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Evolution of Alzheimer's Disease Research

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Evolution of Alzheimer's Disease Research Celebrating 20 Years of Alzforum (1996 - 2016) FDG-PET tracks normal-MCI-AD Default mode network Active immunotherapy CAD106; progression, activity is impaired Staging diagram for BACE inhibitor CNP520 enter becomes marker for in symptomatic and successive biomarker phase 2/3 in cognitively normal neurodegeneration and preclinical AD, overlaps ApoE4/4 carriers First Aβ active change proposed First Bayesian differential diagnosis with regions of amyloid immunotherapy First DIAN adaptive trial, in mice prevention trial BAN-2401 Tau PET ligands enter EVOLUTION OF ALZHEIMER’S DISEASE RESEARCH in ADAD Aβ seeds induce β-sheet human testing structure, cerebral Head amyloidosis Lysosomal degradation Cognitive decline injury impaired early on in AD correlates with increases Avagacestat, soluble Aβ risk Ponezumab, Tideglusib fail in phase 2 ApoE infl uences Multiphoton amyloid microscopy Flurizan™, deposition in through cranial Videos show dynamic Xaliproden fail AGB101 to enter APP cloned and mouse models Reactive G8 holds Tau identifi ed as main window enables microglial surveillance, in phase 3 phase 3 sequenced, astrocytes DIAN-TU forms Dementia component of tangles Morphology of observation interaction with plaques Aβ42 and 43 crowd near Pharma Consortium Summit neurites around of plaque Gamunex fragments identifi ed plaques is distorted plaques, enters CERAD established to clearance by AD prevention degrade Aβ phase 2/3 standardize diagnostic immunotherapy trial of Celecoxib and procedures FDG-PET in ApoE Oligomers Naproxen halted Prospective biomarker CERE-110 fails in First reports of carriers and non- Dominantly Inherited reported as study fi nds 20-year phase 2 hippocampal atrophy carriers reveals AD Alzheimer Network bioactive Aβ 3-D structure of BACE prodrome in late-onset AD and reduced brain signature of brain Successive ε-, launched species Somatic metabolism hint that hypometabolism Neuropathologists ζ-, γ-cleavages transgenics Bapineuzumab MCI may predict AD formulate NIA-Reagan of APP release Aβ peptides via AAV gene NIA-AA diagnostic fails in phase 3 consensus criteria transfer criteria for AD dementia, Azeliragon enters NIA launches ADCS, MCI due to AD, and Gene transfer of phase 3 founded on Leon Thal’s tacrine trial human ApoE changes preclinical AD Presenilin involved Dendritic tau mediates amyloid deposition, in processing APP, Aβ-induced synaptic neurotoxicity AVP-923 mutations change Aβ toxicity, circuit Entorhinal cortex is key AD neurotoxicity att ributed enters Carriers of an generation abnormalities site of AD pathology, to tau mis-sorting to phase 2 for autosomal-dominant Incidence already has profound dendritic compartment and Gantenerumab agitation in AD mutation develop of dementia neuron loss in mild AD PDAPP, Tg2576 interaction with Aβ oligomers enters AD brain changes in decreases in mice express Neprilysin and phase 2/3 in childhood developed Indiana, Swedish other enzymes prodromal AD Cholinergic degrade A in vivo countries mutations, γ-secretase β hypothesis of respectively, cleaves Notch Alzheimer’s disease Comphrensive Early brain imaging develop plaques meta-analyses Cognitive impairment correlates Induced detects brain atrophy and Amyloid load, ApoE, of fl uid AD with synaptic damage Semagacestat pluripotent reduced perfusion in AD subjective memory biomarkers fails in phase 3 stem cells from complaints predict AD patients fastest decline in recapitulate Complement preclinical AD aspects of eliminates Aβ George Glenner (shown), Colin Aβ stress affects disease Masters isolate Aβ peptide in vivo Retromer implicated excitatory as pathogenic player, from human brains Aβ release into CSF Complement and inhibitory Dimebon fails Robert Terry, Michael Kidd revive Clioquinol drug target prompts search for fl uid circuits in phase 3 interest with electron microscopy implicated in fails in Alois Alzheimer describes biomarker assays Most people FDA approves of neuropathologic lesions AD phase 2 case of Auguste Deter at accumulate brain fi rst amyloid A4 starts, meeting in Tuebingen tracer, Aβ with age, Stages of fi rst secondary Complement and microglia more with AD fl orbetapir Braak amyloid prevention trial eliminate synapses in Neurofi brillary tangles and First staging of AD pathology for LOAD aging and AD brain component proteins fi rst demonstraton Rosiglitazone, neuropathology published isolated from AD brain Phenserine of tau Valproate fail defi ned Alpha cleavage of fails in immunotherapy in phase 3 AD signature NIA-AA updates APP precludes A Tau mutations phase 3 in mice β found in CSF: consensus formation cause First APP tau increased, criteria, neurofi brillary transgenic Aβ42 decreased uncoupling pathology, mouse