2013 ANNUAL REPORT

McCuskerAlzheimer’s Research Foundation Inc Suite 22 Tel: +61 8 9347 4200 Hollywood Medical Centre Fax: +61 8 9347 4299 85 Monash Avenue Email: [email protected] Nedlands WA 6009 Australia

www.alzheimers.com.au THANKS TO ALL OUR SUPPORTERS...

Alzheimer’s disease is one of the most • Spending on Dementia will surpass any Cowan University whose contributions of important public health problems we other health condition laboratory space, salaries and funding of face. It has a devastating impact research costs are invaluable. In 2010 dementia affected 23,000 WA on individuals and their families, people and this figure will rise to 61,000 Particular thanks go to a number of the community and the economy. by 2030. It is estimated that by 2050 significant donors who are acknowledged Unfortunately, compared to many other there will be an estimated 125,000 cases personally by Enzo Sirna in his major health areas such as heart disease in WA with 18 new cases every day. It is Chairman’s Report. and cancer, it receives little funding for predicted that the most rapid growth in research to discover treatments. We are grateful to community groups WA will occur in the next 10 years such as Lions clubs WA, Rotary and Emerging trends in Alzheimer’s disease The support given by the public to the Freemasons who support our efforts to statistics are amazing. fight against Alzheimer’s disease is of find a cure for Alzheimer’s disease. Our • There are 4.6 million new cases every the utmost importance. Without the developing partnership with the Lions year. very generous contributions of time Clubs International (WA) is particularly and money made by individuals and appreciated. • The number of people with Dementia corporations, the major research being is expected to double every 20 years Volunteers make an invaluable undertaken here in WA, at the McCusker and is projected to reach 115 million contribution. Their contributions as Alzheimer’s Research Foundation, would by 2050, with 81.1 million patients by research volunteers and assistance in struggle. 2040. fund raising and promotion are critical We are very grateful to our many to our efforts. Special thanks go to • 43% of cases need significant care supporters who share our vision of a the volunteers of the Lions McCusker (equivalent to a Nursing Home.) world where Alzheimer’s disease is Committee who work tirelessly to support • Total estimated worldwide cost of treatable and preventable and our belief and promote the work of Professor dementia in 2010 was $US604 billion that the research occurring here in Martins and his team. or nearly 1% of global GDP. WA can make major contributions to Finally, there are many more important defeating Alzheimer’s. • “If Alzheimer’s were a country, it would supporters that have not been singled be the 18th largest economy based on We are especially thankful to the out, however we wish to acknowledge GDP.” McCusker family, particularly Malcolm, their generous support, along with the • Within 2 decades dementia will be Carolyn and Tonya for their tremendous support of many members of the public. the third greatest source of health support and assistance over many years. and residential aged care spending – Special mention must also be made to approx. 1% of GDP Hollywood Private Hospital and Edith 2 CONTENTS

Chairman’s Report ...... 4 Research Report ...... 6 Diagnosis ...... 8 Prevention and Treatment ...... 12 Collaborations ...... 26 Publications ...... 28 Grants ...... 32 Visits and Presentations ...... 32 Clinical Trials Division ...... 33 Alzhyme ...... 36 Community Outreach ...... 38 Board Members ...... 40 Annual Report Financial Tables ...... 41 Notes ...... 54

Board of Director 2013

3 ANNUAL REPORT 2013

Seated from left: Rob Davies, Professor Ralph Martins; Enzo Sirna, Dr Terry Bayliss Standing from left: Peter Stephens, Deborah Doncon, Jenny Day, Assoc. Professor David Groth, Ron Bennetts, Russell Delroy. CHAIRMAN’S REPORT - Enzo SirnA

Since its inception, the McCusker aim of bringing important clinical trials “ Alzheimer’s Research Foundation has to Western Australia. Among these we maintained a constant and important have the Testosterone and Fish Oil Study presence in assisting our research team, (where over 3000 people registered so capably led by Prof. Ralph Martins, in interest to participate, but only 200 its goal to find prevention and ultimately, chosen to be assessed), the Tommorrow a cure for Alzheimer’s disease. (Tomm40) Study, the Nutritional The importance of this world class Supplements Study (investigating research has not been underestimated Biocurcumax and Amlamax), the by the 2013 Members of the Board of Australian Imaging, Biomarkers and the McCusker Alzheimer’s Research Lifestyle (AIBL) Project and the Karviah Foundation. The Board has recognised Study (in conjunction with Anglican the challenges associated with the Retirement Homes in Sydney). escalating research demands and Furthermore, the purchase of a new PET the commitment required to give CT Scanner in 2013, due to an innovative Prof. Martins and his team maximum partnership with Oceanic Medical opportunities to continue to be key Imaging, the McCusker Alzheimer’s research contributors at a world level. Research Foundation and the estate The Board also values key partnerships of the late Dr. Jean Murray-Jones, will in assisting with the delivery of enhance Alzheimer’s disease neuro outcomes linked to our research. These imaging. The PET CT Scanner permits partnerships allow the quality of research shorter scan times, decreased radiation to be progressed not only at a state level, exposure and will assist in getting quicker but also at national and international results with more accurate scanning. levels with far reaching benefits. It is a In order to maintain the essential and recognised fact the McCusker Alzheimer’s ongoing support at an operational Research Foundation has one of the level, the Board has identified essential world’s richest databases associated with requirements which will need to be its projects and clinical trials, allowing for implemented as soon as possible to greater depth and quality of research as keep pace with the rapid expansion Prof. Martins and his team strive, with in the research area. It has therefore 4 excellence, in their endeavour to find a commenced a review process aimed cure for this ever growing disease, with at strengthening its infrastructure 4.6 million new cases of Alzheimer’s and providing a key platform for the disease diagnosed each year. implementation of future strategic Prof. Martins and his research team planning requirements. work closely with Dr Roger Clarnette The McCusker Alzheimer’s Research and the Clinical Trials Division with the Foundation is indebted to its many benefactors, partners, donors, the generous contribution towards the the Golf Day at the Royal Perth Golf Club. organisations and sponsors who believe new neuroscience building (of which The McCusker Alzheimer’s Research in the cause and who continue to support the McCusker Foundation will be a key Foundation was pleased to collaborate our endeavours. We are particularly partner) and the Government of Western with Alzheimer’s Australia (WA) for the grateful to our Patron, His Excellency, Australia for assisting with our cause. World Alzheimer’s Day and the combined Malcolm McCusker AC CVO QC, to The McCusker Foundation is pleased to event held at the Government House Mrs Tonya McCusker and to Carolyn have Maggie Beer as an ambassador for Ballroom was very well received. McCusker, for their unwavering support our cause and her presence is always of the Foundation. The McCusker family I would like to thank all members of inspirational. The fundraising dinner the Board, the Executive, staff, Prof. has been the backbone of the Foundation held at the Perth Convention Centre in for many years and has inspired many Martins and the research team for December 2013, “Maggie Beer and the your considerate and passionate other benefactors to contribute as well. Five Chefs”, was a huge success and The Board also recognises the significant commitment to a very important cause. we are indeed grateful for the support I am also appreciative of the support contribution by our Vice-Patron, Mrs received by some of Perth’s leading chefs, Terrie Delroy and her family. you have given me as a very privileged including Chris Taylor, Alain Fabregues, Chairman of the McCusker Alzheimer’s Every contribution made to the Foundation, Neal Jackson, Giuseppe Pagliaricci and Research Foundation. I would also like no matter how big or how small, whether Richard Taylor. Franklin Tate provided to acknowledge the commitment of our financial or in kind, is gratefully accepted excellent wines for the evening and Eric previous Chairman, Mr Graham Nixon, who because it all helps in achieving our goals. Ferrari also assisted with the beverages, retired in 2013, but who worked tirelessly While it is always difficult to list everyone, providing the mineral water and the beer. I for the Foundation for so many years. I would like to make particular mention would like to recognise the efforts of John In conclusion, I am informed Ms Jenny of Mrs Helen Sewell and the Johanna Maiorana in coordinating the chefs, food Gill, our Executive Manager, will be Sewell Memorial Fund, Mr Ron Geary and beverages to ensure the success of retiring in July 2014. On behalf of the and Mrs Glenys Geary, Mr Michael Gregg, the evening. the Rotary Club of West Perth, the Stan Board, I would like to thank her most Our annual fundraising dinner at sincerely for her loyalty and involvement Perron Charitable Trust, Wesfarmers, Maurizio’s Restaurant is always a the Freemasons, the Lions McCusker with the Foundation and wish her well in success and Maurizio Di Ciano and his her retirement. Committee, the Cliff Richard’s Joondalup team, supported by Michael Tamburri for If anyone has been inadvertently left out

Support Ladies Group, the Lions Clubs of the wines, are to be applauded for the

of my report, please accept my sincere WA and those who have supported the excellence of the food and beverages and apologies but understand that your “ Foundation through “Everyday Hero”. The the wonderful atmosphere created, with contribution retains the highest of respect Board recognises and truly appreciates your the highlight being the musical interlude 5 ongoing support and significant contributions. and value for the Foundation.

by the “Musicantes”. ANNUAL REPORT 2013 The Board is also grateful for the Other successful fundraising events significant partnerships established with included the Sportsman’s Lunch, Hollywood Private Hospital and with Edith organised annually by the Claremont Cowan University. Furthermore, the Board Nedlands Lions Club, with part proceeds would like to recognise Lotterywest for donated to the McCusker Foundation and RESEARCH REPORT

Prof Ralph Martins investigating people (and families) Nutritional Supplements Trials: Work Director of Research who have or are at risk of early onset, continues investigating two nutritional inherited Alzheimer’s disease. Some of supplements, BiocurcumaxTM the our study participants are in their 30s active ingredient in the Indian curry spice The“ past year has seen considerable and have now developed this devastating turmeric and a strong anti-oxidant, and growth in the research work undertaken disease, so this is quite a confronting Amlamax, concentrated Indian gooseberry. by our team. The most exciting study. Our participants are very generous The BiocurcumaxTM trial is assessing outcome was the commencement of in attending for follow up as the study whether this spice prevents memory loss the Tommorrow (Tomm40) international involves a large battery of assessments and the final 50 participants will also clinical trial in early Jan 2014, with our and tests. The information learned from undergo brain imaging to help clarify our site only the second in the world starting this group, who develop a rapid, severe findings. In theAmlamax study we are this massive undertaking – following 500 form of Alzheimer’s disease, is invaluable, recruiting participants who have their to 600 people for five years (see below). as well as providing insight into the more cholesterol monitored as it is thought that This success built on work carried out common older onset disease. Arising from Amlamax may help raise good cholesterol over the previous two years with the the DIAN study is the opportunity for some and potentially protect both the head Prepare study. This work is undertaken of our DIAN participants to join the new and heart from disease! This trial is well entirely in our Stirling Highway premises. trial below. At this stage we are one of under way with nearly 50 people having As a result during late 2013 the only a few places in Australia to participate completed the study already. in this work. Foundation established the McCusker KARVIAH – Kerr Anglican Retirement Hollywood Private Hospital Research DIAN Clinical Trial: Current DIAN Village (ARV) Initiative in Ageing Centre enabling all our other ongoing participants who meet particular onerous Health: KARVIAH is examining the physical clinical projects to be undertaken at the criteria will be eligible for this new and dietary health of 200 older people Hollywood site. These achievements Clinical Trial. This will be an international dwelling in Independent Living Units within reflect the invaluable support received intervention trial which will assess three a Sydney retirement village. One hundred 6 from our study participants, our donors new drugs thought to be helpful in the participants will then go on to the stage and the McCusker Foundation. This early stages of Alzheimer’s disease. Prof two curcumin component evaluating support enabled our research team Martins and A/Prof Roger Clarnette, BiocurcumaxTM (as above) over a 12 to achieve a number of important from the Foundation’s Clinical Trials month period. This study has commenced milestones in 2013. Division, are now involved in negotiations recruitment and will move to stage two DIAN (Dominantly Inherited regarding criteria for eligibility of during 2014. It is led by Prof Martins Alzheimer’s disease network) Study: participants for this study. This study in conjunction with the ARV’s Dementia The McCusker Foundation/ECU team has now received its approvals and will Consultancy and Research Manager as is one of only fourteen worldwide commence in May 2014. well as our UWA PhD student, Kathryn

“ My team and I have moved forward on a number of very

exciting fronts in 2013. For this we are very appreciative

of the marvelous support we receive from our“ many supporters and the public during the year.

Goozee, and is receiving invaluable for the Tommorrow study. This new undertaken pioneering work to determine support from both the Anglican Retirement study, which commenced in January whether the eye can play a role in the Village and McCusker Foundations. 2014, has now been taken over by the diagnosis of Alzheimer’s disease and large Japanese pharmaceutical company has published some exciting results in Testosterone and Fish Oil (DHA) Takeda. The trial will determine whether support of his thesis. All three of them Trial: This project involves 200 male a drug usually used in type two diabetes are now playing important roles in the participants and is a ground breaking can help delay the onset of Alzheimer’s Foundation’s ongoing research programs. trial testing laboratory and anecdotal disease. It will also test the validity of a evidence that testosterone and DHA help I am indebted to the McCusker genetic biomarker TOMM 40. It will run delay or prevent the onset of Alzheimer’s Alzheimer’s Research Foundation Inc., over five years with the Foundation/ECU disease. This will be a worldwide first in which continues to provide tremendous team center one of three in the world terms of combining these substances. support to our research. This includes designated Tier One (major) sites. This is To date our 3000 volunteers interested the very generous quarterly contribution a unique prevention trial in that it utilizes in participating have been screened to the CRC for Mental Health, enabling a commonly available medication to and brain imaging is now being utilized our projects to expand by attracting test its potential to prevent the onset of to assess eligibility. The study will run matching funds; as well as support Alzheimer’s disease. for 56 weeks with men receiving a for our Stirling Highway lab; our new testosterone injection every eight weeks. PhD completions: I am proud to McCusker Hollywood Private Hospital lab; announce that three of our PhD students and many of our staff. Memory Study: This project is a 15 year completed their theses with flying duration project and we have 800-900 I am also blessed to have an extremely colors. Dr Belinda Brown investigated participants. In each case we have a talented and dedicated team of highly participants in the Australian Imaging record of their memory and blood tests capable and enthusiastic researchers, Biomarkers and Lifestyle (AIBL) study of over time. In some circumstances where and we can all be very proud of their Ageing and demonstrated that exercise

the individual has passed away we also efforts. A very big thank you is extended protects the brain with people who are

have details of their post mortem brain to all of our donors, both small and large. 7 genetically predisposed obtaining the “ studies. This bank of data will be an Your interest, friendship and support are

greatest benefit. Dr Tejal Shah undertook ANNUAL REPORT 2013 invaluable resource as new markers of critical to our work and you share in our a clinical trial to determine the benefits of the disease are discovered. considerable successes. different types of exercise and computer TOMMORROW study: During based brain training. She demonstrated 2012/13 our group conducted the that both exercise and specific brain Prepare study for USA based Zinfandel training programs were independently Pharmaceuticals, in which we recruited beneficial and together these benefits and assessed 1300 potential participants were synergistic. Dr Shaun Frost has DIAGNOSIS

The Dominantly Inherited Alzheimer’s Network (DIAN) study

Researchers: Researchers Mr Kevin Taddei, Dr Hamid Sohrabi, Dr. Veer B. Gupta, A/Prof Simon M. Laws, Dr. Florence Lim and Professor Ralph Martins PhD student: Miss Pratishtha Chatterjee

