODY OF EVIDENCE NOW SUGGESTS THAT THESE LIFESTYLE FACTORS MAY BE RELATED N %PIDEMIOLOGIC STUDIES SHOW THAT HIGHER LEVELS TO COGNITIVE DECLINE AND !$ 2ESEARCHERS WHO OF PHYSICAL ACTIVITY OR EXERCISE IN OLDER PEOPLE ARE ARE INTERESTED IN DISCOVERING THE CAUSES OF !$ ARE ASSOCIATED WITH REDUCED RISK OF COGNITIVE DECLINE INTENSIVELY STUDYING THESE ISSUES TOO AND REDUCED RISK OF DEMENTIA %VEN MODERATE EXERCISE SUCH AS BRISK WALKING IS ASSOCIATED WITH 0HYSICAL !CTIVITY AND %XERCISE REDUCED RISK %XERCISE HAS MANY BENElTS )T STRENGTHENS MUSCLES N #LINICAL TRIALS SHOW SOME EVIDENCE OF SHORT TERM IMPROVES HEART AND LUNG FUNCTION HELPS PREVENT POSITIVE EFFECTS OF EXERCISE ON COGNITIVE FUNCTION OSTEOPOROSIS AND IMPROVES MOOD AND OVERALL WELL ESPECIALLY EXECUTIVE FUNCTION COGNITIVE ABILITIES BEING 3O IT IS NOT SURPRISING THAT !$ INVESTIGATORS INVOLVED IN PLANNING ORGANIZING AND DECISION BEGAN TO THINK THAT IF EXERCISE HELPS EVERY PART OF MAKING /NE TRIAL SHOWED THAT OLDER ADULTS WHO THE BODY FROM THE NECK DOWN THEN IT MIGHT HELP PARTICIPATED IN A MONTH PROGRAM OF BRISK THE BRAIN AS WELL WALKING SHOWED INCREASED ACTIVITY OF NEURONS IN %PIDEMIOLOGIC STUDIES ANIMAL STUDIES AND KEY PARTS OF THE BRAIN HUMAN CLINICAL TRIALS ARE ASSESSING THE INmUENCE -ORE CLINICAL TRIALS ARE UNDERWAY TO EXPAND OF EXERCISE ON COGNITIVE FUNCTION (ERE ARE A FEW OUR KNOWLEDGE ABOUT THE RELATIONSHIP OF EXERCISE THINGS THESE STUDIES HAVE FOUND TO HEALTHY BRAIN AGING REDUCED RISK OF COGNITIVE DECLINE AND DEVELOPMENT OF !$ 3EE 0ARTICI N !NIMAL STUDIES HAVE SHOWN THAT EXERCISE IN PATING IN A #LINICAL 4RIAL ON PAGE FOR MORE CREASES THE NUMBER OF CAPILLARIES THAT SUPPLY BLOOD INFORMATION TO THE BRAIN AND IMPROVES LEARNING AND MEMORY IN OLDER ANIMALS $IET 2ESEARCHERS HAVE EXPLORED WHETHER DIET MAY HELP PRESERVE COGNITIVE FUNCTION OR REDUCE !$ RISK )F YOU WANT TO KNOW MORE ABOUT THE WITH SOME INTRIGUING lNDINGS &OR EXAMPLE BENElTS OF EXERCISE AND PHYSICAL ACTIVITY STUDIES HAVE EXAMINED SPECIlC FOODS THAT ARE RICH AND LEARN WAYS TO BE ACTIVE EVERY DAY IN ANTIOXIDANTS AND ANTI INmAMMATORY PROPERTIES .)! HAS FREE INFORMATION JUST FOR YOU TO lND OUT WHETHER THOSE FOODS AFFECT AGE RELATED #ALL OR VISIT WWWNIANIHGOV%XERCISE
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 !$ 2ESEARCH "ETTER 1UESTIONS .EW !NSWERS
CHANGES IN BRAIN TISSUE /NE LABORATORY STUDY )N ONE OF THESE STUDIES RESEARCHERS WORKED FOUND THAT CURCUMIN THE MAIN INGREDIENT OF WITH OLDER ADULTS LIVING IN .EW 9ORK WHO ATE THE TURMERIC A BRIGHT YELLOW SPICE USED IN CURRY h-EDITERRANEAN DIETvA DIET WITH LOTS OF FRUITS CAN BIND TO BETA AMYLOID AND PREVENT VEGETABLES AND BREAD LOW TO MODERATE OLIGOMER FORMATION !NOTHER STUDY IN AMOUNTS OF DAIRY FOODS lSH AND MICE FOUND THAT DIETS HIGH IN $(! POULTRY SMALL AMOUNTS OF RED MEAT DOCOSAHEXAENOIC ACID A TYPE OF LOW TO MODERATE AMOUNTS OF WINE HEALTHY OMEGA FATTY ACID FOUND AND FREQUENT USE OF OLIVE OIL 4HE IN FISH REDUCED BETA AMYLOID RESEARCHERS FOUND THAT STICKING AND PLAQUES IN BRAIN TISSUE TO THIS TYPE OF DIET WAS ASSOCIATED /THER STUDIES HAVE SHOWN WITH A REDUCED RISK OF !$ AND THAT OLD DOGS PERFORM BETTER ON THAT THE ASSOCIATION SEEMED TO LEARNING TASKS WHEN THEY EAT DIETS BE DRIVEN BY THE WHOLE APPROACH RICH IN ANTIOXIDANTS SUCH AS VITAMIN RATHER THAN BY ITS INDIVIDUAL DIETARY % AND OTHER HEALTHFUL COMPOUNDS WHILE COMPONENTS ! FOLLOW UP STUDY FOUND LIVING IN AN hENRICHEDv ENVIRONMENT ONE IN THAT THIS PATTERN ALSO WAS ASSOCIATED WITH WHICH THE DOGS HAVE MANY OPPORTUNITIES TO PLAY AND LONGER SURVIVAL IN PEOPLE WITH !$ INTERACT WITH PEOPLE AND OTHER DOGS !LL OF THESE RESULTS ARE EXCITING AND SUGGESTIVE 3CIENTISTS ALSO HAVE EXAMINED THE EFFECTS OF BUT THEY ARE NOT DElNITIVE 4O CONlRM THE RESULTS DIET ON COGNITIVE FUNCTION IN PEOPLE ! VERY LARGE SCIENTISTS ARE CONDUCTING CLINICAL TRIALS TO EXAMINE THE EPIDEMIOLOGIC STUDY OF NURSES FOUND AN ASSOCIATION RELATIONSHIP OF VARIOUS SPECIlC DIETARY COMPONENTS BETWEEN PARTICIPANTS WHO ATE THE MOST VEGETABLES AND THEIR EFFECT ON COGNITIVE DECLINE AND !$ ESPECIALLY GREEN LEAFY AND CRUCIFEROUS VEGETABLES AND A SLOWER RATE OF COGNITIVE DECLINE COMPARED )NTELLECTUALLY 3TIMULATING WITH NURSES WHO ATE THE LEAST AMOUNT OF THESE !CTIVITIES AND 3OCIAL %NGAGEMENT FOODS !N EPIDEMIOLOGIC STUDY OF OLDER ADULTS -ANY OLDER PEOPLE LOVE TO READ DO PUZZLES PLAY LIVING IN #HICAGO FOUND THE SAME ASSOCIATION 4HE GAMES AND SPEND TIME WITH FAMILY AND FRIENDS !LL RESEARCHERS DO NOT KNOW THE EXACT REASON BEHIND THESE ACTIVITIES ARE FUN AND HELP PEOPLE FEEL ALERT THIS ASSOCIATION BUT SPECULATE THAT THE BENElCIAL AND ENGAGED IN LIFE 2ESEARCHERS ARE BEGINNING TO EFFECTS MAY RESULT FROM THE HIGH ANTIOXIDANT AND lND OTHER POSSIBLE BENElTS AS WELL FOR SOME STUDIES FOLATE CONTENT OF THE VEGETABLES HAVE SHOWN THAT KEEPING THE BRAIN ACTIVE IS ASSOCI $IETARY STUDIES SUCH AS THE CURCUMIN STUDY IN ATED WITH REDUCED !$ RISK &OR EXAMPLE OVER A MICE OR THE VEGETABLES STUDY IN NURSES GENERALLY YEAR PERIOD ONE GROUP OF RESEARCHERS TRACKED HOW EXAMINE INDIVIDUAL DIETARY COMPONENTS SO THAT OFTEN A LARGE GROUP OF OLDER PEOPLE DID ACTIVITIES SCIENTISTS CAN PINPOINT THEIR SPECIlC EFFECTS ON AN THAT INVOLVED SIGNIlCANT INFORMATION PROCESSING ISSUE OF INTEREST 4HIS APPROACH HAS OBVIOUS SUCH AS LISTENING TO THE RADIO READING NEWSPAPERS LIMITATIONS BECAUSE PEOPLE DO NOT EAT JUST SINGLE PLAYING PUZZLE GAMES AND GOING TO MUSEUMS 4HE FOODS OR NUTRIENTS 3EVERAL RECENT EPIDEMIOLOGIC RESEARCHERS THEN LOOKED AT HOW MANY OF THE PARTICI STUDIES HAVE TAKEN A DIFFERENT APPROACH AND LOOKED PANTS DEVELOPED !$ 4HE RESEARCHERS FOUND THAT AT AN ENTIRE DIETARY PATTERN
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY THE RISK OF DEVELOPING !$ WAS PERCENT LOWER IN 4HE REASONS FOR THESE lNDINGS ARE NOT ENTIRELY THE PEOPLE WHO DID THEM THE MOST FREQUENTLY CLEAR BUT A NUMBER OF EXPLANATIONS ARE POSSIBLE COMPARED WITH THE PEOPLE WHO DID THE ACTIVITIES !MONG THEM LEAST FREQUENTLY !NOTHER STUDY SUPPORTED THE VALUE N )NTELLECTUALLY STIMULATING ACTIVITIES AND SOCIAL OF LIFELONG LEARNING AND MENTALLY STIMULATING ENGAGEMENT MAY PROTECT THE BRAIN IN SOME WAY ACTIVITY BY lNDING THAT COMPARED WITH OLDER STUDY PERHAPS BY ESTABLISHING A COGNITIVE RESERVE PARTICIPANTS WHO MAY HAVE HAD !$ OR WHO HAD N 4HESE ACTIVITIES MAY HELP THE BRAIN BECOME !$ HEALTHY OLDER PARTICIPANTS HAD ENGAGED IN MORE MORE ADAPTABLE AND mEXIBLE IN SOME AREAS OF MENTALLY STIMULATING ACTIVITIES AND SPENT MORE TIME MENTAL FUNCTION SO THAT IT CAN COMPENSATE FOR AT THEM DURING THEIR EARLY AND MIDDLE ADULTHOOD DECLINES IN OTHER AREAS 3TUDIES OF ANIMALS NURSING HOME RESIDENTS AND N ,ESS ENGAGEMENT WITH OTHER PEOPLE OR IN PEOPLE LIVING IN THE COMMUNITY ALSO HAVE SUGGESTED INTELLECTUALLY STIMULATING ACTIVITIES COULD BE A LINK BETWEEN SOCIAL ENGAGEMENT AND COGNITIVE THE RESULT OF VERY EARLY EFFECTS OF THE DISEASE PERFORMANCE /LDER ADULTS WHO HAVE A FULL SOCIAL RATHER THAN ITS CAUSE NETWORK AND PARTICIPATE IN MANY SOCIAL ACTIVITIES TEND N 0EOPLE WHO ENGAGE IN STIMULATING ACTIVITIES MAY TO HAVE LESS COGNITIVE DECLINE AND A DECREASED RISK OF HAVE OTHER LIFESTYLE QUALITIES THAT MAY PROTECT DEMENTIA THAN THOSE WHO ARE NOT SOCIALLY ENGAGED THEM AGAINST DEVELOPING !$
$ESCRIBING 3CIENTIlC &INDINGS 4HE 4YPE OF 3TUDY -AKES AN )MPORTANT $IFFERENCE
HESE DAYS THE MEDIA ARE FOLLOWED BY THE PARTICIPANTS 4HAT OF CONTROL ALLOWS SCIENTISTS TO BE 4FULL OF STORIES ABOUT SCIENTIlC IS WHY IN EPIDEMIOLOGIC STUDIES OF MORE CERTAIN ABOUT WHY THEY GET STUDIES )T CAN BE HARD TO KNOW !$ SCIENTISTS ONLY SAY THAT A lND THE RESULTS THEY DO )T ALSO ALLOWS WHAT TO CONCLUDE ABOUT THEIR lND ING IS hASSOCIATED WITHv !$ OR NOT THEM TO BE MORE DElNITIVE IN THE INGS +NOWING HOW THE STUDY WAS 4HE EPIDEMIOLOGIC EVIDENCE LINKING WORDS THEY USE TO DESCRIBE THEIR CONDUCTED CAN HELP PUT THE RESULTS A BEHAVIOR AND !$ IS AT BEST SUG RESULTS /F COURSE SHOWING A INTO THE RIGHT PERSPECTIVE GESTIVE BUT WE DO NOT KNOW THAT CAUSE AND EFFECT RELATIONSHIP IN /NE MAIN TYPE OF RESEARCH IS THE BEHAVIOR BY ITSELF ACTUALLY HELPS TISSUE SAMPLES OR EVEN IN ANIMAL THE EPIDEMIOLOGIC STUDY 4HESE TO CAUSE OR PREVENT !$ STUDIES STILL DOES NOT MEAN THAT THE STUDIES ARE OBSERVATIONALTHEY /THER TYPES OF RESEARCHTEST RELATIONSHIP WILL BE THE SAME IN GATHER INFORMATION ABOUT PEOPLE TUBE STUDIES AND STUDIES IN ANI HUMANS #LINICAL TRIALS IN HUMANS WHO ARE GOING ABOUT THEIR DAILY MALSADD TO THE lNDINGS FROM ARE THE GOLD STANDARD FOR DECID LIVES 3TUDY PARTICIPANTS FOLLOW EPIDEMIOLOGIC STUDIES 3CIENTISTS ING WHETHER A BEHAVIOR OR A MANY BEHAVIORS AND PRACTICES )T USE THEM TO EXAMINE THE SAME SPECIlC THERAPEUTIC AGENT IS DIFlCULT THEREFORE TO DETERMINE ISSUE BUT IN WAYS IN WHICH THE ACTUALLY PREVENTS OR DELAYS !$ THE EXACT BENElTS OR RISKS OF ONE VARIOUS FACTORS THAT MIGHT INmU SEE 0ARTICIPATING IN A #LINICAL PARTICULAR BEHAVIOR FROM AMONG ALL ENCE A RESULT ARE CONTROLLED TO 4RIAL ON PAGE FOR MORE ON THE HEALTHY OR HARMFUL BEHAVIORS A GREATER DEGREE 4HIS ELEMENT THIS KIND OF RESEARCH
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 !$ 2ESEARCH "ETTER 1UESTIONS .EW !NSWERS
.EW 4ECHNIQUES (ELP IN$IAGNOSING !$
! MAN IN HIS MID S BEGINS TO NOTICE THAT HIS MIMIC THOSE OF !$ &INDING OUT EARLY THAT THE MEMORY ISNT AS GOOD AS IT USED TO BE -ORE AND MORE OBSERVED CHANGES IN COGNITIVE ABILITIES ARE NOT !$ OFTEN A WORD WILL BE ON THE TIP OF HIS TONGUE BUT BUT SOMETHING ELSE IS ALMOST ALWAYS A RELIEF AND HE JUST CANT REMEMBER IT (E FORGETS APPOINTMENTS MAY BE JUST THE PROD NEEDED TO SEEK APPROPRIATE MAKES MISTAKES WHEN PAYING HIS BILLS AND lNDS THAT MEDICAL TREATMENT SEE #AUSES OF $EMENTIA ON HES OFTEN CONFUSED OR ANXIOUS ABOUT THE NORMAL HUSTLE PAGE FOR MORE INFORMATION &OR THE SMALL AND BUSTLE OF LIFE AROUND HIM /NE EVENING HE SUD PERCENTAGE OF DEMENTIAS THAT ARE TREATABLE OR DENLY lNDS HIMSELF WALKING IN A NEIGHBORHOOD HE EVEN REVERSIBLE EARLY DIAGNOSIS INCREASES THE DOESNT RECOGNIZE (E HAS NO IDEA HOW HE GOT THERE OR CHANCES OF SUCCESSFUL TREATMENT )NCREASING EARLY HOW TO GET HOME DIAGNOSIS AND IMPROVING TREATMENT ARE AMONG .)!S MOST IMPORTANT GOALS OT SO LONG AGO THIS MANS CONDITION %VEN WHEN THE CAUSE OF A LOVED ONES DEMENTIA WOULD HAVE BEEN SWEPT INTO A BROAD TURNS OUT TO BE !$ IT IS BEST TO lND OUT SOONER CATCH ALL CATEGORY CALLED hSENILE RATHER THAN LATER /NE BENElT OF KNOWING IS MEDI DEMENTIAv OR hSENILITYv !LTHOUGH WE CAL 4HE DRUGS NOW AVAILABLE TO TREAT !$ CAN HELP NOW KNOW THAT !$ AND OTHER CAUSES OF DEMENTIA ARE . SOME PEOPLE MAINTAIN THEIR MENTAL ABILITIES FOR DISTINCT DISEASES IN THE EARLY STAGES IT IS DIFlCULT TO MONTHS TO YEARS ALTHOUGH THEY DO NOT CHANGE DIFFERENTIATE BETWEEN THE ONSET OF !$ AND OTHER TYPES THE UNDERLYING COURSE OF THE DISEASE SEE (ELPING OF AGE RELATED COGNITIVE DECLINE 7E HAVE IMPROVED 0EOPLE WITH !$ -AINTAIN THEIR -ENTAL &UNCTION OUR ABILITY TO DIAGNOSE !$ CORRECTLY AND DOCTORS ING ON PAGE FOR MORE ABOUT THESE DRUGS EXPERIENCED IN !$ CAN DIAGNOSE THE DISEASE WITH UP /THER BENElTS ARE PRACTICAL 4HE SOONER THE PER TO PERCENT ACCURACY ! DElNITIVE DIAGNOSIS OF !$ SON WITH !$ AND THE FAMILY HAVE A lRM DIAGNOSIS HOWEVER IS STILL ONLY POSSIBLE AFTER DEATH DURING AN THE MORE TIME THEY HAVE TO MAKE FUTURE LIVING AUTOPSY AND WE ARE STILL FAR FROM THE ULTIMATE GOAL ARRANGEMENTS HANDLE lNANCIAL MATTERS ESTABLISH A RELIABLE VALID INEXPENSIVE AND EARLY DIAGNOSTIC A DURABLE POWER OF ATTORNEY AND ADVANCE DIREC MARKER THAT CAN BE USED IN ANY DOCTORS OFlCE TIVES DEAL WITH OTHER LEGAL ISSUES CREATE A SUPPORT %ARLY DIAGNOSIS HAS SEVERAL ADVANTAGES &OR EXAMPLE MANY CONDITIONS CAUSE SYMPTOMS THAT
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY #URRENT 4OOLS FOR $IAGNOSING !$
ITH THE TOOLS NOW AVAILABLE HOW BEHAVIOR AND PERSONALITY 4HEY MAY DO A COMPUTED 7EXPERIENCED PHYSICIANS HAVE CHANGED MANY TIMES TOMOGRAPHY #4 SCAN OR A CAN BE REASONABLY CONlDENT ABOUT FAMILY AND FRIENDS KNOW SOME MAGNETIC RESONANCE IMAGING MAKING AN ACCURATE DIAGNOSIS OF THING IS WRONG EVEN BEFORE -2) TEST !$ IN A LIVING PERSON (ERE IS CHANGES ARE EVIDENT ON TESTS N # 4 AND -2) SCANS CAN DETECT HOW THEY DO IT STROKES OR TUMORS OR CAN REVEAL 4HEY CONDUCT PHYSICAL AND CHANGES IN THE BRAINS STRUCTURE 4HEY TAKE A DETAILED NEUROLOGICAL EXAMINATIONS THAT INDICATE EARLY !$ PATIENT HISTORY INCLUDING AND LABORATORY TESTS N ! DESCRIPTION OF HOW AND WHEN N "LOOD AND OTHER MEDICAL TESTS %XAMS AND TESTS MAY BE REPEATED SYMPTOMS DEVELOPED HELP DETERMINE NEUROLOGICAL EVERY SO OFTEN TO GIVE PHYSICIANS N ! DESCRIPTION OF THE PERSONS FUNCTIONING AND IDENTIFY POSSIBLE INFORMATION ABOUT HOW THE PERSONS AND HIS OR HER FAMILYS OVERALL NON !$ CAUSES OF DEMENTIA MEMORY AND OTHER SYMPTOMS ARE MEDICAL CONDITION AND HISTORY CHANGING OVER TIME N !N ASSESSMENT OF THE PERSONS 4HEY CONDUCT NEURO "ASED ON lNDINGS FROM THESE EMOTIONAL STATE AND LIVING PSYCHOLOGICAL TESTING EXAMS AND TESTS EXPERIENCED ENVIRONMENT N 1UESTION AND ANSWER TESTS PHYSICIANS CAN DIAGNOSE OR RULE OR OTHER TASKS THAT MEASURE OUT OTHER CAUSES OF DEMENTIA OR 4HEY GET INFORMATION MEMORY LANGUAGE SKILLS ABILITY DETERMINE WHETHER THE PERSON HAS FROM FAMILY MEMBERS OR TO DO ARITHMETIC AND OTHER -#) hPOSSIBLE !$v THE SYMPTOMS CLOSE FRIENDS ABILITIES RELATED TO BRAIN FUNC MAY BE DUE TO ANOTHER CAUSE OR N 0EOPLE CLOSE TO THE PERSON CAN TIONING HELP SHOW WHAT KIND OF hPROBABLE !$v NO OTHER CAUSE FOR PROVIDE VALUABLE INSIGHTS INTO COGNITIVE CHANGES ARE OCCURRING THE SYMPTOMS CAN BE FOUND
NETWORK AND EVEN CONSIDER JOINING A CLINICAL TRIAL WITH THEM FOR AS LONG AS POSSIBLE &INALLY EARLY OR OTHER RESEARCH STUDY "EING ABLE TO PARTICIPATE DIAGNOSIS GIVES FAMILY CAREGIVERS THE OPPORTUNITY TO FOR AS LONG AS POSSIBLE IN MAKING PERSONAL DECISIONS LEARN HOW TO RECOGNIZE AND COPE WITH CHANGES OVER IS IMPORTANT TO MANY PEOPLE WITH !$ TIME IN THEIR LOVED ONE AS WELL AS TO DEVELOP STRATE %ARLY DIAGNOSIS ALSO GIVES FAMILIES TIME TO RECOG GIES THAT SUPPORT THEIR OWN PHYSICAL EMOTIONAL NIZE THAT LIFE DOES NOT STOP WITH A DIAGNOSIS OF !$ AND lNANCIAL HEALTH 4HE PERSON IS STILL ABLE TO PARTICIPATE IN MANY OF THE DAILY ACTIVITIES HE OR SHE HAS ALWAYS ENJOYED AND FAMILIES CAN ENCOURAGE THE PERSON TO CONTINUE
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 !$ 2ESEARCH "ETTER 1UESTIONS .EW !NSWERS
#AUSES OF $EMENTIA
EMENTIA IS THE LOSS OF COGNITIVE FUNCTIONINGTHINKING REMEMBERING AND REASONINGTO SUCH $AN EXTENT THAT IT INTERFERES WITH A PERSONS DAILY LIFE AND ACTIVITIES )T IS NOT A DISEASE ITSELF BUT A GROUP OF SYMPTOMS THAT OFTEN ACCOMPANIES A DISEASE OR CONDITION 3OME DEMENTIAS ARE CAUSED BY NEURODEGENERATIVE DISEASES $EMENTIA ALSO HAS OTHER CAUSES SOME OF WHICH ARE TREATABLE
.EURODEGENERATIVE $ISEASES THAT #AUSE $EMENTIA /THER #AUSES OF $EMENTIA N !LZHEIMERS DISEASE N -EDICATION SIDE EFFECTS N 6ASCULAR DEMENTIA N $EPRESSION N N 0ARKINSONS DISEASE WITH DEMENTIA 6ITAMIN " DElCIENCY N &RONTOTEMPORAL LOBAR DEGENERATION INCLUDING N #HRONIC ALCOHOLISM N FRONTOTEMPORAL DEMENTIA N #ERTAIN TUMORS OR INFECTIONS OF N FRONTOTEMPORAL DEMENTIA WITH PARKINSONISM THE BRAIN LINKED TO CHROMOSOME &4$0 N "LOOD CLOTS PRESSING ON THE BRAIN N 0ICKS DISEASE N -ETABOLIC IMBALANCES INCLUDING N SUPRANUCLEAR PALSY THYROID KIDNEY OR LIVER DISORDERS N CORTICOBASAL DEGENERATION
3CIENTISTS ALSO SEE ADVANTAGES TO EARLY DIAGNOSIS MEASURED THROUGH MEMORY AND RECALL TESTS 4ESTS $EVELOPING TESTS THAT CAN REVEAL WHAT IS HAPPEN THAT MEASURE A PERSONS ABILITIES IN AREAS SUCH AS ING IN THE BRAIN IN THE EARLY STAGES OF !$ WILL HELP ABSTRACT THINKING PLANNING AND LANGUAGE CAN THEM UNDERSTAND MORE ABOUT THE CAUSE AND DEVEL HELP PINPOINT CHANGES IN THESE AREAS OF COGNITIVE OPMENT OF THE DISEASE )T ALSO WILL HELP SCIENTISTS FUNCTION 2ESEARCHERS ARE WORKING TO IMPROVE LEARN WHEN AND HOW TO PRESCRIBE THE USE OF DRUGS STANDARDIZED TESTS THAT MIGHT BE USED TO POINT AND OTHER TREATMENTS SO THEY CAN BE MOST EFFECTIVE TO EARLY !$ OR PREDICT WHICH INDIVIDUALS ARE AT HIGHER RISK OF DEVELOPING !$ IN THE FUTURE %8#)4).' .%7 $%6%,/0-%.43 /THER STUDIES ARE EXAMINING THE RELATIONSHIP ). !$ $)!'./3)3 BETWEEN EARLY DAMAGE TO BRAIN TISSUE AND OUT 3CIENTISTS ARE NOW EXPLORING WAYS TO HELP PHYSICIANS WARD CLINICAL SIGNS 3TILL OTHERS ARE LOOKING FOR DIAGNOSE !$ EARLIER AND MORE ACCURATELY &OR CHANGES IN BIOMARKERS IN THE BLOOD OR CEREBRO EXAMPLE SOME STUDIES ARE FOCUSING ON CHANGES SPINAL mUID THAT MAY INDICATE THE PROGRESSION OF IN MENTAL FUNCTIONING 4HESE CHANGES CAN BE !$ SEE 6ERY %ARLY 3IGNS AND 3YMPTOMS ON PAGE FOR MORE ON THIS WORK /NE OF THE MOST EXCITING AREAS OF ONGOING RESEARCH IN THIS AREA IS NEUROIMAGING /VER THE PAST DECADE SCIENTISTS HAVE DEVELOPED SEVERAL
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY HIGHLY SOPHISTICATED IMAGING SYSTEMS THAT HAVE BEEN USED IN MANY AREAS OF MEDICINE INCLUDING !$ 0%4 SCANS SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY 30%#4 AND -2) ARE ALL EXAMPLES 4HESE hWINDOWSv ON THE LIVING BRAIN MAY HELP SCIENTISTS MEASURE THE EARLIEST CHANGES IN BRAIN FUNCTION OR STRUCTURE IN ORDER TO IDENTIFY PEOPLE WHO ARE AT THE VERY lRST STAGES OF THE DISEASEWELL BEFORE THEY DEVELOP CLINICALLY APPARENT SIGNS AND SYMPTOMS 4O HELP ADVANCE THIS AREA OF RESEARCH .)! LAUNCHED THE MULTI YEAR !$ .EUROIMAGING )NITIATIVE !$.) IN 4HIS PROJECT IS FOL LOWING ABOUT COGNITIVELY HEALTHY INDIVIDUALS AND PEOPLE WITH -#) FOR YEARS AND PEOPLE WITH EARLY !$ FOR YEARS /VER THE COURSE OF THIS STUDY PARTICIPANTS UNDERGO MULTIPLE -2) AND 0%4 SCANS SO THAT STUDY STAFF CAN ASSESS HOW THE BRAIN CHANGES IN THE COURSE OF NORMAL AGING "IOLOGICAL SAMPLES ALSO ARE AVAILABLE FOR APPROVED AND -#) AND WITH THE PROGRESSION OF !$ "Y BIOMARKER PROJECTS .)! HOPES THAT THIS INITIATIVE USING -2) AND 0%4 SCANS AT REGULARLY SCHEDULED WILL HELP CREATE RIGOROUS IMAGING AND BIOMARKER INTERVALS STUDY INVESTIGATORS HOPE TO LEARN WHEN STANDARDS THAT WILL PROVIDE MEASURES FOR THE AND WHERE IN THE BRAIN DEGENERATION OCCURS AS SUCCESS OF POTENTIAL TREATMENTS 4HIS WOULD MEMORY PROBLEMS DEVELOP SUBSTANTIALLY INCREASE THE PACE AND DECREASE THE !NOTHER INNOVATIVE ASPECT OF !$.) IS THAT COST OF DEVELOPING NEW TREATMENTS 4HE !$.) SCIENTISTS ARE CORRELATING THE PARTICIPANTS IMAGING STUDY IS BEING REPLICATED IN SIMILAR STUDIES BY INFORMATION WITH INFORMATION FROM CLINICAL RESEARCHERS IN %UROPE *APAN AND !USTRALIA MEMORY AND OTHER COGNITIVE FUNCTION TESTS AND 4HESE TYPES OF NEUROIMAGING SCANS ARE STILL WITH INFORMATION FROM BLOOD CEREBROSPINAL mUID PRIMARILY RESEARCH TOOLS BUT ONE DAY THEY MAY BE AND URINE SAMPLES 2ESULTS FROM THESE SAMPLES USED MORE COMMONLY TO HELP PHYSICIANS DIAGNOSE MAY PROVIDE VALUABLE BIOMARKERS OF DISEASE !$ AT VERY EARLY STAGES )T IS CONCEIVABLE THAT PROGRESS SUCH AS CHANGING LEVELS OF BETA AMYLOID THESE TOOLS ALSO MAY SOMEDAY BE USED TO MONITOR AND TAU INDICATORS OF INmAMMATION MEASURES OF THE PROGRESS OF THE DISEASE AND TO ASSESS RESPONSES OXIDATIVE STRESS AND CHANGING COGNITIVE ABILITIES TO DRUG TREATMENT !N IMPORTANT !$.) ACHIEVEMENT IS THE CREATION OF A PUBLICLY ACCESSIBLE DATABASE OF IMAGES BIOMARKER DATA AND CLINICAL INFORMATION AVAILABLE TO QUALIlED RESEARCHERS WORLDWIDE
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 !$ 2ESEARCH "ETTER 1UESTIONS .EW !NSWERS
.EW 4ECHNOLOGIES (ELP 0EOPLE 0ARTICIPATE IN !$ 2ESEARCH AT (OME
RADITIONALLY !$ SCIENTISTS HAVE COLLECTED DATA BY 3CIENCE 5NIVERSITY IS EXPLORING THE USE OF UNOBTRUSIVE 4ASKING PEOPLE TO COME TO A CLINIC ONCE OR TWICE A SIMPLE TECHNOLOGY AND INTELLIGENT SYSTEMS TO DETECT YEAR OVER A PERIOD OF YEARS 4HEY GIVE THE PARTICIPANTS AND MONITOR SUBTLE CHANGES IN MOVEMENT THAT MAY A PHYSICAL EXAM AND ASK THEM TO TAKE A SERIES OF INDICATE AGE RELATED COGNITIVE CHANGES 4HIS PROJECT IS MEMORY LANGUAGE AND OTHER COGNITIVE FUNCTION TESTS BUILDING ON RESEARCH THAT HAS SUGGESTED THAT MOTOR 4HESE STUDIES COLLECT MUCH USEFUL INFORMATION BUT FUNCTION CHANGES MAY ARISE BEFORE MEMORY CHANGES THEY HAVE THEIR LIMITATIONS &OR ONE THING PARTICIPANTS BECOME APPARENT SEE 6ERY %ARLY 3IGNS AND ARE SEEN ONLY ONCE OR TWICE DURING THE YEAR SO THE 3YMPTOMS ON PAGE FOR MORE ON THIS RESEARCH DATA COLLECTED REPRESENT ONLY A hSNAPSHOTv IN TIME !LL OF THE STUDY PARTICIPANTS ARE YEARS OR 4HE STUDIES CANNOT EFFECTIVELY CAPTURE DAY TO DAY OLDER OR HAVE A SPOUSE OF A SIMILAR AGE AND LIVE mUCTUATIONS IN BEHAVIORS AND COGNITIVE ABILITIES INDEPENDENTLY IN 0ORTLAND AREA RETIREMENT COMMUNI !NOTHER LIMITATION IS THAT PARTICIPANTS ARE SEEN IN TIES 7IRELESS INFRARED MOTION SENSORS LIKE THOSE A RESEARCH SETTING NOT IN THEIR NATURAL COMMUNITY USED TO AUTOMATICALLY OPEN GROCERY STORE DOORS HAVE ENVIRONMENT &OR MANY COMING TO THE CLINIC CAN BE BEEN PLACED STRATEGICALLY THROUGHOUT THE PARTICIPANTS INCONVENIENT DIFlCULT OR BOTH HOMES TO GATHER DATA ABOUT CHANGES IN THEIR WALKING !DVANCES IN TECHNOLOGY AS SHOWN IN THE TWO OR DRESSING SPEED OVER TIME 3PECIAL SOFTWARE ALSO RESEARCH PROJECTS DESCRIBED HERE OFFER SOME HOPE HAS BEEN INSTALLED ON EACH PARTICIPANTS HOME FOR DEALING WITH THESE CHALLENGES BY BRINGING COMPUTER TO MEASURE MOTOR SKILLS AND SPEED IN TYPING RESEARCH TO PEOPLE RIGHT IN THEIR OWN HOMES OR USING A MOUSE 4HE SENSORS AND COMPUTER SOFTWARE COLLECT DATA ABOUT MOTION NOT WHAT THE VOLUNTEER -/4)/. $%4%#4/23 4%,, IS ACTUALLY DOING 0RIVACY IS LARGELY NOT A CONCERN !. ).4%2%34).' 34/29 THEREFORE BECAUSE THE VOLUNTEERS ARE NOT DIRECTLY 3CIENTISTS WHO ARE TRYING TO DEVELOP METHODS FOR OBSERVED AND NO VIDEO OR PHOTOGRAPHS ARE TAKEN DIAGNOSING !$ AS EARLY AS POSSIBLE CONTINUALLY 4HE YEAR STUDY BEGAN IN EARLY SO RESULTS GRAPPLE WITH TWO CHALLENGES IN CONDUCTING THEIR ARE NOT YET AVAILABLE (OWEVER A SMALL PILOT STUDY RESEARCH &IRST THEY NEED TO lND EASY AND ACCURATE USING THE SAME TYPE OF SENSORS SHOWED A CLEAR WAYS TO COLLECT DATA FROM OLDER PEOPLE WHO OFTEN DIFFERENCE IN THE WALKING SPEEDS OF PEOPLE AGE HAVE PHYSICAL EMOTIONAL OR COGNITIVE PROBLEMS AND OLDER WHO HAD -#) COMPARED WITH COGNITIVELY 3ECOND THEY NEED TO lND WAYS TO ASSESS ACCURATELY HEALTHY PEOPLE OF THE SAME AGE OVER TIME PERIODS THE VERY EARLY CHANGES IN PHYSICAL OR COGNITIVE OF NEARLY A YEAR 4HESE DATA SUGGEST THAT A REMOTE ABILITIES THAT COULD INDICATE THAT !$ IS PROGRESSING SENSING SYSTEM LIKE THIS IS A FEASIBLE TECHNOLOGY AND IS 5NDER AN .)! GRANT THE /REGON #ENTER FOR !GING POTENTIALLY SENSITIVE ENOUGH TO DISTINGUISH ACCURATELY AND 4ECHNOLOGY /2#!4%#( AT /REGON (EALTH BETWEEN AFFECTED AND UNAFFECTED PEOPLE
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 4HIS PHOTO SHOWS /2#!4%#( STUDY PARTICIPANTS AT HOME 4HE SMALL DEVICE BETWEEN THE PHOTO GRAPHS ON THE WALL IS AN INFRARED MOTION SENSOR
53).' 4%#(./,/'9 MOOD 4HIS STUDY IS LOOKING AT QUESTIONS SUCH AS 4/ #/,,%#4 $!4! !4 (/-% HOW LIKELY PEOPLE ARE TO COMPLETE THE QUESTIONS 2ESEARCHERS AT NEARLY SITES NATIONWIDE ARE USING EACH METHOD WHICH METHOD IS THE MOST COMPARING VARIOUS WAYS OF COLLECTING DATA INCLUDING EFlCIENT AND HOW SENSITIVE EACH METHOD IS THE USE OF AN IN HOME hKIOSKv THAT COMBINES A (AVING A DATA COLLECTION SYSTEM THAT IS EASY TO TOUCH SCREEN COMPUTER MONITOR WITH A TELEPHONE USE AND THAT COLLECTS DATA ACCURATELY AND COMPLETELY HANDSET AN INTERACTIVE VOICE RESPONSE SYSTEM AND MAY ENCOURAGE WIDER PARTICIPATION IN !$ CLINICAL TRADITIONAL MAIL AND TELEPHONE !LL THREE METHODS TRIALS )T ALSO MAY REDUCE THE EXPENSE AND BURDEN OF GATHER THE SAME DATA ABOUT SEVERAL AREAS KNOWN TO CONDUCTING !$ RESEARCH %ARLY RESULTS FROM THIS STUDY BE IMPORTANT IN EARLY DETECTION OF COGNITIVE DECLINE SHOW THAT THE OLDER PARTICIPANTS WERE SKEPTICAL AT lRST MEMORY LANGUAGE SKILLS ATTENTION AND CONCENTRATION ABOUT USING THE KIOSK BUT ONCE THEY LEARNED HOW TO ACTIVITIES OF DAILY LIVING QUALITY OF LIFE HEALTH CARE USE IT THEY BECAME ENTHUSIASTIC AND EXCITED ABOUT AND RESOURCE USE AND CHANGES IN hGLOBALv WELL BEING PARTICIPATING AS MEASURED BY SELF RATING OF HEALTH COGNITION AND
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 !$ 2ESEARCH "ETTER 1UESTIONS .EW !NSWERS
4HE 3EARCH FOR .EW 4REATMENTS
ORE AND MORE SCIENTISTS ARE ABLE MOST IMMEDIATE NEED IS FOR TREATMENTS TO CONTROL TO THINK ABOUT WAYS TO TREAT SLOW COGNITIVE LOSS AS WELL AS PROBLEM BEHAVIORS SUCH AS OR PERHAPS EVEN PREVENT !$ AT A AGGRESSION AGITATION WANDERING DEPRESSION SLEEP NUMBER OF POSSIBLE POINTS DURING DISTURBANCES HALLUCINATIONS AND DELUSIONS 3AFE THE YEARS LONG CONTINUUM OF DISEASE PROGRESSION - MEDICATIONS THAT REMAIN EFFECTIVE OVER TIME ARE 4HIS CONTINUUM BEGINS WITH THE VERY EARLIEST NEEDED TO EASE A BROAD RANGE OF SYMPTOMS AND TO DISEASE STAGE EVEN BEFORE SYMPTOMS ARE EVIDENT IMPROVE A PERSONS COGNITIVE FUNCTION AND ABILITY MOVES TO THE lRST SIGNS OF MEMORY AND COGNITIVE TO CARRY OUT ACTIVITIES OF DAILY LIVING 3CIENTISTS ALSO PROBLEMS THEN CONTINUES THROUGH THE MILD AND ARE INVESTIGATING TREATMENTS THAT COMBINE MEDICA MODERATE STAGES AND ENDS WITH THE VERY LATE STAGES TIONS WITH LIFESTYLE STRATEGIES TO LESSEN THE RISK OF AND THE PERSONS DEATH DEVELOPING COGNITIVE DECLINE OR !$ %VENTUALLY !S A RESULT RESEARCHERS WHO FOCUS ON DEVELOPING SCIENTISTS HOPE TO DEVELOP TREATMENTS THAT ATTACK !$ TREATMENTS THINK A LOT ABOUT THE IMPORTANCE THE EARLIEST MANIFESTATIONS AND UNDERLYING CAUSES OF TIMING 7HEN WOULD IT BE BEST TO INTERVENE OF !$ THEREBY SLOWING DELAYING OR PREVENTING AND WHAT INTERVENTIONS ARE MOST APPROPRIATE AT THE DISEASE FROM PROGRESSING AND DAMAGING COG WHICH TIME 4HESE QUESTIONS ARE SIMILAR TO THOSE NITIVE FUNCTION AND QUALITY OF LIFE 3CIENTISTS USE ASKED WITH OTHER CONDITIONS SUCH AS HEART DISEASE CLINICAL TRIALS TO PURSUE ALL THESE GOALS &OR EXAMPLE A PHYSICIAN WOULD PRESCRIBE DIFFERENT 4ODAY .)! OTHER .)( INSTITUTES AND PRIVATE TREATMENTS FOR A PATIENT WHO IS SEEMINGLY HEALTHY INDUSTRY ARE CONDUCTING MANY CLINICAL TRIALS OF BUT WHO IS AT RISK OF HAVING FUTURE HEART DISEASE !$ INTERVENTIONS SEE PAGE FOR MORE ABOUT THAN FOR A PATIENT WHO IS ACTUALLY HAVING A HEART CLINICAL TRIALS 4HESE STUDIES FOCUS ON SEVERAL ATTACK OR WHOSE HEART DISEASE IS WELL ESTABLISHED 4HE KEY AREAS SAME DECISION PROCESS NOW CAN BE APPLIED TO !$ N (ELPING PEOPLE WITH !$ MAINTAIN THEIR MENTAL )T HAS BECOME CLEAR THAT THERE PROBABLY IS NO FUNCTIONING SINGLE hMAGIC BULLETv THAT WILL BY ITSELF PREVENT OR N -ANAGING SYMPTOMS CURE !$ 4HEREFORE INVESTIGATORS ARE WORKING TO N 3LOWING DELAYING OR PREVENTING !$ DEVELOP AN ARRAY OF OPTIONS FROM WHICH PHYSICIANS CAN CHOOSE &OR PEOPLE WHO ALREADY HAVE !$ THE
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY (%,0).' 0%/0,% 7)4( !$ -!).4!). 4(%)2 -%.4!, &5.#4)/.).' )N THE MID S SCIENTISTS DISCOVERED THAT LEVELS OF A NEUROTRANSMITTER A CHEMICAL THAT CARRIES MESSAGES BETWEEN NEURONS CALLED ACETYLCHOLINE FELL SHARPLY IN PEOPLE WITH !$ 4HIS DISCOVERY WAS ONE OF THE lRST THAT LINKED !$ WITH BIOCHEMICAL CHANGES IN THE BRAIN 3CIENTISTS FOUND THAT ACETYLCHOLINE IS A CRITICAL PLAYER IN THE PROCESS OF FORMING MEMORIES )T IS USED BY NEURONS IN THE HIPPOCAMPUS AND CEREBRAL CORTEX WHICH ARE AREAS OF THE BRAIN IMPORTANT TO MEMORY FUNCTION 4HIS DISCOVERY WAS AN IMPORTANT INITIAL BREAKTHROUGH IN THE SEARCH FOR DRUGS TO TREAT !$ &OUR MEDICATIONS TESTED IN CLINICAL TRIALS HAVE BEEN APPROVED BY THE &$! FOR USE IN TREATING !$ SYMPTOMS $ONEPEZIL !RICEPT® RIVASTIGMINE %XELON® AND GALANTAMINE 2AZADYNE® ARE PRE SCRIBED TO TREAT MILD TO MODERATE !$ SYMPTOMS $ONEPEZIL WAS RECENTLY APPROVED TO TREAT SEVERE !$ AS WELL 4HESE DRUGS KNOWN AS CHOLINESTERASE INHIBITORS ACT BY STOPPING OR SLOWING THE ACTION OF ACETYLCHOLINESTERASE AN ENZYME THAT BREAKS DOWN ACETYLCHOLINE 4HEY HELP TO MAINTAIN HIGHER LEVELS OF ACETYLCHOLINE IN THE BRAIN )N SOME PEOPLE THE DRUGS MAINTAIN ABILITIES TO CARRY OUT ACTIVITIES OF DAILY LIVING 4HEY ALSO MAY MAINTAIN SOME THINK ING MEMORY OR SPEAKING SKILLS AND CAN HELP WITH CERTAIN BEHAVIORAL SYMPTOMS (OWEVER THEY WILL NOT STOP OR REVERSE THE UNDERLYING PROGRESSION OF !$ AND APPEAR TO HELP PEOPLE ONLY FOR MONTHS TO A FEW YEARS 4HE NEWEST APPROVED !$ MEDICATION IS MEMANTINE .AMENDA® WHICH IS PRESCRIBED TO TREAT MODERATE TO SEVERE !$ SYMPTOMS 4HIS DRUG APPEARS TO WORK BY REGULATING LEVELS OF GLUTAMATE ANOTHER NEUROTRANSMITTER INVOLVED IN MEMORY FUNCTION ,IKE THE CHOLINESTERASE INHIBITORS MEMANTINE WILL NOT STOP OR REVERSE !$
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 !$ 2ESEARCH "ETTER 1UESTIONS .EW !NSWERS
-!.!').' 39-04/-3 4HE DAMAGE OF !$ AFFECTS MANY DIFFERENT PARTS OF THE BRAIN 4HIS PRESENTS A PROBLEM BECAUSE EVEN h-Y FATHER IS OFTEN AGITATED (E PACES UP AND DOWN SMALL TASKS REQUIRE THE BRAIN TO PROCESS SIGNALS THAT WRINGING HIS HANDS AND CRYING ) KNOW HES SAD OR OFTEN INVOLVE MORE THAN ONE REGION OF THE BRAIN )F ANXIOUS ABOUT SOMETHING BUT HE CANT TELL ME WHATS THIS PROCESSING IS DISRUPTED BECAUSE OF !$ THE BOTHERING HIM !SKING HIM ABOUT IT JUST MAKES HIM PERSON MAY NOT BE ABLE TO DO THE TASK OR MAY ACT MORE UPSETv IN A STRANGE OR INAPPROPRIATE WAY h,AST WEEK ) VISITED -OM IN THE NURSING HOME 7E )N LIGHT OF OUR GROWING UNDERSTANDING ABOUT THE HAD A GREAT TIME 4HEN YESTERDAY ) WENT TO SEE HER EFFECTS OF !$ ON THE BRAIN BEHAVIORS LIKE THE ONES AGAIN 7HEN ) WALKED INTO HER ROOM SHE DIDNT KNOW HIGHLIGHTED ABOVE SUDDENLY MAKE SENSE OR EVEN ME 3HE THOUGHT ) WAS HER SISTERv PROVIDE A LOVING OPPORTUNITY FOR CAREGIVERS h-Y HUSBAND USED TO BE SUCH AN EASY GOING CALM &OR A MAN WHO CAN NO LONGER DISTINGUISH BETWEEN PAST PERSON .OW HE SUDDENLY LASHES OUT AT ME AND USES AND PRESENT THE ANGUISH CAUSED BY THE DEATH OF A PAR AWFUL LANGUAGE ,AST WEEK HE GOT ANGRY WHEN OUR ENT MAY BE AS REAL TODAY AS IT WAS MANY YEARS BEFORE DAUGHTER AND HER FAMILY CAME OVER AND WE SAT DOWN 3ITTING DOWN TO A FAMILY MEAL MAY PRODUCE TO EAT ) NEVER KNOW WHEN ITS GOING TO HAPPEN (ES INTENSE ANXIETY WHEN A PERSON HAS NO IDEA WHAT TO DO CHANGED SO MUCHIT SCARES ME SOMETIMESv WITH THE KNIFE AND FORK IN FRONT OF HIM AND ALL THE h'RAN HUMS ALL THE TIME 3HE USED TO BE A SINGER )S CONVERSATION AND ACTIVITY FEEL OVERWHELMING SHE TRYING TO RELIVE HER PAST v -EMORIES OF FAVORITE SONGS FROM LONG AGO RESURFACE AND !S !$ BEGINS TO AFFECT MEMORY AND MENTAL PROVIDE A COMPELLING LINK TO A HAPPY TIME IN THE PAST ABILITIES IT ALSO BEGINS TO CHANGE A PERSONS EMO "EHAVIORAL SYMPTOMS OFTEN EMOTIONAL AND TIONS AND BEHAVIORS "ETWEEN AND PERCENT UPSETTING ARE ONE OF THE HARDEST ASPECTS OF THE OF PEOPLE WITH !$ EVENTUALLY DEVELOP ONE OR MORE DISEASE FOR FAMILIES AND OTHER CAREGIVERS TO DEAL BEHAVIORAL SYMPTOMS 4HESE SYMPTOMS INCLUDE WITH 4HEY ARE ALSO A VISIBLE SIGN OF THE TERRIBLE SLEEPLESSNESS WANDERING AND PACING AGGRESSION CHANGE THAT HAS TAKEN PLACE IN THE PERSON WITH AGITATION ANGER DEPRESSION AND HALLUCINATIONS !$ 2ESEARCHERS ARE SLOWLY LEARNING MORE ABOUT AND DELUSIONS 3OME OF THESE SYMPTOMS MAY WHY BEHAVIORAL SYMPTOMS OCCUR AND ARE CONDUCT BECOME WORSE IN THE EVENING A PHENOMENON ING CLINICAL TRIALS ON NEW TREATMENTSBOTH DRUG CALLED hSUNDOWNINGv OR DURING DAILY ROUTINES AND NON DRUGTO DEAL WITH DIFlCULT BEHAVIORS ESPECIALLY BATHING