model Certain NSAIDs Solanezumab AD pathology neurodegeneration, modulate Midlife APP duplication BACE inhibitor Atorvastatin enters phase 3 from dementia Oskar Fischer describes FTD, but not AD Midlife γ-secretase to obesity causes AZD3293 enters fails in symptoms Alzheimer pathology in hypertension produce less increases risk autosomal-dominant phase 2/3 phase 3 dementia cases increases Aβ42 AD with CAA risk 1900 1910 1960 1970 1980 1990 1995 2000 2005 2010 2015 The consistent, Low First Sleep affects progressive memory loss in Type 2 diabetes CSF Aβ refl ects AD GWAS Aβ clearance, Verubecestat, Approximately early AD is different from U.S. network of increases risk brain amyloid plaques, TRx0237, Idalopirdine, 80 therapeutics the mild memory loss in federally funded Concept of First mice BACE1 deposition dementia risk Masitinib, Brexpiprazole in phases 1, 2, healthy aging ADRCs starts with cognitive reserve First double- expressing knockout Nilvadipine enter phase 3 or 3 trials initial sites in articulated transgenic mice FTD tau mice are Sorl1 enter phase 3 National Institute Baltimore, Boston, expressing mutations viable variants TREM2 mutation of Aging founded, LA, NYC, and San Microvasculature mutant APP and APP Dutch mutation increase risk found in FTD, AD boosts AD research Diego in brain is PSEN1 Tau causes autosomal- of LOAD APP knockin funding damaged in AD CSF Aβ/tau propagation Emil Kraepelin coins the dominant cerebral mice recap Mixed brain signature hypothesis term “Alzheimer’s disease” amyloid angiopathy only some pathology First identifi es articulated phenotypes, commonly transgenic prodromal “Miliary foci”, later known International pointing to as amyloid plaques, seen Innate immune system discovered rat AD within Working Group Sir Martin Roth equates Mini-mental State Exam Tau cloned overexpression in Auguste Deter’s cortex implicated in AD CSF Aβ, CSF at autopsy models MCI cohorts, revises AD pathology and cognitive (MMSE) developed to artifacts Family history is a Aβ/tau ratio predicts diagnosis, uses decline of common senile screen mental status Congress major risk factor predict decline in cognitive biomarkers to dementia to that of AD — passes for late-onset AD cognitively normal decline capture early then considered a rare, National elderly and FAD stage presenile dementia APP London; Alzheimer’s Infl ammasome fi rst mutation mutation carriers Project Act implicated in AD NINCDS-ADRDA criteria Evidence for Non- Icelandic APP mutation found to cause Mutations in Aβ fi brils of “possible”, “probable”, activated human protects against AD “defi nite” AD microglia in AD autosomal- presenilin-1 and accelerate tangle primate brain dominant AD presenilin-2 formation in mice models ApoE4 major cause Memantine risk factor for autosomal- approved for AD late-onset dominant AD; AD; risk up Colombian ApoE4 Ibuprofen 3fold with one kindred largest Robert Katzman raises genotype The Australian Imaging, fails in Longitudinal study MCI or early AD? allele, 12fold in the world CATEGORIES awareness that AD is infl uences Biomarker & Lifestyle phase 2 tracks biomarkers in Controversy over with 2; ApoE2 common disease of aging Rivastigmine timing and Flagship Study of same ADAD mutation psychometric protective GAP launched approved amount of Ageing launched carriers for 11 years norms vs intra- amyloid Biology of Disease individual decline deposition in Biomarkers human brain Inge (shown) Grundke Galantamine Iqbal and Khalid Iqbal, Age biggest risk Diagnosis Amyloid approved Meta-analysis and other groups found factor: incidence hypothesis marks of four GWAS that tau is abnormally doubles every 5 Epidemiology / Risk Factors conceptual shift identifi es 22 phosphorylated in AD years aft er 65 First anti-Aβ vaccine Physical from descriptive Tacrine is the fi rst drug affects pathology activity susceptibility Genetics Prospective biomarker loci: confi rms to mechanistic approved for AD Toxicity att ributed and atrophy, but protects studies fi nd 20-year previous, fi nds European Prevention of view to pre-fi brillar tau fails in phase 2 over against AD Neuropathology prodrome in new variants Alzheimer’s Dementia aggregates encephalitis First report of amyloid PET in autosomal-dominant AD autosomal-dominant AD Consortium launched In brain, glial cells Aβ peptide toxic to Research Models Alzheimer’s Association synthesize ApoE, cultured neurons founded secrete it in HDL Therapeutics particles FDA issues Mutations in APP guidance and presenilins Alzheimer’s Disease for therapy Community Initiatives change Aβ42/40 Neuroimaging Initiative development ratio Presenilin contains launched in early AD Hypotheses catalytic core of APP Swedish Microdialysis tracks tau in vivo γ-secretase First reports of amyloid PET mutation found at Four proteins make in brain interstitial fl uid First
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