Alzheimer's Disease Research Timeline | Alzforum

Alois Alzheimer describes case of Auguste Deter at meeting in Tuebingen

1906▶

Oskar Fischer describes Alzheimer pathology in dementia cases

Emil Kraepelin coins the term "Alzheimer's Disease"

Robert Terry, Michael Kidd revive interest with electron microscopy of neuropathologic lesions

Sir Martin Roth equates pathology and cognitive decline of common senile dementia to that of AD—then considered a rare, presenile dementia

The consistent, progressive memory loss in early AD is different from the mild memory loss in healthy aging

Neurofibrillary tangles and component proteins first isolated from AD brain

National Institue on Aging founded, boosts AD research funding

Early brain imaging detects brain atrophy and reduced perfusion in AD

Mini-Mental State Exam (MMSE) developed to screen mental status

Robert Katzman raises awareness that AD is common disease of aging

Cholinergic hypothesis of Alzheimer's disease

Alzheimer’s Association founded

First reports of hippocampal atrophy and reduced brain metabolism hint that MCI may predict AD

Innate immune system implicated in AD

Entorhinal cortex is key site of AD pathology, already has profound neuron loss in mild AD

U.S. network of federally funded ADRCs starts with initial sites in Baltimore, Boston, LA, NYC, and San Diego

George Glenner, Colin Masters isolate Aβ peptide from human brains

NINCDS-ADRDA criteria of “possible,” “probable,” “definite” AD

Tau identified as main component of tangles

CERAD established to standardize diagnostic procedures

Tau is abnormally phosphorylated in AD

APP cloned and sequenced, Aβ42 and 43 fragments identified

In brain, glial cells synthesize ApoE, secrete it in HDL particles

Evidence for activated microglia in AD brain

Tau (MAPT) cloned and sequenced

Aβ peptide toxic to cultured neurons

Alpha cleavage of APP precludes Aβ formation

Cognitive impairment correlates with synaptic damage

APP Dutch mutation causes autosomal-dominant cerebral amyloid angiopathy

Concept of cognitive reserve articulated

First APP transgenic mouse model

Amyloid hypothesis marks conceptual shift from descriptive to mechanistic view

APP London: first mutation found to cause autosomal-dominant AD

NIA launches ADCS, founded on Leon Thal's tacrine trial

Braak staging of AD neuropathology defined

MCI or early AD? Controversy over psychometric norms vs. intra-individual decline

Aβ release into CSF prompts search for fluid biomarker assays

Anti-inflammatory treatment approach articulated

APP Swedish mutation found at BACE cleavage site

Calcium homeostasis implicated

Aβ release is part of normal cell metabolism

Tau filaments reassembled in vitro

First clinical trial of an NSAID: cognitive signal comes with toxicity

AD signature found in CSF: tau increased, Aβ42 decreased

Clinical Dementia Rating developed to stage dementia

ApoE4 major risk factor for late-onset AD; risk up threefold with one allele, 12-fold with two; ApoE2 protective

Family history is a major risk factor of late-onset AD

DSM criteria updated to version IV

Microvasculature in brain is damaged in AD

Colombian PS-1 kindred carrying E280A ‘Paisa’ mutation largest in the world

Mutations in presenilin-1 and presenilin-2 cause autosomal-dominant AD

PDAPP, Tg2576 mice express Indiana, Swedish mutations, respectively, develop plaques

First C. elegans model

Oligomers reported as bioactive Aβ species

Tacrine is the first drug approved for AD

Mutations in APP and presenilins change Aβ42/40 ratio

Serial volumetric MRI techniques measure atrophy in multiple regions over time, starting preclinically

FDG-PET in ApoE carriers and non-carriers reveals AD signature of brain hypometabolism

First APP knockout mouse

Alzforum launched

Donepezil approved

Presenilin involved in processing APP, mutations change Aβ generation

NFκB and calcineurin mediate Aβ-induced astrocyte activation, complement release, and neurotoxicity in AD

CSF Aβ, CSF Aβ/tau ratio predicts decline in cognitively normal elderly and FAD mutation carriers

Toward predicting AD from cognitively normal: SPECT identifies regions of reduced brain perfusion in preclinical phase

Most people accumulate brain Aβ with age, more with AD

Tau mutations cause neurofibrillary pathology, neurodegeneration, FTD, but not AD

Age biggest risk factor: incidence doubles every five years after 65

3-D structure of BACE

First mice expressing FTD tau mutations

Structural studies find hexapeptides by which tau aggregates into paired helical filaments

Midlife hypertension increases risk

Galantamine approved

Neprilysin and other enzymes degrade Aβ in vivo

In AD, both neurons and microglia change expression of immune-related genes

Microdialysis tracks tau in vivo in brain interstitial fluid

CSF markers begin international standardization toward certified clinical diagnostic test

NIA-AA diagnosis criteria for AD dementia, MCI due to AD, and preclinical AD

Risk variants in ABCA7 and MS4A6A

DIAN-TU forms Pharma Consortium

Semagacestat fails in Phase 3

Prospective biomarker studies find 20-year prodrome in autosomal-dominant AD

Induced pluripotent stem cells from AD patients recapitulate aspects of disease

TREM2 mutations found in FTD, AD

Icelandic APP mutation protects against AD

Verubecestat enters Phase 3

First Bayesian adaptive trial, BAN-2401

First DIAN prevention trial in ADAD

Type 2 diabetes increases risk

FDA approves first amyloid tracer, florbetapir

NIA-AA updates consensus criteria, uncoupling AD pathology from dementia symptoms