#OPING WITH "EHAVIORAL 3YMPTOMS &OR MORE INFORMATION ON HOW TO DEAL WITH BEHAVIORAL ISSUES AND SYMPTOMS VISIT THE CAREGIVING SECTION OF .)!S !LZHEIMERS $ISEASE %DUCATION AND 2EFERRAL !$%!2 #ENTER WEBSITE AT WWWNIANIHGOV !LZHEIMERS#AREGIVING(OME!ND&AMILY
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 3,/7).' $%,!9).' /2 02%6%.4).' !$ !$ RESEARCH HAS DEVELOPED TO THE POINT WHERE SCIENTISTS ARE LOOKING BEYOND TREATING SYMPTOMS TO ADDRESSING THE UNDERLYING DISEASE PROCESS 3LOWING THE PROGRESS OF !$ COULD DO MUCH TO MAINTAIN THE FUNCTIONING OF PEOPLE WITH !$ AND REDUCE PHYSICAL AND EMOTIONAL STRESS ON CAREGIVERS $ELAYING !$S EFFECTS ALSO COULD HELP TO POSTPONE OR PREVENT PLACEMENT IN AN ASSISTED LIVING FACILITY OR NURSING HOME AND REDUCE THE lNANCIAL COSTS OF THE DISEASE 0REVENTING !$ ALTOGETHER IS OF COURSE THE ULTIMATE LONG TERM GOAL .)! AND PHARMACEUTICAL COMPANIES SUPPORT TREATMENT CLINICAL TRIALS THAT ARE AIMED AT SLOW ING DELAYING OR PREVENTING !$ 4HE ADVANCES IN OUR KNOWLEDGE ABOUT THE MECHANISMS AND RISK FACTORS ASSOCIATED WITH !$ HAVE EXPANDED THE MEMORY PERFORMANCE 4HE TRIAL WILL PROVIDE TYPES OF INTERVENTIONS UNDER STUDY 4HESE TRIALS USEFUL DATA ON THE SAFETY FEASIBILITY AND ARE EXAMINING A HOST OF POSSIBLE INTERVENTIONS POTENTIAL EFFECTIVENESS OF THIS INNOVATIVE TREATMENT INCLUDING CARDIOVASCULAR TREATMENTS HORMONES APPROACH )NVESTIGATORS MAY BE ABLE TO USE THE TYPE DIABETES TREATMENTS ANTIOXIDANTS OMEGA RESULTS TO PLAN FUTURE FULL SCALE CLINICAL TRIALS FATTY ACIDS IMMUNIZATION COGNITIVE TRAINING AND "EYOND PILOT STUDIES INVESTIGATORS ALSO ARE EXERCISE AMONG OTHERS CONDUCTING FULL SCALE !$ CLINICAL TRIALS OF VARIOUS &OR EXAMPLE .)! FUNDS PILOT TRIALS TO LEARN INTERVENTIONS /NE OF THESE TRIALS THE !LZHEIMERS WHETHER TREATING ONE OR ANOTHER ASPECT OF TYPE $ISEASE #OOPERATIVE 3TUDY !$#3 IS TESTING DIABETES WILL AFFECT COGNITIVE HEALTH AND !$ PRO WHETHER ONE OMEGA FATTY ACID $(! FOUND IN GRESSION ! PILOT TRIAL IS A RELATIVELY SMALL CLINICAL THE OIL OF CERTAIN lSH CAN SLOW THE PROGRESSION OF TRIAL THAT COLLECTS INITIAL DATA ON THE SAFETY COGNITIVE AND FUNCTIONAL DECLINE IN PEOPLE WITH EFFECTIVENESS AND BEST DOSAGE OF A POTENTIAL MILD TO MODERATE !$ $URING THE MONTH TREATMENT 4HIS INFORMATION HELPS INVESTIGATORS CLINICAL TRIAL INVESTIGATORS WILL MEASURE THE DECIDE WHICH TREATMENTS SHOULD BE TESTED IN PROGRESS OF THE DISEASE USING STANDARD TESTS FOR LARGER FULL SCALE TRIALS /NE MONTH PILOT TRIAL FUNCTIONAL AND COGNITIVE CHANGE 2ESEARCHERS ALSO HAS EXAMINED THE EFFECTS ON !$ OF ADMINISTERING WILL EVALUATE WHETHER TAKING $(! SUPPLEMENTS A NASAL SPRAY FORM OF INSULIN 4HIS TRIAL IS HAS A POSITIVE EFFECT ON POSSIBLE PHYSICAL AND FOUNDED ON EVIDENCE THAT !$ IS ASSOCIATED WITH BIOLOGICAL MARKERS OF !$ SUCH AS BRAIN ATROPHY REDUCED LEVELS OF INSULIN IN CEREBROSPINAL mUID AND THAT TREATMENT WITH INSULIN IMPROVES
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 !$ 2ESEARCH "ETTER 1UESTIONS .EW !NSWERS
AND PROTEINS IN BLOOD AND SPINAL mUID 4HE !$#3 #ANCER 0REVENTION 4RIAL 3%,%#4 3%,%#4 IS A FEDERALLY ESTABLISHED CONSORTIUM CONDUCTING IS EVALUATING WHETHER TAKING SELENIUM ANDOR CLINICAL TRIALS ON !$ WITH SITES ACROSS THE 5NITED VITAMIN % SUPPLEMENTS CAN PREVENT PROSTATE 3TATES AND #ANADA CANCER IN HEALTHY MEN OLDER THAN YEARS &ULL SCALE !$ PREVENTION TRIALS ARE UNDER 02%!$6)3% IS EVALUATING WHETHER THESE WAY AS WELL /NE SUCH TRIAL 0REVENTION OF SUPPLEMENTS CAN HELP PREVENT MEMORY LOSS AND !LZHEIMERS $ISEASE WITH 6ITAMIN % AND DEMENTIA BY PROTECTING BRAIN CELLS FROM OXIDATIVE 3ELENIUM 02%!$6)3% IS BEING CONDUCTED IN DAMAGE SEE 4HE !GING 0ROCESS ON PAGE FOR CONJUNCTION WITH A .ATIONAL #ANCER )NSTITUTE MORE ON OXIDATIVE DAMAGE !BOUT OF THE FUNDED TRIAL CALLED THE 3ELENIUM AND 6ITAMIN % MORE THAN MEN ENROLLED IN 3%,%#4 ARE PARTICIPATING IN 02%!$6)3%
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0ARTICIPATING IN A #LINICAL 4RIAL
APID ADVANCES IN OUR A TRIAL (ERE ARE SOME FACTS THAT SMALL NUMBER OF PARTICIPANTS AND 2KNOWLEDGE ABOUT !$ HAVE POTENTIAL PARTICIPANTS MIGHT WANT TO EXAMINES ITS ACTION IN THE BODY LED TO THE DEVELOPMENT OF MANY KNOW ABOUT CLINICAL TRIALS AND ITS SAFETY 4HE MAIN GOALS OF PROMISING NEW DRUGS AND TREATMENT 0HASE ) TRIALS ARE TO ESTABLISH THE STRATEGIES (OWEVER BEFORE THESE 7(!4 +).$ /& HIGHEST DOSE OF A NEW DRUG THAT NEW STRATEGIES CAN BE USED IN CLINI 42)!,3 !2% 4(%2% PEOPLE CAN TOLERATE AND TO DElNE CAL PRACTICE THEY MUST BE SHOWN 4REATMENT TRIALS WITH EXISTING DRUGS THE DOSE AT WHICH PEOPLE MAY TO WORK IN PEOPLE 4HIS MEANS OR BEHAVIORAL STRATEGIES ASSESS BEGIN TO EXPERIENCE HARMFUL SIDE THAT CLINICAL TRIALSAND VOLUNTEER WHETHER AN INTERVENTION ALREADY EFFECTS 4HESE TRIALS GENERALLY LAST PARTICIPANTSARE AN ESSENTIAL APPROVED FOR OTHER PURPOSES MAY ONLY A FEW MONTHS PART OF !$ RESEARCH !DVANCES BE USEFUL IN TREATING AGE RELATED )F RESULTS SHOW THAT THE TREAT IN PREVENTION AND TREATMENT ARE COGNITIVE DECLINE OR !$ &OR MENT APPEARS TO BE SAFE IT WILL POSSIBLE THANKS TO VOLUNTEERS WHO EXAMPLE TRIALS HAVE TESTED WHETHER GO ON TO 0HASE )) AND 0HASE PARTICIPATE IN CLINICAL TRIALS DRUGS USED TO LOWER CHOLESTEROL ))) CLINICAL TRIALS 0HASE )) TRIALS #LINICAL TRIALS ARE THE PRIMARY HELP SLOW PROGRESSION OF !$ INVOLVE LARGER NUMBERS OF PEOPLE WAY THAT RESEARCHERS lND OUT IF 4REATMENT TRIALS WITH EXPERIMENTAL STUDIED OVER LONGER PERIODS OF A PROMISING TREATMENT IS SAFE DRUGS OR STRATEGIES SHOW WHETHER TIME THAN 0HASE ) TRIALS )N THESE #LINICAL TRIALS TELL RESEARCHERS WHICH A NEW DRUG OR TREATMENT APPROACH TRIALS THE STUDY TEAM WANTS TO TREATMENTS ARE THE MOST EFFECTIVE CAN HELP IMPROVE COGNITIVE FUNCTION KNOW WHETHER THE TREATMENT IS AND FOR WHICH PEOPLE THEY MAY OR LESSEN SYMPTOMS IN PEOPLE WITH SAFE AND EFFECTIVE AT CHANGING WORK BEST 4RIALS CAN TAKE PLACE !$ SLOW THE PROGRESSION TO !$ THE COURSE OF THE DISEASE 0HASE IN VARIOUS SETTINGS SUCH AS PRIVATE OR PREVENT IT )NTERVENTIONS TESTED )) TRIALS OCCASIONALLY ALSO INVOLVE RESEARCH FACILITIES TEACHING HOS IN THESE TRIALS ARE DEVELOPED FROM THE USE OF A PLACEBO AN INACTIVE PITALS SPECIALIZED !$ RESEARCH KNOWLEDGE ABOUT THE MECHANISMS SUBSTANCE THAT LOOKS LIKE THE STUDY CENTERS AND DOCTORS OFlCES &$! INVOLVED IN THE !$ PROCESS %XPERI DRUG 2ESULTS FROM 0HASE )) TRIALS APPROVAL IS NECESSARY BEFORE MENTAL DRUGS FOR EXAMPLE ARE GIVE STUDY STAFF AN INDICATION OF SCIENTISTS CAN BEGIN A CLINICAL TRIAL lRST TESTED IN TISSUE CULTURE AND IN THE EFFECTIVE DOSE TO TAKE INTO 0ARTICIPATING IN A CLINICAL TRIAL ANIMALS TO DETERMINE THEIR ACTIONS IN 0HASE ))) TRIALS 0HASE ))) TRIALS ARE IS A BIG STEP FOR ANYONE INCLUDING THE BODY 3AFETY AND EFFECTIVENESS LARGE STUDIES THAT COMPARE AN PEOPLE WITH !$ AND THEIR CARE STUDIES ARE ALSO CONDUCTED IN EXPERIMENTAL TREATMENT WITH A GIVERS 4HAT IS WHY PHYSICIANS AND ANIMALS BEFORE THE COMPOUNDS PLACEBO OR STANDARD TREATMENT CLINICAL TRIALS STAFF SPEND TIME TALKING ARE TESTED IN HUMANS TO DETERMINE SAFETY AND EFlCACY WITH PARTICIPANTS ABOUT WHAT IT IS WHETHER THE TREATMENT HAS THE LIKE TO BE IN A TRIAL AND THE PROS AND 7(!4 !2% 4(% 0(!3%3 POWER TO PRODUCE AN EFFECT CONS OF PARTICIPATING )T IS ALSO WHY /& #,).)#!, 42)!,3 !FTER THESE PHASES ARE COMPLETE THEY GET A SIGNED INFORMED CONSENT $URING 0HASE ) TRIALS A RESEARCH FORM BEFORE A PERSON ENROLLS IN TEAM GIVES THE TREATMENT TO A #ONTINUED ON NEXT PAGE
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 !$ 2ESEARCH "ETTER 1UESTIONS .EW !NSWERS
0ARTICIPATING IN A #LINICAL 4RIAL #ONTINUED
AND INVESTIGATORS ARE SATISlED THAT REPRESENTATIVE USUALLY A FAMILY GROUPS MAY RECEIVE A DIFFERENT THE TREATMENT IS SAFE AND EFFECTIVE MEMBER TO GIVE PERMISSION FOR THE DRUG A PLACEBO OR A DIFFERENT THE STUDY TEAM MAY SUBMIT ITS PERSON TO PARTICIPATE ,AWS AND INTERVENTION #OMPARING RESULTS FOR DATA TO THE &$! FOR APPROVAL &$! REGULATIONS REGARDING INFORMED DIFFERENT GROUPS GIVES RESEARCHERS EXPERTS REVIEW THE DATA AND CONSENT DIFFER ACROSS 3TATES AND CONlDENCE THAT CHANGES IN THE DECIDE WHETHER TO APPROVE THE RESEARCH INSTITUTIONS BUT ALL ARE TEST GROUP ARE THE RESULT OF THE DRUG OR TREATMENT FOR USE IN PATIENTS INTENDED TO ENSURE THAT PARTICIPANTS EXPERIMENTAL TREATMENT AND NOT WITH THE DISEASE UNDER STUDY ARE PROTECTED AND WELL CARED FOR SOME OTHER FACTOR SUCH AS THE .EXT PEOPLE GO THROUGH A PLACEBO EFFECT THIS IS WHEN PEOPLE 7(!4 (!00%.3 7(%. SCREENING PROCESS TO SEE IF THEY FEEL AN EFFECT BECAUSE THEY THINK ! 0%23/. 3)'.3 50 &/2 ! QUALIFY TO PARTICIPATE IN THE TRIAL THEY ARE GETTING THE TEST MEDICA #,).)#!, 42)!, )F THEY QUALIFY AND CAN SAFELY TION EVEN THOUGH THEY ARE REALLY &IRST IT IS IMPORTANT TO LEARN PARTICIPATE THEN THEY ARE ENROLLED GETTING A PLACEBO )N MANY TRIALS ABOUT THE TRIAL 3TAFF AT THE CLINICAL IN THE TRIAL NO ONENOT EVEN THE RESEARCH RESEARCH CENTER EXPLAIN THE TRIAL TEAMKNOWS WHO IS GETTING THE IN DETAIL TO POTENTIAL PARTICIPANTS 7(!4 (!00%.3 TREATMENT AND WHO IS GETTING THE AND DESCRIBE POSSIBLE RISKS $52).' ! 42)!, PLACEBO OR OTHER INTERVENTION 4HIS AND BENElTS 3TAFF ALSO TALK )F PARTICIPANTS AGREE TO JOIN THE MEANS THAT THE PARTICIPANT FAMILY ABOUT THE PARTICIPANTS RIGHTS AS TRIAL AND AN EVALUATION PROCESS MEMBER AND THE STAFF ARE hBLINDv RESEARCH VOLUNTEERS INCLUDING SHOWS THEY MEET ALL THE CRITERIA FOR TO THE TREATMENT BEING RECEIVED THEIR RIGHT TO LEAVE THE TRIAL AT PARTICIPATION THEN A hBASELINEv 4HIS KIND OF TRIAL IS CALLED A DOUBLE ANY TIME 0ARTICIPANTS AND THEIR VISIT IS SCHEDULED WITH THE TRIAL BLIND PLACEBO CONTROLLED TRIAL FAMILY MEMBERS ARE ENTITLED TO STAFF 4HIS VISIT GENERALLY INVOLVES !S THE TRIAL PROGRESSES PARTICI HAVE THIS INFORMATION REPEATED COGNITIVE AND PHYSICAL TESTS 4HIS PANTS AND FAMILY MEMBERS USUALLY AND EXPLAINED UNTIL THEY FEEL THEY GIVES THE TEAM INFORMATION AGAINST MUST FOLLOW STRICT MEDICATION OR UNDERSTAND THE NATURE OF THE TRIAL WHICH TO MEASURE FUTURE MENTAL TREATMENT INSTRUCTIONS AND KEEP AND ANY POTENTIAL RISKS AND PHYSICAL CHANGES DETAILED RECORDS OF SYMPTOMS %VERY !FTER ALL QUESTIONS HAVE BEEN )N MOST CLINICAL TRIALS PARTICI SO OFTEN PARTICIPANTS VISIT THE CLINIC ANSWERED PARTICIPANTS WHO ARE PANTS ARE RANDOMLY ASSIGNED TO OR RESEARCH CENTER TO HAVE PHYSICAL STILL INTERESTED IN JOINING THE TRIAL DIFFERENT STUDY GROUPS SO THAT AND COGNITIVE EXAMS GIVE BLOOD ARE ASKED TO SIGN AN INFORMED EACH STUDY GROUP HAS PEOPLE AND URINE SAMPLES AND TALK WITH CONSENT FORM )N SOME CASES A IN IT OF ABOUT THE SAME AVERAGE TRIAL STAFF 4HESE VISITS ALLOW THE INVES PARTICIPANT MAY NO LONGER BE CHARACTERISTICS SUCH AS AGE SEX TIGATORS TO COLLECT INFORMATION ON THE ABLE TO PROVIDE INFORMED CONSENT EDUCATIONAL LEVEL OR COGNITIVE EFFECTS OF THE TEST DRUG OR TREATMENT BECAUSE OF PROBLEMS WITH MEMORY ABILITY /NE GROUP THE TEST SEE HOW THE DISEASE IS PROGRESSING AND THINKING )N SUCH CASES IT IS GROUP RECEIVES THE EXPERIMENTAL AND SEE HOW THE PARTICIPANT AND STILL POSSIBLE FOR AN AUTHORIZED DRUG OR INTERVENTION /THER THE CAREGIVER ARE DOING
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 7(!4 3(/5,$ CHOOSE WHICH STUDY GROUP TO BE 0%/0,% #/.3)$%2 IN OR NOT KNOWING FOR A LONG TIME "%&/2% 0!24)#)0!4).' ). WHETHER THE STUDY WAS SUCCESSFUL ! #,).)#!, 42)!, /NGOING AND OPEN COMMUNICA 0EOPLE WHO HAVE PARTICIPATED IN TION WITH STUDY STAFF CAN HELP TO !$ CLINICAL TRIALS SAY THAT ITS A GOOD REDUCE THIS FRUSTRATION IDEA TO CONSIDER THE FOLLOWING ISSUES N &INDING THE RIGHT CLINICAL BEFORE DECIDING TO JOIN A TRIAL TRIAL 3OME CLINICAL TRIALS INVOLVE PARTICIPANTS WHO ARE COGNITIVELY N %XPECTATIONS AND MOTIVA HEALTHY OR HAVE ONLY MILD SYMP TIONS 4HE TEST DRUG OR TREATMENT TOMS BECAUSE THEY ARE TESTING A GIVE INSIGHTS INTO WHAT TO EXPECT MAY RELIEVE A SYMPTOM CHANGE DRUG THAT MIGHT DELAY A DECLINE IN THE FUTURE 4HEY ALSO CAN SHARE A CLINICAL MEASUREMENT OR REDUCE IN COGNITIVE FUNCTION /THER TRIALS INFORMATION ABOUT SUPPORT GROUPS THE RISK OF DEATH BUT CLINICAL TRIALS INVOLVE PARTICIPANTS WHO HAVE AND OTHER HELPFUL RESOURCES GENERALLY DO NOT HAVE MIRACULOUS MORE ADVANCED !$ BECAUSE THEY RESULTS AND PARTICIPANTS MAY NOT ARE TESTING A TREATMENT THAT MIGHT &/2 -/2% ).&/2-!4)/. RECEIVE ANY DIRECT BENElT 7ITH LESSEN BEHAVIORAL SYMPTOMS /R A 4O LEARN MORE ABOUT !$ CLINICAL A COMPLEX DISEASE LIKE !$ IT IS TRIAL MAY BE TESTING NEW STRATEGIES TRIALS VISIT THE !LZHEIMERS $ISEASE UNLIKELY THAT ONE TREATMENT WILL TO HELP CAREGIVERS %VEN IF A PAR %DUCATION AND 2EFERRAL !$%!2 CURE OR PREVENT THE DISEASE 3OME TICIPANT IS NOT ELIGIBLE FOR ONE TRIAL #ENTERS #LINICAL 4RIALS $ATABASE PEOPLE CHOOSE NOT TO PARTICIPATE ANOTHER TRIAL MAY BE JUST RIGHT WEBSITE WWWNIANIHGOV OR DECIDE TO DROP OUT OF A STUDY N 4HE BIGGEST BENElT OF ALL !LZHEIMERS2ESEARCH)NFORMATION BECAUSE THIS REALITY DOES NOT MEET -ANY FAMILIES lND THAT THE BIGGEST #LINICAL4RIALS 4HIS .)! WEBSITE THEIR EXPECTATIONS /THERS CHOOSE BENElT OF PARTICIPATING IN A CLINICAL INCLUDES A LIST OF !$ AND DEMENTIA TO STAY IN A TRIAL BECAUSE THEY TRIAL IS THE REGULAR CONTACT WITH THE CLINICAL TRIALS CURRENTLY IN PROGRESS REALIZE THAT EVEN IF THEY GET NO STUDY TEAM 4HESE VISITS PROVIDE AN AT RESEARCH CENTERS THROUGHOUT OR ONLY A SLIGHT BENElT THEY ARE OPPORTUNITY TO GET STATE OF THE ART THE 5NITED 3TATES )T ALSO PROVIDES MAKING A VALUABLE CONTRIBUTION TO !$ CARE AND TO TALK REGULARLY WITH INFORMATION ABOUT THE PHASES KNOWLEDGE THAT WILL HELP PEOPLE !$ EXPERTS WHO HAVE LOTS OF PRACTI OF CLINICAL TRIALS AND HOW TO IN THE FUTURE CAL EXPERIENCE AND A BROAD PER PARTICIPATE EXPLAINS THE DRUG N 5NCERTAINTY 3OME FAMILIES SPECTIVE ON THE DISEASE 4HE STUDY DEVELOPMENT PROCESS AND PROVIDES HAVE A HARD TIME WITH THE UN TEAM UNDERSTANDS AND CAN PROVIDE LINKS TO OTHER USEFUL WEBSITES CERTAINTIES OF PARTICIPATIONFOR ADVICE ABOUT THE EMOTIONAL AND !LSO VISIT THE CLINICAL TRIALS WEB EXAMPLE NOT KNOWING WHETHER PHYSICAL ASPECTS OF THE PERSON WITH SITES OF THE .ATIONAL )NSTITUTES THE PERSON IS TAKING THE TEST !$ AND THE CAREGIVERS EXPERI OF (EALTH WWWCLINICALTRIALSGOV TREATMENT A PLACEBO OR A CONTROL ENCE 4EAM MEMBERS CAN SUGGEST OR THE !LZHEIMERS !SSOCIATION TREATMENT NOT BEING ABLE TO WAYS TO COPE WITH THE PRESENT AND WWWALZORG
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY NE OF THE GREATEST COSTS OF !$ CAN /NE OF THE HARDEST DECISIONS THAT MANY BE THE PHYSICAL AND EMOTIONAL TOLL FAMILIES FACE IS WHETHER AND WHEN TO PLACE ON FAMILY MEMBERS CAREGIVERS AND A LOVED ONE WITH !$ IN A NURSING HOME OR FRIENDS OF PEOPLE WITH THE DISEASE OTHER TYPE OF CARE FACILITY /NCE THIS DECISION 4HE CHANGES IN A LOVED ONES PERSONALITY AND / IS MADE FAMILIES MUST DECIDE WHAT TYPE OF MENTAL ABILITIES THE NEED TO PROVIDE CONSTANT CARE IS BEST FOR THE PERSON AND THE FAMILY LOVING ATTENTION FOR YEARS ON END AND THE DEMANDS -ANY INVESTIGATORS ARE WORKING TO IDENTIFY OF BATHING DRESSING AND OTHER CAREGIVING DUTIES IN STRATEGIES THAT CAN LEAD TO IMPROVED QUALITY OF THE LATER STAGES OF THE DISEASE CAN BE HARD TO BEAR CARE IN VARIOUS FACILITIES INCLUDING ADULT DAY -ANY CAREGIVERS MUST ASSUME NEW AND UNFAMILIAR CARE CENTERS ASSISTED LIVING FACILITIES CONTINUING ROLES IN THE FAMILY AND THESE CHANGES CAN BE BOTH CARE RETIREMENT COMMUNITIES NURSING HOMES DIFlCULT AND SAD .OT SURPRISINGLY CAREGIVERS OF AND SPECIAL CARE UNITS SEPARATE AREAS WITHIN PEOPLE WITH DEMENTIA SPEND SIGNIlCANTLY MORE NURSING HOMES OR ASSISTED LIVING FACILITIES TIME ON CAREGIVING TASKS THAN DO CAREGIVERS OF DESIGNED ESPECIALLY FOR PEOPLE WITH PEOPLE WITH OTHER TYPES OF ILLNESSES DEMENTIA
7HO !RE !$ &AMILY #AREGIVERS
-ANY PRIMARY CAREGIVERS ARE FAMILY RAISING CHILDREN OF THEIR OWN "ROTHERS AND SISTERS 3IBLINGS MEMBERS AND .)! FUNDED RESEARCH *UGGLING TWO SETS OF RESPONSIBILITIES MAY ASSUME PRIMARY RESPONSIBILITY HAS SHOWN THAT THE VALUE OF INFORMAL IS OFTEN TOUGH FOR THESE MEMBERS FOR CARE IF THEY LIVE CLOSE BY -ANY FAMILY CAREGIVING OF PEOPLE WITH OF THE hSANDWICH GENERATIONv OF THESE CAREGIVERS ALSO ARE OLDER COGNITIVE IMPAIRMENT ADDS UP TO AND MAY BE COPING WITH THEIR OWN $AUGHTERS IN LAW -ANY WOMEN BILLIONS OF DOLLARS EVERY YEAR 7HO FRAILTIES OR HEALTH PROBLEMS IN THIS GROUP HELP TAKE CARE OF AN ARE THESE FAMILY CAREGIVERS OLDER PERSON WITH !$ 4HEY ARE 'RANDCHILDREN /LDER CHILDREN 3POUSES 4HIS IS THE LARGEST GROUP THE THIRD LARGEST GROUP OF FAMILY MAY BECOME MAJOR HELPERS IN OF CAREGIVERS -OST ARE OLDER TOO CAREGIVERS CARING FOR A GRANDPARENT WITH !$ AND MANY HAVE THEIR OWN HEALTH 'RANDCHILDREN MAY NEED EXTRA 3ONS !LTHOUGH MANY ARE INVOLVED PROBLEMS SUPPORT IF THEIR PARENTS ATTENTION IS IN THE DAILY CARE OF A PARENT WITH HEAVILY FOCUSED ON THE ILL GRAND $AUGHTERS 4HE SECOND LARGEST !$ SONS OFTEN FOCUS ON THE lNAN PARENT OR IF THE GRANDPARENT WITH GROUP OF PRIMARY CAREGIVERS IS CIAL LEGAL AND BUSINESS ASPECTS OF !$ LIVES IN THE FAMILYS HOME #AREGIVERS DAUGHTERS -ANY ARE MARRIED AND CAREGIVING
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 )MPROVING 3UPPORT FOR &AMILIES AND /THER #AREGIVERS
2ESEARCH &INDINGS "ENElT #AREGIVERS
LTHOUGH RESEARCH ON FAMILY CAREGIVER SUPPORT IS STILL IN ITS EARLY DAYS WE HAVE ALREADY LEARNED MUCH ABOUT THE UNIQUE ASPECTS OF CAREGIVERS PERSONALITIES AND SITUATIONS &OR EXAMPLE IT IS WELL ESTABLISHED THAT ! !$ CAREGIVERS OFTEN EXPERIENCE STRESS ANXIETY DEPRESSION AND OTHER MENTAL HEALTH PROBLEMS AS A RESULT OF THE CONTINUING AND DEMANDING NATURE OF !$ CARE 4HIS CHRONIC STRESS CAN HAVE DETRIMENTAL EFFECTS ON THE PHYSICAL HEALTH OF CAREGIVERS 4HE PHYSICAL AND EMOTIONAL EFFECTS OF !$ CAREGIVING CAN LAST A LONG TIME EVEN AFTER THE DEATH OF THE PERSON WITH !$ /N THE OTHER HAND RESEARCH ALSO HAS SHOWN THAT CAREGIVING CAN HAVE IMPORTANT POSITIVE EFFECTS !$ CAREGIVERS DO NOT ALL HAVE THE SAME INCLUDING PSYCHOLOGICAL AND PHYSICAL RESPONSE TO CAREGIVING &OR EXAMPLE CAREGIVERS WHO HAVE STRONG SUPPORT N ! NEW SENSE OF PURPOSE OR MEANING IN LIFE SYSTEMS AND WELL DEVELOPED COPING SKILLS MAY BE N &ULlLLMENT OF A LIFELONG COMMITMENT TO A SPOUSE ABLE TO WEATHER THE STRESSES OF CARING FOR A LOVED N !N OPPORTUNITY TO GIVE BACK TO A PARENT SOME ONE WITH !$ /THERS WHO HAVE FEW BREAKS FROM OF WHAT THE PARENT HAS GIVEN TO THEM CAREGIVING RESPONSIBILITIES ANDOR HAVE PREEXISTING N 2ENEWAL OF RELIGIOUS FAITH ILLNESSES MAY BE MORE VULNERABLE TO THE PHYSICAL N #LOSER TIES WITH PEOPLE THROUGH NEW RELATION AND EMOTIONAL STRESSES ASSOCIATED WITH DEMENTIA SHIPS OR STRONGER EXISTING RELATIONSHIPS CARE #AREGIVER RESEARCH IS BEGINNING TO DISCOVER EFFECTIVE WAYS TO EASE THE BURDEN OF CAREGIVING 2ESEARCHERS HAVE LEARNED THAT
N 4HE INFORMATION AND PROBLEM SOLVING NEEDS OF CAREGIVERS EVOLVE OVER TIME AS !$ PROGRESSES 4HEREFORE SUPPORT PROGRAMS SHOULD BE TAILORED TO THE NEEDS OF THE CAREGIVER AT VARIOUS STAGES OF CAREGIVING 0ROGRAMS CAN RESPOND BY OFFERING
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY SERVICES AND INFORMATION GEARED TO DIFFERENT 7HERE !RE 0EOPLE WITH STAGES OF THE DISEASE !LZHEIMERS $ISEASE #ARED &OR N 4RADITIONS AND ATTITUDES ABOUT CAREGIVING VARY ACROSS CULTURAL GROUPS &OR EXAMPLE SOME N (OME RESEARCHERS HAVE FOUND THAT !FRICAN !MERICAN N !SSISTED LIVING FACILITIES THOSE IN THE EARLY STAGES CAREGIVERS USE FEWER FORMAL IN HOME SERVICES THAN N !DULT DAY CARE CENTERS DO WHITE CARETAKERS 3OME POPULATIONS MAY lND N .URSING HOMES IT DIFlCULT TO PUBLICLY ADMIT THAT A FAMILY MEMBER N 3PECIAL CARE UNITS HAS !$ AND MAY BE RELUCTANT TO SEEK HELP WITH CAREGIVING ISSUES 4HEREFORE PROGRAMS AND SERVICES FOR CAREGIVERS MUST BE CULTURALLY APPROPRIATE AND SENSITIVE TO FACTORS THAT POSITIVELY AND NEGATIVELY INmUENCE CAREGIVERS ATTITUDES AND ABILITY TO CARRY ONES MADE LIFE EASIER FOR THEM IMPROVED THEIR OUT THEIR RESPONSIBILITIES CAREGIVING ABILITY IMPROVED THE CARE RECIPIENTS N 5SE OF MULTIPLE TYPES OF SUPPORT OVER AN LIFE AND HELPED THEM KEEP THEIR LOVED ONE AT EXTENDED PERIOD OF TIME HELPS CAREGIVERS &OR HOME EXAMPLE THE 2ESOURCES FOR %NHANCING !LZHEIMERS N $EVELOPING WAYS TO HELP CAREGIVERS BECOME #AREGIVER (EALTH 2%!#( CLINICAL TRIAL SHOWED EDUCATED ABOUT !$ IMPROVE mEXIBILITY IN THAT CAREGIVERS WHO RECEIVED MONTHS OF INTEN RESPONDING TO CAREGIVING DEMANDS AND LEARN A SIVE HELP WITH CAREGIVING STRATEGIES HAD SIGNIlCANT VARIETY OF PRACTICAL STRATEGIES CAN HELP 3TUDIES IMPROVEMENTS IN OVERALL QUALITY OF LIFE 4HEY ALSO ARE TEACHING CAREGIVERS HOW TO READ THE EMOTIONAL HAD LOWER RATES OF CLINICAL DEPRESSION COMPARED TO AND PHYSICAL CUES OF THE PERSON WITH !$ AND TO CAREGIVERS WHO DID NOT PARTICIPATE IN THE PROGRAM UNDERSTAND THE SEQUENCE OF EVENTS THAT OFTEN 4HE CAREGIVING STRATEGIES INCLUDED INFORMATION LEADS TO INAPPROPRIATE BEHAVIORS 4HEY ARE ALSO SHARING INSTRUCTION ROLE PLAYS PROBLEM SOLVING HELPING CAREGIVERS RESPOND TO THE NEEDS OF THE SKILLS TRAINING STRESS MANAGEMENT TECHNIQUES AND PERSON WITH !$ IN A VARIETY OF CREATIVE WAYS TELEPHONE SUPPORT GROUPS #AREGIVERS REPORTED SUCH AS MAINTAINING mEXIBILITY IN THE FACE OF THAT TAKING PART IN 2%!#( HELPED THEM FEEL MANY DEMANDS BECOMING EDUCATED ABOUT THE MORE CONlDENT IN WORKING WITH THEIR LOVED DISEASE LEARNING PRACTICAL STRATEGIES USING AVAILABLE
&OR )NFORMATION !BOUT !$ 3UPPORT 'ROUPS 4O lND OUT WHETHER AN !$ SUPPORT GROUP IS OPERATING IN YOUR AREA CONTACT N .)!S !LZHEIMERS $ISEASE %DUCATION AND 2EFERRAL !$%!2 #ENTER AT OR VISIT WWWNIANIHGOV!LZHEIMERS2ESEARCH)NFORMATION2ESEARCH#ENTERS N !LZHEIMERS !SSOCIATION AT OR VISIT WWWALZORG
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 )MPROVING 3UPPORT FOR &AMILIES AND /THER #AREGIVERS
RESOURCES INVOLVING OTHER FAMILY MEMBERS AND FRIENDS AND BALANCING THE NEEDS OF THE PERSON WITH THEIR OWN NEEDS N (ELPING CAREGIVERS DEAL WITH THE COMPLICATED ISSUE OF WHETHER AND WHEN TO PLACE A LOVED ONE IN A NURSING HOME IS AN IMPORTANT ASPECT OF CAREGIVER SUPPORT 0EOPLE WITH DEMENTIA ARE AT MUCH GREATER RISK OF NURSING HOME PLACEMENT THAN ARE OTHER OLDER PEOPLE OF THE SAME AGE 0LACING A LOVED ONE IN A NURSING HOME MAY RELIEVE SOME OF THE BURDEN OF CAREGIVING BUT IT DOES NOT NECESSARILY REDUCE CAREGIVER STRESS OR EMOTIONAL DISTRESS -OREOVER NURSING HOME COSTS NOW N (ELPING CAREGIVERS STAY PHYSICALLY ACTIVE HAS AVERAGE MORE THAN PER YEAR BIG BENElTS 2ESEARCHERS HAVE FOUND THAT REGULAR /NE CLINICAL TRIAL TESTED THE EFFECTS OF AN MODERATE EXERCISE IS AN IMPORTANT STRESS RELIEVER FOR ENHANCED COUNSELING AND SUPPORT PROGRAM ON CAREGIVERS %XERCISE HELPS TO REDUCE BLOOD PRESSURE NURSING HOME PLACEMENT AND CAREGIVER HEALTH INCREASES DUE TO STRESS IMPROVES SLEEP QUALITY AND 4HIS PROGRAM FOR CAREGIVERS CONSISTED OF SIX SESSIONS REDUCES PSYCHOLOGICAL DISTRESS AND DEPRESSION OF INDIVIDUAL AND FAMILY COUNSELING SUPPORT GROUP PARTICIPATION AND ON DEMAND TELEPHONE %!2,9 34!'% !$ 3500/24 '2/503 COUNSELING 0ARTICIPANTS IN THE PROGRAM WERE ABLE ! 6)4!, 3/52#% /& (%,0 TO DELAY PLACEMENT OF THEIR LOVED ONES IN NURSING &OR FAMILIES AND FRIENDS WHO CARE FOR A PERSON WITH HOMES BY ABOUT MONTHS 2ESEARCHERS ATTRIBUTED !$ TALKING WITH OTHERS WHO ARE GOING THROUGH THE THE EFFECTS OF THE PROGRAM TO GREATER TOLERANCE FOR SAME EXPERIENCE CAN BE A VITAL LIFELINE !$ SUPPORT MEMORY AND BEHAVIOR PROBLEMS IN THE PERSON WITH GROUPS PROVIDE A PLACE WHERE CAREGIVERS CAN SEEK !$ IMPROVED SATISFACTION WITH THE SUPPORT RESPITE EXPRESS CONCERNS SHARE EXPERIENCES GET PROVIDED BY FAMILY AND FRIENDS AND FEWER TIPS AND RECEIVE EMOTIONAL COMFORT .)! FUNDED SYMPTOMS OF DEPRESSION -OREOVER IT APPEARS !LZHEIMERS $ISEASE #ENTERS THE !LZHEIMERS THAT THE EXTRA TIME AT HOME DID NOT COME AT THE !SSOCIATION AND MANY OTHER ORGANIZATIONS SPONSOR EXPENSE OF THE CAREGIVERS SENSE OF WELL BEING IN PERSON AND ONLINE !$ SUPPORT GROUPS ALL AROUND THE COUNTRY )MPROVED DIAGNOSTIC TESTS AND INCREASING AWARE NESS OF !$ MEAN THAT MORE AND MORE PEOPLE ARE NOW BEING DIAGNOSED AT EARLY STAGES OF !$ 0EOPLE
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY IN THE EARLY STAGES OFTEN STILL HAVE GOOD COPING SEPARATE GROUPS IN OTHERS PEOPLE WITH !$ AND SKILLS AND ARE INTENSELY AWARE OF THEMSELVES AND THEIR CAREGIVERS ARE TOGETHER FOR PART OF THE SESSION THEIR SYMPTOMS 4HEY ALSO MAY FEEL CONSIDERABLE AND APART FOR THE REMAINDER DISTRESS EMBARRASSMENT AND ISOLATION BECAUSE OF A /THER TYPES OF EARLY STAGE SUPPORT GROUPS ARE PERCEIVED STIGMA ASSOCIATED WITH THE DISEASE !S A LESS STRUCTURED -EMBERS DISCUSS TOPICS OF THEIR RESULT A GROWING NUMBER OF PEOPLE WITH EARLY STAGE OWN CHOOSING AND THE GROUPS MEET REGULARLY OVER !$ AND THEIR FAMILY MEMBERS ARE LOOKING FOR COP AN EXTENDED TIME -EMBERS WITH !$ MAY STAY IN ING STRATEGIES MEANINGFUL ACTIVITIES AND MENTAL THE GROUP AS LONG AS THEY ARE ABLE TO MEANINGFULLY STIMULATION 4HEY ARE EAGER TO EDUCATE THEMSELVES TAKE PART IN THE DISCUSSION AND ACTIVITIES ABOUT !$ SHARE COMMON EXPERIENCES AND BREAK %ARLY STAGE SUPPORT GROUPS ARE NOT FOR EVERYONE THE POTENTIAL BARRIERS AND ISOLATION CAUSED BY THEIR 3OME PEOPLE WITH EARLY !$ AND THEIR FAMILIES MAY DIAGNOSIS 4HIS HAS LED TO THE FORMATION OF EARLY NOT BENElT BECAUSE OF FAMILY CONmICT DENIAL COGNI STAGE SUPPORT GROUPS SPECIlCALLY DESIGNED TO MEET TIVE IMPAIRMENT OR DISCOMFORT WITH THE INTIMACY THEIR NEEDS OF A GROUP EXPERIENCE (OWEVER MOST PARTICIPANTS 3OME EARLY STAGE SUPPORT GROUPS FOLLOW A REPORT POSITIVE OUTCOMES SUCH AS A GREATER SENSE STRUCTURED MODEL WITH TO HOUR SESSIONS OF CONTROL OVER THEIR LIVES AND FEELINGS THAT THEY SCHEDULED OVER TO WEEKS 4HE SESSIONS ARE ARE NOT ALONE -ANY PARTICIPANTS lND EARLY STAGE LED BY A FACILITATOR AND DISCUSSION TOPICS ARE SUPPORT GROUPS HELPFUL BECAUSE THEY INSTILL A SPIRIT DETERMINED IN ADVANCE 'UEST SPEAKERS PROVIDE OF CAMARADERIE BUILD COPING SKILLS AND FORGE INFORMATION AND HELP ON SPECIlC TOPICS SUCH AS RELATIONSHIPS AND EMOTIONAL SUPPORT THAT CONTINUE LEGAL AND lNANCIAL PLANNING )N SOME PROGRAMS TO HELP THE PERSON WITH !$ AND THE CAREGIVER EVEN THE PERSON WITH !$ AND THE CAREGIVER MEET IN AFTER THE SESSIONS END
7HAT (APPENS .EXT )T IS A QUESTION MANY PEOPLE AND THEIR FAMILIES ASK WHEN !$ IS lRST DIAGNOSED -EMBERS OF AN EARLY STAGE SUPPORT GROUP AT THE .ORTHWESTERN 5NIVERSITY !LZHEIMERS $ISEASE #ENTER IN #HICAGO WROTE 7HAT (APPENS .EXT TO HELP PEOPLE WITH EARLY STAGE DEMENTIA COPE WITH THEIR FEELINGS AND THE PRACTICAL ASPECTS OF EVERYDAY LIFE &OR A FREE COPY CALL THE !LZHEIMERS $ISEASE %DUCATION AND 2EFERRAL !$%!2 #ENTER AT OR VISIT WWWNIANIHGOV!LZHEIMERS0UBLICATIONS 7HAT(APPENS.EXTHTM
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 0!24 )MPROVING 3UPPORT FOR &AMILIES AND /THER #AREGIVERS
4AKING #ARE OF -OM OR $AD AT A $ISTANCE
AKING CARE OF A PARENT WITH !$ WHO LIVES BROTHERS DECIDED TO SEE WHETHER VIDEOCONFERENCING 4HUNDREDS OF MILES AWAY IS A REAL WORRY FACING COULD BE A WAY TO KEEP IN TOUCH WITH HER 4HEY IN MANY ADULTS h(OW CAN WE MAKE SURE -OM GETS THE STALLED A COMPUTER WITH A VIDEO CAMERA IN HER HOME SO BEST CARE POSSIBLE IF WERE NOT THERE ALL THE TIME v THEY COULD CHECK ON HER DAILY HELPING FULlLL HER WISH TO h7HAT CAN ) DO TO HELP $AD LIVE AT HOME FOR AS LONG CONTINUE LIVING INDEPENDENTLY ON THE FAMILY FARM WHILE AS POSSIBLE v ASSURING THEMSELVES THAT SHE WAS FARING WELL 4HAT WAS THE DILEMMA FACING +EN .IXON AND HIS h7E HAD A NEED AND WE PATCHED THE SYSTEM TWO BROTHERS IN 4HEIR MOTHER LIVED IN AN !RKAN TOGETHER AT lRST v SAYS +EN h)T EXCEEDED OUR SAS FARMING COMMUNITY AND WANTED TO STAY THERE +EN EXPECTATIONS IN BEING ABLE TO KEEP OUR MOTHER AND HIS BROTHERS LIVED TO HOURS AWAYCLOSE BUT INDEPENDENT AND CONNECTED TO THE FAMILY 7E COULD NOT CLOSE ENOUGH CALL AND HAVE COFFEE WITH HER EVERY MORNING AND IT 7ITH FUNDING FROM .)! +EN AND HIS BROTHERS GOT HER DAY STARTED OFF RIGHT 3HE HAD SOMETHING TO CREATED A MULTI PURPOSE )NTERNET BASED SYSTEM CALLED LOOK FORWARD TO EVERY DAYONE OR TWO OF HER BOYS !TTENTIVE#ARE THAT IS CURRENTLY AVAILABLE TO OTHERS FACED WAS GOING TO VISITv WITH THE SAME LONG DISTANCE CAREGIVING CHALLENGES !FTER MONTHS OF USING THE HOME GROWN SYSTEM "ACK IN BROADBAND )NTERNET SERVICE HAD JUST .IXON DECIDED TO DEVELOP IT TO HELP OTHER CAREGIVERS BECOME AVAILABLE IN THEIR MOTHERS COMMUNITY SO THE )N HE APPLIED FOR AND RECEIVED A GRANT FROM .)! TO RElNE THE !TTENTIVE#ARE PROTOTYPE AND TEST ITS FEASIBILITY IN PROVIDING INFORMAL LONG DISTANCE CARE TO PEOPLE WITH !$ (E LATER RECEIVED ANOTHER GRANT TO EVALUATE THE SOFTWARE SERVICES AND CAREGIVER USAGE AND BENElTS OF THE SYSTEM IN A VARIETY OF CAREGIVING SITUATIONS 4HE PARTICIPANTS IN THIS STUDY ARE DISTANCE CAREGIVERS OF PERSONS WITH EARLY TO MODERATE STAGE !$ WHO HAD THE !TTENTIVE#ARE SYSTEM INSTALLED IN THEIR OWN HOMES AND THE HOMES OF THEIR FAMILY MEMBERS WITH !$ !TTENTIVE#ARE NOW FEATURES VIDEOCONFERENCING MULTIMEDIA REMINDERS TO HELP CARE RECIPIENTS FUNCTION INDEPENDENTLY AND SLIDE SHOWS TO KEEP CARE RECIPI ENTS CONNECTED WITH FAMILY 4HE SYSTEMS JOURNAL AND DATA LOGGING CAPABILITY ALSO ALLOWS FAMILY CAREGIVERS TO MAINTAIN AND SHARE INFORMATION ABOUT THE CARE +EN .IXON AND HIS GRANDSON USE !TTENTIVE#ARE TO RECIPIENTS HEALTH AND WELL BEING WHETHER THEY ARE CHECK IN WITH +ENS MOTHER ACROSS THE STREET OR THOUSANDS OF MILES AWAY