The McCusker Alzheimer’s Research disease process develops before there and overseas (plus 12 remote follow-up Foundation and Edith Cowan are any symptoms. Ultimately, knowledge assessments). As of March 2013 DIAN Kevin Taddei University are one of the sites for gained from DIAN may lead to tests that had recruited 378 participants worldwide the Dominantly Inherited Alzheimer’s detect people who still are normal but are with Perth contributing the third most Network (DIAN) study. This US$16 at very high risk of developing dementia to date, with 31 participants. So far million international Network was caused by AD. It is on this basis, and we delivered our commitments to the established by the National Institute supported through preliminary research DIAN study by recruiting the number of on Aging of the National Institutes by Drs Gupta and Lim, that an NHMRC patients required from each site. It should of Health (US) to bring together grant application led by Prof Martins, with be noted that each patient will spend researchers who study genetic forms significant contributions by A/Prof. Laws, at least a week with us to go through of Alzheimer’s disease (AD). The study has been submitted for funding in 2015. all the assessments including medical, is seeking 400 volunteers worldwide All DIAN participants will be members neurological and neuropsychological who are members of families in which of families with dominantly inherited AD tasks as well as fasted and non-fasted AD is dominantly inherited, meaning caused by a known mutation and may be blood samples, brain imaging and lumber that about 50% of the individuals in ideal candidates to participate in future puncture, if they consent to do so. each generation of a family develop studies of drugs that have the potential An interesting, recent development of AD, generally before age 60. These to halt the AD process and prevent DIAN is that a clinical trial for potential rare forms of AD are caused by a dementia. prevention and treatment agents will mutation in one of 3 known genes. Presently, there are 14 DIAN study sites: take place and will be undertaken by the Each child of an affected parent 8 in the US, one in England, three in different DIAN sites, including Australia. has a 50% chance of inheriting the Australia, and two in Germany. Research These trials are aimed at increasing mutation. If they do, they will develop volunteers travel to one of the sites for the quality of life, delay the process the dementia of AD at about the the studies, which are repeated every of neurodegeneration and potentially same age as their parent. Siblings few years. It is expected that each round treating the disease. Only participants who do not have the mutation have of DIAN studies will take between 3 and enrolled in the current DIAN study prior to no greater risk of developing AD than 5 days to complete. Participants may June 1, 2012 may be recruited into the someone without a family history of benefit from the opportunity to talk with first DIAN trial. The DIAN baseline data AD and will participate in DIAN as persons knowledgeable on the autosomal will be utilized as run-in data for the trial. part of a comparison group for their dominant form of Alzheimer’s disease. For participants interested in the DIAN mutation-carrying siblings. Individuals trial, it has already commenced in the US 8 participating in DIAN are not required The Australian sites include the McCusker and will start in mid 2014 in Australia, to know whether or not they carry a Alzheimer’s Research Foundation & participants must be enrolled into the mutation. Should they wish to learn Edith Cowan University, Prince of Wales current ongoing DIAN study right away. their mutation status through genetic Medical Research Institute, University testing following genetic counseling, of New South Wales, Mental Health Further information about DIAN DIAN can assist with this process. Research Institute of Victoria and the can be found at: University of Melbourne. www.dian-info.org or please Research suggests that brain changes contact Athena Paton at the McCusker may occur years before actual In 2013, we, at the McCusker Alzheimer’s Alzheimer’s Research Foundation Inc on Alzheimer’s symptoms are detected. Research Foundation and Edith Cowan (08) 9347 4200, by fax The major goal of DIAN is to study University, recruited 1 new participant (08) 9347 4299, mobile 0418 939 233 these changes in people who carry and performed 12 follow-up assessments or email: [email protected]. an AD mutation to determine how the on previous participants from Australia The McCusker Cognitive Complaints Inventory (McCi) McCusker Alzheimer’s Research Unit: Memory Complainer Study Key Researchers (ECU/McCusker): Dr Hamid R Sohrabi; Professor Ralph Martins

Proper screening of those individuals personality traits rather than actual at risk of developing dementia is a memory or cognitive functions. As challenging task hindering accurate such, we have been working on a Dr Hamid Sohrabi clinical diagnosis and successful clinical comprehensive measure that not only trials. If we find a way to screen for the measures various cognitive functions at-risk individuals then we can examine but is significantly associated with new preventions on the most suitable actual cognitive performance. The participants. Having suitable participants McCusker Cognitive Complaints in a trial allows for examining the Inventory or McCi (pronounced Maxi) efficacy of our preventive measures is such a measure. It is still a work on delaying the onset of Alzheimer’s in progress and we will examine its neurodegenerative process(s) that first version in our clinical studies by is currently irreversible. The self- mid-2014. reported decline or complaint about memory, attention, decision making, judgment, and language and so on is a good indicator for detecting at risk individuals. However, current measures assessing self-reported changes have not proved to be valid and reliable as they are associated with depression and

9 ANNUAL REPORT 2013 DIAGNOSIS

Biomarker discovery: Towards the early diagnosis, prediction and monitoring of Alzheimer’s disease. CRC Project. Researchers (ECU/McCusker): The Biomarker Research Team: A/Prof. Simon M. Laws, Dr. Veer Bala Gupta, Dr. Stephanie Rainey-Smith, Dr. Andrea C. Wilson, Dr. Florence Lim, Dr. Eugene Hone, Mr. Steve Pedrini, Mr. Kevin Taddei, A/Prof. Chiou-Peng Lam, and Prof. Ralph Martins Students: A/Prof Simon Laws Ms Michelle Tegg (Masters), Ms Rhona Creegan (PhD), Ms Samantha Gardener (PhD), Ms Pratishtha Chatterjee (PhD), Ms Tenielle Porter (PhD), Mr James Nelson (Honours) Collaborators: AIBL and CRC for Mental Health collaborators, including; University of Melbourne/Florey Institute for Neuroscience and Mental Health (Prof. Colin Masters, Prof. Ashley Bush, Dr. Noel Faux, Dr. Alan Rembach), CogState (Dr. Paul; Maruff), the CSIRO (Dr. Bill Wilson, Dr. James Doecke, Dr. Samantha Burnham), the Australian Neuromuscular Research Institute (Prof. Frank Mastaglia and Dr. Soumya Ghosh) and the University of Western Australia (Prof. Assen Jablensky). Dementia Collaborative Research Centre– Early Diagnosis and Prevention (DCRC-EDP, Canberra). International collaborators: Prof. Hans Foerstl, Dr. Panos Alexopoulos (Technical University of Munich), Dr. Robert Perneczky (Imperial College, London)

Program Aims: Use multiple discovery and treatment strategies to be initiated when AIBL. The candidate protein biomarkers, approaches to identify biomarkers they are most effective and will also have mentioned above, when validated in the (substances used as an indicator of a applications in the monitoring of medical and AIBL cohort, have the potential to be biological state), such as proteins and lifestyle interventions. combined to create multiplex assays that lipids in plasma or genetic factors, will greatly facilitate achieving the research Our Approach - Major findings and future whose measurable levels or frequencies programs overall aim of identifying optimal directions: Our on-going multidisciplinary are altered between healthy and AD biomarker panels. So, in parallel to the research program combines a wealth of individuals. This approach, when utilised above project, we are also undertaking clinical data available through AIBL with in the thoroughly characterised Australian an in-house multiplex assay development different biological discovery approaches Imaging Biomarkers and Lifestyle (AIBL) project to assess combination of multiple listed below, with significant funding from the Study of Aging cohort and the DIAN cohort analytes within a single assay. In addition CRC for Mental Health. stands the best chance of capturing to the plasma, we are also assessing the most sensitive and specific panel of Protein Discovery (Proteomics): the use of platelets as an alternative biomarkers, which have the potential to “Targeted proteomics” work is focused source of potential AD biomarkers in diagnose, predict and/or monitor AD. Any on the analysis of individual protein collaboration with DCRC-EDP. Further, in diagnostic panel requires cross-validation biomarkers such as amyloid beta, our “Discovery proteomics” stream, we against other neurological disorders to apolipoprotein E, apolipoprotein J, cortisol, are carrying out relative and absolute determine disease specificity. With the Insulin Degrading Enzyme (IDE) and quantitation of differentially expressed advent of the CRC for Mental Health we will Brain-derived neurotrophic factor (BDNF) proteins in AD compared to controls and now have the opportunity to cross validate in AIBL plasma. The results obtained from Mild Cognitive Impaired participants in 10 against other disorders such as Parkinson’s these biomarkers have shed light on the AIBL cohort and presymptomatic and disease and Schizophrenia subtypes, and their significance in AD and need further symptomatic compared to non-carriers in in doing so help our collaborators identify longitudinal comparisons together with the DIAN cohort using Mass spectrometry markers that may assist with the diagnosis other potential biomarkers with diagnostic and 2-Dimensional Gel electrophoresis of these disorders. value. We have validated a number of methods. This project will help us identify potential protein biomarkers on advanced additional candidate markers to be Significance:Advances in medical MSD (Mesoscale) technology in our lab incorporated in our “AD biomarker panel”. treatments and lifestyle interventions for recently and are currently analyzing new AD mean the discovery of biomarkers for a Lipid Discovery (Lipidomics): The protein biomarkers on this platform. reliable method of detecting/predicting the successful 2010 NHMRC project grant, Our focus is on the common top hits disease, at an early stage, is paramount. awarded to Prof. Martins, A/Prof. Laws obtained from recent blood biomarker The identification of such biomarkers will and Dr. Gupta, provides the backbone based studies in characterized population allow for current and future prevention cohorts with AD participants, including to this research, which commenced in and collaborative 3rd party genotyping published by others are screened in our 2011. Dr. Florence Lim, whose pilot study requests, which is now generating revenue own Alzheimer’s cohorts and those of significantly contributed to the awarding for the benefit of the McCusker Alzheimer’s our collaborators in Germany and the of the grant, is working closely with Research Foundation. In general terms United Kingdom. With our collaborator PhD students Ms. Rhona Creegan (near the Genomics program focuses on Professor Paul Maruff (CogState) we completion), Ms. Samantha Gardener and two streams of research, Discovery have shown that variation in the BDNF Ms. Pratishtha Chatterjee in undertaking and Validation. These streams work gene can mediate the rates of memory this work, which involves the profiling synergistically to focus on the identification loss and neuropathology. Through of plasma lipids using a state-of-the-art of genes and underlying genetic factors, the work of our recently completed platform unique in Australia and based at which will help identify additional biomarker honours student, Ms Sara Garin, we ECU. This screening of plasma lipids, when candidates as well as increasing our have identified variants in steroid combined with clinical data from AIBL, will understanding of the pathways leading to synthesis genes not previously linked allow for lipid profiles to be determined the disease. These genomic approaches to AD, work that has been submitted in relation to disease status, clinical will aim to identify new genes involved in for presentation at the Alzheimer’s phenotypes (e.g. memory performance early onset and sporadic AD as well as Association International Conference in or brain imaging) and lifestyle factors the screening of genes in the Australian Copenhagen in July 2014. In addition (e.g. diet and exercise). Currently, lipids population. The Discovery stream, funded to determining genetic associations in over 2000 samples spanning the first through the CRC for Mental Health utilizes with disease, a focus of this research 18-months of the AIBL study had been “Next-generation Sequencing” approaches program is assessing what genes profiled and results are currently being to sequence the coding regions (regions may help determine how an individual tabulated. The results obtained from these that hold information for translation into, responds to a disease intervention, as lipid biomarkers need further longitudinal for example, proteins in the body) across well as what genes are affected by the comparisons together with other potential the entire human genome. This study intervention, whether the intervention biomarkers with diagnostic value. This work uses a population enrichment approach be pharmacological or lifestyle related will be augmented with continued support whereby we selected “super-controls” (e.g. diet). These fields of research, from the CRC for Mental Health extending and compared them to both individuals pharmacogenomics and nutrigenomics, this lipid profiling to subsequent time points with Alzheimer’s disease and Parkinson’s respectively, are of increasing in the AIBL study, to help us determine disease – allowing us to identify disease importance in AD research especially how lipid profiles change over time and specific variations in genes that have the as we move closer to our goal of early with disease progression. Samples from highest functional relevance. This study, diagnosis. An understanding of therapy the DIAN cohort are currently being lipid- the validation of its findings and study response will help ascertain the best profiled. The results obtained from these of the functional consequences is the mode of intervention for a given person. lipid biomarkers might provide insight into focus of the genomics group’s inaugural A collaborative research project, the earlier lipid changes in AD. PhD student – Ms. Tenielle Porter – and between the genetics and lifestyle preliminary findings were presented in programs, sees the co-supervision of Gene Discovery (Genomics): This third March 2013 at the AD/PD international an honours student (Mr James Nelson) 11 and most recent addition to our ‘multiomic’ conference in Florence, Italy. These initial by A/Prof Laws and Drs Rainey-Smith approach, led by A/Prof. Laws, has ANNUAL REPORT 2013 findings have led to the awarding of a and Brown, which is investigating rapidly expanded through bringing core Mason Foundation grant, to A/Prof Laws whether specific gene variants infrastructure components of this research and A/Prof Verdile, to study the functional differentially impact the beneficial ‘in-house’. Not only has this significantly impact of some of these gene variations effects that exercise and diet provide reduce costs and increased productivity and the submission of an NHMRC grant for that our group has previously reported. but also it has allowed this small group to funding in 2015. The Validation stream This hopefully represents the first of establish itself as the central genotyping is the core stream that underlies the many projects in this growing area of hub for both the AIBL study and the CRC genomics research program, where newly research. for Mental Health. The Genomics Group discovered genetic variations or a priori is responsible for undertaking routine candidate genes, either from our group or genotyping in addition to fee-for-service PREVENTION AND TREATMENT Developing agents that selectively target the enzyme responsible for beta amyloid generation

Dr Giuseppe Verdile Researchers (Curtin/ECU/McCusker): Collaborators: Dr Giuseppe Verdile, Professor Paul Fraser A/Prof David Groth, (University of Toronto, Toronto) Mr Mohammad Imran Khan A/Prof Maho Morishima (PhD Student commenced in 2012), (Hokkaido University, Japan) Mr Gorcin Kruejsepi (honours student Dr Imre Berger (EMBL, Grenoble, France) commenced in 2014) Dr Christianne Berger Schaffitzel (EMBL, and Professor Ralph Martins Grenoble, France) Background components that make up the enzyme. France). The PhD student will work in The enzyme, gamma secretase This success was possible through Drs Berger and Berger-Schaffitzel’s is a major target for developing our collaborations with Dr Imre Berger labs to progress the work required. An appropriate specific therapeutic from the European Molecular Biology honours student has also been recruited agents for Alzheimer’s disease. Laboratories (EMBL), Grenoble, France from Curtin University. Supervised by The enzyme is responsible for the who is an expert at reconstructing Assoc. Professors Verdile and Groth and production of a protein called beta complex proteins and identifying their Professor Fraser. This project aims to amyloid, which has a central role in structure. Sudarsan spent 3 months in identify areas within the enzyme that are Alzheimer’s disease pathogenesis. his laboratory where he learnt advanced critical for its activity. The majority of drugs that have been molecular biological techniques that As well as using this model to determine developed targeting the enzyme have he brought back with him. Sudarsan the structure of the enzyme we also aim failed due to its many other functions successfully completed his thesis, which to develop it as a rapid screening method within cells. A better understanding was favourably received, and graduated of drugs trying to reduce beta amyloid of gamma-secretase function and in 2010. His work is currently being production. Another feature of the enzyme structure is required if it is to be drafted into a manuscript and contributed is that it also acts on other proteins pursued as an appropriate target. to data that was included in a project that are important in cell function. Its Using the latest advanced techniques, grant, submitted to the National Health multi-functional nature is a major reason the project will provide significant and Medical Research Council (NHMRC). for the failure of the majority of drugs insight into the function and structure In 2012, we recruited a PhD student that have been developed targeting this of the enzyme, and thus can be (Imran Khan) to continue this work. enzyme. These drugs have shown severe used to develop more specific drugs We are moving to the next stage of the side-effects in pre-clinical trials. directed at gamma secretase. project which is to continue to collaborate By comparing the effect of potential Progress with Dr Berger to purify the enzyme and therapeutic agents on enzyme activity The initial stage of this project involves determine its structure and identify areas on a number of proteins that are acted re-constructing the enzyme in an within the enzyme that are critical for its on by the enzyme, we can rapidly insect cell culture model. We use this activity to generate beta amyloid, in order 12 identify those that specifically target beta model to generate large amounts of to develop specific drugs targeting beta amyloid without altering the production the enzyme so that it can be purified amyloid. We are currently collaborating of the other proteins. This will ultimately and undergo analysis to determine with a team of internationally recognized, generate more specific drugs for the its structure, which currently remains well respected scientists to tackle this disease. to be determined. A PhD student, Mr project. The team includes Professor Paul Sudarsan Krishnaswamy was recruited Fraser (University of Toronto, Canada), A/ to undertake this project in 2007. Professor Maho Morishima (Hokkaido Initial attempts at re-constructing University, Japan), Dr Imre Berger (EMBL, the enzyme failed however, after Grenoble, France) and Dr Christiane many subsequent attempts we finally Berger-Schaffitzel (EMBL, Grenoble, succeeded at re-constructing all 4 Enhancing the clearance of beta amyloid