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY #ONCLUSION
HE FUTURE BUILDS UPON THE EVENTS AND EXPERIENCES OF THE PAST 4HATS CERTAINLY TRUE OF !$ RESEARCH /UR KNOWLEDGE OF !$ IS ADVANCING RAPIDLY AND WE HAVE MUCH TO CELEBRATE IN OUR SCIENTIlC SUCCESSES4 !T THE SAME TIME WE CANNOT FORGET THAT !$ REMAINS AN URGENT PROBLEM FOR OUR .ATION 4HE CHALLENGE IS TO CONTINUE BUILDING ON THESE DISCOVERIES SO THAT WE CAN CREATE A BRIGHTER FUTURE IN WHICH THE POTENTIAL OF SUCCESSFULLY MANAGING !$ OR EVEN PREVENTING THIS TERRIBLE DISEASE CAN BECOME A REALITY 'LOSSARY
!CETYLCHOLINEA NEUROTRANSMITTER THAT PLAYS !XONTHE LONG EXTENSION FROM A NEURON THAT AN IMPORTANT ROLE IN MANY NEUROLOGICAL FUNCTIONS TRANSMITS OUTGOING SIGNALS TO OTHER CELLS INCLUDING LEARNING AND MEMORY "ETA AMYLOIDA PART OF THE AMYLOID PRECURSOR !MYGDALAAN ALMOND SHAPED STRUCTURE PROTEIN FOUND IN PLAQUES THE INSOLUBLE DEPOSITS INVOLVED IN PROCESSING AND REMEMBERING STRONG OUTSIDE NEURONS EMOTIONS SUCH AS FEAR )T IS PART OF THE LIMBIC "RAIN DERIVED NEUROTROPHIC FACTOR SYSTEM AND LOCATED DEEP INSIDE THE BRAIN "$.& A GROWTH FACTOR THAT STIMULATES SURVIVAL !MYLOID PLAQUEA LARGELY INSOLUBLE GROWTH AND ADAPTABILITY OF SOME NEURONS DEPOSIT FOUND IN THE SPACE BETWEEN NERVE CELLS "RAIN STEMTHE PORTION OF THE BRAIN THAT IN THE BRAIN 0LAQUES ARE MADE OF BETA AMYLOID CONNECTS TO THE SPINAL CORD AND CONTROLS AUTOMATIC OTHER MOLECULES AND DIFFERENT KINDS OF NERVE BODY FUNCTIONS SUCH AS BREATHING HEART RATE AND AND NON NERVE CELLS BLOOD PRESSURE !MYLOID PRECURSOR PROTEIN !00 THE #APILLARYA TINY BLOOD VESSEL 4HE BRAIN HAS LARGER PROTEIN FROM WHICH BETA AMYLOID IS FORMED BILLIONS OF CAPILLARIES THAT CARRY OXYGEN GLUCOSE !POLIPOPROTEIN %A PROTEIN THAT CARRIES THE BRAINS PRINCIPAL SOURCE OF ENERGY NUTRIENTS CHOLESTEROL IN BLOOD AND THAT APPEARS TO PLAY SOME AND HORMONES TO BRAIN CELLS SO THEY CAN DO THEIR ROLE IN BRAIN FUNCTION 4HE GENE THAT PRODUCES THIS WORK #APILLARIES ALSO CARRY AWAY CARBON DIOXIDE PROTEIN COMES IN SEVERAL FORMS OR ALLELES ε ε AND CELL WASTE PRODUCTS AND ε 4HE !0/% ε ALLELE IS RELATIVELY RARE AND #EREBELLUMTHE PART OF THE BRAIN MAY PROVIDE SOME PROTECTION AGAINST !$ BUT IT RESPONSIBLE FOR MAINTAINING THE BODYS BALANCE MAY INCREASE RISK OF EARLY HEART DISEASE !0/% AND COORDINATION ε IS THE MOST COMMON ALLELE AND APPEARS TO PLAY A NEUTRAL ROLE IN !$ !0/% ε OCCURS IN ABOUT #EREBRAL CORTEXTHE OUTER LAYER OF NERVE CELLS PERCENT OF ALL PEOPLE WITH !$ WHO DEVELOP SURROUNDING THE CEREBRAL HEMISPHERES THE DISEASE IN LATER LIFE IT INCREASES THE RISK OF #EREBRAL HEMISPHERESTHE LARGEST DEVELOPING !$ PORTION OF THE BRAIN COMPOSED OF BILLIONS OF NERVE CELLS IN TWO STRUCTURES CONNECTED BY THE CORPUS CALLOSUM 4HE CEREBRAL HEMISPHERES CONTROL CONSCIOUS THOUGHT LANGUAGE DECISION MAKING EMOTIONS MOVEMENT AND SENSORY FUNCTIONS
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY #EREBROSPINAL mUIDTHE mUID FOUND IN $.! DEOXYRIBONUCLEIC ACID A LONG AND AROUND THE BRAIN AND SPINAL CORD )T PROTECTS DOUBLE STRANDED MOLECULE WITHIN THE NUCLEUS OF THESE ORGANS BY ACTING LIKE A LIQUID CUSHION AND THE CELL THAT FORMS CHROMOSOMES AND GENES BY PROVIDING NUTRIENTS %ARLY ONSET !LZHEIMERS DISEASEA RARE #HROMOSOMEA THREADLIKE STRUCTURE IN FORM OF !$ THAT USUALLY AFFECTS PEOPLE BETWEEN THE NUCLEUS OF A CELL THAT CONTAINS $.! $.! AGES AND )T IS CALLED FAMILIAL !$ &!$ IF IT SEQUENCES MAKE UP GENES -OST HUMAN CELLS RUNS IN THE FAMILY HAVE PAIRS OF CHROMOSOMES CONTAINING %NTORHINAL CORTEXAN AREA DEEP WITHIN THE APPROXIMATELY GENES BRAIN WHERE DAMAGE FROM !$ OFTEN BEGINS #LINICAL TRIALA RESEARCH STUDY INVOLVING %NZYMEA PROTEIN THAT CAUSES OR SPEEDS UP A HUMANS THAT RIGOROUSLY TESTS SAFETY SIDE EFFECTS BIOCHEMICAL REACTION AND HOW WELL A MEDICATION OR BEHAVIORAL TREATMENT WORKS &REE RADICALA HIGHLY REACTIVE MOLECULE TYPICALLY OXYGEN OR NITROGEN THAT COMBINES #OGNITIVE FUNCTIONSALL ASPECTS OF CONSCIOUS EASILY WITH OTHER MOLECULES BECAUSE IT CONTAINS AN THOUGHT AND MENTAL ACTIVITY INCLUDING LEARNING UNPAIRED ELECTRON 4HE COMBINATION WITH OTHER PERCEIVING MAKING DECISIONS AND REMEMBERING MOLECULES SOMETIMES DAMAGES CELLS #OMPUTED TOMOGRAPHY #4 SCAN 'ENETHE BIOLOGIC UNIT OF HEREDITY PASSED FROM A DIAGNOSTIC PROCEDURE THAT USES SPECIAL X RAY PARENT TO CHILD 'ENES ARE SEGMENTS OF $.! AND EQUIPMENT AND COMPUTERS TO CREATE CROSS SECTIONAL CONTAIN INSTRUCTIONS THAT TELL A CELL HOW TO MAKE PICTURES OF THE BODY SPECIlC PROTEINS #ORPUS CALLOSUMTHICK BUNDLES OF NERVE CELL 'ENETIC RISK FACTORA VARIANT IN A CELLS lBERS THAT CONNECT THE TWO CEREBRAL HEMISPHERES $.! THAT DOES NOT CAUSE A DISEASE BY ITSELF BUT $EMENTIAA BROAD TERM REFERRING TO A DECLINE MAY INCREASE THE CHANCE THAT A PERSON WILL IN COGNITIVE FUNCTION TO THE EXTENT THAT IT INTERFERES DEVELOP A DISEASE WITH DAILY LIFE AND ACTIVITIES $ENDRITEA BRANCH LIKE EXTENSION OF A NEURON THAT RECEIVES MESSAGES FROM OTHER NEURONS
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 'LOSSARY
'LIAL CELLA SPECIALIZED CELL THAT SUPPORTS RELEASE ENERGY )N OTHERS THE CELLS USE ENERGY TO PROTECTS OR NOURISHES NERVE CELLS MAKE COMPLEX COMPOUNDS OUT OF SIMPLER ONES LIKE MAKING PROTEINS FROM AMINO ACIDS (IPPOCAMPUSA STRUCTURE IN THE BRAIN THAT PLAYS A MAJOR ROLE IN LEARNING AND MEMORY AND IS -ICROTUBULEAN INTERNAL SUPPORT STRUCTURE FOR INVOLVED IN CONVERTING SHORT TERM TO LONG TERM A NEURON THAT GUIDES NUTRIENTS AND MOLECULES FROM MEMORY THE BODY OF THE CELL TO THE END OF THE AXON (YPOTHALAMUSA STRUCTURE IN THE BRAIN -ILD COGNITIVE IMPAIRMENT -#) UNDER THE THALAMUS THAT MONITORS ACTIVITIES SUCH A CONDITION IN WHICH A PERSON HAS MEMORY AS BODY TEMPERATURE AND FOOD INTAKE PROBLEMS GREATER THAN THOSE EXPECTED FOR HIS OR HER AGE BUT NOT THE PERSONALITY OR COGNITIVE ,ATE ONSET !LZHEIMERS DISEASETHE PROBLEMS THAT CHARACTERIZE !$ MOST COMMON FORM OF !$ )T OCCURS IN PEOPLE AGED AND OLDER -UTATIONA PERMANENT CHANGE IN A CELLS $.! THAT CAN CAUSE A DISEASE ,IMBIC SYSTEMA BRAIN REGION THAT LINKS THE BRAIN STEM WITH THE HIGHER REASONING ELEMENTS -YELINA WHITISH FATTY LAYER SURROUNDING OF THE CEREBRAL CORTEX )T CONTROLS EMOTIONS AN AXON THAT HELPS THE AXON RAPIDLY TRANSMIT INSTINCTIVE BEHAVIOR AND THE SENSE OF SMELL ELECTRICAL MESSAGES FROM THE CELL BODY TO THE SYNAPSE -AGNETIC RESONANCE IMAGING -2) A DIAGNOSTIC AND RESEARCH TECHNIQUE THAT USES .ERVE GROWTH FACTOR .'& A SUBSTANCE MAGNETIC lELDS TO GENERATE A COMPUTER IMAGE OF THAT MAINTAINS THE HEALTH OF NERVE CELLS .'& ALSO INTERNAL STRUCTURES IN THE BODY -2)S ARE VERY CLEAR PROMOTES THE GROWTH OF AXONS AND DENDRITES THE AND ARE PARTICULARLY GOOD FOR IMAGING THE BRAIN PARTS OF THE NERVE CELL THAT ARE ESSENTIAL TO ITS ABILITY AND SOFT TISSUES TO COMMUNICATE WITH OTHER NERVE CELLS -ETABOLISMALL OF THE CHEMICAL PROCESSES .EURODEGENERATIVE DISEASEA DISEASE THAT TAKE PLACE INSIDE THE BODY )N SOME METABOLIC CHARACTERIZED BY A PROGRESSIVE DECLINE IN THE REACTIONS COMPLEX MOLECULES ARE BROKEN DOWN TO STRUCTURE ACTIVITY AND FUNCTION OF BRAIN TISSUE 4HESE DISEASES INCLUDE !$ 0ARKINSONS DISEASE FRONTOTEMPORAL LOBAR DEGENERATION AND DEMENTIA WITH ,EWY BODIES 4HEY ARE USUALLY MORE COMMON IN OLDER PEOPLE
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY .EUROlBRILLARY TANGLEA lLAMENTOUS 3YNAPSETHE TINY GAP BETWEEN NERVE CELLS COLLECTION OF TWISTED AND HYPERPHOSPHORYLATED TAU ACROSS WHICH NEUROTRANSMITTERS PASS FOUND IN THE CELL BODY OF A NEURON IN !$ 4AUA PROTEIN THAT HELPS TO MAINTAIN THE .EURONA NERVE CELL STRUCTURE OF MICROTUBULES IN NORMAL NERVE CELLS !BNORMAL TAU IS A PRINCIPAL COMPONENT OF THE .EUROTRANSMITTERA CHEMICAL MESSENGER PAIRED HELICAL lLAMENTS IN NEUROlBRILLARY TANGLES BETWEEN NEURONS 4HESE SUBSTANCES ARE RELEASED BY THE AXON ON ONE NEURON AND EXCITE OR INHIBIT 4HALAMUSA SMALL STRUCTURE IN THE FRONT OF THE ACTIVITY IN A NEIGHBORING NEURON CEREBRAL HEMISPHERES THAT SERVES AS A WAY STATION THAT RECEIVES SENSORY INFORMATION OF ALL KINDS AND .UCLEUSTHE STRUCTURE WITHIN A CELL THAT RELAYS IT TO THE CORTEX IT ALSO RECEIVES INFORMATION CONTAINS THE CHROMOSOMES AND CONTROLS MANY FROM THE CORTEX OF ITS ACTIVITIES 4RANSGENICAN ANIMAL THAT HAS HAD A GENE /XIDATIVE DAMAGEDAMAGE THAT CAN OCCUR LIKE HUMAN !00 INSERTED INTO ITS CHROMOSOMES TO CELLS WHEN THEY ARE EXPOSED TO TOO MANY FREE -ICE CARRYING THE MUTATED HUMAN !00 GENE OFTEN RADICALS DEVELOP PLAQUES IN THEIR BRAINS AS THEY AGE 0OSITRON EMISSION TOMOGRAPHY 0%4 6ENTRICLEA CAVITY WITHIN THE BRAIN THAT IS AN IMAGING TECHNIQUE USING RADIOISOTOPES THAT lLLED WITH CEREBROSPINAL mUID ALLOWS RESEARCHERS TO OBSERVE AND MEASURE ACTIVITY IN DIFFERENT PARTS OF THE BRAIN BY MONITORING BLOOD 6ESICLEA SMALL CONTAINER FOR TRANSPORTING mOW AND CONCENTRATIONS OF SUBSTANCES SUCH AS NEUROTRANSMITTERS AND OTHER MOLECULES FROM ONE OXYGEN AND GLUCOSE AS WELL AS OTHER SPECIlC PART OF THE NEURON TO ANOTHER CONSTITUENTS OF BRAIN TISSUES 3INGLE PHOTON EMISSION COMPUTED TOMOGRAPHY 30%#4 AN IMAGING TECHNIQUE THAT ALLOWS RESEARCHERS TO MONITOR BLOOD mOW TO DIFFERENT PARTS OF THE BRAIN
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY &OR-ORE )NFORMATION
).&/2-!4)/. !.$ REFERRALS TO LOCAL RESOURCES AND SERVICES AND SPON 3500/24 2%3/52#%3 SOR SUPPORT GROUPS AND EDUCATIONAL PROGRAMS /NLINE AND PRINT PUBLICATIONS ARE ALSO AVAILABLE !LZHEIMERS $ISEASE %DUCATION AND 2EFERRAL !$%!2 #ENTER 4HE !SSOCIATION ALSO FUNDS !$ RESEARCH 0/ "OX !LZHEIMERS &OUNDATION OF !MERICA 3ILVER 3PRING -$ %IGHTH !VENUE TH &LOOR TOLL FREE .EW 9ORK .9 WWWNIANIHGOV!LZHEIMERS TOLL FREE 4HIS SERVICE OF THE .ATIONAL )NSTITUTE ON !GING WWWALZFDNORG .)! OFFERS INFORMATION AND PUBLICATIONS ON 4HE !LZHEIMERS &OUNDATION OF !MERICA PROVIDES DIAGNOSIS TREATMENT PATIENT CARE CAREGIVER CARE AND SERVICES TO INDIVIDUALS CONFRONTING NEEDS LONG TERM CARE EDUCATION AND TRAINING DEMENTIA AND TO THEIR CAREGIVERS AND FAMILIES AND RESEARCH RELATED TO !LZHEIMERS DISEASE 3TAFF THROUGH MEMBER ORGANIZATIONS DEDICATED TO MEMBERS ANSWER TELEPHONE EMAIL AND WRITTEN IMPROVING QUALITY OF LIFE 3ERVICES INCLUDE A REQUESTS AND MAKE REFERRALS TO LOCAL AND NATIONAL TOLL FREE HOTLINE CONSUMER PUBLICATIONS AND RESOURCES 4HE !$%!2 WEBSITE OFFERS FREE ONLINE OTHER EDUCATIONAL MATERIALS AND CONFERENCES AND PUBLICATIONS IN %NGLISH AND 3PANISH EMAIL ALERTS WORKSHOPS AND ONLINE #ONNECTIONS NEWSLETTER REGISTRATION AN !$ CLINICAL TRIALS DATABASE THE !$ ,IBRARY $ANA !LLIANCE FOR "RAIN )NITIATIVES DATABASE AND MORE &IFTH !VENUE 3UITE .EW 9ORK .9 !LZHEIMERS !SSOCIATION .ORTH -ICHIGAN !VENUE 3UITE WWWDANAORGDANAALLIANCES #HICAGO ), TOLL FREE 4HE $ANA !LLIANCE FOR "RAIN )NITIATIVES A NON WWWALZORG PROlT ORGANIZATION OF MORE THAN LEADING NEUROSCIENTISTS HELPS ADVANCE PUBLIC AWARENESS 4HE !LZHEIMERS !SSOCIATION IS A NATIONAL ABOUT THE PROGRESS AND PROMISE OF BRAIN RESEARCH NON PROlT ORGANIZATION WITH A NETWORK OF AND DISSEMINATES INFORMATION ABOUT THE BRAIN LOCAL CHAPTERS THAT PROVIDE EDUCATION AND SUPPORT FOR PEOPLE DIAGNOSED WITH !$ THEIR FAMILIES AND CAREGIVERS #HAPTERS OFFER
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY #!2%')6).' 3500/24 !.$ 3%26)#%3 .ATIONAL &AMILY #AREGIVERS !SSOCIATION #HILDREN OF !GING 0ARENTS #ONNECTICUT !VENUE 3UITE 0/ "OX +ENSINGTON -$ 2ICHBORO 0! TOLL FREE TOLL FREE WWWCAPSCAREGIVERSORG WWWTHEFAMILYCAREGIVERORG 4HIS NONPROlT ORGANIZATION PROVIDES INFORMATION 4HE .ATIONAL &AMILY #AREGIVERS !SSOCIATION HELPS AND REFERRALS FOR NURSING HOMES RETIREMENT EDUCATE AND SUPPORT PEOPLE WHO CARE FOR LOVED COMMUNITIES ELDER LAW ATTORNEYS ADULT DAY CARE ONES WITH CHRONIC ILLNESS DISABILITY OR THE FRAILTIES CENTERS INSURANCE PROVIDERS RESPITE CARE ASSISTED OF OLD AGE 4HE !SSOCIATION OFFERS AN ONLINE LIBRARY LIVING CENTERS SUPPORT GROUPS AND 3TATE AND OF INFORMATION AND EDUCATIONAL MATERIALS WORK COUNTY AGENCIES )T ALSO OFFERS FACT SHEETS A NEWS SHOPS AND OTHER RESOURCES LETTER AND CONFERENCES AND WORKSHOPS .ATIONAL (OSPICE AND %LDERCARE ,OCATOR 0ALLIATIVE #ARE /RGANIZATION TOLL FREE $IAGONAL 2OAD 3UITE WWWELDERCAREGOV !LEXANDRIA 6! %LDERCARE ,OCATOR IS A NATIONWIDE DIRECTORY TOLL FREE ASSISTANCE SERVICE HELPING OLDER PEOPLE AND THEIR WWWNHPCOORG CAREGIVERS LOCATE LOCAL SUPPORT AND RESOURCES )T IS 4HIS NONPROlT ORGANIZATION WORKS TO ENHANCE THE FUNDED BY THE 53 !DMINISTRATION ON !GING WHOSE QUALITY OF LIFE FOR PEOPLE WHO ARE TERMINALLY ILL )T WEBSITE AT WWWAOAGOV ALSO FEATURES !$ INFORMATION PROVIDES INFORMATION RESOURCES AND REFERRALS TO FOR FAMILIES CAREGIVERS AND HEALTH PROFESSIONALS LOCAL HOSPICE SERVICES AND OFFERS PUBLICATIONS AND ONLINE RESOURCES &AMILY #AREGIVER !LLIANCE -ONTGOMERY 3TREET 3UITE 7ELL 3POUSE !SSOCIATION 3AN &RANCISCO #! 7EST -AIN 3TREET 3UITE ( TOLL FREE &REEHOLD .* WWWCAREGIVERORG TOLL FREE 4HE &AMILY #AREGIVER !LLIANCE IS A NONPROlT WWWWELLSPOUSEORG ORGANIZATION THAT OFFERS SUPPORT SERVICES AND 4HE NONPROlT 7ELL 3POUSE !SSOCIATION GIVES INFORMATION FOR PEOPLE CARING FOR ADULTS WITH SUPPORT TO SPOUSES AND PARTNERS OF PEOPLE WHO ARE !$ STROKE TRAUMATIC BRAIN INJURIES AND CHRONICALLY ILL ANDOR DISABLED )T OFFERS SUPPORT OTHER COGNITIVE DISORDERS GROUPS AND A NEWSLETTER
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY &OR-ORE )NFORMATION
2%3%!2#( !.$ #,).)#!, 42)!,3 2%#/--%.$%$ 2%!$).' !LZHEIMERS $ISEASE #OOPERATIVE 3TUDY 4HE !$%!2 #ENTER OFFERS FACT SHEETS EASY TO 5NIVERSITY OF #ALIFORNIA 3AN $IEGO READ MATERIALS BOOKLETS ABOUT TOPICS SUCH AS BEING 'ILMAN $RIVE DIAGNOSED WITH EARLY STAGE !$ CAREGIVING HOME ,A *OLLA #! SAFETY AND COMFORT AND CARE AT THE END OF LIFE AND MORE 3EE THE !$%!2 #ENTER LISTING UNDER WWWADCSORG h)NFORMATION AND 3UPPORT 2ESOURCESv ABOVE FOR CONTACT INFORMATION 4HE !LZHEIMERS $ISEASE #OOPERATIVE 3TUDY !$#3 IS A COOPERATIVE AGREEMENT BETWEEN .)! #ONSUMERS AND PROFESSIONALS INTERESTED IN !$ ALSO AND THE 5NIVERSITY OF #ALIFORNIA 3AN $IEGO TO MAY WISH TO REFER TO THE FOLLOWING MATERIALS ADVANCE RESEARCH IN THE DEVELOPMENT OF DRUGS TO TREAT !$ 4HE !$#3 IS A CONSORTIUM OF MEDICAL "ALLARD %, 0OER #- ,ESSONS ,EARNED RESEARCH CENTERS AND CLINICS WORKING TO DEVELOP 3HARED %XPERIENCES IN #OPING $URHAM .# CLINICAL TRIALS OF MEDICINES TO TREAT BEHAVIORAL 4HE $UKE &AMILY 3UPPORT 0ROGRAM SYMPTOMS OF !$ IMPROVE COGNITION SLOW THE RATE !VAILABLE FOR FROM THE !$%!2 #ENTER OF DECLINE CAUSED BY !$ DELAY THE ONSET OF !$ 0/ "OX 3ILVER 3PRING -$ OR PREVENT THE DISEASE ALTOGETHER 4HE !$#3 ALSO WWWNIANIHGOV!LZHEIMERS DEVELOPS NEW AND MORE RELIABLE WAYS TO EVALUATE 4HIS BOOK DOCUMENTS THE EXPERIENCES OF PEOPLE PATIENTS ENROLLED IN CLINICAL TRIALS CARING FOR LOVED ONES WITH !$ &ILLED WITH SHORT STORIES AND ADVICE IT IS INTENDED FOR CAREGIVERS !LZHEIMER 2ESEARCH &ORUM WHO WISH TO TAKE COMFORT AND LEARN FROM THE WWWALZFORUMORG EXPERIENCES OF OTHERS #AREGIVERS DISCUSS THE 4HE !LZHEIMER 2ESEARCH &ORUM AN ONLINE COM CAREGIVING PROCESS SUCH AS GETTING A DIAGNOSIS MUNITY AND RESOURCE CENTER OFFERS PROFESSIONALS AND lNDING SUPPORT SERVICES MAKING DECISIONS ABOUT THE GENERAL PUBLIC ACCESS TO AN ANNOTATED INDEX OF TREATMENT AND LIVING ARRANGEMENTS AND COPING SCIENTIlC PAPERS RESEARCH NEWS MODERATED DISCUS WITH STRESS AND CAREGIVER BURDEN SIONS ON SCIENTIlC TOPICS LIBRARIES OF ANIMAL MODELS AND ANTIBODIES AND DIRECTORIES OF CLINICAL TRIALS $ASH 0 6ILLEMARETTE 0ITTMAN . CONFERENCES JOBS AND RESEARCH FUNDING SOURCES !LZHEIMERS $ISEASE .EW 9ORK !MERICAN !CADEMY OF #LINICAL4RIALSGOV .EUROLOGY WWW#LINICAL4RIALSGOV 4HIS CONCISE VOLUME PROVIDES AN OVERVIEW OF #LINICAL4RIALSGOV IS A REGISTRY OF FEDERALLY AND RECENT lNDINGS REGARDING THE CAUSES DIAGNOSIS AND PRIVATELY SUPPORTED CLINICAL TRIALS CONDUCTED IN THE TREATMENT OF !$ )T IS DESIGNED TO HELP CAREGIVERS 5NITED 3TATES AND AROUND THE WORLD 5SERS CAN AND FAMILY MEMBERS GAIN A BETTER UNDERSTANDING SEARCH FOR CLINICAL TRIALS AND lND INFORMATION ABOUT EACH TRIALS PURPOSE WHO MAY PARTICIPATE LOCATIONS AND PHONE NUMBERS FOR MORE DETAILS
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY OF !$ AND THE AVAILABLE OPTIONS FOR COPING -ACE ., 2ABINS 06 4HE (OUR $AY WITH AND MANAGING THIS ILLNESS 3IXTEEN CHAPTERS ! &AMILY 'UIDE TO #ARING FOR 0EOPLE 7ITH ANSWER QUESTIONS ABOUT TOPICS SUCH AS THE !LZHEIMERS $ISEASE /THER $EMENTIAS AND DElNITION OF !$ AND DEMENTIA !$ VERSUS OTHER -EMORY ,OSS IN ,ATER ,IFE TH ED "ALTIMORE CAUSES OF DEMENTIA TREATMENTS FOR BEHAVIORAL *OHNS (OPKINS 5NIVERSITY 0RESS SYMPTOMS AND OTHER COMPLICATIONS OF !$ 4HIS BOOK OFFERS GUIDANCE AND COMFORT FOR FAMILIES AND PRACTICAL ISSUES FOR THE PATIENT AND FAMILY CARING FOR LOVED ONES WITH !$ OTHER DEMENTIAS )LLUSTRATIONS A GLOSSARY AND A LIST OF RESOURCES AND MEMORY LOSS IN LATER LIFE 4HE FOURTH EDITION ARE ALSO INCLUDED INCLUDES CHAPTERS ON TOPICS SUCH AS GETTING MEDICAL HELP FOR THE PERSON WITH DEMENTIA $ORAISWAMY 0- 'WYTHER , WITH !DLER BEHAVIORAL SYMPTOMS OF DEMENTIA NURSING HOMES 4 4HE !LZHEIMERS !CTION 0LAN 4HE %XPERTS AND OTHER LIVING ARRANGEMENTS AND RESEARCH IN 'UIDE TO THE "EST $IAGNOSIS AND 4REATMENT FOR DEMENTIA .EW INFORMATION DISCUSSES DIAGNOSTIC -EMORY 0ROBLEMS .EW 9ORK 3T -ARTINS 0RESS EVALUATION CAREGIVER RESOURCES LEGAL AND lNANCIAL INFORMATION NURSING HOMES AND OTHER COMMUNAL LIVING ARRANGEMENTS AND THE LATEST 4HIS BOOK BY A PHYSICIAN AND SOCIAL WORKER AT UPDATES ON RESEARCH MEDICATIONS AND THE $UKE 5NIVERSITY OFFERS INFORMATION ABOUT HOW TO BIOLOGICAL CAUSES AND EFFECTS OF DEMENTIA GET AN EARLY AND ACCURATE !$ DIAGNOSIS AND WHY !VAILABLE IN A LARGE PRINT VERSION IT MATTERS LIFE AFTER THE DIAGNOSIS STATE OF THE ART TREATMENTS COPING WITH BEHAVIORAL AND EMOTIONAL CHANGES THROUGH THE EARLY AND MIDDLE STAGES OF -ESSER - 0RESSURE 0OINTS !LZHEIMERS AND !$ ACCESSING THE LATEST CLINICAL TRIALS AND !NGER $URHAM .# $UKE &AMILY 3UPPORT UNDERSTANDING THE FUTURE OF !$ 0ROGRAM !VAILABLE FOR FROM THE !$%!2 #ENTER 0/ "OX 3ILVER 3PRING -$ WWWNIANIH +UHN $ "ENNETT $! !LZHEIMERS %ARLY GOV!LZHEIMERS 3TAGES &IRST 3TEPS FOR &AMILY &RIENDS AND #AREGIVERS ND ED !LAMEDA #! (UNTER (OUSE )N SIMPLE EASY TO READ LANGUAGE THIS BOOK 0UBLISHERS ADDRESSES ISSUES SUCH AS SETTING BOUNDARIES MANAGING ANGER POSITIVELY AND RISK FACTORS FOR 7ITH INCREASED AWARENESS OF THE SYMPTOMS OF !$ ANGER IN !$ CARE )T OFFERS TANGIBLE ACTION STEPS FOR AND IMPROVED DIAGNOSTIC TECHNIQUES MORE PEOPLE RESPONDING APPROPRIATELY RATHER THAN ABUSIVELY ARE LEARNING THAT THEY OR A FAMILY MEMBER HAVE A MEMORY DISORDER 4HIS BOOK WRITTEN BY EXPERTS AT 2USH 5NIVERSITY !LZHEIMERS $ISEASE #ENTER IN #HICAGO HELPS READERS UNDERSTAND AND lND WAYS TO COPE WITH THE EARLY STAGES OF THE DISEASE )T ALSO INCLUDES AN EXTENSIVE RESOURCE LIST OF WEBSITES ORGANIZATIONS AND REFERENCES TO CONSUMER AND PROFESSIONAL LITERATURE
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY &OR-ORE )NFORMATION
WHEN FEELING ANGRY 0ARTICIPANTS IN !LZHEIMERS 0ETERSEN 2 ED -AYO #LINIC 'UIDE TO SUPPORT GROUPS SHARE HELPFUL TECHNIQUES AND !LZHEIMERS $ISEASE 4HE %SSENTIAL 2ESOURCE FOR COPING MECHANISMS AS WELL AS ENLIGHTENING 4REATMENT #OPING AND #AREGIVING 2OCHESTER ANECDOTES ABOUT CARING FOR A LOVED ONE WITH !$ -. -AYO #LINIC (EALTH 3OLUTIONS #AREGIVERS FAMILY MEMBERS OF !$ PATIENTS 4HIS GUIDE IS DESIGNED TO HELP NONPROFESSIONALS CLERGY AND HEALTH PROFESSIONALS ALL MAY BENElT UNDERSTAND DEMENTIA AND ITS EFFECTS ON THE MIND FROM THIS PUBLICATION 4WO COMPANION THE DIFFERENCES BETWEEN DEMENTIA AND CHANGES BOOKLETS ARE ALSO AVAILABLE FROM THE !$%!2 ASSOCIATED WITH NORMAL AGING AND HOW TO IMPROVE #ENTER h(IT 0AUSEv (ELPING $EMENTIA &AMILIES MEMORY AND MAINTAIN GOOD MENTAL FUNCTION )T $EAL WITH !NGER FOR HEALTH PROFESSIONALS INCLUDES INFORMATION ABOUT CHANGES THAT OCCUR IN AND 7AIT A -INUTE 7HEN !NGER 'ETS 4OO -UCH NORMAL AGING THE PROCESS OF DIAGNOSING DEMENTIA FOR FAMILIES AND CAREGIVERS NON !$ FORMS OF DEMENTIA HOW !$ DEVELOPS AND !$ STAGES DIAGNOSIS AND TREATMENT .EW 0ERRY ' ED !LZHEIMERS $ISEASE ! #ENTURY INFORMATION ABOUT MILD COGNITIVE IMPAIRMENT OF 3CIENTIlC AND #LINICAL 2ESEARCH *OURNAL OF WAYS TO STAY MENTALLY SHARP AND RESEARCH TRENDS !LZHEIMERS $ISEASE BOOK EDITION &AIRFAX 6! )/3 ALONG WITH AN ACTION GUIDE FOR CAREGIVERS ARE 0RESS )NC ALSO INCLUDED 4HIS VOLUME BRINGS TOGETHER THE IMPORTANT DISCOVERIES IN THE !$ lELD SINCE THE DISEASES ORIGINAL DESCRIPTION BY $R !LOIS !LZHEIMER A CENTURY AGO )T TRACES HOW THE IMPORTANCE OF !$ AS THE MAJOR CAUSE OF LATE LIFE DEMENTIA CAME TO LIGHT AND NARRATES THE EVOLUTION OF THE CONCEPTS RELATED TO !$ THROUGHOUT THE YEARS &IFTY PAPERS ARE ORGANIZED INTO SECTIONS ON HISTORICAL PERSPECTIVE NEUROPATHOLOGY SYNAPTIC CHANGES AMYLOID TAU DISEASE MECHANISMS GENETICS AND DIAGNOSIS AND TREATMENT
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY 2ESTAK 2 4HE 3ECRET ,IFE OF THE "RAIN 4ANZI 2% 3ISODIA 33 !LZHEIMERS $ISEASE 7ASHINGTON $# *OSEPH (ENRY 0RESS !DVANCES IN 'ENETICS -OLECULAR AND #ELLULAR "IOLOGY .EW 9ORK 3PRINGER 0UBLISHING #OMPANY 4HIS COMPANION TO THE 0"3 DOCUMENTARY TAKES THE READER ON A FASCINATING JOURNEY THROUGH THE DEVELOPING BRAIN FROM INFANCY AND CHILDHOOD 4HIS BOOK EXAMINES EVERY MAJOR ASPECT OF !$ THROUGH ADULTHOOD AND OLD AGE 4HE AUTHOR EX CLINICAL EPIDEMIOLOGIC STRUCTURAL CHEMICAL AMINES BRAIN DISORDERS AND MECHANISMS OF BRAIN GENETIC MOLECULAR AND THERAPEUTIC 4HIS EDITION REPAIR AND HEALING INCLUDES EXPANDED COVERAGE OF RELATED DEMENTING DISORDERS INCLUDING PRION DISEASES 0ICKS DISEASE FRONTOTEMPORAL DISORDERS AN IN DEPTH DISCUSSION 3HENK $ 4HE &ORGETTING !LZHEIMERS 0ORTRAIT OF TRANSGENIC MODELS AND THE BIOCHEMISTRY OF AN %PIDEMIC .EW 9ORK 2ANDOM (OUSE )NC OF PRESENILINS )T ALSO DISCUSSES TREATMENT OF SYMPTOMS WITH THERAPEUTIC DRUGS AND !$ CLINI !N ELOQUENT AND MOVING DESCRIPTION OF !$ 4HE CAL TRIALS 4HE BROAD COVERAGE OF !$ IN THIS BOOK &ORGETTING IS AN EXPLORATION OF AND MEDITATION ON WILL BE OF SPECIAL INTEREST TO CLINICIANS EDUCATORS THE NATURE OF MEMORY AND PERCEPTIONS OF SELF )T INVESTIGATORS AND HEALTH ADMINISTRATORS IS A READABLE ACCESSIBLE DESCRIPTION OF THE HISTORY OF !$ RESEARCH AND THE HUMAN IMPACT OF THE 5ETZ $ ,INDSAY ! )NTO THE -IST DISEASE #ALLING !$ A hDEATH BY A THOUSAND 7HEN 3OMEONE 9OU ,OVE (AS !LZHEIMERS SUBTRACTIONS v THE AUTHOR DESCRIBES THE SCIENCE 0HILADELPHIA 8LIBRIS #ORPORATION OF !$ IN CLEAR AND EASY TO UNDERSTAND TERMS 4HIS BOOK COMBINES INFORMATION FROM RESEARCHERS EXPERTS AND FAMILIES IN A 3NOWDON $ !GING 7ITH 'RACE 7HAT THE COMPREHENSIVE GUIDE FOR !$ CAREGIVERS )T .UN 3TUDY 4EACHES 5S !BOUT ,EADING ,ONGER OFFERS PERSONAL ACCOUNTS OF THREE FAMILIES CARING (EALTHIER AND -ORE -EANINGFUL ,IVES .EW FOR A LOVED ONE FROM THE EARLIEST STAGES TO THE 9ORK 2ANDOM (OUSE )NC LAST STAGES ILLUSTRATING THE COMMONALITIES AND 4HIS BOOK DESCRIBES THE PARTICIPANTS AND lNDINGS DIFFERENCES AMONG !$ PATIENTS AND THE WAYS THEIR FROM THE .UN 3TUDY A LONG TERM PROJECT EXAMIN FAMILIES HANDLE THE MOST DIFlCULT CHALLENGES )T ING AGING AND !$ IN A UNIQUE POPULATION OF ALSO PROVIDES INFORMATION TO HELP FAMILIES COPE #ATHOLIC SISTERS 4HE NUNS GAVE $R 3NOWDON WITH THE PSYCHOLOGICAL ASPECTS OF !$ BEHAVIOR ACCESS TO THEIR MEDICAL AND PERSONAL RECORDS AND PROBLEMS AND COMMUNICATION DIFlCULTIES 4HE AGREED TO DONATE THEIR BRAINS UPON DEATH 4HE BOOK COVERS SUCH TOPICS AS THE STAGES OF !$ BOOK DISCUSSES THE RELATIONSHIP OF EARLY LINGUISTIC -EDICARE -EDICAID LONG TERM CARE INSURANCE ABILITY TO RISK OF !$ THE ASSOCIATION OF STROKE AND GERIATRIC CARE MANAGEMENT THE DIAGNOSIS OF !$ DEPRESSION WITH !$ AND THE ROLE OF HEREDITY AND CAUSES AND PREVENTION AND DRUG TREATMENTS LIFESTYLE IN HEALTHY AGING
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY #REDITS 7RITER 0HOTOGRAPHY !NNE "ROWN 2ODGERS &RONT #OVER n $OUG 3ANFORD 0HOTOGROUP )NSIDE FRONT COVER PAGE n "LEND )MAGES -EDICAL )LLUSTRATOR 0AGE n "LEND 3TOCK 3TACY *ANNIS *ANNIS 0RODUCTIONS 0AGES n 0HOTODISC 0AGE n $YNAMIC 'RAPHICS SCANS ON COMPUTER $ -ODELING SCREEN COURTESY OF 7ILLIAM *AGUST -$ 5NIVERSITY OF "ILL $EMPSEY #ALIFORNIA "ERKELEY 2EBEKAH &REDENBURG 0AGE n &ANCY 0HOTOGRAPHY 'RAPHIC $ESIGN 0AGE n #OMSTOCK &ATIMA !MEEN AND *EFFREY $EVER 0AGE n 5NIVERSITY OF 0ITTSBURGH $EVER $ESIGNS 0AGE n #OGNITIVE .EUROLOGY AND !LZHEIMERS $ISEASE #ENTER .ORTHWESTERN 5NIVERSITY 0ROJECT #OORDINATOR 0AGE BACK COVER n 4HINKSTOCK 3USAN 2 &ARRER *"3 )NTERNATIONAL )NC 0AGES n #ORBIS 0AGE n "ERISLAV :LOKOVIC -$ 0H$ 5NIVERSITY OF 3PECIAL 4HANKS 2OCHESTER AND 3TACY *ANNIS *ANNIS 0RODUCTIONS .)! APPRECIATES THE EXTRAORDINARY CONTRIBUTIONS 0AGE n 0IXLAND 3TOCK OF THE FOLLOWING PEOPLE TO THE VISION AND CREATION OF THIS BOOK 0AGE INSIDE BACK COVER n "RAND 8 0ICTURES -ARCELLE -ORRISON "OGORAD 0H$ AND THE STAFF 0AGE n *EFF -ILLER 5NIVERSITY OF 7ISCONSIN -ADISON OF THE .)! $IVISION OF .EUROSCIENCE 0AGE n /REGON #ENTER FOR !GING AND 4ECHNOLOGY 0ATRICIA $ ,YNCH FORMER SENIOR PUBLIC AFFAIRS /REGON (EALTH 3CIENCE 5NIVERSITY SPECIALIST .)! /FlCE OF #OMMUNICATIONS AND 0AGE n 0LAINPICTURE 0HOTOGRAPHY 0UBLIC ,IAISON 0AGE n $IGITAL 6ISION $AVID - "URTON *"3 )NTERNATIONAL )NC 0AGE n !LLOY 0HOTOGRAPHY 0AGE n -ARTY +ATZ 0AGE n #AREGIVER 4ECHNOLOGIES )NC 0AGE n &LIRT 0HOTOGRAPHY 0AGE n 3TOCKBYTE
!,:(%)-%23 $)3%!3% 5NRAVELING THE -YSTERY Introduction lzheimer’s disease (AD) is an age-related brain An Urgent National Health Priority disorder that develops over many years. Its The search for more effective ways to treat or prevent symptoms typically first appear after age 60. A AD is increasingly urgent. Today, it is estimated that 2.4 The course of AD varies from person to person, but in million to 5.1 million people in the United States have most people, the first symptom is memory loss. Memory AD. While estimates vary, depending on how AD is decline becomes more serious as the disease progresses, measured, scientists agree that without scientific break- and people often begin having problems with other cog- throughs in prevention or early treatment of the disease, nitive functions, such as decision making (including the number of people with AD will increase significantly financial) and language skills. People with Alzheimer’s as society ages. may also experience behavior and personality changes. Studies suggest that the number of people with the Eventually, the loss of mental function becomes so disease doubles for every 5-year age interval beyond age severe that it impairs daily living and the ability to rec- 65. The U.S. Census Bureau estimates that the 65-and- ognize family and friends. These losses are related to the older population will double to about 72 million during breakdown of the connections between different classes the next 20 years, starting with the oldest “baby boom- of neurons (nerve cells) in the brain and the associated ers” who turn 65 in 2011. The ranks of the very elderly, death of many of these cells. those 85 years old and older and at the highest risk of Although AD was first described by Dr. Alois AD, will increase as well, potentially tripling their num- Alzheimer more than 100 years ago, scientific study of bers by 2050. the disease began in earnest only in the early 1970s. The costs of AD are at the same time deeply personal Since then, a broad and increasingly productive research and broadly societal. Families, friends, and caregivers program led by the National Institute on Aging (NIA) experience emotional, physical, and financial stress as at the National Institutes of Health (NIH) has revealed they watch a loved one become more and more forgetful, much about the basic biology of the disease and the frustrated, confused, and lost. As the disease runs its factors that influence its development and progression. course and the person with AD loses the ability to live or This program applies the expertise of many scientific function independently, family members and other care- disciplines in an attempt to answer complex questions: givers face difficult decisions about long-term care. What causes AD? How can it be diagnosed early and Frequently, they turn to assisted living facilities, then accurately? How can it be treated? How might it ulti- nursing homes, for care and support. The number of mately be prevented? A current focus of research seeks to caregivers—and their need for practical and psychological accelerate the pace of “translational research”—the support—is expected to escalate rapidly as the population transfer of knowledge gained in the laboratory to the ages and the number of people with AD grows. clinical arena.
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 6 Executive Summary