Researchers (ECU/McCusker): Collaborators: Graduated Student: Dr Veer Gupta (ECU/McCusker) Mr Kevin Taddei, Dr Veer Gupta, Dr Ian Martins, Professor Sam Gandy (Mount Ms Tenielle Porter received Dr Renae Barr, A/Prof Giuseppe Verdile, A/Prof Simon Laws, Sinai, Medical School, New first class honours and now Dr Prashant Bharadwaj, Miss Elham Teimoori (PhD Student), Ms York); Professor Paul Fraser has joined our laboratory as Tenielle Porter (Honours Student), , A/Prof David Groth, Miss Linda (University of Toronto, Toronto) PhD student. Wijaya, Mr Mike Morrici, and Professor Ralph Martins

In addition to the over-production of toxicity) at enhancing the clearance diseases including Huntington’s beta amyloid, the impaired clearance (or of beta amyloid in the presence of the disease and AD. This pathway appears removal) of this toxic protein from the APOE-ε4 gene. Preliminary data with this to have a role in removing protein brain plays a key role in its accumulation peptide (which we refer to as amyloid aggregates from the cell. Dr Prashant in the AD brain and the resulting neutralizing agent- ANA) shows that Bharadwaj, developed a yeast model to neurodegeneration. As such enhancing it binds beta amyloid and we will now show for the first time that autophagy the clearance of beta amyloid from the determine if administering this peptide is involved in the degradation of beta brain is a potential therapeutic strategy to a mouse model of AD, can reduce the amyloid. Prashant also showed that a that we are currently investigating. accumulation of beta amyloid in their drug that is currently in human clinical brains and promote its degradation/ trials called Latreperdine (previously In collaboration with Professor Sam clearance by peripheral organs such known as Dimebon) can enhance the Gandy (now of Mount Sinai School of as the liver. Dr Renae Barr has been degradation of beta amyloid in yeast Medicine, New York) and funded by the investigating the activity of this peptide cells by activating autophagy. Our prestigious funding agency, the National further to provide further insight into collaborator Professor Gandy showed Institute of Health (NIH) in the US, we how the peptide could be modified to similar results in neuronal cells and in investigated the role of the genetic risk generate a more potent agent. This mice. This work was presented by Dr factor for AD, APOE ε4, in impairing beta work was presented at the Combined Verdile at the Society for Neurosciences amyloid clearance in the brain and the Biological Sciences Meeting, 2012 meeting (Washington), November periphery. Here we showed that mice held in Adelaide. A provisional patent 2011 and the Alzheimer’s Association containing the APOE ε4 gene did not (P1078AU000) on this work was filed in International Conference (AAIC) in clear/degrade beta amyloid as well as September 2012. Based on evidence Vancouver in July 2012. These findings those mice that didn’t contain the gene, from our laboratory that our peptide binds have now been published in the providing evidence that the presence of Aβ, we are also exploring its potential journals Journal of Alzheimer’s disease this gene impacts how efficiently, beta as a specific imaging agent of not only and Molecular psychiatry. We will be amyloid is cleared. In 2010, we received amyloid plaques but the intermediates evaluating whether latreperdine related NHMRC funding to continue this research that accumulate early in the disease molecules have greater potency in to investigate mechanisms by which APOE process, small beta amyloid aggregates activating autophagy and enhancing 13 ε4 impairs clearance/degradation of beta called oligomers. beta amyloid clearance in cell culture. amyloid in liver cells (the liver is the major ANNUAL REPORT 2013 This work will be undertaken by and Dr organ that degrades beta amyloid). We are also investigating another Prashant Bharadwaj, under supervision mechanism by which beta amyloid can In 2010, we also received NHMRC of A/Prof Giuseppe Verdile. be efficiently cleared/degraded by cells. funding to assess the efficacy of a novel Evidence exists that a pathway within the Prashant’s data was key to small peptide, (which we identified cell called autophagy plays an important successfully obtaining NHMRC and showed to neutralize beta amyloid role in a number of neurodegenerative funding for this project, in which Enhancing the clearance of beta amyloid

funding commenced in 2011. The and commenced in 2011. Recently an Communications. Tenielle has continued NHMRC funding allowed us to employ honours student (Miss Tenielle Porter), working with our group and has joined Prashant as a post-doctoral fellow to supervised by A/Prof Giuseppe Verdile as a PhD student. Supervised by A/ continue this work. The project will and Dr Prashant Bharadwaj and A/Prof Professors Simon Laws, Giuseppe Verdile extend these findings to assessing David Groth, completed her honours with and David Groth, her project aims to the ability of Latrepirdines to activate first class and showed that latrepirdine identify and study the function of genetic autophagy in neuronal cells and also regulated beta amyloid aggregation. variations (“polymorphisms”) that are its ability to enhance the clearance This work was presented at the closely linked to AD risk. Preliminary data of beta amyloid from the brains of Australian Society for Medical Research has identified a gene involved in a cellular mouse models of AD. A PhD student, (ASMR) Symposium and the COMBiol pathway involved in the removal of beta Miss Elham Teimoori (supervised by conferences held in Perth. The findings amyloid. This data was included in an Professor Ralph Martins, Dr Giuseppe have been prepared as a manuscript NHRMC grant submitted in 2014. Verdile and Dr Prashant Bharadwaj) and will be submitted to the Journal has been recruited for this work Biochemical and Biophysical Research

14

Professor Ralph Martins with some of his team members. PREVENTION AND TREATMENT Developing a Zebrafish Model for Alzheimer’s Disease: Towards developing a high-throughput drug screening tool.

Researchers: Collaborator: Graduated Student: (ECU/McCusker): Miss Mengqi Chen (PhD Student), Mr Avdesh Dr Michael Lardelli (The University Mr Avdesh Chaudhary Chaudhary (PhD Student) A/Prof Giuseppe Verdile, A/Prof David of Adelaide).Prof Matthew Martin Groth), A/Prof Simon Laws, Miss Tenielle Porter (PhD Student) Iverson (The University of Western and Professor Ralph Martins Australia)

The current drugs for AD only temporarily Once developed, the AD zebrafish model showed that an enzyme that degrades treat disease symptoms without targeting will provide the appropriate model to beta amyloid plays an integral role in the underlying pathology and cause rapidly screen and identify drugs that fish development. Furthermore, this of neurodegeneration. Therefore, new target the underlying pathogenesis of student has shown that zebrafish have treatments for the disease are urgently the disease. similar enzyme activity to humans. required. The overall aim of this project is This work was presented at the Progress to develop a novel animal model for AD Alzheimer’s Association International During the past 4 years we have that can facilitate rapid screening in pre- Conference (AAIC) in Vancouver in established a small PC2, AQIS approved clinical stages of drug development. July 2012 and at the Society for West aquatic facility at the School of Medical Australian Neuroscientists (SWAN) The use of current mice models to Sciences, Edith Cowan University. The conference in Perth. A manuscript of validate potential therapeutic agents majority of this time period was spent the work is being prepared. Another are limited to only assessing one or two setting up the facility and establishing PhD student, Mr Avdesh Chaudhary, drugs, thereby slowing down the progress wild-type zebrafish lines. During this developed assays that assess learning of drug development. Further, the majority period we also undertook preliminary and memory in zebrafish. These of drugs that show benefits in transgenic experiments to show that the pathological assays will be essential in providing mouse models fail in human clinical trials. beta amyloid species, Aβ42 induces cell a functional assessment that can It is clear that further in vivo screening of death in zebrafish embryos. Although, be implemented in a screening of potential therapeutic agents is required these findings provided first evidence potential drug agents. A manuscript prior to entering clinical trials. In addition, to show that beta amyloid is toxic to was published in the Journal of a model that will allow rapid screening of zebrafish, the concentrations used in the Alzheimer’s disease outlining the numerous drug agents/libraries will be preliminary study were supraphysiological use of two methods called the colour of great benefit to increase the capacity and do not represent the levels preference box and T-maze to assess and potential to identify and validate observed in an AD brain. This project the colour preference of zebrafish. effective treatments, in pre-clinical will extend these studies to develop a The results show that zebrafish prefer stages of drug development. Features of more physiological model that exhibits certain colours over others. This the zebrafish make them a particularly pathological hallmarks more closely information is essential in designing attractive model; in particular, their rapid representing that occurring in the AD 15 further assays assessing memory development, availability in large numbers brain. Our PhD student, Miss Mengqi and learning in zebrafish. Avdesh has ANNUAL REPORT 2013 and lower maintenance costs (1/1000th Chen, undertook this work and is in the also developed a high throughput that of mice). These features facilitate the final stages of completing her thesis. The functional assay to assess embryo development of a cost effective high- students’ scholarship was co-funded by behaviour. Avdesh successfully through put in vivo drug screening tool. the West Perth Rotary club and McCusker completed his thesis in 2013 and has Foundation. Mengqi for the first time obtained a post-doctoral position at Developing a Zebrafish Model for Alzheimer’s Disease: Towards developing a high-throughput drug screening tool.

the prestigious Max Planck Institute in We continue utilizing the zebrafish as Dr Michael Lardelli, (Adelaide) and A/Prof Frankfurt, Germany. a model to understand gene function. Giuseppe Verdile have been collaborating The data generated by Mengqi has also for many years on the role of proteins Mengqi and Avdesh also played provided preliminary data for a NHMRC called presenilins that are essential in the essential roles in maintenance of the project grant application that was production of beta amyloid. They have zebrafish and our zebrafish facility. submitted on March 2013. The grant discovered that a certain variant of the This includes zebrafish husbandry to identifies genetic variants associated presenilin protein has an impact on beta provide efficient embryo production. with increased AD risk and investigate amyloid accumulation in the brain. The The protocols in which they have their functions in cell culture and in vivo levels of this variant in the brain increase developed were recently published using zebrafish. Our honours student, under conditions of oxidative stress and in a novel concept for a journal, the Ms Tenielle Porter, who completed her high cholesterol and this is associated Journal of Visualised Experiments. studies with first class honours, was with increases in beta amyloid levels. Drs The article is a step by step guide successful at obtaining a scholarship to Verdile and Lardelli, in collaboration with to maintaining a zebrafish facility undertake a PhD at ECU in 2013. This will Dr Matthew Sharman, will investigate and outlines optimal conditions to be supervised by A/Prof Simon Laws, A/ the role of this presenilin variant in beta breed zebrafish and is useful for Prof Giuseppe Verdile and A/Prof David amyloid metabolism, and using zebrafish, researchers’ world-wide who are Groth as she undertakes this project. identify critical sites within the protein considering establishing a zebrafish Further, Prof. Martins and A/Profs Verdile that are responsible for its activity. This research facility. More recently two and Laws were among a team of WA has implications in the development of additional PhD students, Mr Imran researchers who were awarded an ARC agents that selectively attenuate beta Khan and Ms Tenielle Porter, have LIEF grant of $400k to establish a larger amyloid levels. An NHMRC project grant taken up the role of maintaining Zebrafish facility that will not only support was recently awarded to A/Prof Verdile, the Zebrafish facility in addition to our increased research utilization of Dr Lardelli and Dr Sharman to fund this their respective PhD projects. This Zebrafish, but that also of the entire WA work, which commenced in 2014. significant contribution they have research community. made is very much appreciated and The support of Perpetual is acknowledged acknowledged by Prof Martins and the through their grant to the McCusker 16 senior members of his team. Alzheimer’s Research Foundation. PREVENTION AND TREATMENT The potential of testosterone as a therapeutic strategy for AD

Researchers: Collaborators: Graduated Student: Prof Ralph Martins Professor Ralph Martins Dr Eka Dr Malcolm Carruthers Dr Eka Wahjoepramono successfully Wahjoepramono (PhD Student) A/Prof (Centre for Men’s Health, London) completed his PhD in 2012 Giuseppe Verdile, Mr Kevin Taddei, A/ Prof Simon Laws, Dr. Hamid Sohrabi, Dr. Stepahnie Rainey-Smith, Miss Linda Wijaya, Ms. Kathryn Quirke, Ms Prita Riana Asih (Honours student)

Several studies have reported that Findings from the animal studies In addition an open labeled study compared to controls, men with AD indicate that testosterone replacement has continued in Perth with 25 men and other dementias have lower serum at physiological and higher doses recruited. The data from these men testosterone levels. Professor Martins, reduces beta amyloid levels in both the clearly demonstrate that testosterone together with Professors Almeida blood and the cerebrospinal fluid, which treatment lowers beta amyloid levels and Gandy have shown that reducing could possibly be a result of clearance in 4 months in most of the men in blood levels of testosterone in men is of beta amyloid from the brain into this study and lowers the hormone associated with an increase in blood the blood. This work was published LH, a major contributor to Alzheimer’s levels of beta amyloid. In addition, in the Journal of Alzheimer’s disease disease, in all participants. A supplementing neuronal cells in culture (Wahjoepramono Wijaya et al., 2008, manuscript describing these results is with testosterone has been shown Journal of Alzheimer’s disease, 15: currently in preparation. Our findings to reduce beta amyloid levels and 129-37. thus far indicate that this approach attenuate its toxicity. Taken together, provides a promising avenue for The human clinical study, undertaken these studies suggest that the reduction effective prevention and treatment in Indonesia, involved 50 men with in testosterone during aging could of Alzheimer’s disease, which has memory complaints and low levels of contribute to the development of, and the advantage over other agents of testosterone, who are administered the underlying causes of AD. being rapidly implemented following cream containing placebo or testosterone successful clinical trials, as it is a drug This project investigated the role of for a total of 56 weeks. The recruitment that is already on the market. testosterone in beta amyloid production and neuropsychological assessment of and assesses testosterone replacement these men have been completed and We will be undertaking a 56 therapy in animal and human clinical blood samples have been collected and week randomised double blinded study as a potential therapy for the Eka successfully completed his thesis placebo-controlled trial to assess effective treatment of AD. The work in 2012. One of the major findings is the benefits of testosterone in is part of a PhD undertaken by Dr the demonstration that testosterone 200 male subjects with Pittsburgh Eka Wahjoepramono, a neurosurgeon administration increased the more Compound B (PiB) PET brain imaging from Siloam Hospital, Lippo Karawaci, positivity. Results from the Australian potent form of testosterone (DHT) and 17 Tangerang, Indonesia. improved memory in elderly men who Imaging, Biomarkers and Lifestyle were deficient in this hormone. These (AIBL) study of ageing have revealed ANNUAL REPORT 2013 results were presented at the AD/PD that one-third of asymptomatic conference in Florence in March 2013 elderly individuals (over the age of and manuscripts outlining the major 60 years) show the presence of findings are currently being prepared. The potential of testosterone as a therapeutic strategy for AD