he U.S. investment in Alzheimer’s disease (AD) Earlier AD Diagnosis research through the National Institutes of Researchers from the Alzheimer’s Disease Neuroimaging THealth (NIH) has resulted in accelerating prog- Initiative (ADNI) showed that changes in the levels of ress on several research fronts and has laid the ground- certain proteins in cerebrospinal fluid (CSF) may correlate work for future discovery. This report highlights key AD with the risk and progression of AD. These biomarkers research findings and activities in 2009, conducted or may be used in the future to identify individuals at risk of supported by public funding for the National Institute developing AD. In addition, measuring amyloid in the on Aging (NIA) at NIH and other NIH Institutes and brain may prove promising as a diagnostic tool. A prelim- Centers. NIA leads the Federal Government’s research inary study showed that the presence of high levels of effort to understand and combat this devastating disease brain amyloid in cognitively normal people is linked with and is mandated by Congress to prepare this report. greater risk of later cognitive decline. (For details, see the sections Biomarkers and ADNI, page 33, and Brain 2009 Highlights Amyloid an Early Warning Sign of Possible Cognitive Decline in “Normal” Individuals, page 19.) New AD Genes International teams studying AD genetics have identi- Vascular Disease Linked to AD fied three new genes that are associated with increased AD is typically a disease of old age, which means that risk of late-onset AD. Two of these genes contain many people with AD also suffer from other age-related instructions for the synthesis of proteins that may be diseases and conditions, such as high blood pressure, cere- involved in clearing beta-amyloid from the brain and brovascular disease, or diabetes. Researchers are learning preventing its interference with communication among that these “co-morbid” conditions may increase the risk of brain cells, which is thought to be a major factor in the AD and speed its clinical progression. For example, there development of AD. These genetic discoveries come at is now a growing body of evidence that the cellular a time when researchers are increasingly interested in abnormalities associated with vascular disease feed into harnessing the brain’s own beta-amyloid clearance mech- and exacerbate those associated with AD. Researchers are anisms as a therapeutic strategy. (See the sections New exploring in clinical trials whether the therapeutic inter- human AD genes identified, page 23, and Clearing out ventions known to reduce risk of heart disease and diabe- beta-amyloid, page 37.) tes may also reduce risk of AD. Reports published in
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 7 | Executive Summary
This Progress Report highlights key 2009 Alzheimer’s disease research findings and activities supported by public funding.
2009 suggest that the Mediterranean diet, exercise, and progression. For example, treatment with the drug controlling high blood pressure may be associated with donepezil reduced the risk of progression to AD reduced risk of AD. (See the sections Links with Other among MCI patients with depressive symptoms. Diseases, page 14; Interactions Between AD and Vascular (See the sections Other Early Signs and Symptoms, page Disease, page 28; and AD Clinical Trials, page 38.) 32, and Slowing progression to AD in people with MCI and depression, page 39.) Cognitive Exercise and Successful Cognitive Aging Sleep and AD The popularly held belief that brain exercise can AD may also be linked to sleep problems. Many people improve cognitive function in older people is now being with AD suffer from sleep disturbances, which can con- tested. In two different clinical trials, significant cogni- tribute to cognitive impairment through a variety of tive performance gains were seen in people over 65 who mechanisms. Researchers are starting to study the possi- received training interventions aimed at improving bility that therapeutic interventions to improve sleep either attention or speed and accuracy of verbal informa- quality may help alleviate some symptoms of AD. (See tion processing. (See Clinical Trials to Maintain or the sections Amyloid and Sleep, page 17, and Treatment Improve Cognitive Function with Age, page 46.) However, of sleep apnea may slow cognitive decline, page 39.) as in previous trials, there was no evidence that training in one dimension improved function in another, so AD Caregiving questions remain about the overall usefulness of this Two clinical trials, REACH I and REACH II, were pre- type of training in real-world settings. viously funded to develop and test strategies for helping caregivers manage the stress and emotional burden of AD Is Not Just a Memory Disorder caring for people with dementia. The REACH OUT Our view of AD is undergoing a transformation. In the Program is beginning to implement these strategies past, AD was seen primarily as a memory disorder, and through local social service agencies. The first such study intervention focused on memory symptoms. However, showed a significant improvement in caregivers’ sense of mood and behavioral problems, such as depression, anx- burden, social support, depression, and health, as well as iety, and displays of socially inappropriate behavior, are in care recipients’ behavior problems and mood. (See increasingly recognized as co-occurring conditions with Supporting AD Caregivers, page 51.) AD. Mood and behavioral disturbances also appear to be associated with more rapid progression from mild cognitive impairment (MCI) to dementia, and early treatment of these symptoms may help slow that
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 8 | Executive Summary
Recovery Act Funds Advance volume, metabolic measures, and dementia status in Research on AD and Age-Related aging and in people with AD. Cognitive Decline Genetic and Other Risk Factors In 2009, the American Recovery and The ability to identify people at risk for AD is increas- Reinvestment Act (ARRA) provided a ingly important as preventive measures are developed novel opportunity to spark additional and as we learn more about how those at risk may Alzheimer’s disease research. NIA tar- reduce their odds of developing the disease. ARRA- geted promising areas of research in supported investigators are: awarding more than 100 Alzheimer’s or Alzheimer’s-related ARRA research grants, Using genome-wide association studies to compare totaling $77 million. Projects conducted the entire genomes of individuals with and without the within a short timeframe (2009-2010) included both new disease to identify potential genetic risk factors for cog- and ongoing studies to understand the biological mecha- nitive decline and AD. nisms of the disease, identify additional risk-factor genes Investigating whether changes to the brain “histone associated with Alzheimer’s, improve diagnostic tools, find code,” which helps determine the activity of specific biomarkers, develop therapies, conduct clinical trials, and genes, can mediate the effect of life experiences on the explore preventive measures. ARRA funding also provided development of age-related cognitive decline and AD. an opportunity to support research on age-related cognitive decline, a condition even more prevalent than AD in the Exploring the association of AD with vascular risk older population. factors (e.g., high blood pressure), markers of inflamma- tion, and pathology pathways in diverse populations. Basic Research Basic research to better understand the development and Biomarkers for Detection and Diagnosis progression of AD will lay the foundation for new pre- Research suggests that the earliest AD damage begins to vention and treatment interventions. ARRA-supported develop in the brain long before clinical symptoms researchers are: appear. Finding ways to diagnose AD as early as possible is critical so that researchers can test interventions and, Investigating how AD and vascular disease may influ- ultimately, treat the disease as early as possible. ARRA- ence and exacerbate one another. Findings may suggest supported investigators are: strategies for preventing dementia. Building on the highly successful ADNI to determine Investigating how amyloid, a protein implicated in the clinical, cognitive, imaging, genetic, and biochemical AD brain changes, contributes to the formation of clots biomarker characteristics of MCI, often a precursor to AD. in the brain and blood vessels. Identifying best practices for collecting samples of CSF Examining how energy metabolism influences brain and its analysis for proteins that may be associated with aging by looking for correlations among the loss of brain AD onset and progression, with the goal of identifying biomarkers that appear before cognitive symptoms do.
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 9 | Executive Summary
The American Recovery and Reinvestment Act (ARRA) provided a novel opportunity to spark additional Alzheimer’s disease research.
Comparing the effectiveness of brain imaging and Trial (ADAPT) to assess the long-term effects of blood biomarkers to diagnose AD. naproxen and celecoxib on cognitive health.
Possible Prevention and Understanding Normal Aging and Treatment Strategies Preventing Loss of Cognitive Function ARRA-supported investigators are studying a range of A growing body of evidence suggests that various inter- potential strategies to prevent MCI or AD. This research ventions may exert a protective effect on the brain in includes: older age, but little is known about the underlying mechanisms and more intervention testing is needed. Evaluating the drug levetiracetam in a clinical trial as ARRA-supported researchers are working to: a treatment for MCI, potentially preventing progression to AD by reducing the hyperactivity of neurons in the Understand the role that neurotrophic factors (pro- hippocampus, a part of the brain important to learning teins that promote the development of new neurons and and memory. the repair of damaged ones) play in healthy and abnormal brain aging. Animal and human studies have Evaluating the effects of exercise in combination with shown that circulating levels of neurotrophic factors two dietary supplements—the omega-3 fatty acid DHA increase with exercise and also with a calorie-restricted and curcumin—on AD biomarkers and cognition in an diet or one rich in fruits and vegetables. animal model. Elucidate the neural mechanisms that contribute to Testing whether blocking a key inflammation robust age-related decline in prospective memory—the pathway alleviates the consequences of high cholesterol act of remembering to carry out an intention such as on the brain in mouse models of AD. High cholesterol sending a grandchild a birthday card, paying bills on is believed to increase AD risk by triggering inflamma- time, or taking needed medication. tion pathways that ultimately damage brain cells. Develop automated technologies to map functional Studying how the outer shell, or capsid, of certain activity of brain networks, which will help expand our viruses might be used to carry protective or therapeutic understanding of the neural basis of episodic and molecules into the brains of AD patients. This early semantic memory and how this function changes with work is being carried out in a mouse model of AD and, normal aging. if successful, might be used in other neurodegenerative diseases as well. Test a home-technology based cognitive health coaching approach to improve function and quality of Studying the drug methylphenidate as a treatment for life for older adults. apathy, one of the most common behavioral symptoms of AD and one for which there is currently no effective treatment. Closely following participants who were enrolled in the Alzheimer’s Disease Anti-inflammatory Prevention
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 10 A Brief Primer on Alzheimer’s Disease and theBrain
he healthy human brain is made up The function and survival of neurons How Does AD Affect Tof tens of billions of neurons that depends on several interdependent the Brain? are connected through chemical and processes: In healthy aging, most types of brain neu- electrical signals. The function of these Communication. When a neuron rons are not lost in large numbers. In AD, neurons is supported and regulated by receives enough messages from sur- however, where damage is widespread, other brain cells, called glial cells, and by rounding cells, an electrical charge is many neurons stop functioning, lose con- the brain’s rich supply of blood vessels. A generated that travels from the cell body nections with other neurons, and die typical neuron has a cell body, an axon, to the end of the axon. There, it triggers because communication, metabolism, and and many dendrites. The cell body con- the release of chemicals called neuro- repair are disrupted. tains the cell’s nucleus. As in other cell transmitters that move across a gap, or At first, AD typically destroys neurons types, the nucleus contains the neuron’s synapse, to the dendrites of neighboring and their connections in parts of the brain genetic blueprint and helps regulate neurons. The neurotransmitters bind to that control memory, including the ento- changes in the neuron’s activity, metabo- specific receptor sites on the dendrites of rhinal cortex and the hippocampus. It lism, and structure in response to signals neighboring neurons, triggering chemical later attacks areas in the cerebral cortex from outside and inside the cell. The axon or electrical changes in those neurons. In responsible for language and reasoning. is a cable-like structure that extends from some cases, neurotransmitter binding Eventually, many other areas of the brain one end of the neuron’s cell body and stimulates a neuron. In others, it inhibits are damaged, and a person with AD transmits messages to other neurons. the neuron’s activity. Scientists estimate becomes helpless and unresponsive to Dendrites are branch-like structures that that at any one time the average neuron the outside world. radiate from the other side of the neu- makes 7,000 synaptic connections to ron’s cell body and receive messages other neurons. What Are the Main from the axons of other neurons. Metabolism. This process encom- Characteristics of the passes all the chemical reactions that AD Brain? View a short video take place in the cell. These reactions Many changes take place in the brain of showing the progression require chemical energy in the form of a person with AD. Some of these changes of Alzheimer’s disease oxygen and glucose, which is supplied by can be observed under the microscope in the brain. the brain’s blood circulation. The brain after death. The three abnormalities most has an exceptionally high energy demand evident in the brains of people who have and so has one of the richest blood sup- died with AD are: plies of any organ. Amyloid plaques. Found in the Repair. Unlike many short-lived cells spaces between neurons, plaques consist in the body, neurons have evolved to live a of largely insoluble deposits of a protein long time—more than 100 years in fragment called beta-amyloid, which is humans—so they must constantly main- generated from a protein called amyloid tain and repair themselves. Neurons also precursor protein (APP). Plaques also continuously remodel themselves—for contain other proteins, remnants of example, by breaking down synaptic con- degenerating neurons and glia, and other nections with one neighboring neuron and cellular material. Scientists used to think forming new ones with a different neighbor. that amyloid plaques were the primary
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 11 | A Brief Primer on Alzheimer’s Disease and the Brain
cause of the damage to neurons seen in AD. Now, however, many think that more soluble forms of beta-amyloid, seen ear- lier in the plaque formation process, may be the major culprits. Neurofibrillary tangles. Found inside neurons, neurofibrillary tangles are abnormal aggregates of a protein called tau. Healthy neurons are internally supported in part by structures called microtubules, which help guide nutrients and molecules from the cell body to the Healthy neuron Dying neuron end of the axon. Normally, tau binds to microtubules and helps stabilize them. In AD, tau undergoes abnormal chemical What Causes AD? How Is AD Diagnosed? changes that cause it to disengage from In some rare cases, people develop AD in Clinicians use a range of tools to diag- microtubules and come together with their 40s or 50s. This form of the disease, nose “possible AD” (dementia that could other threads of tau, eventually forming called “early-onset” AD, often runs in fam- be due to another condition) or “probable neurofibrillary tangles. The microtubules ilies and is caused by a mutation in one of AD” (no other cause of dementia can be disintegrate, and the neuron’s transport three genes that a person has inherited found). Some people with memory prob- system collapses. As with beta-amyloid, from a parent. The causes of other early- lems have a condition called amnestic some scientists think that early soluble onset cases are not yet understood. mild cognitive impairment (MCI) that often forms of abnormal tau may cause the More than 90 percent of AD cases precedes AD. People with MCI have more most damage to neurons. occur in people older than 60. The devel- memory problems than normal for people Loss of neuronal connections and opment and pathology of this “late-onset” their age, but their symptoms are not as cell death. In AD, the synaptic connec- form of the disease are very similar to severe as those seen in AD. Importantly, tions between certain groups of neurons those of early-onset AD. The causes of not all people with MCI develop AD. stop functioning and begin to degenerate. late-onset AD are not yet completely Tools for diagnosing AD include a med- This feature of AD likely results from the understood, but they probably include a ical history, a physical exam and tests— accumulation of beta-amyloid and combination of genetic, environmental, preferably over time—that measure abnormal tau. When neurons lose their and lifestyle factors. The importance of memory, language skills, and other abilities connections, they cannot function properly any one of these factors in increasing or related to brain functioning. The physician and eventually die. As neuronal injury and decreasing the risk of developing AD may may also perform a brain scan. Information death spreads through the brain, connec- differ from person to person. provided by family members or other care- tions between neurons break down, and Much basic research in AD has givers about changes in a person’s day-to- affected regions begin to shrink in a pro- focused on the genes that cause early- day function and behavior also help in cess called brain atrophy. By the final onset AD, and how mutations in these diagnosis. At this time, AD can be diag- stage of AD, damage is widespread, and genes disrupt cellular function and lead to nosed conclusively only by an autopsy of brain tissue has shrunk significantly. disease. Scientists hope that what they the brain after death. However, in special- learn about early-onset AD can be applied ized research facilities such as the NIA- to the late-onset form of the disease. funded Alzheimer’s Disease Centers, Perhaps the greatest mystery is why clinicians can diagnose AD in a living AD largely strikes people of advanced person with up to 90 percent accuracy. age. Why does it take 60 to 80 years or Early, accurate diagnosis is crucial more for people to develop signs of the because it tells people whether they have disease? Research on how the brain Alzheimer’s or whether their symptoms are changes normally as people age will answer this important question, as will studying the disease itself.
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 12 | A Brief Primer on Alzheimer’s Disease and the Brain caused by something else. Stroke, tumor, Donepezil (Aricept®), rivastigmine moderate to severe AD symptoms. Parkinson’s disease, sleep disturbances, or (Exelon®), and galantamine (Razadyne®, This drug appears to work by blocking side effects of medications are all known formerly known as Reminyl® and now receptors for glutamate, another to affect cognitive function and memory, available as a generic drug) are prescribed neurotransmitter involved in memory and some of these conditions are revers- to treat mild to moderate AD symptoms. function. Studies in animals suggest that ible. When AD is diagnosed, knowing early Donepezil also is approved to treat severe memantine may have disease-modifying on can help families plan for the future AD. These drugs act by stopping or slow- effects, although this has not yet been while the person with AD can still partici- ing the action of acetylcholinesterase, an demonstrated in humans. pate in making decisions. Researchers are enzyme that breaks down acetylcholine (a In addition to these medications, phy- developing increasingly accurate diagnos- neurotransmitter that helps in memory sicians may use other drugs and nondrug tic tests for telltale biomarkers that may formation). The drugs maintain some approaches to treat behavioral and psy- one day be used in general medical prac- patients’ abilities to carry out everyday chiatric problems associated with AD. tice to detect the disease before memory activities and may slow down symptoms These problems include agitation, verbal loss or cognitive impairment is evident. related to thinking, memory, or speaking and physical aggression, wandering, skills. They also may help with certain depression, sleep disturbances, and delu- How Is AD Treated? behavioral symptoms. However, they do sions. (It is important to note, however, Only a few medications have been not stop or reverse AD and appear to help that since no drugs are specifically approved by the U.S. Food and Drug patients only for months to a few years. approved by the FDA to treat behavioral Administration (FDA) to help control the Another type of medication, meman- or psychiatric symptoms in dementia, this cognitive loss that characterizes AD. tine (Namenda®), is prescribed to treat practice constitutes “off-label” usage.)
NIA’s ADEAR Center Offers Free AD Information and Resources
fforts to educate and inform people with AD, their families, the public, providers, and others interested in the disease complement NIH’s research initiatives. E The NIA Alzheimer’s Disease Education and Referral (ADEAR) Center provides free informa- tion and publications for families, caregivers, and professionals on research, diagnosis, treatment, patient care, caregiver needs, long-term care, and education and training related to AD. For example, the publication Alzheimer’s Disease: Unraveling the Mystery explains the disease, highlights ongoing research, and describes efforts to support caregivers of people with AD. An animated companion video brings to life the latest knowledge about AD and the brain. Other ADEAR Center publications include Can Alzheimer’s Disease be Prevented?, which summarizes the latest research findings on AD risk factors and potential prevention strategies, and Caring for a Person with Alzheimer’s Disease: Your Easy- to-Use Guide from the National Institute on Aging, which provides caregiving information and advice. ADEAR fact sheets cover a variety of topics, including basic information, AD genetics, and participating in AD clinical trials and studies. Many ADEAR publications also are available in Spanish. ADEAR staff members answer telephone, email, and written requests and can suggest local and national resources. In addition, the ADEAR Center website offers email alerts, the online Connections newsletter, an AD clinical trials database, and the AD Library database. To read and order these publications, view the AD video, and take advantage of many other resources, visit the ADEAR Center at www.nia.nih.gov/Alzheimers or call the Center toll-free at 800-438-4380.
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 13 Research Advances
he NIH scientific portfolio for AD covers a wide but specific data are lacking for the over-97 age group, range of disciplines and research programs. In or “oldest old,” living in rural communities. Compared T2009, NIH-supported researchers forged new with those living in and near cities, people living in rural understanding of the disease that could lead to future communities are relatively isolated and may have differ- breakthroughs in how to prevent, treat, and cope with its ent lifestyles, decreased access to some resources, and impact. The following pages highlight important findings potentially different rates of dementia. Researchers at and explore their potential relevance to the field. Oregon Health & Science University in Portland assessed dementia prevalence in a sample of people aged 97 or Recognizing the older living in the Klamath Basin, a large rural region in Scope of AD southern Oregon (Kaye et al., 2009). The study showed 1 this population to be within the typical range for people A first step toward curing or preventing a disease is to of advanced age. Sixty-one percent of the sample had get a clear picture of how the disease appears in individ- dementia, 29 percent suffered from MCI, and 10 percent uals and across large populations. Critical questions for were still cognitively intact. Better understanding of fac- physicians, research scientists, and public policy makers tors that enable nearly 40 percent of people age 97 and involved in AD treatment and prevention include: How older to remain dementia-free could help identify strate- widespread (or prevalent) is the disease? Is it more or less gies for preventing progress to dementia in younger elders. common in certain populations? What is the relation- ship of AD to other chronic or age-related diseases? Additional advance in estimating prevalence: How is it different from normal cognitive aging? Wilson et al. (2009a) Biracial population study of mortality in mild cognitive impairment and Alzheimer disease. Rush Prevalence of Dementia Alzheimer’s Disease Center. Supported by NIA and NIEHS. As the average age of the U.S. population rises, developing a reliable estimate of the current and future prevalence of AD becomes increasingly urgent. Knowing how many Links with Other Diseases people have or are likely to develop AD can help manage private and public health resources in the coming years. Plaques and tangles are usually the most obvious disease For example, the number of people living to 100 or features seen under the microscope in brain tissue from beyond is expected to be 15 times greater in 50 years deceased AD patients. However, individuals diagnosed than it is today. Since the risk of AD increases with age, with AD also often suffer from other diseases affecting pertinent questions are: What proportion of centenari- the brain, such as vascular disease. In a postmortem ans will be affected by AD? How many more relatives study of 349 people who had been diagnosed before will be impacted? death with either AD or MCI, neuropathologists at the Data are available on the current prevalence of AD Rush University Alzheimer’s Disease Center in Chicago, in a number of communities and on a national level, IL, found evidence of other disease processes in almost half of the AD brains and 20 percent of the MCI brains
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 14 | Research Advances
Is AD more or less common in certain populations? What is the relationship of AD to other chronic or age-related diseases?
(Schneider JA et al., 2009). Most common were micro- is not surprising, given that diabetes is a risk factor for infarcts—small spaces in brain tissue where cells have cerebral atherosclerosis (accumulation of fatty deposits died due to blockage of blood vessels that once nour- inside brain blood vessels that restrict or block blood ished them—which are associated with cerebrovascular flow). Interestingly, the people who had diabetes in disease.The next most common disease signature was addition to dementia actually carried less amyloid on Lewy bodies in the cortex. Lewy bodies are abnormal average at the time of their deaths than did nondiabetics clumps of protein often found in the brains of older with dementia. The brains of nondiabetics with demen- people that differ in structure and composition from tia also had higher levels of free radical damage. These plaques and tangles. They are associated with dementia different patterns of injury suggest different underlying with Lewy bodies, and are also found in the brains of mechanisms of pathology and may have implications people with Parkinson’s disease. both for mechanisms of disease development and A key finding was that people whose brains showed possible therapies. “mixed” disease (plaques and tangles plus microinfarcts, for example) were more cognitively impaired when they Deciphering died than those whose brains contained only comparable AD Biology levels of plaques and tangles. Microinfarcts and Lewy 2 bodies may compound the negative effects of plaques Scientists believe that the accumulation of beta-amyloid and tangles on neural function, so that fewer plaques fragments around neurons and blood vessels interferes and tangles are required to produce noticeable cognitive with communications between cells. This communica- decline. This study highlights the need to understand tion breakdown is followed by loss of synapses and how other disease processes contribute to brain dysfunc- death of neurons (see A Brief Primer on Alzheimer’s tion in people diagnosed with AD. In addition, the Disease and the Brain, page 11). Much research has finding that microinfarcts seem to exacerbate the nega- focused on exactly how beta-amyloid disrupts inter- tive impact of plaques and tangles on neural function is cellular communication. Key questions to be answered consistent with increasing evidence of overlap between include: risk factors for AD and vascular disease (see Interactions With which molecules does beta-amyloid interact at Between AD and Vascular Disease, page 28). the synapse? Diabetes is another disease that often coexists with AD in older adults. Neuropathologists at the University With which specific cellular processes does beta- of Washington in Seattle found that the brains of people amyloid interfere? who had died with diabetes and dementia had more Which brain “circuits” (systems of interconnected neuroinflammation and more microinfarcts than those neurons) are most affected by beta-amyloid and why? with dementia alone (Sonnen et al., 2009). This finding What mechanisms support normal cognitive function in older individuals who also display substantial levels of brain amyloid?