Aβ in the brain (PiB-PET positive). every two months. CSF beta amyloid Hormonal changes associated with It is suggested that therapy aimed levels will be assessed at baseline and 56 ageing have been implicated in the to reduce the neurodegenerative weeks. Brain scans will to be conducted increased risk of developing Alzheimer’s process should be commenced in at baseline and 56 weeks. disease. Many studies have provided pre-symptomatic individuals with evidence to show that low levels of Work is also continuing to identify high PiB. Therefore we will enrich oestrogen or testosterone increase the agents that can increase testosterone for 200 PiB-PET positive men to risk of developing AD. This effect may be and other neuronal specific steroids in participate in this trial. This trial will due to these hormones altering the levels the brain. Our former PhD Student, Dr be the first to assess the effect of of beta amyloid (Aβ), a molecule that is Anna Barron, now a research fellow at testosterone supplementation on thought to be central to AD pathogenesis. the National Institute of Radiological cognition, plasma beta amyloid levels, Sex hormones are under the control of Sciences in Japan, identified brain glucose metabolism (FDG-PET complex feedback loops that involve compounds that can increase brain imaging) and brain amyloid load (PIB- hormones called gonadotropins. High steroid production and reduce amyloid PET imaging). Testosterone will be in levels of the gonadotropin, luteinizing deposition and improve cognition in the form of an injection. Testosterone hormone (LH), have also been implicated mice. However, these compounds are or placebo will be administered every in the increased risk of developing thought to have toxic side effects. In 8 weeks. A number of parameters AD and in disease pathogenesis. The collaboration with Dr Barron and Dr will be measured at baseline (before clinical significance of LH and the sex Andrew Katsifis (Royal Prince Alfred treatment), mid-way during the hormones and their relative contribution Hospital, Sydney), we are now trialing trial (26 weeks) and the end of the to the pathogenesis of AD remain to be in cell culture the ability of similar trial (56 weeks). The parameters determined. This is an ongoing project compounds to enhance brain steroid to be measured will include that investigates the role of LH in AD production. An honors student, Ms Prita neuropsychological assessments to pathogenesis and assesses in animal Asih has been recruited to undertake assess whether benefits to cognition studies the use of gonadotropin lowering this work and is supervised by A/Prof and memory are observed, brain agents as a therapeutic strategy for this Giuseppe Verdile, Dr Veer Gupta and Dr imaging, including MRI, FDG-PET (to disease. Robert Trengrove (Murdoch University). determine if there are improvement in 18 In 2004, we published findings showing brain glucose metabolism), and PIB- that LH can increase the production PET (to determine if there is lowering of beta amyloid in neuronal cells. In of brain amyloid load). In addition, a small study of elderly men (40) we blood plasma beta amyloid levels and have recently shown that increases blood biochemistry will be assessed PREVENTION AND TREATMENT Investigating the Role of Gonadotropins in the Pathogenesis of Alzheimer’s Disease

Researchers: Graduated Student: Prof Ralph Martins A/Prof Giuseppe Verdile, Dr Eka Dr Eka Wahjoepramono successfully Wahjoepramono (PhD Student), Mr completed his PhD in 2012. Kevin Taddei, Ms Linda Wijya, A/Prof Simon Laws, Ms Prita Riana Asih and Professor Ralph Martins in blood levels of LH are associated Increasing evidence is suggesting that been presented at a number of with increases in blood levels of beta SMC may be an important clinical feature conferences (including Alzheimer’s amyloid, providing further evidence the before the onset of clinical symptoms Association International Conference LH can modulate beta amyloid levels. We of cognitive impairment is evident. The and the Japan Neuroscience Society). published these results in 2008 in the correlation between LH and amyloid These findings were also recently Journal of Alzheimer’s disease (Verdile deposition is lost at the stages when published in a journal that is listed et al., Journal of Alzheimer’s Disease. cognitive impairment is evident (MCI in the top 10 journals in the field of 14:201-208). In addition we showed and AD). This result also suggests that endocrinology (Barron, Verdile et al., that age related increases in LH serum increases in serum LH levels may have a 2010, Endocrinology 151(11):5380- levels are associated with a reduction greater impact on AD pathology at earlier 8). Similar results were shown in in cognition in a large cohort (n=450) stages in the disease process. These another rodent model where the direct of elderly women without dementia findings were recently published, by A/ exposure of LH to the brain resulted which provides further evidence for a Profs Verdile and Laws, in the journal in accumulation of beta amyloid, role for LH in AD risk (Rodrigues et al., Molecular Psychiatry. Data collection for possibly through activating a signaling 2008; Journal of Alzheimer’s disease. an 18 month follow-up has recently been pathway in the brain. These findings 13:267-274). Access to samples and collected and a 36 month followup will were published in Neuroendocrinology data from AIBL study provided an commence soon. These follow-up studies (Wahjoepramono, Wijaya et al. 2011, opportunity to extend our initial results will determine if these associations still 94:313-22 ). Overall, this project has to investigate associations between sex hold with conversion of mild cognitive provided significant evidence for a steroid and gonadotropins and plasma decline (MCI) to AD. role of LH in AD risk and pathogenesis Aβ40 and Aβ42 and cerebral amyloid through experimental methods that In an NHMRC funded project, we deposition (as assessed by PIB-PET have seperated the actions of sex investigated potential mechanisms brain imaging). We have shown that hormones from gonadotropins. by which LH could impact on AD testosterone and LH impact on plasma Further insight into these mechanisms pathogenesis. This project was Aβ40 and Aβ42 levels and cerebral will provide therapeutic or preventative completed in early 2010. Some of the amyloid deposition at different clinical strategies for AD. most significant results included the stages of cognitive decline in men. finding that a more potent analogue 19 We have shown a significant positive of LH impaired memory in a mouse correlation between increases in LH and ANNUAL REPORT 2013 model for AD and also increased the amyloid accumulation (as assessed by levels of beta amyloid within the brain PiB-PET brain imaging) in a cohort of of these animals. These results have subjective memory complainers (SMC). PREVENTION AND TREATMENT PEACS Study – Effects of physical activity and cognitive stimulation on plasma beta amyloid and on cognitive functioning in the elderly

Dr Tejal Shah Researchers: Graduated Student: Dr Tejal Shah (PhD Student), A/Prof Dr Tejal Shah Giuseppe Verdile, and Professor Ralph Martins

With the rising tide of elderly study recruited 224 volunteers that were activity and cognitive stimulation did not population there is a marked increase allocated into a physical activity group, a correlate with changes in blood biomarkers, in the incidence of AD among these brain training group, a combination group associations were observed with increased populations globally. With no current that includes physical activity and brain cerebral glucose metabolism, indicating effective treatment, there is a major training and a control group. The 16 week that the benefits obtained are due to focus on either preventing or delaying intervention study was designed with a improvements in neuronal activity. the onset of AD. Researchers all over battery of assessments at baseline (prior The results presented here contribute to the world are targeting lifestyle as a to intervention), at 8 weeks and 16 week the body of knowledge that is leading to a prime factor that could play a vital role in time points. These assessments included better understanding and development of diverting the course of AD. This lifestyle neuropsychological tests, blood biomarkers, physical activity and cognitive training as a includes staying physically and mentally body composition scans (which measures protective factor for cognitive decline and active, eating a healthy diet and also body mass and fat) and brain imaging to AD. It also provides pilot information that is staying socially engaged. investigate brain glucose uptake in certain useful for the design of future intervention regions of the brain. Furthermore, two types There is now robust observational trials utilizing physical activity or cognitive of brain training software programs-auditory literature available demonstrating that training. and visual were implemented. people who are mentally and physical A PhD student, Dr Tejal Shah, under the active can ward off the risk of dementia, The findings from the study showed that supervision of Professor Ralph Martins and however, there are very few clinical compared to the control (non-training A/Prof Giuseppe Verdile, undertook the trials conducted on healthy community group), a combination of physical activity study. Tejal recently successfully completed dwelling older adults that actually show and cognitive brain training (using here PhD and will graduate in 2014 . The that physical and mental exercises computerized software programs that work has been presented at the Alzheimer’s administered over a fixed duration with have been validated in clinical trials), disease International Conference (London) certain intensity and frequency can truly showed improvements in certain cognitive in March 2012 and at the Alzheimer’s avoid the risk of cognitive decline in the domains (particularly verbal memory). Association International Conference (AAIC) healthy elderly. Such a trial would enable The improvement in verbal memory was in Vancouver, Canada in July 2012 and us to establish the clinical significance maintained on follow-up after completion Society for Neurosciences in San Diego. of these non Pharmacological strategies of the training, suggesting long lasting Manuscripts outlining these findings have and may take us a step further in effects on this particular cognitive domain. 20 recently been submitted for publication. understating the pathological course of In addition novel data is presented to AD as well as a potentially providing us suggest that the order in which auditory or pathways for therapeutic approach. visual stimulation is administered via these brain training programs can impact on With these goals in mind, a pilot study the amount of benefits obtained in certain referred to as the PEACS (physical cognitive domains. Although improvements activity and cognitive stimulation) observed with the combination of physical study was designed. The PEACS Impact of Nutrition on Cognition and its Association with Blood and Brain Alzheimer DiseaseTM Related Biomarkers

Researchers: Miss Samantha Miss Samantha Gardener (PhD student), Dr Stephanie Rainey-Smith Gardener and Professor Ralph Martins

The focus of the current research A MeDi score was generated for each foods and beverages of particular climate is shifting from understanding participant (0-9 point scale): higher interest to AD researchers. The Alzheimer’s disease (AD) pathology and scores indicate higher adherence. A modified questionnaire is currently diagnosis, to primary prevention and western and prudent diet score was undergoing a ‘validation study’ intervention strategies. Early detection assigned to each participant using factor involving AIBL participants which combined with intervention strategies analysis to establish the dietary pattern. evaluates the repeatability and could reduce disease effects. Diet reliability of this FFQ with the new In October 2012 we published a represents one potential intervention questions, and will compare daily paper in Translational Psychiatry titled strategy accessible to all. Recent reports intake of foods measured from the ‘Adherence to a Mediterranean Diet and suggest adherence to the Mediterranean answers to the FFQ with daily intake Alzheimer’s disease Risk in an Australian diet (MeDi) may affect AD risk and the of foods measured from four day Population’. This reported cross progression of pre-dementia syndromes weighed food records. Once this sectional results showing that healthy to overt dementia. Adherence to other ‘validation study’ is complete, the control participants have a higher dietary patterns such as the western modified CSIROFFQ will be completed adherence to the MeDi than AD and diet has been shown to correlate by the whole AIBL cohort at the 90 mild cognitively impaired participants. with risk factors for AD. However, the month follow up assessment. Currently we are working on longitudinal investigation of dietary factors, AD risk analysis from the baseline and 36 Our work has been presented at and disease course, is a relatively young month follow up assessment and finding several conferences including field of research and there is a critical associations between the three dietary the Lifestyle Approaches for the need for data collected from a well- pattern scores and cognitive decline Prevention of Alzheimer’s disease characterised ageing cohort. (measured from the neuropsychological Conference in Perth, Western The aim of this project is to investigate test battery participants complete at Australia in March 2012, the the association between dietary patterns each follow up assessment). Our results, Alzheimer’s disease International and cognition, and other blood and brain which will be published in early 2014, Conference (London) in March AD biomarkers. The study will include indicate a beneficial effect of the MeDi 2012, the Alzheimer’s Association analysis of dietary, cognitive, functional, and a detrimental effect of the Western International Conference in behavioural and physical assessments diet on memory and thinking abilities Vancouver, Canada in July 2012 and within the AIBL cohort at a baseline over 3 years. We have commenced the Dementia Collaborative Research 21 visit and at 18, 36 and 54 month follow analyses that we believe will provide Centres Conference in Canberra, ANNUAL REPORT 2013 up assessments. Levels of known insight into the mechanisms underlying Australia in September 2012 and AD risk factor markers which may be the observed effects. in Brisbane in September 2013. affected by nutrient intake in the diet, An abstract has been submitted to There are currently no Alzheimer’s- will be analyzed. Dietary assessment present our longitudinal results at the specific diet questionnaires available involves analysis of data acquired Alzheimer’s Association International to the research community. To address from administration of the Cancer Conference in Copenhagen, Denmark this deficit, we have added questions to Council of Victoria food frequency in July 2014. an online food frequency questionnaire questionnaire and the CSIRO food designed by the CSIRO that focus on frequency questionnaire (CSIROFFQ). PREVENTION AND TREATMENT Combinational nutritional supplement therapies in the prevention of Alzheimer’s Disease

Dr Stephanie Researchers: In Collaboration with: Rainey-Smith Dr Matthew Sharman (University of Tasmania) A/Prof Gerald Munch (University of Western Sydney) Dr Stephanie Rainey-Smith (McCusker Fnd, ECU) A/Prof Marcus Wenk (National University of Singapore) Dr Binosha Fernando (ECU) Prof Barry Halliwell (National University of Singapore) Professor Ralph Martins (McCusker Foundation, ECU) Prof R Vijayalakshmi (National Brain Research Institute, India)

Significance of the project: is critical if we are to reduce the number Major Findings to date: Work on this Lifestyle modifications such as dietary of people that are expected to develop project is still ongoing, with a number interventions, and physical activity Alzheimer’s disease over the next 50 of different dietary combinations being programs, have long played a central years, due to the rapidly aging population. trialed in a mouse model of Alzheimer’s role in the management of several disease. Analysis of samples is currently We have previously demonstrated in an diseases such as cardiovascular underway and expected to be completed animal model of Alzheimer’s disease, that disease, diabetes and cancer. It is well in 2014. This work is critical to establish both a Green Tea diet and a Fish Oil diet known that one of the most important the efficacy of these potential therapies, were able to reduce the levels of beta- lifestyle factors, diet, strongly before progressing to clinical trials in amyloid in the brain and cerebrospinal influences the incidence and outcome humans. The development of effective fluid. However, the Fish Oil diet which is of major age-related pathologies. preventative strategies for the treatment high in the omega-3 essential fatty acids Diet can also strongly influence of Alzheimer’s disease is critical if we resulted in significantly greater reductions the risk of developing late-onset are to reduce the number of people that in beta-amyloid levels compared to the Alzheimer’s disease, with several are expected to develop Alzheimer’s Green Tea diet. Based on these initial studies across the world showing disease over the next 50 years, due findings we have now begun work that fruits, vegetables and fish oils to the rapidly aging population. This investigating whether combinations of are associated with improving health is an exciting approach that builds on a number of nutritional-based-CAM and decreasing an individual’s risk our long-term understanding of both compounds have a great effect on for developing Alzheimer’s disease. different antioxidants and beta amyloid reducing the pathology caused by This is supported by research which metabolism resulting in a combination Alzheimer’s disease in an animal model. shows that low dietary intake of fruits, of these compounds to provide maximal Some of the compounds we are currently vegetables and fish oils increase synergy. If the current animal study is examining include, EGCG (a compound your risk for developing late-onset successful, it has the advantage of being extracted from Green Tea), curcumin Alzheimer’s disease. If nutritional- able to progress rapidly to clinical trials (the main ingredient extracted from the based complementary and alternative as these antioxidants are food products spice turmeric), DHA (one of the main medicine (CAM) therapies could be known to be very safe for human components in fish oil), ALA (a natural developed to prevent or delay the consumption. antioxidant) and Short Chain Fatty Acids onset for Alzheimer’s disease, the 22 (manufactured in the gut following intake This project is funded by a National impact on disease burden could of dietary fibre). Health & Medical Research Council be substantial. However, these Complementary and Alternative Medicine CAM therapies need to be critically Strategic Grant as well as a grant from evaluated for their mechanisms, the Hollywood Private Hospital Research efficacy and safety. The development Foundation. of effective preventative strategies for the treatment of Alzheimer’s disease The Effect of Physical Activity on Cognition, the Development of Alzheimer’s disease and Associated Blood Biomarkers (AIBL study)

Researchers: Dr Belinda Dr Belinda Brown, Dr Stephanie Rainey-Smith and Professor Ralph Martins Brown

The objective of this research is To date, we have reported promising We aim to build on this research to determine the effect of physical results that suggest physical activity by investigating the mechanisms in activity on factors associated with the is an important protective factor for which physical activity is changing development of Alzheimer’s disease Alzheimer’s disease. Our findings levels of amyloid in the brain. It will (AD). More specifically, we are indicate that people undertaking also be important to identify the level evaluating the relationship between higher levels of physical activity have (i.e. intensity) of physical activity that physical activity and AD biomarkers lower levels of the toxic beta-amyloid is most beneficial to brain health, (biological markers of disease) that have protein in their blood. We also report a and thus an exercise intervention been measured in both the blood and similar finding in the brain, with higher trial is currently being designed. brain (via neuroimaging). We have also exercising individuals having lower Collectively, the current research, investigated the association between levels of beta-amyloid, as measured and proposed future research, will be physical activity and performance on PiB PET brain imaging. Furthermore, used to establish physical activity as memory and cognitive functioning tasks. it appears that genetics plays a role a protective factor against AD. Data used in this research has been in this association, with carriers of the collected from the Australian Imaging APOE ε4 allele (a genetic risk factor for Biomarkers and Lifestyle (AIBL) Study AD), receiving the greatest benefit from cohort. All participants undergo memory physical activity. testing, blood collection and complete In addition to physical activity detailed lifestyle and physical activity influencing important Alzheimer’s questionnaires. A subset of individuals disease biomarkers, we have also also wore Actigraph activity monitors for demonstrated that intense physical seven consecutive days, which enables activity is associated with better memory us to accurately capture the quantity and cognitive function. This may be due and intensity of physical activity that our to an increase in hippocampal volume, participants are undertaking. A further the structure of the brain important for group of individuals completed brain learning and memory, which we have imaging, including positron emission also found to be associated with higher tomography with Pittsburgh compound levels of physical activity. 23 B (known as PiB PET; to measure brain ANNUAL REPORT 2013 amyloid) and magnetic resonance imaging (MRI). PREVENTION AND TREATMENT A pilot clinical study to evaluate the potential of a nutritional extract Amlamax TM on raising HDL levels

Key Researchers: In Collaboration with: Dr Stephanie Rainey-Smith (McCusker A.R. Foundation, ECU) Dr Benny Antony (Arjuna Natural Extracts, Kerala, India) Dr Hamid Sohrabi (McCusker A.R. Foundation, ECU) Dr Binu Kuruvilla (Arjuna Natural Extracts, Kerala, India) Dr Tejal Shah (McCusker A.R. Foundation, ECU) Mr Kevin Taddei (McCusker A.R. Foundation, ECU) Professor Ralph Martins ((McCusker A.R. Foundation, ECU)

Significance of the project: and beta-amyloid levels in 198 study Project Progress One of the most prevalent lifestyle- participants, providing further evidence We have commenced a study evaluating associated diseases today in Western for a link between cardiovascular disease in a pilot clinical trial, the effectiveness of society is cardiovascular disease. A and Alzheimer’s disease. This has this herbal Amla Extract on raising HDL-C growing body of literature also indicates suggested that strategies designed to levels in a population of subjects with that the presence of cardiovascular improve cardiovascular health, namely low HDL-C levels. This study also aims disease is associated with increased raising HDL-C levels, may protect against to determine whether directly raising risk of developing late-onset cognitive decline and Alzheimer’s disease. HDL-C levels can result in a decrease in Alzheimer’s disease. Considerable While drugs that lower cholesterol plasma beta-amyloid levels. This work evidence has been provided in support and LDL-C levels are currently being is being conducted in collaboration with of the notion that increases in total considered and tested as potential Arjuna Natural Extracts Ltd., a global plasma cholesterol, low-density therapies for the treatment of Alzheimer’s manufacturer and exporter of herbal and lipoprotein-cholesterol (LDL-C), and disease, there are no effective drugs spice extracts, located in Kerala, India. decreased high-density lipoprotein- available to raise HDL-C levels - although, This Amla extract, known as AmlamaxTM cholesterol (HDL-C) known risk factors HDL-C levels are known to be modified was developed by the R&D lab of Arjuna for cardiovascular disease, are also by a number of environmental factors, Natural Extracts Limited. Amlamax is associated with increased Alzheimer’s including diet and exercise. a reconstituted dry extract from fresh disease risk. Numerous studies have fruits of Amla and has recently shown The Indian plant Amla (Emblica officinalis) demonstrated that elevated total remarkable results in increasing HDL-C commonly known as Indian gooseberry plasma cholesterol results in increased levels in patients with dyslipidemia. has widely been utilized in traditional deposition of beta-amyloid in the However, its possible role in helping to Ayurvedic medicine preparations for use brain and increases individuals’ risk decrease Alzheimer’s disease risk has not against a variety of disease conditions. for developing Alzheimer’s disease. been previously explored. The findings The natural herbal extract Amla has been Thus, one factor which may link from our pilot study will contribute recently identified for its ability to increase cardiovascular disease and Alzheimer’s towards assessing the ability of the HDL-C levels. As low HDL-C levels are disease is HDL-C, as epidemiological Amla extract to effectively treat patients thought to be an important risk factor for studies have reported that high identified as having low HDL-C levels, late-onset Alzheimer’s disease this has an concentrations of HDL-C or “good” and subsequently evaluating the potential 24 important implication for future work. cholesterol (>1.5mMol/L) may also be role of Amla in helping to decrease the protective against Alzheimer’s disease. risk of developing late-onset Alzheimer’s disease. At the time of writing 49 trial Previous work performed at the participants have completed a 6 month McCusker Alzheimer’s Research course of Amlamax or placebo. Foundation/ECU, by Dr Kristyn Bates and colleagues has demonstrated a relationship between HDL-C levels Evaluation of the Nutritional Extract Biocurcumax (BCM-95) to Preserve Cognitive Functioning.

Key Researchers: In Collaboration with: Dr Stephanie Rainey-Smith (McCusker Fnd, ECU) Dr Benny Antony (Arjuna Natural Extracts, Kerala, India) Dr Hamid Sohrabi (McCusker Fnd, ECU) Dr Binu Kuruvilla (Arjuna Natural Extracts, Kerala, India) Dr Tejal Shah (McCusker Fnd, ECU) Mr Kevin Taddei (McCusker Fnd, ECU) Professor Ralph Martins (McCusker Fnd, ECU)

Significance of the project: Project Progress placebo regimen; this will enable the Curcumin, the main bioactive ingredient We commenced work in September effect of BiocurcumaxTM on brain of the Indian curry spice turmeric has 2011, within the McCusker Foundation, amyloid load over 12 months to be been reported to have many beneficial evaluating in a pilot clinical trial, examined. We are currently in the effects including showing promise the ability of this nutritional extract process of recruiting the final 35 as a neuroprotective agent in the BiocurcumaxTM to preserve cognitive participants for this study. prevention of Alzheimer’s disease (AD). function in subjects with memory Epidemiological studies have suggested complaints, over a 12 month period. This curcumin is protective against study also aims to determine whether cognitive decline, whilst animal studies BiocurcumaxTM can alter plasma and have shown that mice, genetically brain beta-amyloid levels. This work is predetermined to develop AD and fed a being conducted in collaboration with diet rich in curcumin, exhibit significantly Arjuna Natural Extracts Ltd., a global reduced beta amyloid levels. Moreover, manufacturer and exporter of herbal curcumin has been shown to be and spice extracts, located in Kerala, clinically safe with no adverse effects India. BiocurcumaxTM was developed by reported following administration of the R&D lab of Arjuna Natural Extracts doses up to 8g/day. However, the Limited. The ability of BiocurcumaxTM low bioavailability of curcumin in the to prevent cognitive decline, alter body (due to poor absorption and Alzheimer’s disease-related biomarkers, uptake) has limited its clinical impact. and therefore its potential role in helping Indeed, a recent clinical trial for AD, to decrease the risk of developing 6 month administration of 1-4 g/day, late-onset Alzheimer’s disease has not had no significant effect on cognitive been previously explored. At the time of impairment. Consequently, methods writing 88 participants have completed to increase the oral bioavailability of the 12 month study. An additional curcumin are a subject of intense 35 participants have undergone an current research. Reconstituting added component of the study where 25 curcumin with the non-curcuminoid the amyloid load in their brain is components of turmeric has been visualised (using PiB-PET brain imaging) ANNUAL REPORT 2013 found to increase the bioavailability immediately prior to commencement of substantially. BiocurcumaxTM, is a novel the BiocurcumaxTM or placebo regimen. bio-enhanced preparation of curcumin. These 35 participants will undergo a Human studies have shown increased second brain scan immediately following (7-fold) bioavailability of BiocurcumaxTM cessation of the BiocurcumaxTM or compared to curcumin. COLLABORATIONS

CRC The CRC for Mental Health has 20 participant organizations, each of which brings a unique set of skills to the discovery program. Educational Institutions Edith Cowan University The University of Melbourne The University of Western Australia Research Organizations CSIRO Florey Neuroscience Institutes Mental Health Research Institute National Ageing Research Institute Commercial Entities Alzhyme Pty Ltd CogState Lawley Pharmaceuticals Nucleus Network Oceanic Medical Imaging Pty Ltd Pfizer Inc Health Care Providers Austin Health Barwon Health Hall and Prior Mercy Health Aged Care Philanthropic Organizations Alzheimer’s Association McCusker Alzheimer’s Research Foundation Inc Parsemus Foundation

International: Collaboration has been ongoing for the last 16 years with Professor Sam Gandy initially from Farber Institute for Neurosciences, Thomas Jefferson University Philadelphia and now with Professor Gandy at the Mount Sinai Centre for Cognitive Health in New York into an interdisciplinary approach to Alzheimer Drug discovery. The collaboration with Professor Sam Gandy has resulted in his visit in 2000 to the University of Western Australia as the Raine Visiting Professor and several joint publications including a publication in JAMA and the subsequent 4 month (April-July 2003) visit to Professor Gandy’s Farber Institute by Professor Ralph Martins to further progress our ongoing collaborative partnership. Close collaboration has been established since 2004 with Dr Markus Wenk and Dr RH Yang from the National University of Singapore. Project entitled “Lipodomics of neuronal membranes – Identification of lipids involved in neurosecretion and 26 neurodegenerative diseases. Professor Martins and Associate Professor Giuseppe Verdile have an ongoing collaboration with Professors Peter Hyslop and Paul Fraser from the University of Toronto to identify genetic risk factors in Alzheimer’s disease. This collaboration has involved exchange of students and staff between Western Australia and the American and Canadian institutes. An ongoing collaboration with Professor John Morris and Professor Randy Bateman from the Washington University was established in 2006. This resulted in collaboration on the DIAN Clinical Study and DIAN Clinical Trial. Professor Judith Miklossy from the University Institute of Pathology, University of Laussanne in Switzerland and latterly from Center for NeuroVirology and Cancer Biology, College of Science and Technology, Temple University, Philadelphia has supplied 200 brain samples from post-mortem confirmed Alzheimer’s disease cases for biochemical and genetic studies. This collaboration has resulted in several publications. COLLABORATIONS

The role of oestrogen in Alzheimer’s disease is being undertaken in collaboration with Professor Suzanne Craft from the University of Washington. The structure and function of the amyloid precursor protein in Alzheimer’s disease is being studied in collaboration with Professor Toshihara Suzuki of Tokyo University, Japan. A study into the role of gonadotropins in the development and progression of Alzheimer’s disease is being undertaken in a joint collaboration with Ass. Professor Craig Atwood from Wisconsin University Maddison Medical School, USA. Collaboration has been instituted with Professor D. Allan Butterfield from the Dept of Chemistry and Center of Membrane Sciences, University of Kentucky, Lexington USA. This collaboration is to study oxidative stress in Alzheimer’s disease and this resulted in one of our PhD students spending 6 months with Professor Butterfield investigating the protective effects of apoE isoforms on Abeta induced oxidative stress in cell culture. Collaboration is ongoing with Associate Professor Joachim Hallmayer from Stanford University Department of Psychiatry and Behavioural Science to identify genetic and molecular risk factors in neurodegenerative diseases. This collaboration has resulted in several papers.

Interstate: Ongoing collaboration has been established with Dr Lautenschlager and Professor Forstl into identification of biomarkers for cognitive decline in subjective memory complainers. Ongoing collaboration has been established with the three major research groups working on Alzheimer’s disease in Australia led by Professor Colin Masters at the University of Melbourne, Associate Professor Peter Schofield from the Garvan Institute in Sydney and Professor Tony Broe from the Prince of Wales Medical Research Institute, Sydney, New south Wales. Dr Elizabeth Milward from the University of Newcastle New South Wales, ongoing research into ‘Iron-related genes and neurodegenerative disorders”. Local: Collaboration is ongoing with Professor Alan Harvey (Department of Anatomy, University of Western Australia) on the development of animal models for Alzheimer’s disease. Collaboration is ongoing with Professor Dharmarajan from the CSIRO Western Australia on studying the function of beta amyloid. This seminal work has been published. University of Melboiurne. Research is ongoing Dr Ian Martins (ECU) who has a strong background in lipoprotein research which is aimed at obtaining a better understanding of the molecular mechanism(s) by which apolipoprotein E acts as a major risk factor for Alzheimer’s disease. Professor David Bruce and Dr Bu Yeap from University of W.A. School of Medicine and Pharmacology, Fremantle Hospital, Effect of androgens on cognitive function and evolution of dementia in older men.

Collaboration has been established with Professor Leon Flicker from the Department of Geriatric Medicine and 27 Professor Osvaldo Almeida from the University Department of Psychiatry, Queen Elizabeth II Medical Centre, to ANNUAL REPORT 2013 undertake an intervention study in patients with memory disorders. Collaboration has recently been established with Professor Gary Hulse, from University of Western Australia’s Unit for Research and Education in Drugs and Alcohol to analyse the effectiveness of a therapeutic agent for Alzheimer’s disease. A collaboration has been established with Professor Vijay Jayasena from the School of Public Health, Curtin University, Associate Professor Roz Walker and Associate Professor Juli Coffin from the Centre for Research Excellence in Aboriginal Health and Wellbeing, Telethon Institute for Child Health Research, Professor Sven Silburn, Centre for Child Development and Education Menzies School of Health Research and Professor Carmela Pestell, School of Psychology, University of Western Australia to develop Innovative foods that will potentially prevent chronic disease in Aboriginal children. PROFESSOR RALPH MARTINS - PUBLICATIONS 2012-2013