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 15 | Research Advances
There is also increasing research interest in apparent detail than had previously been possible. They discovered points of overlap between cellular and molecular that plaques are surrounded by halos of soluble beta- changes occurring in AD and in “normal” brain aging. amyloid, and that spines first begin to collapse upon con- tact with these halos (Koffie et al., 2009). Thus, plaques Synaptic Dysfunction may serve as a reservoir for soluble beta-amyloid, which in turn triggers collapse of spines and loss of synaptic contacts. How beta-amyloid interferes with memory formation One mechanism the brain uses to store memories is a pro- Other advances related to synaptic dysfunction: cess called “long-term potentiation” (LTP). LTP is a López-Hernández et al. (2009) Positive modulation of alpha 7 strengthening of the synaptic connection between two neu- n AChR responses in rat hippocampal neurons. University of Florida. Supported by NIA and NIGMS. rons that allows the second neuron to fire more readily. This process is thought to contribute to memory formation. Polydoro et al. (2009) Age-dependent impairment of cognitive Beta-amyloid has been shown to interfere with this and synaptic function in the htau mouse model of tau pathology. process. Understanding how it does might reveal potential Albert Einstein College of Medicine. Supported by NINDS. molecular targets for AD drug development. In particular, Sun et al. (2009) Imbalance between GABAergic and glutama- researchers would like to identify the proteins involved in tergic transmission impairs adult neurogenesis in an animal LTP-beta-amyloid interactions. Reports from the model of Alzheimer’s disease. University of California, San University of Southern California Alzheimer’s Disease Francisco. Supported by NIA, NINDS, and NCRR. Research Center, State University of New York at Buffalo, and Harvard University identified three different synaptic proteins interacting with beta-amyloid (Williams et al., Selective Neuronal Death 2009; Gu et al., 2009; Li et al., 2009). All three are AD affects neurons sooner and more severely in certain involved in signaling by the neurotransmitter glutamate. brain regions than in others. Particularly vulnerable are Another study suggests an alternative or additional neurons in the entorhinal cortex, hippocampus, and cer- beta-amyloid “receptor”: cellular prion protein (PrPc). tain other cortical regions. A key question is, Why are Prion protein in its abnormal form causes mad cow disease neurons in certain regions especially vulnerable to AD? in cattle and Creutzfeldt-Jacob disease in humans. Scientists In some cases, it may be because these neurons experi- at Yale University in New Haven, CT, supported by NIA ence higher-than-average levels of functional activity (see and NINDS found that beta-amyloid binds to hippocam- Cortical “Hubs” and Amyloid, page 17). pal nerve-cell membranes at or near sites where PrPc is Neurons may also be more affected in AD because found. Moreover, binding to PrPc appears to be necessary they synthesize certain proteins that render them vulner- for beta-amyloid to disrupt LTP (Laurén et al., 2009). If it able. An example is neurons in the basal forebrain, a is ultimately shown that PrPc is the receptor through which brain region severely affected in AD. These neurons syn- beta-amyloid binds to nerve cells and disrupts LTP, then thesize high levels of a receptor for nerve growth factor, drugs that block beta-amyloid binding to PrPc could be which usually helps ensure their survival. However, pursued aggressively as potential AD therapeutics. investigators at the Buck Institute for Age Research in Novato, California, supported by NIA and NINDS, Beta-amyloid and synapse loss showed that when the receptor is bound by APP, two Beta-amyloid appears not only to disrupt LTP, but to cause toxic events take place: the APP is cleaved into beta- the collapse of dendritic spines (specialized protrusions on amyloid, and neurons die (Fombonne et al., 2009). the surfaces of dendrites that receive input from other neu- rons). Loss of dendritic spines is evident around amyloid Additional advance related to selective neuronal death: plaques in both human AD and transgenic mouse models Robertson et al. (2009) Amyloid-beta expression in retrosplenial of AD. Scientists at the Massachusetts General Hospital cortex of triple transgenic mice: relationship to cholinergic axonal Alzheimer’s Disease Research Center in Boston sought to afferents from medial septum. University of California, Irvine. discover whether this loss is caused by the plaque itself or Supported by NIA and NINDS. by soluble beta-amyloid shed from the plaque. Using a new microscopic imaging technique, the researchers were able to see amyloid plaques and nearby dendritic spines in greater
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 16 | Research Advances
Cortical “Hubs” and Amyloid
f there were a map of the neural con- nections within the brain’s cortex, it Iwould look something like an airline route map, with airport “hubs” such as Atlanta, Chicago, and Dallas serving many different routes and showing much higher activity levels than other points in the sys- tem. Human brain hubs include hot spots in several regions of the cortex. They can be observed using functional magnetic reso- nance imaging (fMRI), an imaging technique that monitors levels of nerve-cell activity in Like airline route maps, the human brain has “hubs” in several regions of the cortex. different brain regions. Some cortical hubs are busier when a person is at rest, others AD. They found that the regions of highest are active both at rest and during task when a specific task is being performed. amyloid accumulation coincided with the performance, consistent with mounting Researchers at Harvard University locations of highly active cortical hubs evidence that the presence and deposi- compared patterns of this activity to pat- (Buckner et al., 2009). The study sug- tion of amyloid is associated with high terns of amyloid deposition in people with gests that these amyloid-associated hubs neuronal activity levels.
Amyloid and Sleep common in the elderly and cause damage to certain The idea that amyloid deposition is correlated with high brain regions. This study provides further impetus for levels of neuronal activity has received further support testing whether measures that promote healthy sleep also from a study showing increased beta-amyloid deposition reduce risk of brain dysfunction and AD. (Read about a after sleep deprivation. Active neurons are known to sleep apnea treatment study, page 39.) secrete beta-amyloid into the fluid surrounding them. Investigators at Washington University in St. Louis, sup- Additional advance related to amyloid and sleep: ported by NIA, NINDS, and NIMH, measured beta- O’Hara et al. (2009) Sleep apnea, apolipoprotein epsilon 4 amyloid levels in AD model mice at different points in allele, and TBI: mechanism for cognitive dysfunction and devel- the sleep-wake cycle. They found levels to be highest at opment of dementia. Sierra-Pacific Mental Illness Research, the end of the wakeful period and decreased during Education, and Clinical Center (MIRECC), Stanford University. Supported by NIMH. sleep (Kang et al., 2009). A similar pattern was seen for beta-amyloid levels in the CSF of human volunteers (10 young healthy males). Additional studies in AD model mice showed that beta-amyloid levels and plaque deposi- Cellular Energy Deficits tion were increased by chronic sleep deprivation and by Neurons need exceptionally high levels of energy to orexin, a neurohormone that promotes wakefulness. support their signaling. Indeed, although the brain Treating mice with a drug that blocks orexin receptors represents only about 2 percent of the body weight of blocked the daily rise in beta-amyloid. an average adult human, it uses about 20 percent of the The possibility that chronic sleep deprivation exac- body’s energy. Neurons are also especially sensitive to erbates amyloid deposition is especially interesting given energy deficits. Failures in energy-generating mecha- evidence that sleep disturbances, such as sleep apnea, are nisms that occur as neurons age may contribute to the development of AD.
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 17 | Research Advances
Mitochondrial fission and fusion Another finding also points to the impact of normal Often called the cellular “powerhouses,” mitochondria aging and AD on cellular energy production. While are responsible for energy production. Mitochondria are nerve cells usually use glucose as their main energy highly dynamic—they move around inside cells and can source, researchers at the University of Kentucky in fuse with one another or break apart into smaller pieces Lexington, studying the brains of aging rats, observed a (fission). If the balance between mitochondrial fusion shift to other fuel sources, such as fats and amino acids. and fission tips too much toward fission, the result is This metabolic shift was accompanied by the breakdown abnormally small, malformed mitochondria that may of myelin, the fat- and protein-rich sheath that insulates not function properly. Such abnormal mitochondria axons. The earliest stages of cognitive impairment in rats have been observed in the brains of people with AD. coincided with the changes in myelin metabolism. The Researchers at Case Western Reserve University in investigators hypothesize that these processes damage Cleveland, OH, found that the proteins responsible for neuron structure and deplete energy needed for cell-to- mitochondrial fission and fusion are abnormally regu- cell signaling (Kadish et al., 2009). lated in the AD brain. They also found that applying Insulin-like growth factor-1 (IGF-1) is a hormone beta-amyloid to rat hippocampal neurons caused the that promotes cell growth. The brain IGF signaling mitochondria in the neurons’ dendrites to break apart pathway also appears to be involved in aging, as block- (Wang X. et al., 2009). Thus, abnormal mitochondrial ing this pathway prolongs lifespan in organisms ranging dynamics may be a link between beta-amyloid and syn- from worms to mammals. The pathway may also con- aptic degeneration. tribute to AD. Investigators at the Salk Institute for In related work, a research team at the Burnham Biological Studies in La Jolla, CA, discovered that reduc- Institute for Medical Research in La Jolla, California, ing IGF signaling in AD model mice prevented the supported by NICHD, NEI, NIEHS, and NINDS, development of AD-like disease symptoms, including showed that nitric oxide (NO), thought to be a key brain inflammation, behavioral impairment, and neuro- mediator of beta-amyloid’s neurotoxic effects, stimulates nal death. Of great interest, the beta-amyloid plaques in the activity of an enzyme that accelerates mitochondrial the brains of these mice differed from those normally fission (Cho et al., 2009). Drugs that inhibit activity of seen in AD: the fibrils making up the plaques were more this fission-accelerating enzyme might therefore be use- orderly and tightly packed than usual. These more ful to explore as a possible therapeutic for AD. tightly packed beta-amyloid aggregates are less likely to shed the soluble form of beta-amyloid, and are therefore Changes in brain metabolism in less likely to be toxic to neurons (Cohen E. et al., 2009). normal aging and AD Since age is the best known risk factor for AD, it seems Additional advances in brain metabolism, normal aging, likely that some of the cellular changes that occur with and AD: aging contribute to the development of AD. One such Bishop et al. (2009) Review: Neural mechanisms of ageing and change, depressed mitochondrial function, was exam- cognitive decline. Harvard University. ined by scientists at the University of Southern Cohen AD et al. (2009b) Basal cerebral metabolism may modulate California in Los Angeles, supported by NIA and the cognitive effects of Abeta in mild cognitive impairment: an exam- NIMH. The researchers investigated the possible link ple of brain reserve. University of Pittsburgh. Supported by NIA. between mitochondrial dysfunction and events in the AD disease pathway using a mouse model of AD. They Salthouse, TA. (2009) Review: When does age-related cognitive decline begin? University of Virginia. found an age-dependent decline in mitochondrial func- tion in both normal and AD model mice, which pre- ceded the onset of amyloid plaque formation (Yao et al., 2009). Thus, mitochondrial dysfunction might contrib- ute to amyloid deposition, as well as vice versa.
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 18 | Research Advances
Brain Amyloid an Early Warning Sign of Possible Cognitive Decline in “Normal” Individuals
he year 2009 saw intense investiga- Massachusetts General Hospital indicated Together, the studies suggest the fol- tion of the relationship between abnormalities in the brain’s “default net- lowing sequence of disease events in AD: Tbrain amyloid deposits and cognitive work,” a system of brain regions that is Amyloid deposition occurs first, and in function. It has been known for many years most active when a person is not perform- its earliest stages is not associated with that some cognitively normal individuals had ing a task, but rather focused inward (e.g., cognitive impairment. high levels of brain amyloid at autopsy. More during daydreaming, envisioning or plan- Loss of synapses, neurons, and brain recently, methods became available for imag- ning the future, or recollecting the past) volume occurs next, and is accompanied or ing amyloid in the brains of living people using (Sheline et al., 2010; Sperling et al., 2009; shortly followed by loss of cognitive func- positron emission tomography (PET) and Hedden et al., 2009). The pattern of net- tion (see AD Progression figure, page 30). radioactive Pittsburgh Compound B (PiB) as an work disruption seen in these cognitively More studies are needed to determine amyloid marker. Subsequent imaging studies normal, high amyloid load-bearing individ- the best ways of accurately predicting supported by NIA and NIMH funding at the uals is similar to that seen in people with who will go on to develop AD and who University of Pittsburgh, Mayo Clinic, and clinical AD. It involves cortical “hubs” that will not before clinical symptoms emerge. Banner Alzheimer’s Institute produced an participate in memory formation (see This scenario may seem discouraging important result: Amyloid deposits were found Cortical “Hubs” and Amyloid, page 17). but in fact offers hope. Because signifi- in the brains not only of people with MCI and cant amyloid deposition seems to occur AD, but also in some older people who were PiB-PET Scans Key years before clinical diagnosis of AD, cognitively normal (Aizenstein et al., 2008; Most importantly, several studies in 2009 there may be a window of time in which Jack et al., 2009; Reiman et al., 2009). In fact, found that cognitively normal people with therapeutic intervention might prevent the percentage of nondemented older adults high amyloid loads were more likely to disease progression. Accumulation of with significant levels of brain amyloid ranged suffer eventual cognitive decline than brain amyloid could serve as a warning from 20 to 50 percent in different studies. peers with low amyloid levels. For exam- sign that additional testing is necessary ple, one research team at the Washington and therapeutic intervention should be Questions to Explore University Alzheimer’s Disease Research considered. Thus, just as people are now These findings opened the door to explor- Center (ADRC) in St. Louis, MO, longitudi- routinely checked for high cholesterol and ing the future implications of differences nally studied 135 cognitively normal counseled about lifestyle changes and in amyloid levels among cognitively nor- people who had annual cognitive testing medications to reduce their risk of heart mal people. Could some older people who starting in 1985 and PiB-PET scans start- disease and stroke, in the future they have high brain amyloid nonetheless ing in 2004. All of these individuals scored may also be checked for brain amyloid maintain good cognitive function for within the normal range on cognitive tests and counseled about AD prevention. decades to come? Or, if one scrutinized when they first entered the study. PiB-PET Another encouraging finding is that it is these apparently normal people more rig- scans showed that 29 participants had possible for a person to have a lot of amyloid orously, would they show the very earliest high brain amyloid loads. This group also in his or her brain without significant cogni- signs of cognitive loss and eventually showed shrinkage of brain areas typically tive decline. Thus, in some people the brain develop AD? The weight of evidence from affected by AD, as seen in MRI scans, and somehow compensates for the presence of studies supports the second scenario. declining performance on visuospatial, beta-amyloid, at least for some period of Many cognitively normal people with high episodic, and working memory tasks over time. The brain’s capacity to compensate for brain amyloid levels exhibit other abnor- time (Storandt et al., 2009). AD pathology, called “cognitive reserve,” is malities associated with cognitive decline. In a related study, the Washington also being intensively studied. Further longitudinal studies will be needed University ADRC showed that positive PiB- to distinguish between those who will PET scans at baseline were predictive of Additional advance: progress and those who will not. developing very mild AD but not of other Mormino et al. (2009) Episodic memory Imaging of neuronal activity patterns causes of dementia up to 5.5 years later loss is related to hippocampal-mediated in individuals with high levels of brain (Morris et al., 2009). This study was limit- beta amyloid deposition in elderly subjects. amyloid in three studies at Washington ed by the small number of people who University of California, Berkeley. (ADNI) University, Harvard University, and developed AD and the short followup time.
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 19 | Research Advances
What Is Normal Aging? The close association between age and risk of AD raises the question of whether AD is an inevitable consequence of aging, especially since many older people with normal Is there any such thing cognition have substantial levels of brain beta-amyloid. Is there any such thing as “normal” cognitive aging and, as “normal” cognitive aging and, if so, what does it look like? Understanding what constitutes normal brain aging if so, what does it look like? and age-related cognitive decline is an important focus of research. Cognitive decline associated with aging can compromise quality of life for older people and looking at brain aging in this way may help promote healthy cogni- These results suggest that there is a specific trajec- tive outcomes. It is anticipated that such research, both in tory of brain changes that occurs during normal aging, animal models and in humans, can provide critically distinct from that occurring in AD. Brain changes in important insight into effects of normal aging, distinct cellular mitochondria and energy production also occur from AD, as well as providing a biological context for the during normal aging (see Changes in brain metabolism in abnormal brain changes in AD. More detailed descrip- normal aging and AD, page 18). Moreover, a review tions of normal aging will also help in developing early from the University of Virginia in Charlottesville sug- and sensitive AD diagnostic tools. gests that declines in certain aspects of cognitive func- Investigators at NIA’s intramural Laboratory of tion, such as memory and speed of processing, may Personality and Cognition in Baltimore, MD, carried begin as early as a person’s 20s or 30s (Salthouse, 2009). out an exceptionally detailed analysis of brain changes These observations appear to be dependent on the type over time in 138 people who were 64 to 86 years of age of study conducted, cross-sectional or longitudinal, and and nondemented at the beginning of the study. Brain debate continues as to the point at which measurable scans were conducted every year for up to 10 years, and and meaningful change occurs. cognitive status was evaluated. Some participants devel- oped MCI over the course of the study, while others Additional advance in understanding normal aging: remained cognitively normal. Both groups experienced Bishop et al. (2010) Neural mechanisms of ageing and cogni- atrophy (shrinkage) of certain brain areas over time, but tive decline. Harvard University. the specific patterns of atrophy differed. For example, the group who remained cognitively normal showed more atrophy in certain areas of the frontal cortex (the portion of the cortex closest to the forehead), whereas the group who developed MCI had more prominent atrophy in temporal areas (the regions on the sides of the brain, closer to the ears) (Driscoll et al., 2009).
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 20 | Research Advances
Discovering New The Search for New Genes 3 Genetic Mechanisms Four genes affecting the development of AD have been known for many years. Mutations in three of them—the In the early days of AD research, scientists realized that APP gene found on chromosome 21, the presenilin 1 gene some cases of the disease ran in families. When it did, it on chromosome 14, and the presenilin 2 gene on chromo- appeared quite early, in the 40s or early 50s. By analyz- some 1—cause the rare early-onset forms of familial AD. ing the patterns of inheritance of these early-onset cases The AD-associated mutations in each of these genes pro- of AD, researchers proved that these particular forms of mote the breakdown of the large APP protein along a path- the disease had a genetic basis. Those findings opened way that generates more harmful forms of beta-amyloid. an entire area of AD research that continues to be highly The fourth gene, apolipoprotein E (APOE), found productive today. Research into the genetics of early- on chromosome 19, is linked to late-onset AD. Late-onset onset AD has revealed much about the biological basis AD is not “inherited” in the same sense that the early- of the disease, the interrelationship of genetic and envi- onset mutations actually cause AD, but genes involved in ronmental factors in causing it, and molecular pathways late-onset AD can affect the risk of developing it. APOE that might be targeted to prevent or treat both early- was the first gene to be identified as influencing late-onset and late-onset AD. As medical science moves toward AD. APOE has three forms, or alleles: E2, E3, and E4. individualized medicine based on a person’s unique The E2 form may provide some protection against AD, genetic makeup, identification of other genes contribut- and E3 is thought to play a neutral role. The E4 form can ing to the development and progression of AD—includ- increase a person’s risk of developing AD. ing those that may be involved in sporadic, late-onset Research shows that additional genes likely influence disease, the most common form of AD—may help the development of late-onset AD, either as risk factors determine which preventive and treatment strategies are or protective factors. Geneticists worldwide are searching best suited to particular individuals. for these genes.
AD Gene Discovery Timeline
PICALM APOEE4 PS1 First Five APP PS2 CLU published CR1 additional GWAS confirmed genes by GWAS discovered First by GWAS Transgenic to be mouse confirmed models
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 21 | Research Advances
“Normal” Functions of AD Genes
f the genes involved in AD are so troublesome, then why do neurotransmitter acetylcholine on hippocampal LTP, the PS1 humans have them in the first place? Usually, genes remain mutation impaired synaptic connections. (Wang Y. et al., 2009). Iin human or animal populations only if they have a useful Recent work from the Nathan S. Kline Institute in biological function and confer a survival advantage. For example, Orangeburg, NY, indicates yet another role for normal PS1 in there is evidence that the presenilins, particularly PS1, play a neuronal function. It seems to participate in a process called role in the earliest stages of the development of the nervous “macroautophagy,” in which cells dispose of internal debris. system. Better understanding the normal or “good” biological Many cellular proteins and structures wear out with time and functions of the proteins encoded by AD genes could shed light cease to function properly. Most cells have the capacity to target on how mutations or variations in these genes lead to disease. their worn-out components and break them down into smaller pieces, which are either reused or discarded. This process Several findings, including those from investigators at involves lysosomes, parts of cells containing enzymes that Georgetown University in Washington, DC, supported by NIA and digest cellular debris. Mutations in PS1 that cause early-onset NINDS, and Baylor College in Houston, TX, supported by NIA and AD disrupt metabolism in the lysosomes, so that they can no NICHD, indicate a role for APP in the development of synaptic longer digest cellular debris. This debris then accumulates and connections between nerve cells (Hoe et al., 2009a; Wang Z. et may contribute to neuronal death (Lee et al., 2010). al., 2009). In particular, APP appears to promote the growth of Like APP, the ApoE protein promotes the growth of dendrites dendrites, the branch-like structures through which neurons and their spines. However, a genetic study in human ApoE model receive input from the axons of other neurons. APP is also nec- mice from Georgetown University in Washington, DC, suggests essary for neurons to form orderly synaptic contacts with other that the E4 form of APOE, which is associated with higher AD neurons or muscle cells. In both cases, APP seems to act in part risk in humans, is less effective in promoting dendrite and spine by promoting cell-to-cell adhesion, a process in which certain growth than the other forms of APOE (Dumanis et al., 2009). proteins on the membrane of one cell bind to proteins on a This finding may help explain how the APOE E4 allele increases neighboring cell and help “glue” the two cells together. risk of AD. The presenilins have long been recognized as important to the development of neurons. New evidence suggests they also Additional advances in understanding AD genes: regulate the strength and flexibility of synaptic connections in Hoe et al. (2009b) The effects of amyloid precursor protein on the hippocampus. Researchers at Harvard University supported postsynaptic composition and activity. Georgetown University. by NINDS found that inactivating the presenilin genes in mice Supported by NIA and NINDS. reduced the process of hippocampal long-term potentiation (LTP) Maji et al. (2009) Functional amyloids as natural storage of (Zhang C. et al., 2009). Another research group at NIA’s peptide hormones in pituitary secretory granules. Zurich, Laboratory of Neurosciences in Baltimore, MD, found that, Switzerland. Supported by NIDDK. instead of PS1s enhancing the use of an important chemical
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 22 | Research Advances
New human AD genes identified A third gene, CR1 (complement receptor 1), iden- Genetics research has helped to reveal much about the tifed by the Cardiff University investigators, was con- basis of AD, the interrelationship of genetic and envi- firmed as a “hit” in a smaller collaborative GWAS led by ronmental factors in causing AD, and pathways amena- French investigators (Lambert et al., 2009). CR1 is an ble to prevention or treatment. Complicating the study immune system protein involved in inflammation of AD genetics is the fact that the risk of late-onset AD responses and like CLU, may be involved in clearing is probably influenced by many genetic risk factors, each beta-amyloid from the brain. The French study also likely contributing a small risk distributed across differ- identified CLU, confirming its potential role in AD. ent genes affecting a variety of biochemical pathways. A recently published analysis in an independent data These genetic factors may influence the age at onset, the set has confirmed that CR1, CLU, and PICALM are risk of getting the disease, or disease progression. AD susceptibility genes in another population of Technological developments in genetic analysis over European ancestry (Jun et al., 2010). the last few years have played a huge role in pushing this Investigators at Massachusetts General Hospital sup- area of research forward. Genome-wide association study ported by NIMH identified a fourth potential AD gene, (GWAS) technologies let scientists use sophisticated ADAM10. They discovered two rare mutations in this software and hours of computing time to find links gene in individuals from seven different late-onset AD between individual gene variations and observable traits, families. ADAM10 is an alpha-secretase, an enzyme that such as the presence of AD. For just a few hundred dol- cleaves APP in a way that eliminates its potential to lars, scientists can now rapidly test 500,000 to a million form beta-amyloid. A mutation could disrupt this cleav- sites in an individual’s DNA using a gene chip the size age and add to AD risk (Kim M. et al., 2009). of a postage stamp. Research in animal models as well as humans can This year, a large GWAS search “struck gold” with suggest potential human AD genes. An international the discovery of two new late-onset AD genes, CLU and team of researchers, supported by NIA and NINDS and PICALM. Variants of these genes that correlated with led by the Burnham Institute in La Jolla, CA, and the development of late-onset AD were identified in a Xiamen University, China, identified a new gene in collaborative study led by researchers at Cardiff mice—Rps23r1—that reduces levels of both beta- University, Wales (Harold et al., 2009). The group ana- amyloid and phosphorylated tau (another major lyzed more than 16,000 samples collected by dozens of hallmark of AD) when it is turned on either in AD laboratories across Europe and the United States, includ- model mice or in human cells in tissue culture (Zhang ing several funded by NIA and other NIH Institutes. Y.W. et al., 2009). This gene may protect mice against Sometimes newly discovered disease genes are mys- the development of AD-like changes in the brain. If this terious entities of unknown biological function. gene or one like it is present in humans, therapeutics Fortunately, a substantial body of knowledge is already might be designed to mimic its protective effects. available about CLU and PICALM because the proteins encoded by these genes have roles in well-studied cellu- How are people affected by lar pathways. CLU (ApoJ/clusterin) is another apolipo- knowing their risk for AD? protein and, like ApoE, may play a role in clearing As new genetic risk factors for AD are discovered, beta-amyloid out of the brain and into the blood (see measures to assess individual risk will be developed. Clearing out beta-amyloid, page 37). PICALM (phospha- Currently, APOE E4 is the most robust risk marker tidylinositol-binding clathrin assembly protein) appears available for late-onset AD, and requests for APOE to be involved in recycling of cell membrane proteins at genotyping are increasingly common. The REVEAL synapses. Identification of these two new genes should study group led by researchers at Boston University with help researchers home in on novel specific biological support from NHGRI and NIA studied the psychologi- processes that are disrupted in AD. cal consequences of disclosure of APOE genotype test results in a group of 162 symptom-free adults who had a parent with AD. This study found that people who had
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 23 | Research Advances the highest genetic risk for AD and were told their test results did not suffer significantly greater anxiety or depression during the weeks or months after the test CHEMICAL than did people who either tested negative or who did TAG METHYL GROUP not learn their test results (Green et al., 2009). CHROMOSOME
Additional advance in effects of genetic susceptibility testing: DNA
Ashida et al. (2009) Disclosing the disclosure: factors associated with communicating the results of genetic susceptibility testing HISTONE TAIL for Alzheimer’s disease. NHGRI Intramural Program. GENE HISTONE TAIL
DNA hidden, gene turned on
HISTONE Epigenetics: Nature Meets Nurture DNA hidden, gene turned off Until recently, scientists believed that genes and environ- mental factors acted independently to influence an individ- The epigenome can mark DNA in two ways, both of which play a ual’s biological makeup, including a person’s predisposition role in turning genes off or on. The first occurs when certain to different diseases. Now we realize that “nature and nur- chemical tags called methyl groups attach to the backbone of a ture” are not so easily untangled. Genes can be affected by DNA molecule. The second occurs when a variety of chemical environmental factors, such as diet or smoking, which a tags attach to the tails of histones, which are spool-like proteins person may be exposed to, even in the womb. that package DNA neatly into chromosomes. This action affects The study of these interactions is called epigenetics, how tightly DNA is wound around the histones. (Source: NHGRI, and it is emerging as a new frontier of science. Diet and www.genome.gov) exposure to environmental chemicals, among other fac- tors, throughout all stages of human development can There is some evidence that epigenetic mechanisms cause epigenetic changes that may turn on or turn off contribute to AD. That may help explain why one indi- certain genes. Changes in the regulation of genes could vidual in a family develops AD while another does not. make people more or less susceptible to developing a One study, by scientists at the Sun Health Research disease, such as AD, later in life. Institute in Sun City, AZ, looked at certain chemical Unlike gene mutations, epigenetic modifications of modifications in brain tissue samples from deceased iden- genes do not involve changes to the genetic code. They tical twins. The comparison examined levels of DNA involve chemical alterations that make genes more or methylation, a chemical modification that can reduce the less accessible to interactions with enzymes responsible level at which a gene is expressed. One twin had devel- for “reading” each gene’s code and cranking out the pro- oped AD at age 60 and deteriorated until his death at age tein for which it codes. Environmental factors leave their 76; the other died cognitively intact at age 79. Methylated mark on the genome by altering the epigenetic signature DNA levels were significantly lower in the brain tissue of genes. Like gene mutations, epigenetic changes can be from the twin who had AD than in that of his brother passed from one cell to its daughter cells during cell (Mastroeni et al., 2009). The twin with AD had experi- division, and so can persist for an individual’s lifetime. If enced extensive pesticide exposure during his lifetime as the cells involved are egg or sperm cells, the changes can result of his profession. Pesticides are one environmental also be passed to the next generation. (The old phrase factor believed to cause epigenetic changes, although it is “You are what you eat” now could be revised to say, not known if they were a causative factor in this case. “You are what you eat and what your mother ate.”) Recent scientific evidence also points to the involve- ment of epigenetic mechanisms in memory formation and maintenance. One such mechanism involves enzymes that chemically modify histones (proteins
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 24 | Research Advances around which DNA is wrapped inside chromosomes) Preventing AD and Promoting and results in the remodeling of chromosomes, the indi- Healthy Brain Aging vidual coils of DNA and protein storing genetic infor- 4 mation inside cells. Two papers from the Massachusetts Genetic factors cannot fully account for why some peo- Institute of Technology in Boston and Columbia ple develop AD and others do not. There is mounting University in New York, NY, supported by NINDS, evidence that a number of nongenetic factors, such as suggest an involvement of histone-modifying enzymes in diet, lifestyle, and exposure to certain environmental memory formation and AD and point to these enzymes agents, may increase or reduce one’s risk of developing as possible targets for therapeutic development (Guan et AD. Understanding these nongenetic risk factors will al., 2009; Francis et al., 2009). point the way to potential therapies or lifestyle changes that can help prevent AD. Additional 2009 advance in epigenetics: Potential AD Risk Factors Debette et al. (2009) Association of parental dementia with cognitive and brain MRI measures in middle-aged adults. Boston Advancing age and serious head injury are well-estab- University. Supported by NIA, NINDS, NHLBI. lished risk factors for developing AD. Scientists are exploring a wide range of other possible factors.
Estrogen The hormone estrogen has important effects on the brain, many of which are potentially relevant to cogni- Looking to the Future: tive aging and AD. For example, animal studies have Epigenetics shown that estrogen protects neurons against a wide spectrum of toxic insults, some of which are linked to n 2008, NIH announced funding for a new Roadmap AD. Estrogen can also reduce formation of beta-amyloid Epigenomics Program (http://commonfund.nih.gov/ and can counteract some of the effects of normal aging epigenomics/index.asp), committing more than on cognition when administered to nonhuman primates. I In humans, some large observational studies have sug- $190 million during the next 5 years to accelerate this emerging field of biomedical research. The rationale gested a possible protective effect of estrogen for women. behind this trans-NIH program is to promote understand- Clinical trials and studies have attempted to assess whether ing of how and when epigenetic processes control genes estrogen therapy can protect women against age-associated during different stages of development and throughout cognitive decline. In the largest trial to date, reported in life. Scientists hope the effort will lead to more effective 2003, data from the Women’s Health Initiative Memory ways to prevent and treat disease. Study (WHIMS) showed that prolonged treatment with a NIA has played a very active role in the development common type of hormone therapy (conjugated equine and implementation of the Roadmap Epigenomics Program. estrogens) increased the risk of dementia and adversely In 2009, the Program funded 22 projects focused on ex- affected cognition in women age 65 and older. ploring the epigenomic basis of various aspects of human However, in the WHI trial, postmenopausal hormone health and disease. Four of these projects focus on estab- therapy was usually started many years after normal repro- lishing the epigenomic landscape of AD and testing ductive cycles had stopped and involved synthetic hor- whether epigenetic dysregulation is related to the mones. Further, hormone treatment also increased the risk initiation and progression of AD. of stroke, suggesting that impaired cerebrovascular function In 2010, NIA held a workshop “An Integrated Genetic- may have been a factor in participants’ cognitive decline. Epigenetic Approach to Alzheimer’s Disease,” which re- viewed emerging epigenetic approaches to AD, explored synergies between genetic and epigenetic approaches, and spurred interactions between leading experts in AD genetics and epigenetics.
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 25 | Research Advances
A number of nongenetic factors, such as diet, lifestyle, and exposure to certain environmental agents, may increase or reduce one’s risk of developing AD.
To try to understand why hormone therapy impaired General anesthetics cognitive function in the WHIMS study, researchers at An estimated 200 million patients worldwide have sur- Wake Forest University and NIA’s Laboratory of gery with anesthesia each year. Several studies have linked Personality and Cognition in Baltimore, MD, used MRI general anesthesia in surgery with an increased risk of AD to look for brain degeneration in a group of women, ages later in life. Researchers at Massachusetts General 79 to 89, who had participated in the 2003 WHI trial. Hospital and Harvard University in Boston, supported by The women who had received hormone therapy showed NIGMS, NIA, and NINDS, looked at the most com- more shrinkage of the hippocampus and frontal cortex monly used inhalation anesthetic (sevoflurane) and found than those who did not. (These brain regions are impor- increases in beta-amyloid levels and cell death when it was tant for memory and planning, and also show shrinkage applied to a glial tumor cell line in culture. In addition, in AD.) Many of the women who received hormone mice anesthetized for 2 hours showed increased beta- therapy also showed evidence of varying degrees of brain amyloid deposition in the frontal cortex (Dong et al., 2009). damage due to cerebrovascular disease, but the extent of It is important to note that no evidence to date with this that damage was not significantly higher compared with or any other inhalation anesthetic shows similar results in women who had received a placebo (Coker et al., 2009). humans, but further study of effects of anesthetics on This finding suggests that the adverse effects of hormone development of brain pathology may be warranted. therapy on cognition were not due to an increase in cere- brovascular disease (Resnick et al., 2009). Lead The human clinical data highlight the substantial A pilot study of 47 healthy subjects, 55 to 67 years old, gaps in our understanding of ovarian hormone influ- provided additional support for previous research suggest- ences on neurocognitive aging, as recently summarized ing a link between lead exposure and memory impairment. from an NIA-sponsored workshop convened to address Investigators at the University of Rochester, NY, supported these issues (Asthana et al., 2009). One of these ques- by NIEHS, found that higher lead levels in bone, which tions is about timing. Animal studies have shown that indicate accumulated lead exposure over time, were associ- estrogen has positive effects on the brain, but only if ated with impaired performance on two memory tests used administered during or immediately after withdrawal of to detect MCI (van Wijngaarden et al., 2009). ovarian steroids. Thus, estrogen may protect cognition in humans only if administered at a particular age or for Additional advance related to AD risk factors: a specific amount of time after menopause. Two NIA- de la Monte et al. (2009) Mechanisms of nitrosamine-mediated funded clinical trials in progress will compare the effects neurodegeneration: potential relevance to sporadic Alzheimer’s disease. of early and late hormone therapy on cognition, and Rhode Island Hospital/Brown University. Supported by NIAAA. other endpoints: the Kronos Early Estrogen Prevention– Cognitive and Affective Study (KEEPS–CA) and the Early versus Late Intervention Trial with Estrogen (ELITE) (see AD Clinical Trials, page 38).
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 26 | Research Advances
Lifestyle and Successful Cognitive Aging people (average age, 80). Consistent with previous stud- Many individuals stay mentally sharp to age 90 and ies, they found that better cognitive function was corre- beyond, and there has been increasing research emphasis lated with more frequent participation in social on finding out why. Epidemiological–observational– activities, as well as with the subjects’ own perception of studies such as those described below are important to being well-supported socially. This correlation was sig- identify associations between certain lifestyle factors and nificant even after accounting for higher levels of intel- the risk of developing AD. However, even if substantial lectual and physical activity (Krueger et al., 2009). evidence is found for a potential association, observa- tional studies alone cannot establish a cause-and-effect Exercise relationship. To be useful in the clinic, associations Building evidence from epidemiological studies and sev- between some factor and AD risk must be able to yield eral small clinical trials in healthy adults have shown that an intervention that can be randomly assigned to indi- aerobic exercise may help prevent age-associated cogni- viduals in a clinical trial, as randomized trials remain the tive decline, at least in the short term. Studies in animals gold standard for identifying successful treatments (see suggest that exercise may strengthen cognition in part by AD Clinical Trials, page 38). supporting the hippocampus, a brain structure critical for Researchers for the Health ABC Study at the learning and memory that is one of the first to deterio- University of California, San Francisco, and the NIA rate during both normal brain aging and in AD. A report Intramural Research Program identified several factors from investigators at the University of Pittsburgh, PA, associated with continued cognitive health. In a group and the University of Illinois, Urbana-Champaign, sug- of 2,509 older people who were functioning well when gests that exercise supports hippocampal function in they entered the study (at ages 70 to 79), factors con- humans as well. They assessed cardiorespiratory fitness in tributing to enhanced or intact cognitive function 165 older adults using a treadmill test, and found that included at least a high school level of education, not higher fitness levels were associated not only with better smoking, and engaging in moderate to vigorous exercise performance on a spatial memory test but also with on a weekly basis (Yaffe et al., 2009). Similar associa- greater hippocampal volumes (Erickson et al., 2009). tions have been found in a variety of studies. Work by researchers at Washington University, St. Louis, MO, supported by NIA and NIMH, suggests Social interaction some forms of exercise are more beneficial than others, at A number of studies have found that social interaction, least in one animal model. In AD model mice, voluntary whether through work, volunteering, or living with exercise was superior to forced exercise in reducing plaque someone, is associated with maintaining cognitive deposition and improving memory (Yuede et al., 2009). health. It has not been clear, though, whether this corre- Another study, supported by NIA and NIAMS, from the lation is due to the increased intellectual stimulation and University of California, Irvine, on AD model mice bear- physical activity that generally accompany social interac- ing different forms of the APOE gene suggested that exer- tion or whether it was the social interaction itself that cise is especially beneficial for cognitive function in mice with the APOE 4 form (Nichol et al., 2009). was beneficial. Researchers at the Rush University E Alzheimer’s Disease Center in Chicago, IL, addressed Additional advance related to exercise and AD risk: this question in a large study of nondemented older McAuley et al. (2009) Trajectory of declines in physical activity in community-dwelling older women: social cognitive influences. University of Illinois, Urbana-Champaign. Supported by NIA.
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 27 | Research Advances
Interactions Between AD and Vascular Disease
he brain has one of the richest supplies of blood ves- researchers in a multiethnic New York community showed that sels of any organ. Cognitive health depends very much people who maintained a Mediterranean diet had a 28 percent Ton the health of the brain’s blood vessels. Aging is often lower risk of developing MCI and a 48 percent lower risk of pro- accompanied by problems in cardiovascular and/or cerebrovascu- gressing from MCI to AD. A Mediterranean diet includes vegetables, lar function. Two of the most common are high blood pressure and legumes, fruits, cereals, fish, monounsaturated fats such as olive clogging of blood vessels that supply the brain, which can cause oil, mild to moderate amounts of alcohol, and low intake of saturat- stroke. Vascular disease, in turn, can cause cognitive impairment. ed fats, dairy products, meat, and poultry (Scarmeas et al., 2009a). It has become clear in recent years that AD and vascular Physical activity. Another Columbia University study in the disease-associated cognitive impairment are closely intertwined. same multiethnic New York population showed that people who For example, a large proportion of people diagnosed with AD reported regular engagement in “some” physical activity had a also have brain damage due to vascular disease (see Links with 29 to 41 percent lower risk of developing AD, compared to par- Other Diseases, page 14). In addition, two analyses of data from ticipants who said they were not physically active. Engaging in NIA’s Baltimore Longitudinal Study of Aging and the Honolulu-Asia “much” physical activity was associated with a 37 to 50 percent Aging Study found that many of the major risk factors for vascular lower risk (Scarmeas et al., 2009b). disease may also be risk factors for AD. These findings suggest Cholesterol-reducing drugs. Investigators at the University common cellular mechanisms for the two diseases (Wendell et of Alabama, Birmingham, supported by NIA and NHLBI, treated AD al., 2009; Stewart et al., 2009) model mice with a drug that mimics apolipoprotein A-1 (the major The overlap between vascular disease and AD may be impor- protein in high density lipoprotein, or HDL, the “good” form of cho- tant because drugs and lifestyle modifications known to be lesterol) together with a statin for controlling cholesterol. The mice effective in preventing vascular disease may also help prevent treated with this combination of drugs showed improved cognitive AD. In 2009, the following epidemiological and animal studies function, reduced amyloid, and reduced inflammation compared found that some factors known to reduce vascular disease are with untreated AD model mice (Handattu et al., 2009). also associated with reduced risk of AD. Controlling high blood pressure. A postmortem study of Additional 2009 advance related to vascular disease and AD: brains of people who had hypertension while living, from Mount Sinai Schuff et al. (2009a) Cerebral blood flow in ischemic vascular School of Medicine, New York, NY, found significantly fewer plaques dementia and Alzheimer’s disease, measured by arterial spin- and tangles in those who had taken medication to control their blood labeling magnetic resonance imaging. University of California, pressure than in those who had not (Hoffman et al., 2009). San Francisco/VA Medical Center. Supported by NIA. Mediterranean diet. A large study by Columbia University
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 28 | Research Advances
Looking to the Future: Preventing AD and Age-Related Cognitive Decline
ounting epidemiological and when preparing its consensus statement. animal-study findings point to The panel concluded that cognitive Minteresting possibilities for pre- decline and AD are major causes of mor- venting AD and cognitive decline. What can bidity and mortality worldwide and are scientists say definitively now about what substantially burdensome to the people works to prevent Alzheimer’s and age- affected, their caregivers, and society in related cognitive decline? To examine this general. Extensive research during the critical question, the NIH Office of Medical past 20 years has provided important Applications of Research and NIA convened insights on the nature and extent of AD a State-of-the-Science Conference, held and cognitive decline. Currently, however, April 26-28, 2010, with co-sponsorship firm conclusions cannot be drawn about from NICHD, NCCAM, NIMH, NINDS, NINR, the association of any modifiable risk and the Office of Dietary Supplements. factor with cognitive decline or AD. An independent, 15-member panel Further, evidence is insufficient to sup- was convened to review questions and port the use of any pharmaceutical agent evidence. Panel members were not cur- or dietary supplement to prevent cogni- rently involved in Alzheimer’s research tive decline or AD. and represented the fields of preventive However, promising research is under- Further large-scale population-based medicine, geriatrics, internal medicine, way, the panel noted. These efforts need studies and randomized clinical trials are neurology, neurological surgery, psychia- to be increased and added to by new needed to investigate strategies to try, mental health, human nutrition, insights and innovations. For example, the maintain cognitive function in individuals pharmacology, genetic medicine, nursing, panel indicated that ongoing studies, at risk for decline, to identify factors that health economics, health services including those of antihypertensive medi- may delay the onset of AD in people at research, and family caregiving. cations, omega-3 fatty acids, physical risk, and to identify factors that may Experts from pertinent fields were activity, and cognitive engagement, may slow the progression of AD in people invited to present data to the panel and provide new avenues for the prevention or already diagnosed. conference audience. The panel also delay of cognitive decline or AD. As this research continues, there are received a systematic evidence review NIA’s ongoing research programs are very good reasons for adults to adopt or from the Evidence-based Practice Center actively investigating and testing a vari- maintain lifestyle choices and treatments at Duke University’s Clinical Research ety of strategies to prevent or delay AD known to promote healthy aging and Institute, prepared under contract with and cognitive decline. Research includes reduce the risk of diseases like diabetes the Agency for Healthcare Research and clinical trials investigating exercise, or cardiovascular disease. Quality. Conference participants also pro- statins and blood pressure and diabetes For more information on the State-of- vided oral and written comments in medications, hormones, antioxidants, the-Science Conference and consensus response to the conference questions. cognitive training, and other interven- statement, go to http://consensus.nih. The panel considered all of this evidence tions (see AD Clinical Trials, page 38). gov/2010/alz.htm.