Lim YY, Villemagne VL, Laws SM, Ames age. International Psychogeriatrics 2013 Lim YY, Pietrzak RH., Ellis KA, Jaeger J, D, Pietrzak RH, Ellis KA, Harrington KD, (Accepted for publication April 2013). Harrington K., Ashwood T., Szoeke C, Bourgeat P, Bush AI, Martins RN, Masters Martins RN., Bush AI., Masters CL., Burnham SC., Faux NG., Wilson W., CL, Rowe CC, Maruff P; Australian Rowe CC, Villemagne VL, Ames D., Darby Laws SM., Ames D., Bush AI., Doecke Imaging, Biomarkers and Lifestyle D., Maruff P. Rapid decline in episodic J, Ellis KA., Head R., Jones G., Kiiveri (AIBL) Research Group. BDNF Val66Met memory in healthy older adults with high H., Martins RN, Rowe C., Salvado O., moderates Aβ-related memory decline Amyloid-β Journal Alzheimers Disease Macaulay L., Masters CL., Villemagne V and hippocampal atrophy in prodromal 2013; 33: 675-679 [doi: 10.3233/JAD- and the AIBL Research Group. A blood Alzheimer’s disease: A preliminary study. 2012-121516] based predictor for neocortical Amyloid PLoS One. 2014 Jan 27;9(1):e86498 burden in Alzhemer’s disease: Results Villemagne VL, Burnham S., Bourgeat P., Lim YY, Villemagne VL, Laws SM, Ames from the AIBL study. Mol Psychiatry Brown B., Ellis KA., Salvado O., Szoeke D, Pietrzak RH, Ellis KA, Harrington [e-published: April 30, 2012] [doi: C., Macaulay SL., Martins RN., Maruff P., KD, Bourgeat P, Salvado O, Darby D, 10.1038/mp.2013.40] Ames D., Rowe CC., Masters CL. Amyloid Snyder PJ, Bush AI, Martins RN, Masters deposition, neurodegeneration and Rembach A., Doecke J., Roberts B., CL, Rowe CC, Nathan PJ, Maruff P; cognitive decline in sporadic Alzheimer’s Duce JA., Faux NG., Volitakis I., Trounson Australian Imaging, Biomarkers and disease: a prospective cohort study. B., Fowler CJ, Pertile KK, Rumble Lifestyle (AIBL) Research Group. BDNF Lancet Neurol. 2013; 12: 357-367 [doi: BL., Varghese J., Ellis KA., Rowe CC., Val66Met, Aβ amyloid, and cognitive 10.1016/S1474-4422(13)70044-9] Martins RN., Ames D., Masters CL., decline in preclinical Alzheimer’s Bush AI and the AIBL research group. Harrington KD, Lim YY, Ellis KA, Copolov disease. Neurobiol Aging. 2013 Nov; Longitudinal analysis of serum copper C., Darby D., Weinborn M., Ames D., 34(11):2457-64. Epub 2013 Jun 12. and ceruloplasmin in Alzheimer’s disease. Martins RN., Savage G., Szoeke C., PubMed PMID: 23769397. Journal of Alzheimer’s disease 2013; Rowe C., Villemagne VL., Masters CL., Bharadwaj PR, Bates KA, Porter T, 34:171-182 [e-published: Nov 19, Maruff P., The association of Aβ amyloid Teimouri E, Perry G, Steele JW, Gandy S, 2012] [doi:10.3233/JAD-121474] and composite cognitive measures Martins RN and Verdile G. Latrepirdine: in healthy older adults and MCI. Int Ellis KA, Lim YY., Harrington K, Ames molecular mechanisms underlying Psychogeriat. 2013 July 18:1-11. D., Bush AI., Darby D., Martins RN., potential therapeutic roles in Alzheimer’s Masters CL., Rowe CC., Savage G, Frost S., Kanagasingam Y, Sohrabi H., disease, Translational psychiatry 3 (12), Szoeke C., Villemagne VL, Maruff P., AIBL Bourgeat P, Salvado O., Villemagne V, e332, 2013. Research Group. Decline in cognitive Rowe CC., Macaulay SL, Szoeke C., Ellis Valenzuela M., Bartres-Faz D., Bullmore function over 18 months in healthy KA Ames D., Masters CL., Rainey-Smith E., Fjell A., Maletic-Savetic M., Martins older adults with high A-beta amyloid. S., Martins RN., and the AIBL research R., Solowij N., and Yucel M. Less is Journal of Alzheimer’s Disease 2013; group. Retinal vascular biomarkers more – More thinking about less data: 34: 861-871 [e-published: Jan 8, 2012] for early detection and monitoring of a perspective from the 2nd Provence [doi:103233/JAD-122170] Alzheimer’s Disease. Transl. Psychiatry. 28 Summer Workshop. Molecular Psychiatry 2013 Feb 6;3: e233 [eoi: 10.1038/ Carillo MC., Rowe CC., Szoeke C., (2013) 1-2. tp.2012.150] Masters CL., Ames D., O’Meara T., Buckley R., Ames D., Rowe C., Macauley L., Milner A., Ellis K., Maruff Buckley R., Saling M., Lautenschlager Lautenschlager N., Macauley L., Martins P., Rainey-Smith ST., Martins RN., N., Macauley SL., Martins RN., Masters RN., Masters C., O’Meara T., Savage G., Bain LJ, Head RJ. Research and CL, O’Meara T., Rowe CC, Savage G., Szoeke C., Villemagne V., Ellis K., and standardization in Alzheimer’s trials: Szoeke C., Villemagne VL. Ellis KA for the Australian Imaging Biomarkers and Reaching international consensus. the Australian Imaging Biomarkers and Lifestyle Study of Aging (AIBL) Research Alzheimer’s Dementia. 2013; 9: 160- Lifestyle Reserch Group. Factors affecting Group. Factors affecting subjective 168 [doi:10.1017/j.alz.2012.10.006] subjective memory complaints in the AIBL memory complaints in the AIBL ageing Ageing study: biomarker, memory, affct study; biomarkers, memory, affect and and age. Int. Psychogeriatr. [e-published: Journal of Alzheimer’s disease (In press) cognitive phenotype that is independent May 22, 2013] [e-published: Nov 16, 2012] [doi:] from clinical diagnostic status: findings from the Australian Imaging, Biomarkers Frost, SM, Kanagasingama Y, Sohrabi Rembach A, Faux NG., Watt AD., Pertile and Lifestyle study. Brain. Advanced HR, Taddei K, Bateman R, Morris J, KK., Rumble RL., Trounson BO., Fowler online 3 June 2013. [doi:10.1093/brain/ Benzingere T, Goatee A, Masters CL, CJ., Roberts BR., Perez KA., Li QX., awt127] Martins RN, Pupil response biomarkers Laws SM., Taddei K., Rainey-Smith S., distinguish amyloid precursor protein Robertson JS., Vandijck M., Vanderstiche Ellis K, Szoeke C, Bush A, Darby D, mutation carriers from non-carriers H., Barnham KJ., Ellis KA., Szoeke C., Graham P, Lautenschlager N, Macaulay Current Alzheimer’s Research. 2013 Macaulay L., Rowe CC., Villemagne L, Martins R, Maruff P, Masters C, 10:790-796 VL., Ames D., Martins RN., Bush AI., McBride S, Rainey-Smith S, Rembach Masters CL., and the AIBL Research A, Robertson J, Rowe C, Savage G, Frost S, Kangasingam Y, Sohrabi H., Group. Changes in plasma β-amyloid Woodward M, Wilson W, Villemagne Bourgeat P, Villemagne V, Rowe CC, in a longitudinal study of aging and V, Zhang P, Ames D and the AIBL Macaulay SL, Szoeke C., Ellis K, Ames D., Alzheimer’s disease. Alzheimers investigators. Rates of diagnostic Masters CL, Rainey-Smith S., Martins Dementia [e-published:March 9 2013] transition and cognitive change at 18 RN & the AIBL Reseach Group. Pupil [j.alz.2012.006] month follow up among 1112 partcipants Response Biomarkers for Early Detection in the Australian Imaging, Biomarkers and and Monitoring of Alzheimer’s disease. Lim YY, Ellis KA, Harrington K, Kamer A., Lifestyle Flagship study of Ageing (AIBL) Current Alzheimers Research 2013 10, Pietrzak RH., Bush AI., Darby D, Martins Int. Psychogeriat. (Accepted) 931-939. RN., Masters CL., Rowe CC., Savage G., Szoeke C., Villemagne V., Ames D., Lim YY, Pietrzak RH., Ellis KA, Darby D., Lim YY, Ellis KA, Ames D, Darby D, Maruff P., and the AIBL Research Group. Ames D, Harrington K, Bush AI, Martins Harrington K, Martins RN, Masters Cognitive consequences of high A-beta RN, Masters CL, Rowe CC, Szoeke C, CL, Rowe C, Savage G, Villemagne VL, amyloid in mild cognitive impairment Savage G, Villemagne VL, Maruff P for Maruff P. A-Beta amyloid, cognition and and healthy older adults: Implications for the AIBL Research Group. Aβ amyloid Apo E genotype in the preclinical stages early detection of Alzheimer’s disease. and cognitive change: Examining the of Alzheimer’s disease. Alzheimers Neuropsychology (Accepted 2013) preclinical and prodromal stages of Dementia 2013 9: 538-545. Alzheimer’s disease. Alzheimers Dement. Lim YY, Jaeger J., Harrington K., Ashwood Verdile G, Laws S., Henley D, Ames (In Press) T., Ellis T., Ellis KA., Stoffler A., Szoeke D., Bush AI., Ellis KA., Faux NG, Gupta C., Lachovitzki R., Martins RN., Savage Rowe CC, Bourgeat, P, Ellis KA, Brown VB., Li QX., Masters CL, Pike KE., Rowe G., Villemagne VL., Bush A., Masters CL., B, Lim YY, Mulligan R, Jones G, Maruff P, CC, Szoeke C., Taddei K., Villemagne Rowe CC., Ames D., Darby D., Maruff Woodward M, Price R, Robins P, Tochon- VL., Martins RN., and the AIBL P. The Australian Imaging Biomarker Danguy H, O’Keefe G, Pike KE, Szoeke Research Group. Associations between and Lifestyle – Rate of change sub- C, Salvado O, Macaulay SL, O’Mera T, gonadotropins, testosterone and A-beta in study. (AIBL-ROCS): Rationale, design, Head R, Cobiac L, Savage G, Martins men at risk of AD. Molecular Psychiatry. 29 acceptability and pilot data for first R, Masters CL, Ames D & Villemagne (In Press) [e-published: October 23, three months of assessment.) Archives VL. Predicting Alzheimer’s disease with ANNUAL REPORT 2013 2012] [doi:10.1038/mp.2012.147] of Clinical Neuropsychology 2013; 28: beta-amyloid imaging: Results from AIBL. Lim YY, Ellis KA, Harrington K., Robert 320-330. (Accepted Ann Neurol Sept. 2013) PH., Gale J, Ames D, Bush AI., Darby Foster JK, Albrecht MA., Savage G., Rembach A, Watt AD, Wilson, D, Martins RN, Masters CL., Rowe C, Lautensclager NT, Ellis KA., Maruff Villemagne VL., Ellis KA., Ames D., Savage G., Szoeke C., Villemagne VL., P, Szoeke C., Taddei K., Martins R., Rowe CC., Macauley SL., Bush AL., Maruff P., and the AIBL Research Group. Masters CL., Ames D., and the AIBL Masters CL., Doecke JD and the AIBL Cognitive decline in adults with amnestic Research Group. Lack of reliable Research Grpoup. Plasma Aβ Levels mild cognitive impairment and high A-beta evidence for a distinctive ε4-related are significantly associated with a amyloid: Prodromal Alzheimer’s Disease. transition towards Alzheimer’s disease PROFESSOR RALPH MARTINS - PUBLICATIONS 2012-2013

as measured by cognitive decline and Krishnaswamy S, Taddei K, Beloni R, Sohrabi HR, Martins RN, Gandy S, change in neocortical amyloid burden. BP, Mastaglia FL, Martins RN. The Urakami K, Suzuki T. Multiple gamma- Journal of Alzheimer’s Disease. (Accepted Dyanmics of CD147 in Alzheimer’s secretase product peptides are December 2013). Disease Development and Pathology. coordinately increased in concentration in Journal of Alzheimer’s Disease 2011 (In the cerebrospinal fluid of a subpopulation Chetelat G, Villemagne VL, Villain N, press) of sporadic Alzheimer’s disease subjects. Jones G, Ellis KA, Ames D, Martins RN, Mol Neurodegener. 2012 Apr 25;7(1):16. Head R, Masters CL Rowe CC and the Tinsley RB. Kotschet K, Horne MH, Ng H, [Epub ahead of print] PubMed PMID: AIBL Research Group. Accelerated brain Bush A, Martins RB, Masters CL, Shaw G, 22534039. grey matter atrophy in asymptomatic Nagley P, Horned MK. Plasma alpha- elderly with high β-amyloid deposition. synuclein level correlates with risk of Bateman RJ, Xiong C., Benzinger TLS., Neurology 2011; Accepted August 2011. Parkinson’s Disease. (Accepted) Fagan AM., Goate A., Fox NC., Marcus 2012 Feb 14;78(7):477-84. Epub 2012 DS.,Cairns NJ, Xie X., Blazey TM., Faux NG, Ellis KA, Porter L, Fowler CJ, Feb 1. PubMed PMID: 22302548. Hotzman DM, Santacruz A., Buckles V., Laws SM, Martins RN, Pertile KK, Oliver A., Moulder K., Aisen PS., Ghetti Barber B., Ames E., Ellis K., Martins Rembach A, Rowe CC, Rumble RL, B., Klunk WE, McDade E., Martins RN., R, Masters C., and Szoeke C. Lifestyle Szoeke C, Taddei K, Taddei T, Trounson Masters CL., Mayeux R., Ringman JM., and late cognitive health: sufficient BO, Villemagne VL, Ward V, Ames D, Rossor MN., Schofield PR.,Sperling evidence to act now? [Guest Editorial] Int Masters CL, The AIBL Research Group, Ra., Salloway S., Morris JC. Clinical Psychogeriatrics 2012 24: 683-688 [doi: Bush AI. Homocystein, vitamin B12 and biomarker changes in Dominantly 10.1017/s104161021002912] and folic acid level in Alzheimer’s Inherited Alzheimer’s Disease. The New Disease, mild cognitive impairment and Villain N., Chetelat G., Grassiot B., England Journal of Medicine. Published Healthy elderly: baseline characteristics Bourgeat P, Jones G., Ellis KA., Ames D, July 11, 2012 pg 1 – 10. in subjects of the Australian Imaging Martins RN., Eustache F., Salvado O., Biomarker Lifestyle study. Journal of Drummond ES, Martins RN, Handelsman Masters CL., Rowe CC., Villemagne VL Alzheimer’s Disease 2011, Accepted July DJ, Harvey AR. Altered Expression of and the AIBL Research Group. Regional 25 2011. (e-published 2011 Sept. 2) Alzheimer’s Disease-Related Proteins in dynamics of amyloid-beta deposition in Male Hypogonadal Mice. Endocrinology. healthy elderly, Mild Cognitive Impairment Lim YY, Harrington K, Ames D, Martins 2012 Apr 18. [Epub ahead of print] and Alzheimer’s disease: a voxelwsePiB- R, Masters C, Rowe C, Szoeke C, Darby PubMed PMID: 22514046. PET longitudinal study. Brain 2012; 135: D, Maruff P. Use of Cogstate brief 2126-2139 [doi: 10.1093/brain/aws125] battery in the assessment of Alzheimer’s Sohrabi, H.R; Bates, K. A; Weinborn, disease replated cognitive impairment M.G.; Johnston, A.N.B, Bahramian, A.; Lim YY, Ellis KA, Pietrzak RH., Ames D., in the Australian Imaging, Biomarker Taddei, K.; Laws, S.M.; Rodrigues, M. D., Harrington K., Martins RN., Masters and Lifestyle (AIBL) study. J. Clin Exp. ; Moricci, M. ; Howard, M. ; Martins, G. CL., Rowe C., Savage G., Szoeke C., Neuropsychol. (epublished in press) 2012 Mackay-Sim, A. ; Gandy, S. E.; Martins, Villemagne VL, Maruff, P and the AIBL Apr;34(4):345-58. Epub 2012 Jan 17. R.N. (2012). Olfactory discrimination 30 Research Group. Stronger effect of PubMed PMID: 22248010. predicts cognitive decline amongst amyloid load than ApoE genotype community-dwelling older adults. on cognitive decline in healthy older Avdesh A, Martin-Iverson MT, Mondal A, Accepted for publication (April 2012) by adults. Neurology 2912; 79:1645-1652 Chen M, Askraba S, Morgan N, Lardelli the J Transl. Psychiatry. [doi:10.1212/WNL.0b013e31826e9ae6] M, Groth DM, Verdile G, Martins RN. Evaluation of Color Preference in Doecke JD, Laws SM, Faux NG, Wilson Laws SM., Doecke J., Martins RN Zebrafish for Learning & Memory. Journal W, Burnham SC, Lam CP, Mondal A, Bedo In reply: “Blood-based biomarkers in of Alzheimers Disease (2012) 28: (2) J, Bush AI, Brown B, De Ruyck K, Ellis KA, Alzheimer’s disease: where are we now, 459-469 Fowler C, Gupta VB, Head R, Macaulay where have we to go?” – ChristophLaske. SL, Pertile K, Rowe CC, Rembach A, Arch Neurol (In press, Oct 2012)] Hata S, Taniguchi M, Piao Y, Ikeuchi Rodrigues M, Rumble R, Szoeke C, Taddei Kanyenda LJ, Verdile G, Boulous S, T, Fagan AM, Holtzman DM, Bateman K, Taddie T, Trounson B, Ames D, Masters Disease. Journal of Alzhemer’s Disease CL, Martins RN, and the AIBL Research (Accepted for publication November 2012) Group. Blood-based protein biomarkers O’Bryant S., Xiao G., Edwards M., Devpus for diagnosis of Alzheimer’s Disease. M., Gupta VB., Martins RN., Fan Z. & Archives Neurol (Accepted for publication Barber R., for the Texas Alzheimer’s May 2012) Research & Care Consortium (TARCC). Brown BM., Peiffer JJ., Taddei K., Lui JK., Biomarkers of Alzheimer’s Disease Among Laws SM., Gupta VB., Taddei T., Ward VK., Mexican Americans. Journal of Alzhemer’s Rodrigues MA., Burnham S., Rainey- Disease. (In Press December 2012) Smith SR., Bush A., Ellis K., Masters CL., Cyarto EV, Lautenschlager NT, Desmond Ames D., Macaulay SL., Szoeke C., Rowe PM, Ames D, Szoeke C, Salvado O, CC., Martins RN., for the AIBL Research Sharman MJ, Ellis KA, Phal PM, Masters Group. Physical activity and Amyloid-β CM, Rowe CR, Martins RN and Cox KL. plasma and brain levels: Results from Protocol for a randomized controlled The Australian Imaging, Biomarkers and trial evaluating the effect of physical Lifestyle Study of Ageing. Molecular activity on delaying the progression of Psychiatry (Accepted for publication June white matter changes on MRI in older 2012) adults with memory complaints and mild Verdile G.*, Laws SM.*, Hnley D., cognitive impairment: The AIBL Active Bush AI., Ellis K., Faux NG., Gupta trial. BMC Psychiatry 2012, 12:167 V., Li Q., Lui JK., Masters C., Pike doi:10.1186/1471-244X-12-16. KE., Rowe CC., Szoeke C., Taddei K., Doré V, Villemagne VL, Bourgeat P, Fripp Villemagne VL., Matins RN., and the J, Acosta O, Chetélat G, Zhou L., Martins AIBL Research Group. Associations RN, Ellis KL, Masters CL, Ames DA., between gonadotropins, testosterone Salvado O, Rowe CC. Cross-sectional and and A in men at risk of Alzheimer’s β longitudinal analysis of the relationship disease. Molecular Psychiatry (accepted between A deposition, cortical thickness September 2012). Joint First Author. and memory in cognitively unimpaired Gardener, S., Gu Y, Rainey-Smith S., Keogh individuals and in Alzheimer’s disease. J, Clifton P, Groth D, Mathieson SL, Taddei Archives of Neurology 2012. Accepted K., Mondal A., Ward V., Scarmeas N., September. Barnes M., Ellis K., Head R., Masters CL., Carrillo MC, Rowe CC., Szoeke C., Masters Ames D., Macaulay L., Rowe, CC., Szoeke CL., Ames D., O’Meara T., Macaulay SL., C., Masters C. Martins RN. Adherence Milner A., Ellis KA., Maruff P., Rainey- 31 to a Mediterranean Diet and Alzheimer’s Smith SR., Martins RN, Bain LJ, Head Disease risk in an Australian Population. ANNUAL REPORT 2013 RJ. Research and Standardization in Translational Psychiatry (Accepted for Alzheimer’s Trials: Reaching International publication August 2012) Consensus. Alz and Dementia 2012. Ames D., Bush AI., Doecke JD., Ellis KA., Accepted November 2012 Gaux NG, Fowler C., Martins RN., Masters CL., Pertile K., Rembach A., Roberts BR., Rowe CC., Rumble R., Trounson B., Villemagne VL., Volitakis I., Watt AD., Wilson W. Longitudinal analysis of serum copper and ceruloplasmin in Alzheimer’s PROFESSOR RALPH MARTINS GRANTS AWARDED