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 29 | Research Advances
Detecting Cognitive Testing 5 Disease Earlier Extensive cognitive testing has been a key diagnostic tool in AD, refined over many years. Many existing tests were Many researchers believe that therapeutic interventions for designed to diagnose relatively later stages of the dis- AD are more likely to be effective if initiated early in the ease—for example, in people who come to the doctor’s disease process. Since we now know that the brain damage office already complaining of memory problems. What is caused by AD can begin long before cognitive impairment currently lacking are tests that can detect and track the becomes evident, intensive effort has been aimed at devel- earliest, most subtle stages of the disease and tests that oping methods to detect this damage at its earliest stages. can identify who is at risk of eventually developing the disease. Research efforts now concentrate on the develop- ment of a new generation of cognitive tests that are more sensitive to changes in cognition and more reliably dis- criminate between normal aging, early stages of AD, and cognitive impairment due to other diseases, such as cere- brovascular disease or Lewy body disease. Progress toward establishing a detailed account of normal neurocognitive aging will importantly inform this effort. MCI is often a transitional stage between normal aging and AD. Sensitive, accurate diagnostic tests for MCI are critical to identify people at risk of developing AD and to predict the likely progression of symptoms. There has been considerable variability in assessing how common MCI is in the population and the rate at which people with MCI progress to AD, due in part to the use of different criteria for diagnosing MCI. This diagram illustrates current thinking about how Researchers at the University of California, Los Angeles Alzheimer’s changes in the brain contribute to disease progression, from a presymptomatic stage through early Alzheimer’s Disease Center assessed 115 people with and late mild cognitive impairment to Alzheimer’s amnestic or nonamnestic MCI using a battery of tests dementia. The curves on the diagram represent specific for different neuropsychological functions, such as markers as they appear sequentially over time as the memory, attention, and visuospatial processing, then fol- disease progresses. lowed their progress for 16 months. (In amnestic MCI, memory is the dominant problem; in nonamnestic MCI, other cognitive impairments dominate, such as problems with language, visuospatial processing, and attention. People with amnestic MCI are more likely to Scientists are currently exploring three main progress to AD than those with nonamnestic MCI.) In approaches to early diagnosis: cognitive testing, brain both the amnestic and nonamnestic groups, the per- imaging, and measurement of biomarkers in CSF. In addi- centage of people who had performance deficits differed tion, there is a growing body of research on other early significantly for different tests. However, the people who symptoms and changes that may signal the onset of AD. were most impaired on memory tests at the beginning of the study were also the most likely to have persistent memory deficits over the long term (Teng et al., 2009).
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 30 | Research Advances
The Mini Mental State Examination (MMSE) was Another source of diagnostic information, used in con- designed in 1975 and remains the most widely used junction with cognitive tests, is reports from family screening test for dementia. The MMSE is not sensitive members and other caregivers about how well a person to mild cognitive changes, nor is it very useful for dis- is functioning in day-to-day life. However, these infor- tinguishing between AD and other forms of dementia. It mant reports, too, may be affected by ethnic and cul- has remained in use in part because it is simple, quick to tural differences. Investigators from Duke University in administer, and can be used in any doctor’s office. Most Durham, NC, found that family member/caregiver clinical trials use MMSE scores to help determine who is reports were less likely to predict cognitive impairment eligible to participate. A number of new tests are under without dementia in African Americans than in whites development that retain those virtues but provide more (Potter et al., 2009). These results are consistent with sensitive and accurate diagnoses. For example, previous studies suggesting that African Americans are researchers at Mount Sinai Medical Center in Miami, less likely than whites to report cognitive changes in FL, reported on the Florida Brief Memory Screen, family members. This difference may reflect different which shows high sensitivity for detection of MCI and cultural perceptions of “normal” aging. For example, a takes only 3 to 4 minutes to administer. The test is research team at the University of Michigan and Boston available in Spanish and English, an important feature, University Alzheimer’s Disease Centers studied a group as linguistic issues can compromise test performance of 301 people in the Boston area, most of whom had (Loewenstein et al., 2009). personal experience with AD as a caregiver and/or rela- tive. Significantly more of the African American than Several computer-based tests have also been developed, white participants believed that memory impairment is most of which can be used with a standard personal com- an expected part of aging (Connell et al., 2009). puter. Most of these tests have to be administered and scored by a clinician, as is also true for pen and paper- based tests like the MMSE. University of Pittsburgh researchers reported on a new computer-based test, Computer Assessment of Mild Cognitive Impairment Looking to the Future: (CAMCI), that is both self-administered and automati- Cognitive Testing cally scored. The researchers reported a good sensitivity for detection of MCI (Saxton et al., 2009). he AD field is moving toward much earlier diagnosis. More sensitive measures that assess Additional 2009 advance related to cognitive testing: different cognitive domains in more diverse Schneider LS et al. (2009) Characteristics and performance of T populations are needed. To explore these issues, NIA held a modified version of the ADCS-CGIC CIBIC+ for mild cogni- a workshop in spring 2010, “Assessment of Cognition in tive impairment trials. University of Southern California. Supported by NIA, NCRR. Early Dementia.” The purpose was to review a range of computerized cognitive assessments to determine gaps and opportunities for further development, evaluate novel assessment methods and cognitive domains (e.g., spatial Ethnicity and AD diagnosis orientation, prospective memory), and determine the best Several reports have suggested racial and ethnic differ- ways to assess cognition in diverse populations. ences in the prevalence of AD. Studies seeking to Information from this meeting will be used in the near explain these differences have found that cultural factors future to decide which cognitive measures will be incor- and variations in education quality, for example, can porated into particular research studies. affect performance on standardized cognitive tests.
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 31 | Research Advances
Other Early Signs and Symptoms Visuospatial skills allow us to perceive objects and The clinical picture of AD is changing considerably. For the spatial relationships among them and to judge how many years since AD was first described in 1906, clini- close or far away we are from objects in our environ- cians believed that it was a rare disease affecting middle- ment. These skills are crucial for navigating city streets, aged adults. In the 1960s, at about the same time larger our own homes, or an assisted living facility. Researchers numbers of people were living past age 65, it became at the Washington University Alzheimer’s Disease evident that a similar disease occurred in older adults. At Center in St. Louis, MO, studied 444 older people, all the time, the clinical description of AD focused on the of whom were cognitively normal at the start of the symptom of memory loss, specifically, loss of the ability study. About 30 percent of them subsequently developed to form and recall memories of recent events. Now there AD. In this group, performance on tests of visuospatial is growing recognition that, even in its earliest stages, skill began to decline 3 years earlier on average than per- AD can affect other cognitive skills and disrupt mood formance on memory tests (Johnson et al., 2009). and behavior, sometimes even before memory is Investigators at the University of Rochester, NY, affected. Scientists are also increasingly aware that the provided further evidence that visuospatial skills can symptoms and course of AD can vary considerably from decline while memory remains relatively intact (Duffy, person to person, depending in part on whether an indi- 2009). The team studied navigational problems associ- vidual has other common diseases and conditions of old ated with AD, specifically, the question of why people age, such as vascular disease or diabetes. with AD tend to get lost in familiar environments. They found that the brain’s electrical responses to navigation Sensory Changes are reduced in people with early AD, and that this abil- Cognitive changes in the early stages of AD may include ity can be impaired even in people with no measurable deficits in the ability to process sensory information. memory deficits. NIA-supported research published in 2008 showed that Another report this year from the University of some people with AD begin losing their sense of smell Alabama, Birmingham Alzheimer’s Disease Center early in the course of the disease (see 2008 Progress found that in everyday life, people with MCI have worse Report on Alzheimer’s Disease; also additional references driving performance than their cognitively normal peers below). Research reported in 2009 suggests that visuo- (Wadley et al., 2009). The MCI group did not have spatial skills also may falter early on. worse visual acuity (sharpness of vision) than the control group. Thus, it is possible that the MCI group’s impaired driving performance reflected deficits in corti- cal visuospatial processing, similar to the navigation def- icits observed by the Rochester researchers. On the other Looking to the Future: hand, this impaired level of driving performance could Sensory and Motor Changes reflect changes in executive function (e.g., the ability to rapidly choose the appropriate action once you have hese studies and others suggest that examin- detected a potentially dangerous situation), given the ing sensory and motor changes in the context complexity of driving. Tof AD may offer fresh perspectives regarding the course, early detection, assessment, and treatment Additional advances in sensory changes: of AD. To further explore these new avenues for Murphy et al. (2009) Olfaction in aging and Alzheimer’s dis- research, NIA held an exploratory workshop in August ease: event-related potentials to a cross-modal odor-recognition 2010, “Sensory and Motor Dysfunctions in Aging and memory task discriminate ApoE epsilon4+ and ApoE epsilon 4- Alzheimer’s Disease (AD),” focusing on recent findings individuals. San Diego State University. Supported by NIA and in sensory and motor changes occurring early in the NIDCD. course of AD, gaps in knowledge, and strategies for Wilson et al. (2009b) Olfactory impairment in presymptom- advancing this area of research. Participants included atic Alzheimer’s disease. Rush University Alzheimer’s Disease experts from the fields of AD as well as leading Center. Supported by NIA. researchers in the relevant sensory and motor fields.
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 32 | Research Advances
Structural MRI Behavioral and Mood Problems During the course of AD, certain regions of the brain Many people with AD experience behavioral and mood shrink due to the degeneration of synapses and death of disturbances, including depression, irritability, and disin- neurons. Researchers have been using brain scans to try hibition (displays of socially inappropriate behavior). to detect such changes very early, before people have sig- Indeed, such “neuropsychiatric” symptoms are the pri- nificant cognitive impairment. A collaborative team of mary reason caregivers consider moving family members investigators from the University of Pennsylvania in with AD to nursing homes. Philadelphia and NIA’s Laboratory of Personality and Behavioral and mood disturbances also appear to be Cognition in Baltimore, MD, developed a pattern detec- associated with more rapid progression from MCI to tion program to analyze MRI scans obtained from ADNI dementia. Researchers at the Instituto Universitario participants. The program compared patterns of brain CEMIC in Buenos Aires, Argentina, in collaboration area loss over time in people with AD with those of cog- with Johns Hopkins University Alzheimer’s Disease nitively normal people the same age. Based on differences Center scientists, studied 239 people with MCI, of in these patterns, the program generated a kind of whom 36 percent had persistent neuropsychiatric symp- “search image” for AD-like changes, called the “spatial toms in addition to cognitive symptoms. They also pro- patterns of abnormality for recognition of early AD gressed more rapidly to dementia. During the period of (SPARE-AD).” The researchers then used the program to the study, 44 percent of the people with both MCI and analyze people enrolled in NIA’s Baltimore Longitudinal neuropsychiatric symptoms converted to AD, and 18 Study of Aging neuroimaging study. In that investiga- percent converted to frontotemporal dementia (FTD), a tion, people who had either MCI or memory decline degenerative dementia affecting the frontal and temporal with otherwise normal cognition had the highest lobes of the brain and causing changes in personality, SPARE-AD scores (Davatzikos et al., 2009). The study behavior, language, and movement. In contrast, only 18 suggests that sophisticated pattern detection methods percent of the people who had MCI without neuropsy- with MRI imaging may help identify cognitively normal chiatric symptoms converted to AD, and none to FTD individuals who are likely to show cognitive decline. (Taragano et al., 2009). A 1-year structural MRI study of 449 participants by Biomarkers and ADNI ADNI investigators at the University of California, San Francisco, found that people with AD and MCI lost vol- The Alzheimer’s Disease Neuroimaging Initiative (ADNI) ume in the hippocampus more quickly than did cogni- was launched in 2004 to determine which imaging tively normal people The losses were associated with methods and fluid biomarkers can best track and predict deteriorating scores on cognitive assessments. In people clinical change over time (more information on ADNI, with AD, higher rates of loss in hippocampal volume also page 54). As of fall 2010, ADNI scientists had collected 3 years of longitudinal data from more than 800 partici- pants (about 200 normal, 400 with MCI, and 200 with AD) at 59 U.S. and Canadian sites. In 2009, ADNI helped identify a number of precisely measurable, clini- cally relevant biomarkers that will enable more accurate diagnosis and prediction of disease course and also speed and cut the cost of clinical trials.
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 33 | Research Advances
In 2009, ADNI helped identify a number of precisely measurable, clinically relevant biomarkers.
correlated with the presence of the ApoE E4 gene, a risk responds to therapies. Like all ADNI results, these find- factor for Alzheimer’s. In people with MCI, higher rates of ings have been posted to a publicly accessible database hippocampal loss were associated with lower levels of the available to qualified researchers worldwide. peptide beta-amyloid 1-42 (AB1-42) in CSF. The finding of accelerating hippocampal loss is important for under- Additional advances in neuroimaging: standing the natural history of the disease and emphasizes Dickerson et al. (2009) The cortical signature of Alzheimer’s dis- the need for early diagnosis and therapeutic intervention, ease: regionally specific cortical thinning relates to symptom severity the study report noted (Schuff et al., 2009b). in very mild to moderate AD dementia and is detectable in asymp- Other ADNI studies, including one published by tomatic amyloid-positive individuals. Massachusetts General, researchers at the Mayo Clinic in Rochester, MN, have Harvard University. Supported by NIA, NINDS, and NCRR. shown that PET imaging holds potential for a different Fennema-Notestine et al. (2009) Structural MRI biomarkers use: the identification of people with AD pathology who for preclinical and mild Alzheimer’s disease. University of have not yet developed dementia. Detection of brain California, San Diego (ADNI). beta-amyloid could potentially be used as a risk factor to McEvoy et al. (2009) Alzheimer disease: quantitative structural predict future decline to AD (Jack et al., 2009). neuroimaging for detection and prediction of clinical and struc- tural changes in mild cognitive impairment. University of Cerebrospinal fluid California, San Diego. Supported by NIA (ADNI). Researchers took a major step forward in developing a test to diagnose early-stage AD by measuring two bio- Additional advances in biomarkers: markers—tau and beta-amyloid proteins—in CSF. Fagan et al. (2009a) Cerebrospinal fluid tau and ptau(181) Previous imaging studies had shown that AD-like increase with cortical amyloid deposition in cognitively normal indi- changes can occur in the brain years before any cogni- viduals: implications for future clinical trials of Alzheimer’s disease. tive symptoms appear. However, CSF testing costs less Washington University. Supported by NIA, NINDS, and NCRR. than brain imaging, so researchers have sought CSF bio- Fagan et al. (2009b) Decreased cerebrospinal fluid Abeta(42) marker changes correlated with the development and correlates with brain atrophy in cognitively normal elderly. progression of AD. A report from the ADNI Biomarker Washington University. Supported by NIA, NINDS, and NCRR. Core at the University of Pennsylvania School of Jagust et al. (2009) Relationships between biomarkers in aging Medicine in Philadelphia provided strong evidence that and dementia. University of California, Berkeley (ADNI). changes in CSF tau and beta-amyloid signal the onset of mild AD. Researchers also established a method for Okereke et al. (2009) Ten-year change in plasma amyloid beta levels and late-life cognitive decline. Harvard University. standardized testing for these biomarkers (Shaw et al., Supported by NIA and NCCAM. 2009). These results may open the door to the discovery of an entire panel of CSF biomarkers that will predict who is at risk of developing AD and how the disease
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 34 | Research Advances
Developing Novel the discovery of a new therapeutic target to the time a Therapeutic Approaches new drug receives FDA approval for use in the general 6 patient population (Paul et al., 2010). At each step of Translational research is a multidisciplinary effort that the translational process, there is a very high failure rate. enables the transfer of information between basic-science In recognition of the difficulties in moving basic scien- laboratory studies and clinical research for the purpose tific knowledge toward drug development, NIA’s Division of developing novel therapies. The discovery and devel- of Neuroscience instituted a series of funding initiatives opment of new drugs for neurological disorders is aimed at creating a robust AD translational research pro- extremely challenging and very expensive. On average, it gram. The aim is to increase the number of investigational takes more than 13 years and costs $1.78 billion from new drugs that can then be tested in humans.
NIA’s Alzheimer’s Disease Translational Research Program
Target Discovery Basic Research
Target Validation
Assay Development Screening, Hits to Leads PAS 10-151 (R21) Drug Discovery PAR 10-001 (R01) { PAR 10-002 (R21)
Lead Selection and AD Pilot Clinical Trials, PAR 08-062 (R01) Lead Optimization Alzheimer’s Disease Cooperative Study (U01) PAR 10-205 (U01) Investigator Initiated Clinical Trials (R01)
NIA Development Development
Preclinical Preclinical Drug IND-enabling Toxicology Successful Therapeutic { Contract Services IND Clinical Development Intervention for AD
Industry
During the last 5 years, NIA launched a series of funding initiatives 10-001 and PAR 10-002).The U01 program in conjunction with to support early drug discovery and preclinical therapy develop- toxicology services provided through an NIA contract enable ment for AD. The funding opportunity PAS 10-151 supports explor- researchers involved in preclinical development of candidate thera- atory drug discovery research using the R21 grant mechanism, and peutics to secure an Investigational New Drug (IND) status from the the funding opportunity PA 10-205 supports the preclinical devel- FDA. Once a compound has received an IND status, the multiple opment of promising candidate therapeutics through a cooperative steps of testing in humans (clinical development) can be pursued agreement mechanism (U01). In addition, NIA participates in drug either by the pharmaceutical industry or through NIA’s clinical trial discovery funding opportunities initiated by other Institutes (PAR funding opportunities or clinical trial consortium (ADCS).
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 35 | Research Advances
Drug Discovery and agents that inhibit Hsp90 can protect neurons against Preclinical Development beta-amyloid toxicity as well as tau aggregation. A drug NIA support provides critical investments in the riskiest discovery research team from the University of Kansas in early steps of AD drug discovery and preclinical drug Lawrence involved in the design of novel Hsp90 inhibi- development, which the pharmaceutical industry is tors for AD reported that three new analogues of the unlikely to pursue. The NIA Translational Research Hsp90 inhibitor novobiocin provide excellent neuropro- Program funds a diverse portfolio of more than 60 proj- tection, with little, if any, toxicity in a cell culture model ects, ranging from early drug discovery to preclinical of beta-amyloid (Lu Y et al., 2009). development of novel therapeutic compounds aimed at a variety of targets (see Petanceska et al., 2009, for a Old drug, new purpose detailed summary). Memory is governed by long-term changes in nerve cell To date, this Program includes more than a dozen firing patterns, which in turn require changes in the preclinical drug development projects focused on 1) pre- expression of certain neuronal genes. Regulation of gene clinical optimization of novel therapeutic candidates, expression is the business of proteins called “transcrip- 2) repurposing and/or reformulation of drugs currently tion factors.” The activity of one such factor, CREB in use to treat other disease conditions, and 3) preclini- (which seems to be particularly important in memory cal development of naturally occurring compounds. formation) can be increased using the drug sildenafil Following are examples of new candidate therapeutics (Viagra®). When scientists at Columbia University in for each of these three areas. New York, supported by NIA and NINDS, applied sildenafil to hippocampal cells from AD model mice in Novel compounds tissue culture, they saw immediate and long-lasting Tau aggregation inhibitors. One of the hallmarks of improvements in synaptic function. In addition, short- AD is the abnormal clustering of the tau protein into term (2- to 3-week) administration of sildenafil to living neurofibrillary tangles (see A Brief Primer on AD and the AD model mice significantly improved their perfor- Brain, page 11). Tau has emerged as an attractive thera- mance in memory tests up to 3 months later. peutic target for AD and other neurodegenerative dis- Interestingly, the drug also reduced beta-amyloid levels eases, commonly known as tauopathies. A multidisci- in these mice, perhaps through its effects on gene plinary team from the University of Pennsylvania in expression (Puzzo et al., 2009). Philadelphia reported the discovery in mice of two can- didate compounds that are effective inhibitors of tau Nature to the rescue aggregation and can penetrate the blood brain barrier Data from epidemiological studies and laboratory exper- after being orally administered (Ballatore et al., 2010). iments suggest that gonadal steroid hormones (sex ste- The Translational Research Program is supporting the roids) and their metabolites can promote neuronal further preclinical optimization of these compounds. health, while their decline or absence is associated with higher risk of neurodegenerative disease, including Hsp90 inhibitors. Heat shock protein 90 (Hsp90) is a Alzheimer’s (see Estrogen, page 25). One of the steroids member of a large family of molecules that help regulate that declines in the aged brain, and in AD brains in par- the transformation of healthy cells to diseased ones. Until ticular, is allopregnanolone. Previous experimental evi- recently, Hsp90 was mostly known for its involvement in dence demonstrated the ability of this neurosteroid to malignant transformation in cancer. But several laborato- stimulate the production of neuronal progenitor cells ries have now provided evidence that Hsp90 plays a role (cells that ultimately develop into functional neuronal in maintaining the stability of abnormally folded neuro- cells in the brain) in rodent models. A multidisciplinary nal proteins, allowing the accumulation of toxic aggre- team from the University of Southern California in Los gates (Luo et al., 2010). Previous research has shown that Angeles initiated a translational project focused on the preclinical development of allopregnanolone as a regen- erative AD therapeutic. The team reported that allopreg- nanolone can rescue the loss of neurogenic potential in a
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 36 | Research Advances transgenic mouse model of AD and reverse associated These findings indicate that BDNF has multiple protec- cognitive decline (Wang JM et al., 2010). The USC tive effects on the neuronal systems that deteriorate dur- team is currently identifying a formulation and dosing ing AD and suggest that therapeutic delivery of BDNF regimen for allopregnanolone that will result in an opti- or other means of stimulating BDNF activity holds mal efficacy and safety profile for testing in future clini- promise as a therapeutic approach for the disease. cal trials in humans. Stem cell therapy for AD Additional advances in drug discovery and preclinical Neural stem cells—cells present in both embryonic and drug development: adult neural tissue that have the capacity to develop into
Cohen AD et al. (2009a) Anti-amyloid effects of small mole- neurons—have received less consideration as therapy for cule Abeta-binding agents in PS1/APP mice. University of AD than for other neurodegenerative disorders like Pittsburgh. Supported by NIA. Parkinson’s disease and stroke. Because AD affects a wide variety of cell types across widespread regions of Ma QL et al. (2009) Beta-amyloid oligomers induce phosphor- ylation of tau and inactivation of insulin receptor substrate via the brain, it seemed implausible that many different cells c-Jun N-terminal kinase signaling: suppression by omega-3 fatty could be replaced using stem cells. Recently, however, acids and curcumin. University of California, Los Angeles. scientists have realized that stem cells can improve brain Supported by NIA and NCCAM. function not only by replacing lost cells, but also by promoting the survival and function of remaining cells. Researchers at the University of California, Irvine, New Therapeutic Targets supported by NIA and NIAMS, took neural stem cells As scientists continue to learn more about the complexity from newborn normal mice and transplanted them into of the processes and mechanisms of AD, they are also dis- the hippocampal regions of aged AD model mice with covering potential new targets for attacking the disease and widespread plaques and tangles. The transplanted neural new approaches for treating it. These basic research findings stem cells reversed spatial learning and memory deficits in are the stepping stones for translational research efforts that the older mice. They did so not by reducing plaques or ultimately may lead to new, effective drug therapies. tangles in their brains, but by promoting the growth of new synapses in surrounding brain tissue. The beneficial Nourishing the brain with its own growth factor effect of these stem cells turned out to be due to their Brain-derived neurotrophic factor (BDNF), a growth fac- secretion of the growth factor BDNF (Blurton-Jones et al., tor produced by neurons, is essential for early brain 2009). This study is important because it suggests the development and healthy brain function in adulthood. potential of neural stem cell therapy in AD and shows its Among other actions, BDNF supports nerve cell growth beneficial effects in old transgenic mice with substantial and survival and promotes synaptic outgrowth and plas- AD-like pathology in their brains. ticity. In people with AD, BDNF levels are abnormally Clearing out beta-amyloid low in certain brain regions where neurons are dying. To test the possible therapeutic effects of BDNF, researchers A number of potential new therapeutic targets are emerg- at the University of California, San Diego used a gene ing from studies of the multiple mechanisms by which therapy approach in several animal models of AD and beta-amyloid is removed or cleared from the brain. Beta- aging. They found that BDNF had beneficial effects in amyloid clearance is accomplished by proteins on brain all of the models. In AD model mice, it induced recovery blood vessels that bind beta-amyloid and transport it out of synapses and synaptic signaling markers and improved of the brain and into the blood. A research team at spatial memory. In rats, BDNF prevented the death of Washington University in St. Louis, supported by NIA cortical nerve cells that were exposed to beta-amyloid in and the NIH Neuroscience Blueprint, showed that by tissue culture. BDNF gene therapy also had positive experimentally increasing levels of the beta-amyloid effects on spatial learning and memory in the aged rats, transport protein LRP-1 in the mouse brain, it was possi- as well as in nonhuman primates (Nagahara et al., 2009). ble to dramatically enhance beta-amyloid clearance and reduce its accumulation (Kim J et al., 2009). Work by another team of investigators at the University of Rochester, NY, supported by NIA,
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 37 | Research Advances
NINDS, and NHLBI, raised the possibility that beta- Testing Therapies for amyloid clearance by the same transport protein is dis- Prevention and Treatment rupted in some forms of AD. They found that LRP-1 7 production is suppressed by two gene regulatory pro- AD Clinical Trials teins (SRF and myocardin) present in abnormally high Clinical trials, which compare a potential new treatment levels in the brain blood vessels of some people with with a standard treatment or a placebo (an inactive sub- AD. Levels of these regulatory proteins in turn are stim- stance), are the only way to demonstrate whether a drug ulated by low blood oxygen levels, a condition associated or other type of treatment is safe and effective in with AD (Bell et al., 2009). humans. The first stage of human trials, Phase I, involves testing a new treatment in a small group of healthy peo- Additional advances related to translational research and ple to evaluate safety and tolerability. In Phase II, the beta-amyloid clearance: treatment is given to a larger group of people with the
Lakshmana et al. (2009) Novel role of RanBP9 in BACE1 disease to see if it is effective and to further evaluate processing of amyloid precursor protein and amyloid beta pep- safety. In Phase III, the last stage before a treatment is tide generation. University of California, San Diego. Supported approved by the FDA, the treatment is given to a large by NIA. group of people with the disease to confirm its effective-
Lakshmana et al. (2010) A fragment of the scaffolding protein ness and monitor safety. Phase III trials are complex and RanBP9 is increased in Alzheimer’s disease brains and strongly expensive, involving hundreds or even thousands of peo- potentiates beta-amyloid peptide generation. University of ple and often conducted over long periods of time. California, San Diego. Supported by NIA. In AD, some clinical trials focus on treatment—
Oddo et al. (2009) Genetically altering Abeta distribution from strategies to preserve cognitive function for as long as the brain to the vasculature ameliorates tau pathology. University possible and alleviate behavioral or psychiatric problems. of California, Irvine. Supported by NIA. Other trials aim to delay progression from MCI to AD (secondary prevention). Still others focus on primary Persaud-Sawin et al. (2009) Raft aggregation with specific receptor recruitment is required for microglial phagocytosis of prevention—strategies to help cognitively healthy people Abeta42. NIEHS Intramural Program. reduce the risk of developing AD in the future. NIA provides both infrastructure and funding opportunities for clinical development of AD therapeu- tics. The major clinical trial programs are the Alzheimer’s Disease Cooperative Study (ADCS) and the AD Pilot Clinical Trials Initiative (see additional information, pages Looking to the Future: 53 and 56). These programs are in addition to continued Translational Research support of investigator-initiated clinical trials for AD, MCI, and age-related cognitive decline. lthough NIA’s AD Translational Research Program has built significant momentum, much remains to Results from completed AD clinical trials A be done. To this end, NIA held an advisory panel Two trials published in 2009 support the notion that workshop on “Alzheimer’s Disease Preclinical Therapy AD progression can be slowed by targeting symptoms Development” in October 2010. This meeting convened other than memory loss (for example, depression or leading therapy development experts from academia, bio- sleep apnea, in the trials reported here). A third study technology and pharmaceutical companies, and disease- argues against the popular belief that gingko biloba is focused foundations to develop recommendations for effective in preventing cognitive decline. Eleven addi- continued improvements in translational research efforts. tional clinical trials reached completion this year; the results are still being analyzed and/or awaiting publica- tion (see Recently Completed Trials, page 40).
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 38 | Research Advances
Slowing progression to AD among people with MCI and depression People with MCI are at higher risk for progressing to AD if they also have neuropsychiatric symptoms such as Two trials found that AD depression, apathy, or anxiety. The Alzheimer’s Disease Cooperative Study (ADCS) examined the effects of progression can be slowed by targeting depression on progression from amnestic MCI to AD in 208 people who had depression and 548 who did not. symptoms other than memory loss, Symptoms of depression were assessed as a secondary such as depression or sleep apnea. outcome measure as part of the ADCS trial of donepezil (Aricept®), vitamin E, and placebo in participants with MCI. Study investigators reported that depressed patients were more likely to progress from MCI to AD those who discontinued CPAP use. Importantly, caregiv- than nondepressed patients. Also, the proportion of ers of people in the CPAP group reported that their sleep depressed patients progressing to AD was significantly was better and that the patients’ behavioral disturbances lower for the donepezil group than for the combined improved (Cooke et al., 2009). The results of this small vitamin E/placebo group for a little more than 2 years study suggest that long-term CPAP treatment for patients and remained marginally lower for up to 2.7 years. with AD and obstructive sleep apnea may slow cognitive Nondepressed MCI patients who received donepezil decline and produce lasting improvements in sleep and initially exhibited a slower rate of progression compared mood. Larger randomized controlled trials are needed to to the vitamin E and placebo groups, but by 2 years test these findings. (See also Amyloid and Sleep, page 17.) there was no difference between the groups. These findings demonstrate that donepezil can reduce the Gingko not effective in reducing increased risk of progression to AD in MCI patients risk of AD or cognitive decline with depressive symptoms (Lu PH et al., 2009). Gingko biloba is a widely marketed supplement used by people hoping to improve their cognitive health. The larg- Treatment of sleep apnea may slow cognitive decline est double-blind, randomized controlled trial to date, the Obstructive sleep apnea is common among people with Ginkgo Evaluation of Memory (GEM) study, included AD. The condition reduces brain oxygen levels and 3,069 community-dwelling older adults aged 72 to 96 disrupts normal sleep patterns and thus may exacerbate years who had either normal cognition or MCI. The study, cognitive and behavioral problems in people with AD. funded by NCCAM, NIA, and NHLBI, was conducted Researchers at the University of California, San Diego, in six academic medical centers in the United States supported by NIA and NCRR, evaluated the long-term between 2000 and 2008. The primary analysis demon- effects of continuous positive airway pressure (CPAP) strated that gingko was not effective in reducing risk of treatment in a small sample of 10 people who had partici- either AD or dementia overall. To learn if ginkgo has more pated in a larger 6-week randomized controlled trial of subtle effects on cognitive health, GEM investigators ana- CPAP in AD patients with obstructive sleep apnea. Five lyzed additional data from this trial. They found no signif- of the participants had continued CPAP use for a little icant effect on cognitive decline or on more specific more than a year after the larger trial ended, and the other measures of memory, attention, visuospatial skill, language, five had not. Those who continued CPAP use showed less and executive functioning (Snitz et al., 2009). cognitive decline and daytime sleepiness, greater stabiliza- tion of depressive symptoms, and better sleep quality than
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 39 | Research Advances
Observational studies on treatments There has been increasing interest in combination ther- Recently Completed Trials apy for AD—simultaneous administration of two or more drugs or behavioral interventions. Investigators at the University of Pittsburgh Alzheimer’s Disease he following clinical trials supported by NIA were Research Center looked at the effects of combined treat- recently completed and are undergoing data analysis: T ment with drugs from each of the two major classes cur- ACCORD–MIND (Action to Control Cardiovascular Risk in rently approved to treat AD, cholinesterase inhibitors Diabetes–Memory in Diabetes)—NIA-funded primary and an NMDA receptor blocker (memantine). They prevention add-on trial to NHLBI’s ACCORD trial studied data from 943 probable AD patients at the Principal Investigator (PI): Lenore Launer, NIA Intramural Center from April 1983 to December 2004 who had Research Program been treated with a cholinesterase inhibitor alone, a cho- ESPRIT (Evaluating Simvastatin’s Potential Role in Therapy) linesterase inhibitor plus memantine, or no medication. PI: Cynthia Carlsson, University of Wisconsin The researchers found that those treated with two drugs RECALL (Rosiglitazone Effects on Cognition for Adults in delayed admission to a nursing home significantly longer Later Life) than those who took just one drug (Lopez et al., 2009). PI: Suzanne Craft, University of Washington/VA Medical Center Cholinesterase inhibitors may ameliorate some types SNIFF 120 (Study of Insulin to Fight Forgetfulness, 120 Days) of behavioral symptoms in AD patients, but what hap- PI: Suzanne Craft, University of Washington/VA Medical Center pens when those drugs are stopped? Researchers at SHARP-P (Seniors Health and Activity Research Brown University in Providence, RI, found that discon- Program Pilot) tinuation of cholinesterase medications in nursing home PI: Mark Espeland, Wake Forest University residents with dementia who had been treated for 3 to 9 Transdermal Nicotine Treatment of MCI months was associated with some worsening behavioral PI: Paul Newhouse, University of Vermont changes and less time engaged in leisure-related activities compared to residents who received longer-term treat- Investigators are preparing and submitting results for publication ment (greater than 9 months) (Daiello et al., 2009). from the following completed clinical trials supported by NIA: Ongoing clinical trials Huperzine A in Alzheimer’s Disease—ADCS PI: Paul Aisen, University of California, San Diego Alzheimer’s Disease Cooperative Study VALID (Valproate in Dementia)—ADCS The ADCS, a large clinical trials consortium with sites PI: Pierre Tariot, Banner Alzheimer’s Institute throughout the United States and Canada, is a major ini- CLASP (Cholesterol Lowering Agent to Slow Progression tiative for AD clinical trials in the Federal Government. It of Alzheimer’s Disease Study)—ADCS addresses treatments for cognitive and behavioral symp- PI: Mary Sano, Mount Sinai toms (see additional information on page 53). The ADCS Antioxidant Trial (Vitamins E and C, alpha lipoic acid, mission is to advance research in the development of clin- coenzyme Q)—ADCS ical trial designs, instruments, and interventions that PI: Douglas Galasko, University of California, San Diego might be useful for treating patients with AD, particularly PREPARE (Prevention of Postmenopausal Alzheimer interventions that might not be developed by industry. Disease and Cognitive Loss with Replacement Estrogen) The most recent round of new ADCS studies, PI: Mary Sano, Mount Sinai funded in October 2006, explore a variety of approaches: Docosahexaenoic acid (DHA). This completed trial examined whether treatment with DHA, an omega-3 fatty acid found in fish, would slow cognitive decline in people with AD. Observational studies associate high fish con- sumption with reduced risk of AD in people, and studies in mouse models of AD show that dietary DHA reduces
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 40 | Research Advances brain levels of beta-amyloid, oxidative damage associated trials, two are NIA-funded cognitive/AD measure add-ons with beta-amyloid, and neurotoxicity. The manuscript of to large NIH primary prevention trials that address a vari- the results has been accepted for publication in the Journal ety of other primary outcomes. One such trial is NHLBI’s of the American Medical Association (JAMA). Systolic Blood Pressure Intervention Trial (SPRINT), which will evaluate the health effects of lowering systolic Intravenous immunoglobulin (IVIg). IVIg, a blood blood pressure from 140 mmHg to 120 mmHg. The product that is administered intravenously, contains natu- add-on study, SPRINT-MIND, funded by NIA and rally occurring antibodies against beta-amyloid. Preliminary NINDS, will assess the effect of lowering systolic blood studies have shown that IVIg may improve cognition, and pressure on cognitive decline and development of MCI research has demonstrated that IVIg increases levels of anti- and AD. The study will also use brain imaging to measure beta-amyloid antibodies in plasma and promotes clearance treatment effects on brain structure, including white mat- of beta-amyloid from CSF. This ongoing Phase III, double- ter lesions typical of vascular disease. blind randomized controlled trial will demonstrate whether A number of the prevention trials are focusing on IVIg is effective in treating AD. lifestyle interventions, including exercise, cognitive Home-based assessment. This ongoing study, con- training, and a combination of the two. Other preven- ducted in people aged 75 and older, will examine the tion trials examine how treatments for diabetes might development and use of three types of home-based assess- reduce risk of AD. Diabetes is associated with the devel- ments: 1) a low-technology telephone assessment, 2) a opment of AD, and insulin regulation has been shown high-technology automated telephone assessment, and 3) to be disrupted in AD. Two trials are examining the a high-technology computer assessment. Cognition, daily effect of the diabetes medications metformin and piogli- functioning, mood, and other factors will be evaluated in tazone on cognition and progression to AD in MCI each of the methods. These innovative assessment and subjects who are also obese. The trial using pioglitazone data collection tools will be compared to traditional compares the effects of the medication and exercise in-person measures. The findings from this study will (endurance training) as well as a placebo. provide information on how home-based assessments Another recently completed diabetes-related trial might be used in prevention trials. Such methods could (SNIFF-120) examined the effects of intranasal insulin in significantly reduce the cost and increase the feasibility of people with MCI or early AD. The idea is that restoring participation in long-term clinical trials. normal insulin function in the brain may provide cogni- tive benefit and slow disease progression. Administering Resveratrol. This Phase II, double-blind randomized insulin through the nose does not result in increased controlled trial, scheduled to begin in 2011, will eval- peripheral insulin levels, and the drug enters the brain uate the impact of resveratrol treatment on AD bio- within 15 minutes. Data analysis is ongoing for this trial. markers and clinical outcomes in patients with mild to Table 2 summarizes treatment trials to delay the moderate AD. Resveratrol, a compound found in grapes progression of AD and to treat the behavioral distur- and wine, has been shown in animal studies to be neu- bances typical of the disease. It also summarizes several roprotective, and observational studies have shown that trials that are testing biomarkers and performing feasi- moderate consumption of red wine is associated with a bility studies. Taken together, the trials test a wide range lower incidence of AD. of potential therapies. Several are due to be completed in the next 2 years; other longer trials will not finish NIH currently supports 37 active clinical trials, data collection until 2014 or later. It is important to including pilot and large-scale trials, of a wide range of note that the year the trial is completed does not include interventions to prevent, slow, or treat AD and/or MCI the additional time necessary for analysis of data and (see Ta b l e 1 and Ta b l e 2). In particular, the NIA is cur- publication of findings. rently funding seven primary prevention and six second- ary prevention trials (Table 1). Of the primary prevention
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 41 | Research Advances
TABLE 1. Ongoing AD/MCI Prevention Clinical Trials Funded by NIA
Principal Anticipated Investigator/ Type Completion Trial Name Institution Intervention Population of Trial Date Antioxidants PREADVISE (Prevention Frederick Schmitt, Vitamin E, Selenium, Men age 60-90 Primary 2014 of Alzheimer’s Disease Univ. of Kentucky Vitamin E + Selenium Prevention by Vitamin E and Selenium)* Vitamin E in Aging Arthur Dalton, Vitamin E People age 50+ with Primary 2012 Persons with Down NY State Inst. for Basic Down syndrome, at high risk Prevention Syndrome Research in of developing AD Developmental Disabilities Omega-3 Fatty Acids and Antioxidants AREDS2 (Age-Related John Paul San Giovanni Macular xanthophylls People age 50-85 with Primary 2015 Eye Disease Study 2)† (Study Director), NEI (lutein and age-related macular Prevention zeaxanthin) and/or degeneration (AMD) in both omega-3 fatty acids eyes or advanced AMD (DHA and EPA) in one eye Cardiovascular ASPREE (Aspirin in Richard Grimm, Aspirin Healthy adults age 70+ Primary 2017 Reducing Events in Berman Center for Prevention the Elderly) Outcomes & Clinical Research; John McNeil, Monash Univ. SPRINT-MIND David Reboussin, Wake Blood pressure Adults age 55+ with systolic Primary 2017 (Systolic Blood Forest Univ. lowering to blood pressure of 130 mmHg Prevention Pressure Intervention <140 mmHg versus or higher, history of Trial-MIND)* <120 mmHg cardiovascular disease, high risk for heart disease Hormones ELITE (Early Versus Howard Hodis, 17B-estradiol Healthy early (less than 6 Primary 2014 Late Intervention with Univ. of Southern years) or late (10 years+) Prevention Estradiol) California menopausal women
SMART Michael Vitiello, Growth hormone People with MCI and healthy Secondary 2011 (Somatotrophics, Univ. of Washington releasing hormone older adults age 55-80 Prevention Memory, and Aging (GHRH) Research Trial) Testosterone Monique Cherrier, Testosterone Older men with MCI and Secondary 2011 Supplementation in Univ. of Washington low testosterone Prevention Men with MCI
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 42 | Research Advances
Principal Anticipated Investigator/ Type Completion Trial Name Institution Intervention Population of Trial Date Diabetes Metformin in Amnestic Jose Luchsinger, Metformin Overweight/obese older Secondary 2012 MCI Columbia Univ. adults with MCI Prevention Pioglitazone & Exercise Robert Schwartz, Univ. Pioglitazone Overweight/obese older Secondary 2012 Effects on Older Adults of Colorado, Denver adults with MCI Prevention with MCI and Metabolic Syndrome Exercise, Cognitive Training Exercise Versus David Loewenstein, Cognitive training, People with MCI Secondary 2012 Cognitive Interventions Mount Sinai Medical aerobic exercise Prevention for Elders at Risk for Center, Miami training, cognitive Dementia training + aerobic exercise training Lifestyle Interventions Marco Pahor, Aerobic exercise, Adults age 70+ Primary 2015 and Independence for Univ. of Florida resistance, and Prevention Elders (LIFE) flexibility exercises Memory Training Miriam Mintzer, Johns Repetition lag training People with MCI Secondary 2014 Intervention in Mild Hopkins Univ. procedure (RLTP) Prevention Cognitive Impairment
Note: For information on new and currently recruiting trials, visit: www.nia.nih.gov/Alzheimers/ResearchInformation/ClinicalTrials or www.ClinicalTrials.gov. NIA-funded primary prevention add-on trials: PREADVISE (add-on to National Cancer Institute’s SELECT trial); SPRINT-MIND (add-on to National Heart, Lung, and Blood Institute’s and National Institute of Diabetes and Digestive and Kidney Diseases’ SPRINT trial; co-funded with the National Institute of Neurological Disorders and Stroke). † Co-funded primary prevention trial: AREDS2 (National Eye Institute, lead institute).
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 43 | Research Advances
TABLE 2. Ongoing AD/MCI Treatment, Biomarker, and Feasibility Clinical Trials Funded by NIA
Anticipated Principal Investigator/ Completion Trial Name Institution Intervention Population Date Cardiovascular Effects of Simvastatin Gail Li, Univ. of Washington Simvastatin Cognitively normal 2013 on CSF AD Biomarkers adults age 45-64 in Cognitively Normal Subjects Statin Effects on Cynthia Carlsson, Simvastatin Adults at high risk 2013 Beta-Amyloid and Univ. of Wisconsin, Madison of AD (family history, Cerebral Perfusion in APOE4) age 45-65 Adults at Risk for AD Hormones Alzheimer’s Disease: Carey Gleason, Novasoy (soy isoflavones– People with AD 2010 Potential Benefit of Univ. of Wisconsin, Madison phytoestrogens) Isoflavones Estrogen Receptor-beta Lon Schneider, ER2-selective Postmenopausal 2014 phytoSERMs for Univ. of Southern California phytoestrogens women age 50-59 Management (phytoSERMs–selective estrogen receptor modulators) Raloxifene for Women Victor Henderson, Raloxifene Older women 2012 with Alzheimer’s Disease Stanford Univ. with AD Exercise, Cognitive Training Aerobic Fitness in Jeffrey Burns, Aerobic exercise training People with AD 2014 Slowing the Progression Univ. of Kansas of AD Conversational Hiroko Dodge, Oregon Internet-based Adults age 75+ 2014 Engagement as a Means Health & Science Univ. conversational engagement to Delay AD Onset Effects of Standardized Thomas Obisesan, Aerobic exercise training African Americans 2012 Aerobic Exercise Training Howard Univ. with AD on Neurocognition and Neurodegeneration MCI: Cerebrovascular Rong Zhang & Endurance exercise training People with MCI 2014 Dysfunction and Hanzhang Lu, Univ. of Exercise Training Texas Southwestern Neural Effects of Stephen Rao, Cognitive training, Healthy adults age 2012 Exercise, Cognitive, or Cleveland Clinic aerobic exercise training, 65-85 Combined Training in cognitive training + aerobic AD At-Risk Elders exercise training
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 44 | Research Advances
Anticipated Principal Investigator/ Completion Trial Name Institution Intervention Population Date Other Interventions AAV-NGF Gene Delivery Paul Aisen, Univ. of Nerve growth factor (NGF) People with AD 2014 in Alzheimer’s Disease California, San Diego gene delivery ADMIT (Alzheimer’s Disease Chris Callahan, Home-based People with AD 2016 Multiple Intervention Trial) Indiana Univ. occupational therapy fMRI Activation in Mild Michela Gallagher, Levetiracetam People with MCI 2012 Cognitive Impairment Johns Hopkins Univ. Glucose Regulation and Suzanne Craft, Improved insulin resistance, People with AD and 2016 Memory in Alzheimer’s Univ. of Washington 3 studies: diet, triglyceride age-matched healthy Disease emulsion, rosiglitazone older adults Intravenous Immunoglobulin Norman Relkin, Weill IVIg People with AD 2013 (IVIg) for Treatment of AD Medical College, Cornell Univ. (passive immunization)* Lipoic Acid and Omega-3 Lynne Shinto, Oregon Lipoic acid and/or omega-3 People with AD 2014 Fatty Acids in AD Health & Science Univ. fatty acids (DHA and EPA) Thalidomide as BACE1 Marwan Sabbagh, Banner Thalidomide People with AD 2012 Inhibitor in AD Sun Health Research Inst. Therapeutic Effects of Grover Cleveland Gilmore, Cataract removal surgery People with AD 2014 Cataract Removal in AD Case Western Reserve Univ. Behavioral Disturbance Interventions ADMET (Apathy in Jacobo Mintzer, Medical Methylphenidate People with AD 2012 Alzheimer’s Disease Univ. of South Carolina; Methylphenidate Trial) Krista Lanctot, Sunnybrook Health Sciences Center; Paul Rosenberg, Johns Hopkins Univ. Antipsychotic Davangere Devanand, Risperidone People with AD 2011 Discontinuation in AD NYSPI/Columbia Univ. CITAD (Citalopram Constantine Lyketsos, Citalopram People with AD 2014 Treatment for Agitation in Johns Hopkins Univ. Alzheimer Dementia) Light Treatment for Sleep/ Jerome Yesavage, Light treatment People with AD and 2010 Wake Disturbances in AD Stanford Univ. their caregivers Prazosin Treatment for Elaine Peskind, Prazosin People with AD 2013 Disruptive Agitation in Univ. of Washington Alzheimer’s Disease TREA (Treatment Routes Jiska Cohen-Mansfield, TREA-systematic approach Nursing home 2012 for Exploring Agitation) Research Inst. on Aging to individualizing residents with nonpharmacological AD/dementia interventions for persons with dementia Note: For information on new and currently recruiting trials, visit: www.nia.nih.gov/Alzheimers/ResearchInformation/ClinicalTrials or www.ClinicalTrials.gov. *Alzheimer’s Disease Cooperative Study trial
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 45 | Research Advances
Looking to the Future: Biomarkers and AD Clinical Trials
D clinical trials have progressed Prevention Trial) and GEMS (Ginkgo disease in the living brain. Their use in from a focus on symptomatic Evaluation of Memory Study), that using clinical trials may show whether a partic- A treatment to disease modifica- as endpoints the progression from nor- ular intervention affects underlying brain tion to halting the progression from MCI mal cognition to a clinical diagnosis of pathology more quickly than traditional to AD (secondary prevention) to prevent- MCI/AD or changes in cognition takes 8 clinical/neuropsychological outcome ing MCI/AD (primary prevention). Many to 10 years and costs tens of millions of measures would. These biomarkers could researchers believe that prevention trials dollars. also be used as selection factors to that are started before AD pathology has Based on the results of ADNI and determine which normal subjects, for taken hold have the best chance of a similar imaging and fluid biomarker stud- example, have significant beta-amyloid positive result. However, the conduct of ies, the AD clinical trials community is loads in their brains and may be at high- prevention trials needs to become more starting to consider the use of biomark- er risk of progression to MCI/AD in a clin- efficient by reducing the time and/or ers as potential endpoints in prevention ical trial. Discussions about the feasibility number of subjects involved, each of trials. Biomarkers such as structural MRI, and cost of such biomarker prevention which would reduce the cost. It is clear amyloid PET imaging, FDG PET, and CSF trials are ongoing, but this is certainly an from completed AD prevention trials, protein concentrations may ultimately area of research that will be much more such as ADAPT (AD Anti-Inflammatory provide a window into the course of the prominent in the near future.
Clinical Trials to Maintain or Improve Trial results Cognitive Function with Age There is widespread popular belief that mental fitness As the population ages, there is growing interest not can be increased with consistent brain exercise (e.g., only in preventing AD but in maintaining general good crossword puzzles, Web-based games). To date, clinical cognitive function and health throughout life. Although trials have yielded little clear evidence to support this modest in comparison with AD, cognitive decline asso- notion. This year, however, two clinical trials reported ciated with normal aging significantly compromises that different cognitive training protocols improved quality of life and independent living. Terms like “use it certain aspects of cognitive function in older adults. or lose it” refer to mental fitness and perhaps how exer- The Improvement in Memory with Plasticity-based cise or diet might keep cognitive decline at bay. NIA is Adaptive Cognitive Training (IMPACT) study tested a testing a number of interventions to see if they might computer-based training intervention designed to directly benefit cognitive health. As these tests move for- improve speed and accuracy of auditory information ward, NIH encourages the adoption of healthy lifestyle processing in a randomized trial with 487 cognitively practices, as some, like exercise and social engagement, normal older adults age 65 and older in San Francisco are known to reduce risk of other diseases or are other- and Los Angeles, CA, and Rochester, MN. wise important as people age. Investigators found that training on one particular set of auditory tasks can improve a person’s performance
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 46 | Research Advances
NIA is testing a number of different interventions to see if they might directly benefit cognitive health.
on other auditory tasks and that participants who correlated with increased activity in prefrontal cortex rel- received training later showed improved performance on ative to controls (Carlson et al., 2009). The results indi- not only the specific exercises they had been trained cate that an intervention designed to promote better with, but other auditory memory and attention exercises cognitive function through everyday activity may as well. (Smith et al., 2009) enhance plasticity in relevant brain regions. Larger stud- In another study of 66 cognitively normal adults ies will be necessary to validate these findings. ages 65 to 75 at Wake Forest University in Winston- Salem, NC, supported by NIA, NINDS, and NCRR, Additional advance in remediating age-related cognitive researchers observed significant benefits of an interven- impairment: tion aimed at improving the brain’s ability to focus on Hertzog et al. (2009) Enrichment effects on adult cognitive one set of visual or auditory signals while resisting dis- development: can the functional capacity of older adults be traction by irrelevant ones (Mozolic et al., 2009). These preserved and enhanced? trials showed training effects on highly related tasks, but leave the question unanswered as to what sort of brain exercise, or combination of exercises, could improve Ongoing trials on age-related cognitive function cognitive performance more broadly. NIA currently supports 27 active clinical trials, includ- The Experience Corps study from Johns Hopkins ing pilot and large-scale trials as well as treatment stud- University in Baltimore, MD, supports the concept that ies, to better understand the mechanisms related to activities aimed at enriching life experience can lead to cognitive decline and to better target interventions (see positive changes in specific brain circuits in older people. Table 3). Approaches include cognitive training, exercise, Employing an “immersion” intervention that combined nutritional supplementation, hormone therapy, combi- physical, social, and cognitive activity simultaneously nations of these, and pharmacological intervention. In through participation in a volunteer program for young addition, interventions to control hypertension and to children in Baltimore City public schools, the researchers regulate kidney dialysis to improve cognitive function examined cognitive improvements and brain function in are underway. Even though the range of interventions is eight older female study participants who were already in wide, the trials share the common focus of trying to the study compared to nine matched controls who were remediate age-related cognitive decline. on the wait list to participate. The study revealed improved executive function—the ability to exercise control over cognitive function, such as switching quickly and accu- rately from task to task or carrying out a sequence of tasks appropriately—in the study participants that was
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 47 | Research Advances
TABLE 3. Ongoing Age-Related Cognitive Decline Clinical Trials Funded by NIA
Anticipated Principal Investigator/ Completion Trial Name Institution Intervention Population Date Cognitive Training Active Interventions for Denise Park, Cognitive enrichment Healthy adults 2012 the Aging Mind Univ. of Texas, Dallas through training in digital age 60+ photography or quilting Brain-Based Approach Mark D’Esposito, Univ. of Cognitive training Healthy adults 2012 to Enhancing Executive California, Berkeley age 50+ Control Functions in Healthy Aging Expanding the Helga Noice, Cognitive enrichment Healthy adults 2010 Implementation of an Elmhurst College through training in acting age 65+ Effective Cognitive Aging Intervention Experience Corps Trial: George Rebok, Health promotion for older Healthy adults 2011 Improving Health in Older Johns Hopkins Univ. adults embedded within a age 60+ Populations through social engagement program Generativity (volunteering in schools) Senior Odyssey: A Test Elizabeth Stine-Morrow, Cognitive enhancement Healthy adults 2012 of the Engagement Univ. of Illinois, through participation in the age 60+ Hypothesis of Urbana-Champaign Odyssey of the Mind program Cognitive Aging Speed of Processing Modes Fredric D. Wolinsky, Comparison of standard Healthy adults 2011 to Prevent Cognitive Decline Univ. of Iowa versus enhanced visual age 50+ in Older Adults processing training
Omega-3 Fatty Acids and Antioxidants Omega-3 and Blueberry Robert Krikorian, Omega-3 and blueberry Healthy adults 2012 Supplementation in Univ. of Cincinnati supplements age 62-80 Age-Related Cognitive Decline Cardiovascular Aging and the Ihab Hajjar, Hebrew Angiotensin receptor Adults age 60+ 2012 Renin-Angiotensin Rehabilitation Center for Aged blocker, angiotensin-converting with uncontrolled System in Elderly enzyme inhibitor, diuretic hypertension and Hypertensive Individuals cognitive impairment
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 48 | Research Advances
Anticipated Principal Investigator/ Completion Trial Name Institution Intervention Population Date Hormones Estrogen Effects on Paul Newhouse, Acute or chronic 17B-estradiol Healthy women 2014 Cholinergic Function in Univ. of Vermont + muscarinic and nicotinic age 50+ Older Women cholinergic antagonist Estrogen Use in Protection Natalie Rasgon, Continuation of or removal Healthy women 2011 from Cognitive Decline Stanford Univ. from postmenopausal age 50-65 estrogen treatment Hormones and Cognitive Yolanda Smith, Estradiol and prometrium Healthy early 2011 Processing in Early Univ. of Michigan (progesterone) postmenopausal Postmenopausal Women women age 45-55 KEEPS-CA (Kronos Early Sanjay Asthana, Oral conjugated equine Healthy 2012 Estrogen Prevention Study– Univ. of Wisconsin, Madison estrogen and transdermal postmenopausal Cognitive and Affective 17B-estradiol women age 42-58 Study) Mechanisms for Sex Jeri Janowsky, Gonadotropin releasing Healthy adults 2009 Steroid Effects on Oregon Health & Science hormone agonist, testosterone, age 60-80 and Cognition in Aging Univ. testosterone + aromatase 25-35 inhibitor Sex Steroids and Elliot Hirshman, Dehydroepiandrosterone Healthy 2011 Cognition in George Washington Univ. (DHEA) postmenopausal Postmenopausal Women women age 55-65 and 70-80 Testosterone Trial Peter Snyder, Univ. of Testosterone gel Older men 2015 Pennsylvania
Exercise Cognitive Benefits of Yaakov Stern & Stretching/toning or Healthy adults 2015 Aerobic Exercise Richard Sloan, aerobic conditioning age 25-65 Across the Lifespan Columbia Univ. Dose-Response Study of Jeffrey Burns, Aerobic exercise Healthy older adults 2012 Exercise in Older Adults Univ. of Kansas Exercise, Age-Related Scott Small & Exercise training or Healthy adults 2015 Memory Decline, and Richard Sloan, maintenance of sedentary age 20-65 Hippocampal Function Columbia Univ. lifestyle Exercise, Cognitive Training Brain and Cognitive Sandra Chapman, Cognitive training, Adults age 60-75 2011 Changes after Reasoning Univ. of Texas, Dallas aerobic exercise or Physical Training in Cognitively Normal Seniors Combined Exercise and Yaakov Stern, Aerobic exercise and Healthy adults 2012 Cognitive Training Columbia Univ. cognitive training age 65-75 Intervention in Normal Aging
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 49 | Research Advances
Anticipated Principal Investigator/ Completion Trial Name Institution Intervention Population Date Exercise, Cognitive Training (Continued) Combining Exercise and Ellen Binder & Aerobic exercise and Healthy adults 2012 Cognitive Training to Mark McDaniel, cognitive training age 55-75 Improve Everyday Function Washington Univ. Impact of Exercise and Denise Park, Walking, exercise regimen Healthy adults 2011 Engagement on Cognition Univ. of Texas, Dallas (aerobic tasks); quilting, age 60-85 in Older Adults photography (cognitive tasks) Improvement of Visual Karlene Ball, Univ. of Combination of visual Healthy adults 2011 Processing in Older Adults Alabama, Birmingham processing training age 65+ and exercise Influence of Fitness and Arthur Kramer, Univ. of Aerobic training (walking), Adults age 60-75 2015 Cognitive Training on Illinois, Urbana-Champaign combined aerobic training/ Brain and Cognition cognitive training (dancing) Tai Chi and Guided Victor Henderson, Low-impact Tai Chi exercise Healthy adults 2012 Autobiography for Stanford Univ. and autobiographical writing age 70+ Remediation of Age-Related Cognitive Decline Other Guanfacine Treatment Christopher Van Dyck, Guanfacine Healthy adults 2011 for Prefrontal Cognitive Yale Univ. age 75+ Dysfunction in Elderly Subjects Mechanisms of Cognitive Manjula Kurella Tamura, Frequent hemodialysis Adults age 55+ 2012 Impairment in Chronic Stanford Univ. Kidney Disease Note: For information on new and currently recruiting trials, visit: www.nia.nih.gov/Alzheimers/ResearchInformation/ClinicalTrials or www.ClinicalTrials.gov.
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 50 | Research Advances
Supporting Occupational therapy 8 AD Caregivers Participation in meaningful activity is known to pro- mote well-being in older adults, and its potential to Family members often bear much of the burden of car- reduce symptoms of dementia is now receiving more ing for people with AD. This includes the time and attention. The Tailored Activity Program (TAP) is a energy spent on caretaking, worry about the mental and home-based occupational therapy plan that assesses the physical decline of a loved one, and frustration in trying interests and capabilities of individuals with dementia, to communicate with and help them. While caregiving provides a program of customized activities for each can be rewarding, it can also be incredibly stressful and individual, and trains their families to use those activi- contribute to physical and emotional health problems ties as part of their daily care routines. A preliminary for the caregiver. Understanding caregivers’ needs and study of 57 people with dementia and their caregivers, health risks and supporting them are critical for reduc- conducted by researchers at Thomas Jefferson University ing the personal and public health burden of AD. in Philadelphia, PA, and funded by NIMH, found that Starting in 1995, NIA and NINR funded two clini- the TAP program improved overall levels of pleasure and cal trials, REACH I and REACH II, to develop and test engagement in the demented individuals, as assessed by strategies for helping dementia caregivers manage their their caregivers. It also reduced the extent to which care- stress and emotional burden. The interventions included givers were upset by the behavioral symptoms of the education on dementia, training in specific caregiving individuals they were caring for, and improved their skills, and encouragement and techniques for physical sense of skill and personal control in dealing with and emotional self-care. The REACH findings are now behavioral problems (Gitlin et al., 2009). being put into practice through two Federal agencies, the Veterans Administration (VA) and the Administration on Aging (AoA). Additional advances in support for caregivers: The VA successfully used REACH strategies in a Hilgeman et al. (2009) Testing a theoretical model of the stress demonstration project with 19 of its home health care process in Alzheimer’s caregivers with race as a moderator. University of Alabama, Tuscaloosa. Supported by NIA and NINR. services and is now considering the use of REACH throughout the VA system. AoA’s REACH OUT Mitchell et al. (2009) The clinical course of advanced demen- Program is beginning to implement these strategies tia. Hebrew SeniorLife Institute for Aging Research, Boston. through local social service agencies. Researchers Supported by NIA. reported on one of the AoA-funded efforts, a partner- Norton et al. (2009) Caregiver-recipient closeness and symp- ship between the Alabama Department of Senior tom progression in Alzheimer disease. Utah State University. Services and the University of Alabama. An analysis of Supported by NIA.
236 caregivers showed significant improvement in care- Skarupski et al. (2009) Race differences in emotional adapta- givers’ sense of burden, social support, depression, and tion of family caregivers. Rush University. Supported by NIA. health, as well as care recipient behavior problems and Vitaliano et al. (2009) Depressed mood mediates decline in mood (Burgio et al., 2009). cognitive processing speed in caregivers. University of Efforts are underway to develop tests to gauge the Washington. Supported by NIDDK, NCRR, and NIMH. emotional well-being of caregivers and identify areas where they may need support. One of these, the Risk Appraisal Measure (RAM), was tested on participants in the REACH II trial. The test probes six areas in which caregivers are at risk: depression, burden, self-care, health behavior, physical safety, and problem behaviors in the care recipients. RAM shows promise as a test to identify caregivers who might benefit from assistance in specific areas, for use in future research on supportive measures, and as a guide for clinicians and community health agencies (Czaja et al., 2009).
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 51 | Advancing the Future of AD Research
Advancing the Future of AD Research: resources and collaboration
lzheimer’s researchers are gaining better under- discuss new science and opportunities for new invest- standing of AD pathology and using new insights ments; and by partnering with other NIH Institutes and A to develop therapies more likely to be successful Federal agencies, not-for-profit groups, and industry. in clinical trials. The outpouring of AD-related applica- Collaboration has been key for NIA’s coordinating tions in response to the 2009 American Recovery and mechanisms and initiatives. By pooling and sharing data Reinvestment Act (ARRA) initiative, many of which widely, and efficiently using the well-established AD were successful in review, demonstrated the vitality of research infrastructure, NIA is advancing AD science new ideas in the scientific community. Several of these even within the limits of existing resources. ideas, now supported by ARRA and non-ARRA funds, resulted in large collaborative projects designed to address the multifaceted nature of aging and AD Research Infrastructure research. However, the profusion of good ideas com- NIA Intramural Research Program (IRP). In addition bined with investment in more expensive collaborative to funding a broad portfolio of aging-related and AD grants has its downside, and that is that the overall suc- research at institutions across the country, NIA supports cess rate for grants is very low and may be difficult to its own laboratory and clinical research program based improve in the current economic climate. in Baltimore, MD. The NIA IRP focuses on under- As planners and stewards of Federally funded sci- standing age-related changes in physiology and behavior, ence, NIA must both develop and sustain the research the ability to adapt to biological and environmental infrastructure necessary for productive research and at stresses, and developing insight about the pathophysiol- the same time phase out approaches that may have out- ogy of age-related diseases, including AD. Laboratory lived their usefulness. In this endeavor, it is critical to research ranges from basic science, such as neurogenetics maintain and encourage lines of research that hold and cellular and molecular neurosciences, to personality promise for new therapies while reducing investment in and cognition. The IRP also leads the Baltimore research less crucial to the mission. The Institute keeps Longitudinal Study of Aging, America’s longest-running current and looks to the future in several ways—by con- scientific study of human aging, begun in 1958, along vening and collaborating in forward-looking workshops with other clinical research studies. in these new areas; by working within NIA to vigorously Alzheimer’s Disease Centers. NIA’s Alzheimer’s Disease Centers (ADCs) form the backbone of the national AD research effort. These multidisciplinary centers, located
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 52 | Advancing the Future of AD Research at 30 institutions nationwide, promote research, training and education, and technology transfer. With participa- tion by the community, the Centers conduct longitudi- nal multicenter and collaborative studies of AD As planners and stewards diagnosis and treatment, age-related neurodegenerative diseases, and predictors of future change in people with- of Federally funded science, NIA must out dementia that may indicate the initial stages of development of AD. Complementary studies, such as develop and sustain the infrastructure imaging studies and autopsy evaluations, also are con- necessary for productive research. ducted at ADCs. All people enrolled in the Centers receive a standard annual evaluation. Data from those evaluations are collected and stored by the National Alzheimer’s Coordinating Center (NACC, see below) as the Uniform Data Set. determined not to have dementia before death, some The ADCs serve as sites for other major studies, did have mild cognitive impairment. The researchers such as the ADCS and ADNI (see descriptions below). concluded that it is likely that neuropathological pro- Recently, DNA from 10,000 individuals enrolled in cesses related to AD in persons without dementia are the ADCs was collected for use by the Alzheimer’s associated with this mild cognitive decline. By age 80-85 Disease Genetics Consortium (ADGC) for whole years, many nondemented older adults had substantial genome analysis. AD pathology. (Price et al., 2009) The NACC data are helping to reveal different National Alzheimer’s Coordinating Center (NACC). symptom patterns in different subsets of AD patients— NIA established NACC in 1999 with the goal of pool- patterns that would not have become apparent without ing and sharing data on participants in ADC studies. analyzing a dataset of this size. NACC has also been The longitudinal clinical data from living subjects and involved in coordinating other NIA efforts, such as the the brain material and pathological data collected at identification and selection of appropriate postmortem autopsy give scientists opportunities to conduct clinical- material from the individual ADCs to send to the pathological studies with much larger patient samples National Cell Repository for Alzheimer’s Disease for use collected from multiple centers than they could working in the ADGC GWAS studies. independently. NACC helps coordinate these studies and, in some cases, provides limited funding. Alzheimer’s Disease Cooperative Study (ADCS). NIA By 2009, NACC had collected information on more launched the ADCS in 1991 to develop and test new than 90,000 ADC study participants and neuropatho- interventions and treatments for AD that might not logic data on more than 10,000 brains from autopsied otherwise be developed by industry. Operated under a participants. Much of these data and autopsy materials cooperative agreement with the University of are available to qualified AD researchers worldwide. California, San Diego, the large clinical trials consor- Since 2000, there have been over 60 publications by tium, a significant component of NIA’s AD Prevention external researchers using NACC data, 51 publications Initiative, comprises more than 75 sites throughout the by NACC personnel, and 95 publications from NACC- United States and Canada. The ADCS focuses on test- funded collaborative ADC projects. ing agents that lack patent protection, patented drugs One such study quantitatively assessed pathological plaques and neurofibrillary tangles at autopsy in 97 non- demented participants age 60 years or older (average age 84 years) who had been enrolled in one of seven differ- ent ADCs. While all of the research subjects had been
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 53 | Advancing the Future of AD Research that are marketed for other indications, and novel com- distribute the results of large-scale GWAS analyses. pounds developed by individuals, academic institutions, Through dbGaP, data sets from multiple GWAS done and small biotech companies. It also develops new eval- on different platforms can be merged, and data from uation instruments for clinical trials and innovative thousands of study participants can be analyzed approaches to clinical trial design. The group also pro- together, increasing the probability of gene discovery. vides infrastructure support to other Federally funded clinical efforts, including ADNI and the Dominantly Inherited Alzheimer Network (DIAN, a study of famil- Initiatives ial AD). (See Alzheimer’s Disease Cooperative Study, Alzheimer’s Disease Neuroimaging Initiative (ADNI). page 40, for a summary of current trials and studies In 2004, NIA launched this groundbreaking initiative, conducted by the ADCS.) the largest public-private partnership to date in AD research. The goal was to find neuroimaging and other The National Cell Repository for Alzheimer’s Disease biological markers that could be used to detect AD (NCRAD). This NIA-funded repository, located at progression and measure the effectiveness of potential Indiana University Medical Center in Indianapolis, pro- therapies. The study recruited 800 participants, a mix of vides resources that help researchers identify the genes cognitively healthy people and those with AD or MCI. that contribute to AD and other types of dementia. To speed the pace of analysis and findings, ADNI investi- NCRAD collects and maintains biological specimens gators agreed to make their collected data widely avail- and associated data on almost 43,000 people from a able. MRI and PET scan brain images as well as clinical, variety of sources, including genetically informative, genetic, and fluid biomarker data are available to qualified phenotypically well-characterized families with multiple researchers worldwide through a Web-based database. individuals affected by AD, as well as people enrolled in The first phase of ADNI has already borne remark- ADNI, ADGC, and the Ginkgo Evaluation of Memory able fruit: more than 170 papers using ADNI data have Study. Qualified research scientists may apply to been published from investigators around the world, and NCRAD for samples and data to conduct genetic many more will come as further data are collected and research. Since it was funded, more than 52,000 DNA analyzed. These early findings have generated excitement samples have been requested and sent to investigators about using brain and fluid markers to identify people across the U.S., resulting in 204 publications. who may be at risk for developing AD or for cataloguing their pace of deterioration. Accomplishments include NIA Genetics of Alzheimer’s Disease Data Storage new findings about how changes in the structure of the Site (NIAGADS). Located at the University of hippocampus may help detect disease progression and Pennsylvania, NIAGADS is a Web-based data warehouse effectiveness of potential treatments, and the establish- for AD genetic data. All genetic data derived from NIA- ment of biomarker and imaging measures that predict funded studies on the genetics of late-onset AD are risk for cognitive decline and conversion to dementia in deposited at NIAGADS, another NIA-approved site, or this clinical cohort. (See Biomarkers and ADNI, page 33, both. Data from GWAS that are stored at NIAGADS for descriptions of several published studies.) The success are also made available through the database of of ADNI has inspired similar efforts in Europe, Japan, Genotype and Phenotype (dbGaP) at the National and Australia. A follow-on effort, ADNI-GO, was Library of Medicine’s National Center for Biotechnology launched with ARRA funds in 2009, and ADNI 2 was Information, which was developed to archive and launched in fall 2010. ADNI 2 will enroll a new cohort
ADNI has already borne remarkable fruit: more than 170 papers using ADNI data have been published from investigators around the world.