Australian Research Council. LIEF Grant. candidates targeting toxic aggregates in ECU- Small Faculty Grant : Genome wide Hunt DM, Martins R, Verdile G, Laws S, Alzheimer’s Investigators: Dr R Barr (ECU), screening of oligomer Aβ toxicity using a Lister R, Collin SP, Pavlos N, and Davies WIL. Prof R Martins (ECU), Dr G Verdile (ECU), yeast gene deletion library. Bharadwaj P. Establishing a zebrafish facility in Western Prof Paul Watt (Phylogica Ltd), Dr R Hopkins Martins RN. 2012 $10,000 Australia. ARC LE140100116. 2014: (Phylogica Ltd). ECU- Small Faculty Grant : Serum beta- $400,000 Hollywood Private Hospital Research Amyloid 1-42, olfactory functioning and Mason Foundation National Medical Program Foundation RF062 Efficacy of Biocurcumax cognitive decline in the elderly; Hamid Project Grant. Laws SM, Verdile G. “Validation and Docosahexaenoic acid (DHA) in slowing Sohrabi, RN Martins, 2013. $ 7500 of genetic variants and their functional accumulation of Beta Amyloid and preventing ECU- Small Faculty Grant for Early Carrier implications in Alzheimer’s Disease” 2014: cognitive decline in an older population. Researchers: Personality dimensions and $40,000 Martins RN, Goozee K. Rainey-Smityh S. & increased risk of late onset Alzheimer’s Pedrini S. November 2012 $15,000. ECU Early Career Researcher Award, 2013:: disease; Hamid Sohrabi, 2013; $ 15000 $10,000, “Protective role of autophagy genes Neurotrauma Research Program Grant: Head in Alzheimer’s disease”, Dr. Bharadwaj P Injury & Testosterone Study (HIT) RN Martins, H. Sohrabi, NW Knuckey, M Weinborn, M FCHS Research Grant ($9982) for “Angels Carruthers, N, Lenzo, K. Taddei $148,701 1 and Demons” – Phylomers® as novel year 2013.

INVITED PRESENTATIONS

Invited by Roma Lester to make a presentation Invited to present a talk at the 6th Annual 2. Early diagnosis and prevention of AD: The to the ORA Womens’ Cultural Group, Jewish Biopharma Asia Convention, Santosa Singapore Australian Imaging Biomarkers and Lifestyle Centre in Perth February 12, 2013. Latest March 18-21 2013. Presentation entitled: Study of Ageing (30 mins) Advances in Alzheimer’s disease. Developing disease modifying therapeutic Invited to make a presentation to members and peptides and diagnostics for Alzheimer’s disease. Presentation entitled Alzheimer’s disease guests at the South of Perth yacht Club at their development, Early Detection and Life Style Presentation at the AD/PD Conference in Florence Prestigious Spring Fundraising Luncheon for Prevention Factors – The Australian Imaging March 10th 2013 entitled: Testosterone and the year. Mrs Tonya McCusker also presented Biomarker & Lifestyle Study (AIBL) at the Health Luteinizing Hormone Levels; Association with at this luncheon. September 12, 2013. Aging – Strategies to Meet Healthy & Lifestyle Alzheimer’s disease Related endophenotypes & Invited by Alzheimer’s Australia (South Australia) Challenges Singapore. March 2013. therapeutic Efficacy in a Pilot study. to present at the “Mindful of Dementia” Invited by Roma Lester to make a presentation Presentation at the AD/PD Conference in Florence conference in Port Lincoln and at the Queen to the ORA Womens’ Cultural Group, Jewish March 10th 2013 entitled: Testosterone and Elizabeth Hospital in Adelaide, a talk entitled 32 Centre in Perth February 12, 2013. Latest Luteinizing Hormone Levels; Association with Alzheimers Disease – Development, Early Advances in Alzheimer’s disease. Alzheimer’s disease Related endophenotypes & Detection, and Lifestyle Prevention Factors” therapeutic Efficacy in a Pilot study. October 2- 5 2013. Presentation entitled Alzheimer’s disease development, Early Detection and Life Style Invited as Plenary speaker at the Science of Invited by UNI HealthCare to give the keynote Prevention Factors – The Australian Imaging Nutrition in Medicine and Healthcare Sydney presentation at the EQUIP Expo Claremont Biomarker & Lifestyle Study (AIBL) at the Health New South Wales May 3- 5th 2013. Two Showgrounds November 22 & 23rd 2013, Aging – Strategies to Meet Healthy & Lifestyle presentations: Entitled “Understanding Alzheimers”. Challenges Singapore. March 2013. 1. Role of testosterone & Luteinizing Hormone on the Pathogenesis of Alzheimer’s Disease (30 mins) CLINICAL TRIALS DIVISION

While there is currently no cure for brains and therefore prevent the disease. humans and potentially slow progression Alzheimer’s disease, there are five Understanding this rare early onset form in subjects with prodromal AD. The trial prescription drugs approved to treat of Alzheimer’s disease may provide clues enrolls subjects who meet the criteria for its symptoms. These drugs modestly to decoding the most common age related prodromal AD defined as subjects who improve symptoms but do not alter sporadic form Alzheimer’s disease and have amnestic aMCI and are positive for disease progression. No new drugs have therefore help develop new dementia an AD biomarker. The primary biomarker been approved by the TGA or FDA for treatments. to be used for this study is cortical amyloid Alzheimer’s disease treatment since 2003 load measured with a PET scan using an The CTD plays an important part in despite numerous clinical drug trials investigational ligand flutemetamol. We The McCusker Alzheimer’s Research worldwide. Novel pharmacological agents require participants for this trial in 2014. Foundation’s vision of a world without that slow or halt the progression of AD are Alzheimer’s disease. Our goal is to TauRx THERAPEUTICS LTD therefore desperately needed. eliminate Alzheimer’s disease through the TRx-237-015: Randomised, The Clinical Trials Department (CTD) of advancement of research and to provide Double-Blind, Placebo-Controlled, the McCusker Alzheimer’s Research and enhance care and support for all Parallel-Group, 15-Month Trial Foundation has been conducting clinical affected. The trial participants and their of Leuco-methylthioninium drug trials since 2003 with Associate families receive medical care and support bis(hydromethanesulfonate) in Professor Roger Clarnette as Principal provided by a multidisciplinary team who Subjects with Mild to Moderate Investigator. A/Prof Roger Clarnette is are experts in this field. Participants also Alzheimer’s Disease a Consultant Geriatrician at Fremantle gain access to new treatments which may This 15 month trial is being conducted Hospital and Director of their specialised benefit them and will definitely benefit in 120 study sites worldwide with a Memory Clinic with expertise and future generations by adding to the body of recruitment target of 833 participants. particular interest in memory loss and scientific knowledge in this area. The primary development of the study Alzheimer’s disease. He has been the If you or someone you know is interested medication methylthioninium (MT) in Principal Investigator for more than 50 in participating in a clinical trial please call Alzheimer’s disease is focused in its clinical trials over a period of 20 years. 93896433 and speak to one of the study activity as a Tau Aggregation Inhibitor. The There are promising new treatments coordinators. Tau hypothesis is that processes leading for Alzheimer’s disease being tested by to abnormal aggregation of Tau protein All trials are double blind, randomised, the CTD. We are currently trialing new lead to the formation of tangles within parallel group, placebo controlled treatments for the very early or prodromal the nerve cells in the brain and lead to multicentre trials. During 2013, the stage of Alzheimer’s disease. It is known clinical dementia. The Protein Aggregation Clinical Trials Division was engaged in the the pathology of the disease commences Inhibitors target the underlying pathology following clinical trials: 10-20 years before the onset of clinical of dementia with the aim of modifying symptoms warranting early intervention MERCK SHARP & DOHME CORP or halting disease progression and an and early treatment. Testing new An Efficacy and Safety Trial of MK- ultimate goal of prevention. We require treatments in mild to moderate Alzheimer’s 8931 (SCH 900931) in Subjects with participants for this trial. Recruitment is 33 amnestic Mild Cognitive Impairment disease have not proven effective probably ongoing. ANNUAL REPORT 2013 because the brain damage is difficult to (aMCI) due to Alzheimer’s Disease The DIAN-TU-001 Prevention Trial reverse at these stages and a slowing (Prodromal AD) (Dominantly Inherited Alzheimer’s of disease progression may be all that is This is a 24 month trial of 1500 Network) possible. The DIAN-TU-001 trial will enroll participants in subjects with amnestic mild A Phase II/III randomized, double- participants at our site with a rare genetic cognitive impairment due to Alzheimer’s blind, placebo-controlled, multi-centre form of Alzheimer’s disease when they are disease (or prodromal Alzheimer’s disease) study of 2 potential disease modifying cognitively normal or have mild cognitive The study medication is a potent β-site therapies in individuals at risk for and impairment. Patients chosen for the APP cleaving enzyme 1(BACE1) Inhibitor with dominantly inherited Alzheimer’s trial will test drugs that may prevent the so may reduce beta-amyloid production in Disease. buildup of beta amyloid plaques in their CLINICAL TRIALS DIVISION

This 4 year study of 210 participants • There are 11 ongoing patients and 3 Recruitment has finished for this study. worldwide will assess the safety, patients have withdrawn. 2. Efficacy and safety of 3 doses of tolerability and biomarker efficacy of • Recruitment has finished. We were the S 38093 (2, 5 and 20mg/day) versus gantenerumab and solanezumab in top recruiter in Australia for this study placebo, in co-administration with subjects who are known to have a rare donepezil (10mg/day) in patients Alzheimer’s disease-causing mutation by F.HOFFMAN-LA ROCHE LTD with moderate Alzheimer’s Disease. A determining if treatment with the study A Phase 2 multicentre, randomised, 24-week international, multi-centre, drug improves primary and secondary double-blind, parallel-group, placebo- randomized, double-blind, placebo- outcome disease-related biomarkers. The controlled study to investigate the controlled phase 11b study. 2 drug treatments being administered efficacy and safety of RO4602522 are humanised anti beta amyloid peptide added to the background therapy of the This trial is using the same study antibodies which may prevent, inhibit or acetylcholinesterase inhibitors donepezil medication as the previous trial with no reduce the accumulation of beta amyloid. or rivastigmine in patients with moderate extension phase. We have 3 patients Gantenerumab is given as an injection severity Alzheimer’s Disease participating in this 6 month treatment study and are still looking for suitable and solanezumab is given intravenously This study medication is a selective participants. (IV) every month for 24 months in this inhibitor of MAO-B being tested in patients study. Participants will have 8 PET scans with moderate severity Alzheimer’s disease TROPISETRON (PIB, FDG and Florbetapir F-18) 9 MRIs, to ascertain its capacity to improve A randomized, double-blind, placebo- lumbar punctures as well as cognitive cognition, functionality and behavior in this controlled, sequential cohort, multi- testing throughout the study to assess the population. The study medication is given centre study to evaluate the safety, outcome measures. for 12 months added to background AD tolerability, pharmacokinetics, ROCHE PRODUCTS PTY LIMITED treatment. A total of 354 patients have pharmacodynamics and preliminary Protocol Number: WN25203D been recruited worldwide for this study efficacy of F03 in subjects with Multicenter, randomised, double-blind, which was the recruitment target. mild cognitive impairment due to Alzheimer’s Disease. placebo-controlled, parallel-group SERVIER two year study to evaluate the effect 1. Protocol Number: CL2 38093 011 This 8 week treatment study of 36 of subcutaneous Gantenerumab on - Efficacy and safety of 3 doses of participants is a Phase 1b/2a study cognition and function in prodromal S38093 (2, 5 and 20mg/day) versus designed to evaluate the safety, tolerability, Alzheimer’s Disease. placebo in patients with mild to pharmacokinetics (PK), pharmacodynamics 770 subjects were selected worldwide who moderate Alzheimer’s Disease. A and preliminary efficacy of oral F03 met the criteria of memory impairment 24-week international, multicentre, (tropisetron) compared to placebo in and reduced CSF Aβ1-42 levels so have randomised, double-blind, placebo- males and females with Mild Cognitive likely Prodromal AD. The study medication controlled phase IIb study followed by Impairment due to Alzheimer’s Disease. is a human anti beta amyloid peptide a 24 week extension period Tropisetron is a currently approved anti- 34 emetic drug in 49 countries across the antibody which may prevent, inhibit or The purpose of this trial is to assess the world, including Australia. reduce the accumulation of beta amyloid. efficacy and safety of S 38093 versus Subcutaneous study treatment are given placebo in patients with mild to moderate This study will commence in 2014. every 4 weeks for 26 administrations and AD. The primary objective of this study the total treatment duration is approximately is to assess the efficacy of 3 fixed doses 2 years. There is optional participation in of S 38093 (2, 5 and 20 mg/day) versus Part 2 of the study for years 3 and 4 with placebo after 24 weeks of treatment, on monthly study treatment. cognitive performance measured with the ADAS-Cog 11-items in patients with mild to moderate AD. DIAN Clinical Trial Unit Chief Investigator: Prof Randall Bateman Washington University School of Medicine Researchers (ECU/McCusker): A/Prof Roger Clarnette and Professor Ralph Martins Sponsor: Washington University School of Medicine Pharmaceuticals Collaborators: Eli Lilly and Company Hoffmann-La Roche Alzheimer’s Association (USA) National Institute on Aging (NIA) Avid Radiopharmaceuticals Autosomal-dominant Alzheimer’s disease is a rare but aggressive form of Alzheimer’s disease that result in memory loss and other cognitive problems in individuals aged 30-60yrs old. The DIAN Clinical Trial aims to examine the efficacy of drugs potentially able to change the course of the disease. The DIAN Trial will examine if these drugs can prevent the disease, treat the symptoms, or delay its onset and whether they are safe, tolerated by patients, and are effective. The study started by screening potential participants at the Washington University School of Medicine in St. Louis, Missouri USA, in late 2013. Our Perth site will be the first in Australia to start this clinical trial. To be eligible for this study participants must be offspring of a patient with one of the three known Alzheimer’s related gene mutations 35 and have been registered for the study. ANNUAL REPORT 2013