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 54 | Advancing the Future of AD Research
Revising AD Diagnostic Criteria. NIA and the Alzheimer’s Association organized two meetings in spring 2009 to discuss new data and technologies for The ADGC improving the clinical diagnosis of AD and a research agenda for diagnosis at earlier stages of the disease. The confirmed the likely role of current system of AD classification has deficiencies that limit its utility for drug development, research, and three newly discovered late-onset practice. Existing standards for diagnosis of the demen- AD genes and is now working tia stage of AD, the NINCDS-ADRDA clinical criteria, are more than 25 years old and do not address very early to confirm additional genes. and presymptomatic AD. They were developed without the knowledge available from more recent studies on the epidemiology of AD, clinical-pathologic correlations, and diagnostic imaging and fluid biomarkers. Following discussion at the meetings, three working of participants with very early MCI and continue to fol- groups were set up, one to revise the NINCDS- low participants in the other ADNI cohorts, with the ADRDA criteria for Alzheimer’s dementia; a second to goal of identifying and tracking early changes in the better define the stage(s) between normal and brain before the onset of AD symptoms. Alzheimer’s dementia, often termed MCI; and a third to examine factors in older individuals with no symp- Alzheimer’s Disease Genetics Initiative (ADGI) and toms or very minor symptoms that may predict MCI Alzheimer’s Disease Genetics Consortium (ADGC). and Alzheimer’s dementia. The study of AD genetics is complicated by the likeli- The overall goals of this project are to better define hood that the risk of late-onset AD is influenced by the natural history of AD, from its asymptomatic stages many genes, each of which confers a relatively small risk. to clinically diagnosed dementia, and to attempt to Identifying these genes requires analyzing the genomes relate clinical symptoms as they emerge to underlying of large numbers of people. ADGI was launched in pathophysiology. An overarching goal is to stimulate 2003 to identify at least 1,000 families containing both research on how imaging and fluid biomarkers can con- members who have late-onset AD and members who do tribute to the identification of people at risk for cogni- not. The ADGC was funded in 2009 to support the use tive dysfunction and to better diagnose them after of large-scale, high-throughput genetics technologies by symptoms appear. researchers studying late-onset AD. The groups presented their preliminary proposals at The ADGC confirmed the likely role of three newly the International Conference on Alzheimer’s Disease discovered genes in contributing to the risk of LOAD (ICAD) in July 2010. The three committees are review- (see Discovering New Genetic Mechanisms, page 21) and ing public comments and will publish proposed guide- is now working to confirm additional genes in collabora- lines in a scientific journal in 2011. The guidelines, tion with research groups in Europe. In addition to pro- primarily for use in research studies, will likely be revis- viding additional insight into AD pathogenesis and ited and revised periodically as new data emerge from suggesting therapeutic targets, these new gene discover- imaging and biomarker research studies. ies may also one day help predict who is at risk for AD. AD Translational Initiative. Launched in 2004, the AD Translational Initiative supports early drug discovery and drug development research by academic scientists and small biotechnology companies, with the goal of
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 55 | Advancing the Future of AD Research
The AD Translational Initiative is broadening the range of potential treatments and therapeutic targets by supporting critical research steps not traditionally supported by industry. finding ways to treat and prevent AD, MCI, and age- logical decline. A second Summit, held in October related cognitive decline. This effort is broadening the 2010, shared progress from funded studies and identi- range of potential treatments and therapeutic targets by fied future research directions. supporting critical steps of translational research that are traditionally not supported by the pharmaceutical indus- NIH Toolbox for Assessment of Neurological and try. In 2009, the NIA committed $5 million to continue Behavioral Function. Awarded in 2006, this contract is two funding initiatives for early drug discovery and pre- supported by the NIH Blueprint for Neuroscience clinical drug development through 2012. (See more Research and the NIH Opportunity Network for Basic about translational research, page 35.) Behavioral and Social Science Research. The goal is to develop a set of brief tests to assess cognitive, sensory, AD Pilot Clinical Trials Initiative. This initiative, motor, and emotional function, particularly in studies begun in 1999, is aimed at increasing the number and with many people (such as epidemiological studies and quality of preliminary clinical evaluation of interventions clinical trials). The tests will be available in English and for AD, MCI, and age-associated cognitive decline. The Spanish and applicable for use in individuals age 3 to goal is not to duplicate or compete with pharmaceutical 85, enabling direct comparison of cognitive and other companies but to encourage, complement, and accelerate abilities at different ages across the lifespan. the process of testing new, innovative, and effective treat- ments. Initially focused on drug interventions, the pro- NIH Blueprint for Neuroscience Research Initiative gram has been broadened to nonpharmacologic as well as on the Human Connectome Project. The Human pharmacologic interventions. NCCAM and NINR also Connectome Project was started in 2010 to develop and participate in this initiative. (See AD Clinical Trials, share knowledge about the structural and functional page 38, for summaries of pilot clinical trials.) connectivity of the healthy human brain. This collabora- tive effort will use state-of-the-art imaging instruments, Research Partnership on Cognitive Aging. Through analysis tools, and informatics technologies to map the the Foundation for NIH, NIA and the McKnight Brain neural pathways underlying human brain function. The Research Foundation convened a Cognitive Aging project will map the connectomes in 1,200 healthy Summit in 2007 focused on healthy brain aging and adults—twin pairs and their siblings—and will study function. This summit helped galvanize the field and anatomical and functional connections between regions served as a catalyst for two subsequent research initia- of the brain, which will be related to behavioral test tives. The first, “Remediation of Age-Related Cognitive data. The goal is to reveal the contributions of genes and Decline,” is funding research on pilot interventions to environment in shaping brain circuitry and the variabil- reverse age-related decline or maintain successful func- ity in such connectivity. The human connectome map of tion. The second, “Neural and Behavioral Profiles of the healthy adult brain will serve as a foundation to fur- Cognitive Aging,” is funding studies to understand ther understand how brain networks change with age neural and behavioral mechanisms involved the mainte- and neurological diseases like Alzheimer’s. nance of cognitive health and to identify characteristics that distinguish normal age-related change from patho-
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 56 References Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Carlson MC, Erickson KI, Kramer AF, Voss MW, Bolea N, Mielke M, Tsopelas ND, Ziolko SK, James JA, Snitz BE, Houck PR, McGill S, Rebok GW, Seeman T, Fried LP. Evidence for neurocognitive Bi W, Cohen AD, Lopresti BJ, DeKosky ST, Halligan EM, plasticity in at-risk older adults: the experience corps program. Klunk WE. Frequent amyloid deposition without significant Journals of Gerontology, Series A: Biological Sciences and Medical Sciences cognitive impairment among the elderly. Archives of Neurology 2009;64(12):1275-1282. www.ncbi.nlm.nih.gov/pubmed/19692672 2008;65(11):1509-1517. www.ncbi.nlm.nih.gov/pubmed/19001171 Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA. Ashida S, Koehly LM, Roberts JS, Chen CA, Hiraki S, S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial Green RC. Disclosing the disclosure: factors associated with fission and neuronal injury. Science 2009;324(5923):102-105. communicating the results of genetic susceptibility testing www.ncbi.nlm.nih.gov/pubmed/19342591 for Alzheimer’s disease. Journal of Health Communication Cohen AD, Ikonomovic MD, Abrahamson EE, Paljug WR, Dekosky ST, 2009;(8):768-784. www.ncbi.nlm.nih.gov/pubmed/20029710 Lefterov IM, Koldamova RP, Shao L, Debnath ML, Mason NS, Asthana S, Brinton RD, Henderson VW, McEwen BS, Mathis CA, Klunk WE. Anti-amyloid effects of small molecule Morrison JH, Schmidt PJ; Frontiers proposal. National Institute Abeta-binding agents in PS1/APP mice. Letters in Drug Design & on Aging “bench to bedside: estrogen as a case study.” Age (Dordr). Discovery 2009a;6(6):437. www.ncbi.nlm.nih.gov/pubmed/20119496 2009;31(3):199-210. www.ncbi.nlm.nih.gov/pubmed/19277902 Cohen AD, Price JC, Weissfeld LA, James J, Rosario BL, Bi W, Ballatore C, Brunden KR, Piscitelli F, James MJ, Crowe A, Yao Y, Nebes RD, Saxton JA, Snitz BE, Aizenstein HA, Wolk DA, Hyde E, Trojanowski JQ, Lee VM, Smith AB 3rd. Discovery of Dekosky ST, Mathis CA, Klunk WE. Basal cerebral metabolism brain-penetrant, orally bioavailable aminothienopyridazine inhibi- may modulate the cognitive effects of Abeta in mild cognitive tors of tau aggregation. Journal of Medicinal Chemistry 2010; impairment: an example of brain reserve. Journal of Neuroscience 53(9):3739-3747. www.ncbi.nlm.nih.gov/pubmed/20392114 2009b;29(47):14770-14778. www.ncbi.nlm.nih.gov/pubmed/19940172
Bell RD, Deane R, Chow N, Long X, Sagare A, Singh I, Streb JW, Cohen E, Paulsson JF, Blinder P, Burstyn-Cohen T, Du D, Estepa G, Guo H, Rubio A, Van Nostrand W, Miano JM, Zlokovic BV. SRF and Adame A, Pham HM, Holzenberger M, Kelly JW, Masliah E, Dillin A. myocardin regulate LRP-mediated amyloid-beta clearance in brain Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. vascular cells. Nature Cell Biology 2009;11(2):143-153. Cell 2009;139(6):1157-11569. www.ncbi.nlm.nih.gov/pubmed/20005808 www.ncbi.nlm.nih.gov/pubmed/19098903 Coker LH, Hogan PE, Bryan NR, Kuller LH, Margolis KL, Bishop, NA, Lu T, Yankner BA. Neural mechanisms of ageing Bettermann K, Wallace RB, Lao Z, Freeman R, Stefanick ML, and cognitive decline. Nature 2010;464(7288):529-535. Shumaker SA. Postmenopausal hormone therapy and subclinical www.ncbi.nlm.nih.gov/pubmed/20336135 cerebrovascular disease: the WHIMS-MRI Study. Neurology. 2009;72(2):125-134. www.ncbi.nlm.nih.gov/pubmed/19139363 Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Müller FJ, Loring JF, Yamasaki TR, Poon WW, Green KN, LaFerla FM. Connell CM, Scott Roberts J, McLaughlin SJ, Akinleye D. Neural stem cells improve cognition via BDNF in a transgenic model Racial differences in knowledge and beliefs about Alzheimer disease. of Alzheimer disease. Proceedings of the National Academy of Science Alzheimer’s Disease and Associated Disorders 2009;23(2):110-116. 2009;106(32):13594-13599. www.ncbi.nlm.nih.gov/pubmed/19633196 www.ncbi.nlm.nih.gov/pubmed/19474569
Buckner RL, Sepulcre J, Talukdar T, Krienen FM, Liu H, Hedden T, Cooke JR, Ayalon L, Palmer BW, Loredo JS, Corey-Bloom J, Natarajan L, Andrews-Hanna JR, Sperling RA, Johnson KA. Cortical hubs Liu L, Ancoli-Israel S. Sustained use of CPAP slows deterioration of revealed by intrinsic functional connectivity: mapping, assessment of cognition, sleep, and mood in patients with Alzheimer’s disease and stability, and relation to Alzheimer’s disease. Journal of Neuroscience obstructive sleep apnea: a preliminary study. Journal of Clinical Sleep 2009;29(6):1860-1873. www.ncbi.nlm.nih.gov/pubmed/19211893 Medicine 2009;5(4):305-309. www.ncbi.nlm.nih.gov/pubmed/19968005
Burgio LD, Collins IB, Schmid B, Wharton T, McCallum D, Czaja SJ, Gitlin LN, Schulz R, Zhang S, Burgio LD, Stevens AB, Decoster J. Translating the REACH caregiver intervention for use by area Nichols LO, Gallagher-Thompson D. Development of the risk appraisal agency on aging personnel: the REACH OUT program. Gerontologist measure: a brief screen to identify risk areas and guide interventions 2009;49(1):103-116. www.ncbi.nlm.nih.gov/pubmed/19363008 for dementia caregivers. Journal of the American Geriatrics Society 2009;57(6):1064-1072. www.ncbi.nlm.nih.gov/pubmed/19453305
Daiello LA, Ott BR, Lapane KL, Reinert SE, Machan JT, Dore DD. Effect of discontinuing cholinesterase inhibitor therapy on behavioral and mood symptoms in nursing home patients with dementia. American Journal of Geriatric Pharmacotherapy 2009;7(2):74-83. www.ncbi.nlm.nih.gov/pubmed/19447360
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 57 | References
Davatzikos C, Xu F, An Y, Fan Y, Resnick SM. Longitudinal progression Fagan AM, Head D, Shah AR, Marcus D, Mintun M, Morris JC, of Alzheimer’s-like patterns of atrophy in normal older adults: the Holtzman DM. Decreased cerebrospinal fluid Abeta(42) correlates SPARE-AD index. Brain 2009;32(Pt. 8):2026-2035. with brain atrophy in cognitively normal elderly. Annals of Neurology www.ncbi.nlm.nih.gov/pubmed/19416949 2009b;65(2):176-183. www.ncbi.nlm.nih.gov/pubmed/19260027 de la Monte SM, Tong M. Mechanisms of nitrosamine-mediated Fennema-Notestine C, Hagler DJ Jr, McEvoy LK, Fleisher AS, neurodegeneration: potential relevance to sporadic Alzheimer’s disease. Wu EH, Karow DS, Dale AM. Structural MRI biomarkers for Journal of Alzheimer’s Disease 2009;17(4):817-825. preclinical and mild Alzheimer’s disease. Human Brain Mapping www.ncbi.nlm.nih.gov/pubmed/19542621 2009;30(10):3238-3253. www.ncbi.nlm.nih.gov/pubmed/19277975
Debette S, Wolf PA, Beiser A, Au R, Himali JJ, Pikula A, Auerbach S, Fombonne J, Rabizadeh S, Banwait S, Mehlen P, Bredesen DE. Decarli C, Seshadri S. Association of parental dementia with Selective vulnerability in Alzheimer’s disease: amyloid precursor cognitive and brain MRI measures in middle-aged adults. Neurology protein and p75(NTR) interaction. Annals of Neurology 2009;73(24):2071-2078. www.ncbi.nlm.nih.gov/pubmed/20007524 2009;65(3):294-303. www.ncbi.nlm.nih.gov/pubmed/19334058
Dickerson BC, Bakkour A, Salat DH, Feczko E, Pacheco J, Greve DN, Francis YI, Fà M, Ashraf H, Zhang H, Staniszewski A, Latchman DS, Grodstein F, Wright CI, Blacker D, Rosas HD, Sperling RA, Atri A, Arancio O. Dysregulation of histone acetylation in the APP/PS1 Growdon JH, Hyman BT, Morris JC, Fischl B, Buckner RL. The mouse model of Alzheimer’s disease. Journal of Alzheimer’s Disease cortical signature of Alzheimer’s disease: regionally specific cortical 2009;18(1):131-139. www.ncbi.nlm.nih.gov/pubmed/19625751 thinning relates to symptom severity in very mild to mild AD dementia Gitlin LN, Winter L, Vause Earland T, Adel Herge E, Chernett NL, and is detectable in asymptomatic amyloid-positive individuals. Cerebral Piersol CV, Burke JP. The Tailored Activity Program to reduce behavioral Cortex 2009;19(3):497-510. www.ncbi.nlm.nih.gov/pubmed/18632739 symptoms in individuals with dementia: feasibility, acceptability, and Dong Y, Zhang G, Zhang B, Moir RD, Xia W, Marcantonio ER, replication potential. Gerontologist 2009;49(3):428-439. Culley DJ, Crosby G, Tanzi RE, Xie Z. The common inhalational www.ncbi.nlm.nih.gov/pubmed/19420314 anesthetic sevoflurane induces apoptosis and increases beta-amyloid Green RC, Roberts JS, Cupples LA, Relkin NR, Whitehouse PJ, protein levels. Archives of Neurology 2009;66(5):620-631. Brown T, Eckert SL, Butson M, Sadovnick AD, Quaid KA, Chen www.ncbi.nlm.nih.gov/pubmed/19433662 C, Cook-Deegan R, Farrer LA. Disclosure of APOE genotype Driscoll I, Davatzikos C, An Y, Wu X, Shen D, Kraut M, Resnick SM. for risk of Alzheimer’s disease. New England Journal of Medicine Longitudinal pattern of regional brain volume change differentiates 2009;361(3):245-254. www.ncbi.nlm.nih.gov/pubmed/19605829 normal aging from MCI. Neurology 2009;72(22):1906-1913. Gu Z, Liu W, Yan Z. {beta}-Amyloid impairs AMPA receptor www.ncbi.nlm.nih.gov/pubmed/19487648 trafficking and function by reducing Ca2+/calmodulin-dependent Duffy CJ. Visual motion processing in aging and Alzheimer’s protein kinase II synaptic distribution. Journal of Biological Chemistry disease: neuronal mechanisms and behavior from monkeys to man. 2009;284(16):10639-10649. www.ncbi.nlm.nih.gov/pubmed/19240035 Annals of the New York Academy of Sciences 2009;1170:736-744. Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, www.ncbi.nlm.nih.gov/pubmed/19686221 Gao J, Nieland TJ, Zhou Y, Wang X, Mazitschek R, Bradner JE, Dumanis SB, Tesoriero JA, Babus LW, Nguyen MT, Trotter JH, DePinho RA, Jaenisch R, Tsai LH. HDAC2 negatively regulates memory Ladu MJ, Weeber EJ, Turner RS, Xu B, Rebeck GW, Hoe HS. formation and synaptic plasticity. Nature 2009;459(7243):55-60. ApoE4 decreases spine density and dendritic complexity in cortical www.ncbi.nlm.nih.gov/pubmed/19424149 neurons in vivo. Journal of Neuroscience 2009;29(48):15317-15322. Handattu SP, Garber DW, Monroe CE, van Groen T, Kadish I, www.ncbi.nlm.nih.gov/pubmed/19955384 Nayyar G, Cao D, Palgunachari MN, Li L, Anantharamaiah GM. Erickson KI, Prakash RS, Voss MW, Chaddock L, Hu L, Morris KS, Oral apolipoprotein A-I mimetic peptide improves cognitive function White SM, Wójcicki TR, McAuley E, Kramer AF. Aerobic fitness is and reduces amyloid burden in a mouse model of Alzheimer’s disease. associated with hippocampal volume in elderly humans. Hippocampus Neurobiology of Disease 2009;34(3):525-534. 2009;19(10):1030-1039. www.ncbi.nlm.nih.gov/pubmed/19123237 www.ncbi.nlm.nih.gov/pubmed/19344763
Fagan AM, Mintun MA, Shah AR, Aldea P, Roe CM, Mach RH, Marcus D, Morris JC, Holtzman DM. Cerebrospinal fluid tau and ptau(181) increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer’s disease. EMBO Molecular Medicine 2009a;1(8-9):371-80. www.ncbi.nlm.nih.gov/pubmed/20049742
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 58 | References
Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Jagust WJ, Landau SM, Shaw LM, Trojanowski JQ, Koeppe RA, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Reiman EM, Foster NL, Petersen RC, Weiner MW, Price JC, Mathis CA. Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Relationships between biomarkers in aging and dementia. Neurology Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, 2009;73(15):1193-1199. www.ncbi.nlm.nih.gov/pubmed/19822868 Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Johnson DK, Storandt M, Morris JC, Galvin JE. Longitudinal study Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, of the transition from healthy aging to Alzheimer disease. Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, van den Bussche H, Archives of 2009;66(10):1254-1259. Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Neurology www.ncbi.nlm.nih.gov/pubmed/19822781 Hüll M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Jun G, Naj AC, Beecham GW, Wang LS, Buros J, Gallins PJ, Buxbaum JD, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Ertekin-Taner N, Fallin MD, Friedland R, Inzelberg R, Kramer P, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Rogaeva E, St George-Hyslop P, Arnold SE, Baldwin CT, Barber R, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Beach T, Bigio EH, Bird TD, Boxer A, Burke JR, Cairns N, Carroll SL, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Chui HC, Clark DG, Cotman CW, Cummings JL, Decarli C, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Diaz-Arrastia R, Dick M, Dickson DW, Ellis WG, Fallon KB, Farlow MR, Holmans PA, O’Donovan M, Owen MJ, Williams J. Genome-wide Ferris S, Frosch MP, Galasko DR, Gearing M, Geschwind DH, Ghetti B, association study identifies variants in CLU and PCALM associated Gilman S, Giordani B, Glass J, Graff-Radford NR, Green RC, with Alzheimer’s disease. Nature Genetics 2009;41(10):1088-1093. Growdon JH, Hamilton RL, Harrell LE, Head E, Honig LS, Hulette CM, www.ncbi.nlm.nih.gov/pubmed/19734902 Hyman BT, Jicha GA, Jin LW, Johnson N, Karlawish J, Karydas A, Kaye JA, Kim R, Koo EH, Kowall NW, Lah JJ, Levey AI, Lieberman A, Hedden T, Van Dijk KR, Becker JA,Mehta A, Sperling RA, Johnson Lopez OL, Mack WJ, Markesbery W, Marson DC, Martiniuk F, KA, Buckner RL. Disruption of functional connectivity in functionally Masliah E, McKee AC, Mesulam M, Miller JW, Miller BL, Miller CA, normal older adults harboring amyloid burden. Journal of Neuroscience Parisi JE, Perl DP, Peskind E, Petersen RC, Poon W, Quinn JF, Raskind M, 2009;29(40):12686-12694. www.ncbi.nlm.nih.gov/pubmed/19812343 Reisberg B, Ringman JM, Roberson ED, Rosenberg RN, Sano M, Hertzog C, Kramer AF, Wilson RS, Lindenberger U. Enrichment Schneider JA, Schneider LS, Seeley W, Shelanski ML, Smith CD, Spina S, effects on adult cognitive development: can the functional capacity Stern RA, Tanzi RE, Trojanowski JQ, Troncoso JC, Van Deerlin VM, of older adults be preserved and enhanced? Psychological Science in Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Woltjer RL, the Public Interest 2008;9(1):1-5. Younkin SG, Cantwell LB, Dombroski BA, Saykin AJ, Reiman EM, Bennett DA, Morris JC, Lunetta KL, Martin ER, Montine TJ, Goate AM, Hilgeman MM, Durkin DW, Sun F, DeCoster J, Allen RS, Gallagher- Blacker D, Tsuang DW, Beekly D, Cupples LA, Hakonarson H, Kukull W, Thompson D, Burgio LD. Testing a theoretical model of the stress Foroud TM, Haines J, Mayeux R, Farrer LA, Pericak-Vance MA, process in Alzheimer’s caregivers with race as a moderator. Gerontologist Schellenberg GD; Alzheimer’s Disease Genetics Consortium, Arnold SE, 2009;49(2):248-261. www.ncbi.nlm.nih.gov/pubmed/19363019 Baldwin CT, Barber R, Beach T, Bigio EH, Bird TD, Boxer A, Burke JR, Hoe HS, Lee KJ, Carney RS, Lee J, Markova A, Lee JY, Howell BW, Cairns N, Carroll SL, Chui HC, Clark DG, Cotman CW, Cummings JL, Hyman BT, Pak DT, Bu G, Rebeck GW. Interaction of reelin with Decarli C, Diaz-Arrastia R, Dick M, Dickson DW, Ellis WG, Fallon KB, amyloid precursor protein promotes neurite outgrowth. Farlow MR, Ferris S, Frosch MP, Galasko DR, Gearing M, Geschwind DH, Journal of Neuroscience 2009a;29(23):7459-7473. Ghetti B, Gilman S, Giordani B, Glass J, Graff-Radford NR, Green RC, www.ncbi.nlm.nih.gov/pubmed/19515914 Growdon JH, Hamilton RL, Harrell LE, Head E, Honig LS, Hulette CM, Hyman BT, Jicha GA, Jin LW, Johnson N, Karlawish J, Karydas A, Hoe HS, Fu Z, Makarova A, Lee JY, Lu C, Feng L, Pajoohesh-Ganji A, Kaye JA, Kim R, Koo EH, Kowall NW, Lah JJ, Levey AI, Lieberman A, Matsuoka Y, Hyman BT, Ehlers MD, Vicini S, Pak DT, Rebeck GW. Lopez OL, Mack WJ, Markesbery W, Marson DC, Martiniuk F, The effects of amyloid precursor protein on postsynaptic composition Masliah E, McKee AC, Mesulam M, Miller JW, Miller BL, Miller CA, and activity. Journal of Biological Chemistry 2009b;284(13):8495-8506. Parisi JE, Perl DP, Peskind E, Petersen RC, Poon W, Quinn JF, Raskind M, www.ncbi.nlm.nih.gov/pubmed/19164281 Reisberg B, Ringman JM, Roberson ED, Rosenberg RN, Sano M, Schneider JA, Schneider LS, Seeley W, Shelanski ML, Smith CD, Spina S, Hoffman LB, Schmeidler J, Lesser GT, Beeri MS, Purohit DP, Stern RA, Tanzi RE, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Grossman HT, Haroutunian V. Less Alzheimer disease neuropathology Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Woltjer RL, in medicated hypertensive than nonhypertensive persons. Neurology Younkin SG. Meta-analysis confirms CR1, CLU, and PICALM as 2009;72(20):1720-1726. www.ncbi.nlm.nih.gov/pubmed/19228583 Alzheimer disease risk loci and reveals interactions with APOE genotypes. Jack CR Jr, Lowe VJ, Weigand SD, Wiste HJ, Senjem ML, Knopman DS, Archives of Neurology. 2010 Sep 3. www.ncbi.nlm.nih.gov/pubmed/20697030 Shiung MM, Gunter JL, Boeve BF, Kemp BJ, Weiner M, Petersen RC. Kadish I, Thibault O, Blalock EM, Chen KC, Gant JC, Porter NM, Serial PIB and MRI in normal, mild cognitive impairment and Landfield PW. Hippocampal and cognitive aging across the lifespan: Alzheimer’s disease: implications for sequence of pathological events a bioenergetic shift precedes and increased cholesterol trafficking parallels in Alzheimer’s disease. Brain 2009;132(Pt. 5):1355-1365. memory impairment. Journal of Neuroscience 2009;29(6):1805-1816. www.ncbi.nlm.nih.gov/pubmed/19339253 www.ncbi.nlm.nih.gov/pubmed/19211887
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 59 | References
Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Nishino S, Holtzman DM. Amyloid-beta dynamics are regulated by Combarros O, Zelenika D, Bullido MJ, Tavernier B, Letenneur L, orexin and the sleep-wake cycle. Science 2009;326(5955):1005-1007. Bettens K, Berr C, Pasquier F, Fiévet N, Barberger-Gateau P, Engelborghs S, (E-publication.) www.ncbi.nlm.nih.gov/pubmed/19779148 De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O; European Alzheimer’s Disease Initiative Investigators, de Pancorbo MM, Kaye J, Michael Y, Calvert J, Leahy M, Crawford D, Kramer P. Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Exceptional brain aging in a rural population-based cohort. Journal of Mancuso M, Panza F, Nacmias B, Bossù P, Piccardi P, Annoni G, Seripa D, Rural Health 2009;25(3):320-325. www.ncbi.nlm.nih.gov/pubmed/19566620 Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Kim J, Castellano JM, Jiang H, Basak JM, Parsadanian M, Pham V, Blanché H, Dartigues JF, Tzourio C, Gut I, Van Broeckhoven C, Mason SM, Paul SM, Holtzman DM. Overexpression of low-density Alpérovitch A, Lathrop M, Amouyel P. Genome-wide association lipoprotein receptor in the brain markedly inhibits amyloid deposition study identifies variants at CLU and CR1 associated with and increases extracellular A beta clearance. Neuron 2009;64(5):632-644. Alzheimer’s disease. Nature Genetics 2009 41(10):1094-1099. www.ncbi.nlm.nih.gov/pubmed/20005821 www.ncbi.nlm.nih.gov/pubmed/19734903
Kim M, Suh J, Romano D, Truong MH, Mullin K, Hooli B, Norton D, Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM. Tesco G, Elliott K, Wagner SL, Moir RD, Becker KD, Tanzi RE. Cellular prion protein mediates impairment of synaptic plasticity by Potential late-onset Alzheimer’s disease-associated mutations in the amyloid-beta oligomers. Nature 2009;457(7233):1128-1132. ADAM10 gene attenuate { alpha} -secretase activity. Human Molecular www.ncbi.nlm.nih.gov/pubmed/19242475 Genetics 2009;18(20):3987-3996. www.ncbi.nlm.nih.gov/pubmed/19608551 Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, Koffie RM, Meyer-Luehmann M, Hashimoto T, Adams KW, Mielke ML, Wolfe DM, Martinez-Vicente M, Massey AC, Sovak G, Uchiyama Y, Garcia-Alloza M, Micheva KD, Smith SJ, Kim ML, Lee VM, Hyman BT, Westaway D, Cuervo AM, Nixon RA. Lysosomal proteolysis and Spires-Jones TL. Oligomeric amyloid beta associates with postsynaptic autophagy require presenilin 1 and are disrupted by Alzheimer-related densities and correlates with excitatory synapse loss near senile plaques. PS1 mutations. Cell 2010;141(7):1146-1158. Proceedings of the National Academy of Sciences 2009;106(10):4012-4017. www.ncbi.nlm.nih.gov/pubmed/20541250 www.ncbi.nlm.nih.gov/pubmed/19228947 Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM, Selkoe D. Krueger KR, Wilson RS, Kamenetsky JM, Barnes LL, Bienias JL, Soluble oligomers of amyloid Beta protein facilitate hippocampal Bennett DA. Social engagement and cognitive function in old age. long-term depression by disrupting neuronal glutamate uptake. Neuron Experimental Aging Research 2009;35(1):45-60. 2009;62(6):788-801. www.ncbi.nlm.nih.gov/pubmed/19555648 www.ncbi.nlm.nih.gov/pubmed/19173101 Loewenstein DA, Acevedo A, Agron J, Ownby R, Barker W, Strauman S, Lakshmana MK, Yoon IS, Chen E, Bianchi E, Koo EH, Kang DE. Duara R. The utility of a brief memory screen in the diagnosis of mild Novel role of RanBP9 in BACE1 processing of amyloid precursor memory impairment in the elderly: preliminary study. American Journal protein and amyloid beta peptide generation. The Journal of of Geriatric Psychiatry 2009;17(5):437-440. Biological Chemistry 2009;284(18):11863-11872. www.ncbi.nlm.nih.gov/pubmed/19390301 www.ncbi.nlm.nih.gov/pubmed/19251705 Lopez OL, Becker JT, Wahed AS, Saxton J, Sweet RA, Wolk DA, Lakshmana MK, Chung JY, Wickramarachchi S, Tak E, Bianchi E, Klunk W, Dekosky ST. Long-term effects of the concomitant use of Koo EH, Kang DE. A fragment of the scaffolding protein RanBP9 memantine with cholinesterase inhibition in Alzheimer disease. is increased in Alzheimer’s disease brains and strongly potentiates beta- Journal of Neurology, Neurosurgery, and Psychiatry 2009;80(6):600-607. amyloid peptide generation. Journal of the Federation of American www.ncbi.nlm.nih.gov/pubmed/19204022 Societies for Experimental Biology 2010;24(1):119-127. López-Hernández GY, Thinschmidt JS, Morain P, Trocme-Thibierge C, www.ncbi.nlm.nih.gov/pubmed/19729516 Kern WR, Soti F, Papke RL. Positive modulation of alpha7- nAChR responses in rat hippocampal interneurons to full agonists and the alpha- selective partial agents, 40H-GTS-21 and S 24795.Neuropharmacology 2009;56(4):821-830. www.ncbi.nlm.nih.gov/pubmed/19705574
Lu PH, Edland SD, Teng E, Tingus K, Petersen RC, Cummings JL. Donepezil delays progression to AD in MCI subjects with depressive symptoms. Neurology 2009;72(24):2115-2121. www.ncbi.nlm.nih.gov/pubmed/19528519
Lu Y, Ansar S, Michaelis ML, Blagg BS. Neuroprotective activity and evaluation of Hsp90 inhibitors in an immortalized neuronal cell line. Bioorganic & Medicinal Chemistry 2009 17(4):1709-1715. www.ncbi.nlm.nih.gov/pubmed/19138859
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 60 | References
Luo W, Sun W, Taldone T, Rodina A, Chiosis G. Heat shock protein Murphy C, Solomon ES, Haase L, Wang M, Morgan CD. Olfaction in 90 in neurodegenerative diseases. Molecular Neurodegeneration aging and Alzheimer’s disease: event-related potentials to a cross-modal 2010 Jun 3;5:24. www.ncbi.nlm.nih.gov/pubmed/20525284 odor-recognition memory task discriminate ApoE epsilon4+ and ApoE epsilon 4- individuals. Annals of the New York Academy of Sciences Ma QL, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant DJ, Chen PP, 2009;1170:647-657. www.ncbi.nlm.nih.gov/pubmed/19686207 Hudspeth B, Chen C, Zhao Y, Vinters HV, Frautschy SA, Cole GM. Beta-amyloid oligomers induce phosphorylation of tau and inactivation Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, of insulin receptor substrate via c-Jun N-terminal kinase signaling: sup- Shaked GM, Wang L, Blesch A, Kim A, Conner JM, Rockenstein E, pression by omega-3 fatty acids and curcumin. Journal of Neuroscience Chao MV, Koo EH, Geschwind D, Masliah E, Chiba AA, Tuszynski MH. 2009;29(28):9078-9089. www.ncbi.nlm.nih.gov/pubmed/19605645 Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nature Medicine Maji SK, Perrin MH, Sawaya MR, Jessberger S, Vadodaria K, 2009;15(3):331-337. www.ncbi.nlm.nih.gov/pubmed/19198615 Rissman RA, Singru PS, Nilsson KP, Simon R, Schubert D, Eisenberg D, Rivier J, Sawchenko P, Vale W, Riek R. Functional amyloids as natural Nichol K, Deeny SP, Seif J, Camaclang K, Cotman CW. Exercise storage of peptide hormones in pituitary secretory granules. Science improves cognition and hippocampal plasticity in APOE epsilon4 mice. 2009;325(5938):328-332. www.ncbi.nlm.nih.gov/pubmed/19541956 Alzheimer’s & Dementia 2009;5(4):287-294. www.ncbi.nlm.nih.gov/pubmed/19560099 Mastroeni D, McKee A, Grover A, Rogers J, Coleman PD. Epigenetic differences in cortical neurons from a pair of monozygotic Norton MC, Piercy KW, Rabins PV, Green RC, Breitner JC, Ostbye T, twins discordant for Alzheimer’s disease. PloS One 2009;4(8):e6617. Corcoran C, Welsh-Bohmer KA, Lyketsos CG, Tschanz JT. Caregiver- www.ncbi.nlm.nih.gov/pubmed/19672297 recipient closeness and symptom progression in Alzheimer disease. The Cache County Dementia Progression Study. Journals of Gerontology McAuley E, Hall KS, Motl RW, White SM, Wójcicki TR, Hu L, Series B: Psychological Sciences and Social Sciences 2009;64(5):560-568. Doerksen SE. Trajectory of declines in physical activity in community- www.ncbi.nlm.nih.gov/pubmed/19564210 dwelling older women: social cognitive influences. Journals of Gerontology Series B: Psychological Sciences and Social Sciences 2009;64(5):543-550. Oddo S, Caccamo A, Cheng D, LaFerla FM. Genetically altering www.ncbi.nlm.nih.gov/pubmed/19528360 Abeta distribution from the brain to the vasculature ameliorates tau pathology. Brain Pathology 2009;19(3):421-430. McEvoy LK, Fennema-Notestine C, Roddey JC, Hagler DJ Jr, www.ncbi.nlm.nih.gov/pubmed/18657136 Holland D, Karow DS, Pung CJ, Brewer JB, Dale AM. Alzheimer’s Disease Neuroimaging Initiative. Alzheimer disease: quantitative structural O’Hara R, Luzon A, Hubbard J, Zeitzer JM. Sleep apnea, apolipoprotein neuroimaging for detection and prediction of clinical and structural epsilon 4 allele, and TBI: mechanism for cognitive dysfunction and changes in mild cognitive impairment. Radiology 2009;251(1):195-205. development of dementia. Journal of Rehabilitation Research and Development www.ncbi.nlm.nih.gov/pubmed/19201945 2009;46(6):837-850. www.ncbi.nlm.nih.gov/pubmed/20104407
Mitchell SL, Teno JM, Kiely DK, Shaffer ML, Jones RN, Prigerson HG, Okereke OI, Xia W, Selkoe DJ, Grodstein F. Ten-year change in plasma Volicer L, Givens JL, Hamel MB. The clinical course of advanced amyloid beta levels and late-life cognitive decline. Archives of Neurology dementia. New England Journal of Medicine 2009;361(16):1529-1538. 2009;66(10):1247-1253. www.ncbi.nlm.nih.gov/pubmed/19822780 www.ncbi.nlm.nih.gov/pubmed/19828530 Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Mormino EC, Kluth JT, Madison CM, Rabinovici GD, Baker SL, Lindborg SR, Schacht AL. How to improve R&D productivity: the Miller BL, Koeppe RA, Mathis CA, Weiner MW, Jagust WJ. Episodic pharmaceutical industry’s grand challenge. Nature Reviews: memory loss is related to hippocampal-mediated beta amyloid Drug Discovery 2010;9:203-214. deposition in elderly subjects. Brain 2009;132(Pt. 5):1310-1323. Persaud-Sawin DA, Banach L, Harry GJ. Raft aggregation with specific www.ncbi.nlm.nih.gov/pubmed/19042931 receptor recruitment is required for microglial phagocytosis of Abeta42. Morris JC, Roe CM, Grant EA, Head D, Storandt M, Goate AM, Glia 2009;57(3):320-335. www.ncbi.nlm.nih.gov/pubmed/18756527 Fagan AM, Holtzman DM, Mintun MA. Pittsburgh compound B Petanceska S, Ryan L, Silverberg N, Buckholtz N. Commentary on imaging and prediction of progression from cognitive normality to “a roadmap for the prevention of dementia II. Leon Thal Symposium symptomatic Alzheimer disease. Archives of Neurology 2008.” Alzheimer’s disease translational research programs at the 2009;66(12):1469-1475. www.ncbi.nlm.nih.gov/pubmed/20008650 National Institute on Aging. Alzheimer’s & Dementia 2009;5(2):130-132. Mozolic JL, Long AB, Morgan AR, Rawley-Payne M, Laurienti PJ. www.ncbi.nlm.nih.gov/pubmed/19328442 A cognitive training intervention improves modality-specific attention Polydoro M, Acker CM, Duff K, Castillo PE, Davies P. Age-dependent in a randomized controlled trial of healthy older adults. Neurobiology of impairment of cognitive and synaptic function in the htau mouse model Aging 2009 May 8. (E-publication ahead of print.) of tau pathology. Journal of Neuroscience 2009;29(34):10741-10749. www.ncbi.nlm.nih.gov/pubmed/19428142 www.ncbi.nlm.nih.gov/pubmed/19710325
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 61 | References
Potter GG, Plassman BL, Burke JR, Kabeto MU, Langa KM, Schneider LS, Raman R, Schmitt FA, Doody RS, Insel P, Clark CM, Llewellyn DJ, Rogers MA, Steffens DC. Cognitive performance and Morris JC, Reisberg B, Petersen RC, Ferris H. Characteristics and per- informant reports in the diagnosis of cognitive impairment and formance of a modified version of the ADCS-CGIC CIBIC+ for mild dementia in African Americans and whites. Alzheimer’s & Dementia cognitive impairment clinical trials. Alzheimer Disease and Associated 2009;5(6):445-453. www.ncbi.nlm.nih.gov/pubmed/19896583 Disorders 2009;23(3):260-267. www.ncbi.nlm.nih.gov/pubmed/19812469
Price JL, McKeel DW Jr, Buckles VD, Roe CM, Xiong C, Grundman M, Schuff N, Matsumoto S, Kmiecik J, Studholme C, Du A, Ezekiel F, Hansen LA, Petersen RC, Parisi JE, Dickson DW, Smith CD, Davis DG, Miller BL, Kramer JH, Jagust WJ, Chui HC, Weiner MW. Cerebral Schmitt FA, Markesbery WR, Kaye J, Kurlan R, Hulette C, Kurland BF, blood flow in ischemic vascular dementia and Alzheimer’s disease, Higdon R, Kukull W, Morris JC. Neuropathology of nondemented measured by arterial spin-labeling magnetic resonance imaging. aging: presumptive evidence for preclinical Alzheimer disease. Alzheimer’s & Dementia 2009a;5(6):454-462. Neurobiology of Aging. 2009;30(7):1026-1036. www.ncbi.nlm.nih.gov/pubmed/19896584 www.ncbi.nlm.nih.gov/pubmed/19376612. Schuff N, Woerner N, Boreta L, Kornfield T, Shaw LM, Trojanowski JQ, Puzzo D, Staniszewski A, Deng SX, Privitera L, Leznik E, Liu S, Thompson PM, Jack CR Jr, Weiner MW. MRI of hippocampal Zhang H, Feng Y, Palmeri A, Landry DW, Arancio O. Phosphodiesterase volume loss in early Alzheimer’s disease in relation to ApoE genotype 5 inhibition improves synaptic function, memory, and amyloid-beta and biomarkers. Brain 2009b;132(Pt. 4):1067-1077. load in an Alzheimer’s disease mouse model. Journal of Neuroscience www.ncbi.nlm.nih.gov/pubmed/19251758 2009;29(25):8075-8086. www.ncbi.nlm.nih.gov/pubmed/19553447 Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Reiman EM, Chen K, Liu X, Bandy D, Yu M, Lee W, Ayutyanont N, Petersen RC, Blennow K, Soares H, Simon A, Lewczuk P, Dean R, Keppler J, Reeder SA, Langbaum JB, Alexander GE, Klunk WE, Siemers E, Potter W, Lee VM, Trojanowski JQ. Cerebrospinal fluid Mathis CA, Price JC, Aizenstein HJ, DeKosky ST, Caselli RJ. Fibrillar biomarker signature in Alzheimer’s disease neuroimaging initiative amyloid-beta burden in cognitively normal people at 3 levels of genetic subjects. Annals of Neurology 2009;65(4):403-413. risk for Alzheimer’s disease. Proceedings of the National Academy of Sciences www.ncbi.nlm.nih.gov/pubmed/19296504 2009;106(16):6820-6825. www.ncbi.nlm.nih.gov/pubmed/19346482 Sheline YI, Raichle ME, Snyder AZ, Morris JC, Head D, Wang S, Resnick SM, Espeland MA, Jaramillo SA, Hirsch C, Stefanick ML, Mintun MA. Amyloid plaques disrupt resting state default mode network Murray AM, Ockene J, Davatzikos C. Postmenopausal hormone connectivity in cognitively normal elderly. Biological Psychiatry therapy and regional brain volumes: the WHIMS-MRI Study. Neurology 2010;67(6):584-587. www.ncbi.nlm.nih.gov/pubmed/19833321 2009;72(2):135-142. www.ncbi.nlm.nih.gov/pubmed/19139364 Skarupski KA, McCann JJ, Bienias JL, Evans DA. Race differences Robertson RT, Baratta J, Yu J, LaFerla FM. Amyloid-beta expression in emotional adaptation of family caregivers. Aging & Mental Health in retrosplenial cortex of triple transgenic mice: relationship to cholin- 2009;13(5):715-724. www.ncbi.nlm.nih.gov/pubmed/19882410 ergic axonal afferents from medial septum. Neuroscience 2009;164(3): Smith GE, Housen P, Yaffe K, Ruff R, Kennison RF, Mahncke HW, 1334-1346. www.ncbi.nlm.nih.gov/pubmed/19772895 Zelinski EM. A cognitive training program based on principles of Salthouse TA. When does age-related cognitive decline begin? Neurobiology brain plasticity: results from the Improvement in Memory with of Aging 2009;30(4):507-514. www.ncbi.nlm.nih.gov/pubmed/19231028 Plasticity-based Adaptive Cognitive Training (IMPACT) study. Journal of the American Geriatrics Society 2009;57(4):594-603. Saxton J, Morrow L, Eschman A, Archer G, Luther J, Zuccolotto A. www.ncbi.nlm.nih.gov/pubmed/19220558 Computer assessment of mild cognitive impairment. Postgraduate Medicine 2009;121(2):177-185. www.ncbi.nlm.nih.gov/pubmed/19332976 Snitz BE, O’Meara ES, Carlson MC, Arnold AM, Ives DG, Rapp SR, Saxton J, Lopez OL, Dunn LO, Sink KM, DeKosky ST. Ginkgo biloba Scarmeas N, Stern Y, Mayeux R, Manly JJ, Schupf N, Luchsinger JA. for preventing cognitive decline in older adults: a randomized trial. Mediterranean diet and mild cognitive impairment. Archives of Neurology Journal of the American Medical Association 2009;302(24):2663-2670. 2009a;66(2):216-225. www.ncbi.nlm.nih.gov/pubmed/19204158 www.ncbi.nlm.nih.gov/pubmed/20040554
Scarmeas N, Luchsinger JA, Schupf N, Brickman AM, Cosentino S, Sonnen JA, Larson EB, Brickell K, Crane PK, Woltjer R, Montine TJ, Tang MX, Stern Y. Physical activity, diet, and risk of Alzheimer disease. Craft S. Different patterns of cerebral injury in dementia with or . 2009b;302(6):627-637. Journal of the American Medical Association without diabetes. Archives of Neurology 2009;66(3):315-322. www.ncbi.nlm.nih.gov/pubmed/19671904 www.ncbi.nlm.nih.gov/pubmed/19139294
Schneider JA, Aggarwal NT, Barnes L, Boyle P, Bennett DA. The neuro- Sperling RA, Laviolette PS, O’Keefe K, O’Brien J, Rentz DM, Pihlajamaki M, pathology of older persons with and without dementia from community Marshall G, Hyman BT, Selkoe DJ, Hedden T, Buckner RL, Becker JA, versus clinic cohorts. Journal of Alzheimer’s Disease 2009;18(3):691-701. Johnson KA. Amyloid deposition is associated with impaired default www.ncbi.nlm.nih.gov/pubmed/19749406 network function in older persons without dementia. Neuron 2009;63(2):178-188. www.ncbi.nlm.nih.gov/pubmed/19640477
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 62 | References
Stewart R, Xue QL, Masaki K, Petrovitch H, Ross GW, White LR, Wang Z, Wang B, Yang L, Guo Q, Aithmitti N, Songyang Z, Zheng H. Launer LJ. Change in blood pressure and incident dementia: a 32-year Presynaptic and postsynaptic interaction of the amyloid precursor protein prospective study. Hypertension 2009;54(2):233-240. promotes peripheral and central synaptogenesis. Journal of Neuroscience www.ncbi.nlm.nih.gov/pubmed/19564551 2009;29(35):10788-10801. www.ncbi.nlm.nih.gov/pubmed/19726636
Storandt M, Mintun MA, Head D, Morris JC. Cognitive decline and Wendell CR, Zonderman AB, Metter EJ, Najjar SS, Waldstein SR. brain volume loss as signatures of cerebral amyloid-beta peptide deposi- Carotid intimal medial thickness predicts cognitive decline among tion identified with Pittsburgh compound B: cognitive decline associated adults without clinical vascular disease. Stroke 2009;40(10):3180-3185. with Abeta deposition. Archives of Neurology 2009;66(12):1476-1481. www.ncbi.nlm.nih.gov/pubmed/19644063 www.ncbi.nlm.nih.gov/pubmed/20008651 Williams C, Mehrian Shai R, Wu Y, Hsu YH, Sitzer T, Spann B, Sun B, Halabisky B, Zhou Y, Palop JJ, Yu G, Mucke L, Gan L. McCleary C, Mo Y, Miller CA. Transcriptome analysis of synaptoneuro- Imbalance between GABAergic and glutamatergic transmission impairs somes identifies neuroplasticity genes overexpressed in incipient adult neurogenesis in an animal model of Alzheimer’s disease. Cell Stem Alzheimer’s disease. PLoS One 2009;4(3):e4936. E-publication. Cell 2009;5(6):624-633. www.ncbi.nlm.nih.gov/pubmed/19951690 www.ncbi.nlm.nih.gov/pubmed/19295912
Taragano FE, Allegri RF, Krupitzki H, Sarasola DR, Serrano CM, Loñ L, Wilson RS, Aggarwal NT, Barnes LL, Bienias JL, Mendes de Leon CF, Lyketsos CG. Mild behavioral impairment and risk of dementia: Evans DA. Biracial population study of mortality in mild cognitive a prospective cohort study of 358 patients. Journal of Clinical Psychiatry impairment and Alzheimer disease. Archives of Neurology 2009;70(4):584-592. www.ncbi.nlm.nih.gov/pubmed/19323967 2009a;66(6):767-772. www.ncbi.nlm.nih.gov/pubmed/19506138
Teng E, Tingus KD, Lu PH, Cummings JL. Persistence of neuropsy- Wilson RS, Arnold SE, Schneider JA, Boyle PA, Buchman AS, Bennett DA. chological testing deficits in mild cognitive impairment. Dementia and Olfactory impairment in presymptomatic Alzheimer’s disease. Annals of Geriatric Cognitive Disorders 2009;28(2):168-178. the New York Academy of Sciences 2009b;1170:730-735. www.ncbi.nlm.nih.gov/pubmed/19707017 www.ncbi.nlm.nih.gov/pubmed/19686220 van Wijngaarden E, Campbell JR, Cory-Slechta DA. Bone lead Yaffe K, Fiocco AJ, Lindquist K, Vittinghoff E, Simonsick EM, levels are associated with measures of memory impairment in older Newman AB, Satterfield S, Rosano C, Rubin SM, Ayonayon HN, adults. NeuroToxicology 2009;30(4):572-580. Harris TB. Predictors of maintaining cognitive function in older adults: www.ncbi.nlm.nih.gov/pubmed/19477197 the Health ABC study. Neurology 2009;72(23):2029-2035. www.ncbi.nlm.nih.gov/pubmed/19506226 Vitaliano PP, Zhang J, Young HM, Caswell LW, Scanlan JM, Echeverria D. Depressed mood mediates decline in cognitive processing Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD. speed in caregivers. Gerontologist 2009;49(1):12-22. Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in www.ncbi.nlm.nih.gov/pubmed/19363000 female mouse model of Alzheimer’s disease. Proceedings of the National Academy of Sciences 2009;106(34):14670-14675. Wadley VG, Okonkwo O, Crowe M, Vance DE, Elgin JM, Ball KK, www.ncbi.nlm.nih.gov/pubmed/19667196 Owsley C. Mild cognitive impairment and everyday function: an investigation of driving performance. Journal of Geriatric Psychiatry and Yuede CM, Zimmerman SD, Dong H, Kling MJ, Bero AW, Holtzman DM, Neurology 2009;22(2):87-94. www.ncbi.nlm.nih.gov/pubmed/19196629 Timson BF, Csernansky JG. Effects of voluntary and forced exercise on plaque deposition, hippocampal volume, and behavior in the Tg2576 Wang JM, Singh C, Liu L, Irwin RW, Chen S, Chung EJ, Thompson RF, mouse model of Alzheimer’s disease. Neurobiology of Disease Brinton RD. Allopregnanolone reverses neurogenic and cognitive 2009;35(3):426-432. www.ncbi.nlm.nih.gov/pubmed/19524672 deficits in mouse model of Alzheimer’s disease. Proceedings of the National Academy of Sciences 2010;107(14):6498-6503. Zhang C, Wu B, Beglopoulos V, Wines-Samuelson M, Zhang D, www.ncbi.nlm.nih.gov/pubmed/20231471 Dragatsis I, Südhof TC, Shen J. Presenilins are essential for regulating neurotransmitter release. Nature 2009;460(7255):632-636. Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, Zhu X. www.ncbi.nlm.nih.gov/pubmed/19641596 Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. Journal of Neuroscience 2009;29(28):9090-9103. Zhang YW, Liu S, Zhang X, Li WB, Chen Y, Huang X, Sun L, Luo W, www.ncbi.nlm.nih.gov/pubmed/19605646 Netzer WJ, Threadgill R, Wiegand G, Wang R, Cohen SN, Greengard P, Liao FF, Li L, Xu H. A functional mouse retroposed gene Rps23r1 Wang Y, Greig NH, Yu QS, Mattson MP. Presenilin-1 mutation reduces Alzheimer’s beta-amyloid levels and tau phosphorylation. impairs cholinergic modulation of synaptic plasticity and suppresses Neuron 2009;64(3):328-340. www.ncbi.nlm.nih.gov/pubmed/19914182 NMDA currents in hippocampal slices. Neurobiology of Aging 2009;30(7):1061-1068. www.ncbi.nlm.nih.gov/pubmed/18068871
2OO9 PROGRESS REPORT on ALZHEIMER’ S DISEASE 63
“This course was developed from the public domain document: Alzheimer’s Disease: Unraveling the Mystery and the Progress Report on Alzheimer’s Disease Translating New Knowledge – U.S. Department of Health and Human Services.”