“Commercialising technologies to prevent Alzheimer’s disease”

Alzhyme Pty Limited is a brain. Accumulation of beta-amyloid in • improved management of clinical biotechnology company specialising the brain is believed by many to be of trials by facilitating better and earlier in the development of novel drugs major importance in the pathogenesis patient recruitment; and diagnostics for the effective of Alzheimer’s disease. Alzhyme’s lead • monitoring of the response to detection, prevention and treatment of peptide candidate has been shown to treatment with new disease modifying Alzheimer’s disease. significantly inhibit beta-amyloid-induced therapies being developed. neurotoxicity in several animal models. Alzhyme was formed in December Alzhyme is collaborating to develop 2002 out of the University of Western Through Prof. Martins and his team, a diagnostic tool involving the use of Australia to commercialise the Alzhyme is working to establish that Alzhyme proprietary peptides. Because research of Prof Ralph Martins and the Alzhyme peptides can be used to the Alzhyme peptides bind to a specific his team,. Alzhyme was established progressively reduce beta-amyloid in site within the human beta-amyloid through initial capital investment from the brain through a process known protein, with the successful radio labeling its founding shareholder and Chairman, as peripheral clearance. Importantly of the compound, the potential exists for Mr. Harold Clough. Alzhyme is seeking this process obviates the need for the the development of an early diagnostic to raise additional capital to advance Alzhyme peptides to cross the blood brain and imaging test for Alzheimer’s disease, its pipeline of technologies through barrier. using Positron Emission Tomography pre-clinical development. The research group is also developing an (PET) imaging techniques. Alzhyme Today, Alzhyme has four patent orally available analogue of the Alzhyme peptides are being developed as a application families and four peptide for the treatment of Alzheimer’s radiopharmaceutical agent to image development project streams: disease. amyloid deposits in the brains of living patients. 1. Peptides to enhance peripheral Diagnostics clearance of β-amyloid as a In parallel to its therapeutic program of CRC for Mental Health and treatment for Alzheimer’s disease. research, Alzhyme has is committed to Testosterone Clinical Trial Jointly funded with federal improving early diagnosis of Alzheimer’s Alzhyme joined the McCusker Foundation government support. disease. as one of the founding participants in the successful bid for the CRC for Mental 2. Peptide therapeutic treatments for The pathological processes of Alzheimer’s Health, which commenced in July 2011 early intervention in Alzheimer’s disease begin many years before and was launched in November 2011. disease. clinical symptoms are observed. Early, The CRC allows researchers from all over cost-effective diagnostic methods have 3. Diagnostic imaging agents for early Australia to collaborate on two major the potential to minimise the enormous detection of Alzheimer’s disease. programs: neurodegeneration and the impact that Alzheimer’s disease will have psychoses. Prof. Martins will head major 4. Partnership in a major new on health, quality of life and healthcare AD studies in the neurodegeneration clinical trial of testosterone for the costs through: 36 prevention of Alzheimer’s disease program. Alzhyme and the McCusker • accurate diagnosis of Alzheimer’s (in collaboration with the CRC for Alzheimer’s Research Foundation will disease early in the disease course Mental Health and the McCusker conduct two of the initial research and before significant memory loss Alzheimer’s Research Foundation) projects related to Novel Therapeutics occurs; for AD – Testosterone Trial and Novel Therapeutic Pipeline • earlier and more appropriate Peptide. The CRC is funded for seven Through the research efforts of Prof treatment and management of years and the institutions involved will Ralph Martins and his team, Alzhyme Alzheimer’s disease patients; receive $23 million of Commonwealth has identified a family of peptides that funding in this timeframe. specifically neutralize the damaging • identification of mild cognitive potential of beta-amyloid in the impairment patients likely to progress to Alzheimer’s disease;

As part of the CRC for Mental Health, By establishing such productive Alzhyme will participate in the major partnerships and pursuing an integrated testosterone clinical study commenced in pipeline approach encompassing 2013. Prof. Martins’ research group will diagnostic imaging agents and disease- conduct the clinical trial to assess the role modifying drugs, Alzhyme expects to of testosterone and DHA in preventing meaningfully impact the Alzheimer’s the development of AD in patients with disease market, and help ease the Subjective Memory Complaint (SMC). suffering of millions of patients, creating If the outcome of the study is positive a future in which Alzheimer’s is a there is the potential to develop and treatable disease. commercialise a combination therapy More information can be found at for the prevention of AD in patients with www.alzhyme.com Subjective Memory Complaint (SMC). Alzhyme and the McCusker Alzheimer’s Research Foundation Inc Alzhyme is proud to have had a long association with Professor Martins and the McCusker Alzheimer’s Research Foundation Inc including having an Access and Option pipeline agreement in place since 2009. This gives Alzhyme a first-right-to acquire and commercialize intellectual property for the treatment and diagnosis of Alzheimer’s disease arising out of the Foundation and Alzhyme with a wonderful opportunity to increase its R & D pipeline and reduce development risk.

37 ANNUAL REPORT 2013 2013 started in a flurry of activity. In mid-January the Minister for Health Dr Kim Hames launched our Testosterone Jenny Gill and Fish Oil study recruitment drive. Executive Manager As a result we had 3000 men register their interest. This will be a worldwide first in terms of combining these substances. The study will run for 56 weeks and has the support of the WA Government and private funding, which is very much appreciated. The New Year also saw the arrival of our new PET Camera in which the Foundation has an interest. As a result brain imaging can now be more regularly and conveniently undertaken. This has assisted our ongoing AIBL (Australian Imaging, Biomarkers and Lifestyle) Project as it is allowing us to compare brain scans with eye scans in a sub group of AIBL participants, to try and develop a simple diagnostic eye

How to Contact Us test. The AIBL project is now regarded Please feel free to contact us: McCusker Alzheimer’s Research Foundation Inc. Suite 22, Hollywood Medical Centre 85 Monash Ave, Nedlands WA 6009 internationally as a cutting edge project Tel: 9347 4200 Jenny Gill, Executive Manager [email protected] www.alzheimers.com.au because of the cooperation of our participants as well as the data that is starting to emerge. The purchase was made possible by an innovative partnership between Oceanic Medical Imaging, (a private medical imaging provider) the McCusker Alzheimer’s Research Foundation and the estate of the late Dr Jean Murray- Jones. Dr Jean Murray-Jones (1921 – 2009) was a pioneering Western Australian woman, 38 recognised for her strong interest and commitment to improving the health and welfare particularly women. Sir Cliff Richard, Knight Bachelor, OBE has had personal experience with Alzheimer’s disease, his mother, Dorothy, aged 87, died after a decade with Alzheimer’s disease. Sir Cliff said by speaking publicly about his mother’s battle with Alzheimer’s, he is significantly boosting efforts to raise COMMUNITY OUTREACH AND FOUNDATION ACTIVITIES awareness of this devastating disease. Adelaide and Dr Matthew Sharman from We held our Annual Fund Raising Dinner Sir Cliff is a Patron of Alzheimer’s the University of Tasmania. Assoc Prof at Maurizio’s Restaurant in Fitzgerald Research UK. We were fortunate to be Verdile is part of ECU’s Neuroscience Street. VIP Guests included His Excellency able to attend Sir Cliff’s concert held Research Group, led by the Inaugural Malcolm McCusker, Governor of Western at the Sandalford Winery earlier this Chair in Ageing & Alzheimer’s, Professor Australia, Dott. Adriano Tedde, Consul year, courtesy of Peter, Debra and Gary Ralph Martins. Poscript: In January of Italy in WA and West Coast Eagles Prendiville. The Cliff Richard’s Joondalup 2014 Assoc Prof Verdile moved to Curtin favorite, Dean Cox. We sincerely thank Support Ladies Group, led by Susan University. all who contributed to the success of this Lynch, have been fundraising throughout annual event Perth Convention Bureau ASPIRE the year for the Foundation, and Sir Cliff Program The Foundation is extremely grateful presented a cheque to His Excellency, The Perth Convention Bureau, with its for the contributions of the Lions Clubs Patron of our Foundation. Our sincere major stakeholders, the City of Perth in Western Australia. Their ongoing thanks go to these wonderful ladies for and Tourism WA, annually convenes the support is invaluable to Professor Ralph their ongoing support. Aspire Scholarship and Professional Martins work. The Lions McCusker Maggie Beer, Celebrity Cook and food Development Awards. The Awards offer Committee meet monthly, not only to producer, is a strong supporter of the financial support for the professional brain-storm fund-raising options, but Foundation launching the KARVIAH study development of non-profit association also to discuss strategies to spread the in Sydney in 2012. Maggie was very kind members and university staff through work of the Foundation to the community. to offer her services for two fundraising attendance at an international conference The Claremont Nedlands Lions Club events in Perth in 2013 – “Valentine’s within their discipline. One of the benefits held their Annual Sportsman’s Lunch Day Cocktail with Maggie Beer” and of International conferences secured by with part proceeds being donated to “Maggie Beer and 5 Chefs,” Our the program is the sharing of substantial the Foundation. Michael Thompson very sincere thanks for these events go to knowledge, international profiling and kindly donated his time as MC for the the Perth Arena, Perth Convention and advancement of the state’s many sectors event, with David Wirrpanda attending as Exhibition Centre; Deborah Kennedy, of expertise. guest speaker. Maurizio Di Cino, Michael Tamburri; Winner: Dr Hamid Sohrabi, The community are availing themselves Musicantes; John Mairiorana; Franklyn Postdoctoral Research Fellow at the of the EVERYDAY HERO website which Tate; Alain Fabregues; Neal Jackson; School of Medicine at ECU enables them to spread the word of the Giuseppe Pagliaricci; Chris Taylor; Dr Hamid Sohrabi is a postdoctoral Foundation, inspire support and raise Richard Taylor and all of our supporters. research fellow in Professor Ralph money for Alzheimer’s research and ECU scientists lead the way on Martins’ laboratory at ECU, investigating for this, we thank you all for your most Alzheimer’s research – supported by different aspects of Alzheimer’s disease. generous support. the McCusker Alzheimer’s Research This award enabled him to participate in National Science Week 2013 Events: Foundation. Research Fellow Assoc the Alzheimer’s Association International 10-17Aug 2013. Researchers set up an Prof Giuseppe Verdile has received Conference (AAIC) in Boston, United information stall to raise awareness in 39 $536,949 from the National Health and States in July last year. Dr Sohrabi is

the community of the current medical ANNUAL REPORT 2013 Medical Research Council. A team led supported in his work by the McCusker research in Alzheimer’s disease by ECU’s School of Medical Science Foundation. (Science week Launch event, Perth Research Fellow, Ass/Prof Giuseppe Due to the overwhelming success of our Cultural Centre, 10Aug), they also held Verdile has received one of just six Inaugural Golf Day, we held another very a public lecture series entitled “Battling grants - and the only one in WA – from successful event again last year at the Alzheimer’s disease: From Diagnosis to the National Health and Medical Research Royal Perth Golf Club. We are extremely Care and Prevention” followed by tours Council (NHMRC) to look at therapies grateful to the Commonwealth Bank of of the research lab. (ECU, Joondalup for dementia. Assoc Prof Verdile will Australia who came on-board as our campus.) conduct the study with co-investigators Naming Sponsors for the second time. Dr Michael Lardelli from the University of BOARDS MEMBERS 2013

His Excellency Mr Malcolm McCusker AO CVO QC (Patron) Mrs Terrie Delroy (Vice Patron)

Mr Enzo Sirna AM (Chairman) Mr Russell Delroy President Italo–Australian Welfare and Managing Director of a boutique Cultural Centre resource fund, board member of variety of private companies and not for profit Dr Terry Bayliss (Deputy Chair and organisations Representing Hollywood Private Hospital) Manager Development Projects and Ms Deborah Doncon Research, Hollywood Private Hospital. Extensive experience as a CEO and membership of boards of management. Mr Rob Davies (Treasurer) Accountant. Actively involved in Ms Jenny Day fundraising for the Foundation through Chief Executive Officer of the Community the Lions Club of Bullcreek and the Lions Development Foundation. McCusker partnership. Mr Larry Lopez Professor Ralph Martins AO (Director of Partner, Australian Venture Consultants Research) with extensive experience in executive Director of Research, Sir James management and membership in McCusker Alzheimer’s Disease Research public, private and non-profit boards of Laboratory. management Mr Peter Stevens Assoc Prof Giuseppe Verdile (Alternate Chartered Accountant, former Company Director of Research) Director. Deputy Director of Research, Principal Research Fellow McCusker Alzheimer’s Assoc Prof David Groth (Representative Research Foundation. Scientific Advisory Committee) Biomedical Science Curtin University of Ms Jenny Gill Technology. Executive Manager, McCusker Alzheimer’s Research Foundation. Mr Ron Bennetts Former partner of a leading international advisory group; board member of a variety of not for profit organisations; 40 published author in the field of finance, stock market, real estate and financial planning. Chair of the Foundation’s finance committee.

Board notes In accordance with the Constitution, Board sitting fees are not payable to any member. No Board member sought to be reimbursed for any expense incurred on behalf of the Foundation. Indemnity Insurance The Foundation has indemnity insurance cover up to $10 million in aggregate to protect funds, board members, staff and volunteers against claims for damage and other legal actions. 41 ANNUAL REPORT 2013 42 43 ANNUAL REPORT 2013 44 45 ANNUAL REPORT 2013 46 47 ANNUAL REPORT 2013 48 49 ANNUAL REPORT 2013 50 51 ANNUAL REPORT 2013 52 53 ANNUAL REPORT 2013 NOTES

54 NOTES

55 ANNUAL REPORT 2013 2013 ANNUAL REPORT

McCuskerAlzheimer’s Research Foundation Inc Suite 22 Tel: +61 8 9347 4200 Hollywood Medical Centre Fax: +61 8 9347 4299 85 Monash Avenue Email: [email protected] Nedlands WA 6009 Australia

www.alzheimers.com.au