Masitinib enters Phase 3

PS-1 mutations alter γ-secretase function toward more generation of longer Aβ peptides

Nilvadipine enters Phase 3

Gamunex enters Phase 2/3

Tideglusib fails in Phase 2

Bapineuzumab fails in Phase 3

Ponezumab fails in Phase 2

Avagacestat fails in Phase 2

AVP-923 enters Phase 2 for agitation in AD

Tau PET ligands enter human testing

Neuronal activity stimulates secretion of physiological tau

Cognitive composites developed to track preclinical AD

Incidence of dementia decreases in developed countries

Inflammasome implicated in AD

A4 starts, first secondary prevention trial for LOAD

Meta-analysis of four GWAS ID's 22 susceptibility loci: confirms previous, finds new variants

G8 Holds Dementia Summit

Crenezumab enters Colombian ADAD prevention trial

Prospective biomarker study finds 20-year prodrome in late-onset AD

Push for combination trials begins

Brexpiprazole enters Phase 3

Integrated systems approaches find disruption of genetic node around microglial Trem2

Vanutide cridificar discontinued in Phase 2

Idalopirdine enters Phase 3

FDA issues guidance for therapy development in early AD

Gammagard® fails in Phase 3

BACE inhibitor LY2886721 fails in Phase 2

Global Alzheimer's Platform Foundation launched

Comprehensive meta-analyses of fluid AD biomarkers

TRx0237 fails Phase 3

Approximately 80 therapeutics in Phase 1, 2, or 3 trials

◀2016

NIA-AA diagnosis criteria for AD dementia, MCI due to AD, and preclinical AD
[Copyright 2011 Elsevier Inc.]
Graphic of proposed staging framework for preclinical AD. Some people will not progress beyond Stage 1 or 2. People in Stage 3 are postulated to be more likely to progress to MCI and AD dementia. (From Sperling et al., 2011.)
Primary Papers
- Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):280-92. Epub 2011 Apr 21 PubMed.
- McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):263-9. PubMed.
- Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):270-9. Epub 2011 Apr 21 PubMed.
Primary Links
- Two New Sets of Diagnostic Criteria—Which Is Right for Your Clinic?
DIAN-TU forms Pharma Consortium
Further Reading
News
- DIAN Forms Pharma Consortium, Submits Treatment Trial Grant
Microdialysis tracks tau in vivo in brain interstitial fluid
[Copyright 2011 Society of Neuroscience.]
Proposed diagram of tau release in the presence or absence of tau aggregates. (A) Neurons release tau under normal conditions. (B) Once tau aggregates form inside (1) or potentially outside (2) of cells, they can sequester intracellular and extracellular soluble tau and lower the level of monomeric tau in the extracellular space. (From Yamada et al., 2011.)
Primary Papers
- Yamada K, Cirrito JR, Stewart FR, Jiang H, Finn MB, Holmes BB, Binder LI, Mandelkow EM, Diamond MI, Lee VM, Holtzman DM. In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci. 2011 Sep 14;31(37):13110-7. PubMed.
Further Reading
News
- Brain Microdialysis Reveals Tau, Synuclein Outside of Cells
CSF markers begin international standardization toward certified clinical diagnostic test
[Copyright 2011 Elsevier Inc.]
Results for enzyme-linked immunosorbent assay (A–C), xMAP (D–F), and Meso Scale Discovery (G–I) of global biomarker standardization program show large variance in rounds 1 (1A and 1B) and 2 (2A and 2B). Panels B, C, E, and F have secondary y-axes owing to large differences between samples. Different symbols indicate different kit batches for ELISA and xMAP, and different assays for Meso Scale Discovery (6E10, blue triangle; 4G8, red square). (From Mattsson et al., 2011.)
Primary Papers
- Mattsson N, Andreasson U, Persson S, Arai H, Batish SD, Bernardini S, Bocchio-Chiavetto L, Blankenstein MA, Carrillo MC, Chalbot S, Coart E, Chiasserini D, Cutler N, Dahlfors G, Duller S, Fagan AM, Forlenza O, Frisoni GB, Galasko D, Galimberti D, Hampel H, Handberg A, Heneka MT, Herskovits AZ, Herukka SK, Holtzman DM, Humpel C, Hyman BT, Iqbal K, Jucker M, Kaeser SA, Kaiser E, Kapaki E, Kidd D, Klivenyi P, Knudsen CS, Kummer MP, Lui J, Lladó A, Lewczuk P, Li QX, Martins R, Masters C, McAuliffe J, Mercken M, Moghekar A, Molinuevo JL, Montine TJ, Nowatzke W, O'Brien R, Otto M, Paraskevas GP, Parnetti L, Petersen RC, Prvulovic D, de Reus HP, Rissman RA, Scarpini E, Stefani A, Soininen H, Schröder J, Shaw LM, Skinningsrud A, Skrogstad B, Spreer A, Talib L, Teunissen C, Trojanowski JQ, Tumani H, Umek RM, Van Broeck B, Vanderstichele H, Vecsei L, Verbeek MM, Windisch M, Zhang J, Zetterberg H, Blennow K. The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers. Alzheimers Dement. 2011 Jul;7(4):386-395.e6. PubMed.
- Leinenbach A, Pannee J, Dülffer T, Huber A, Bittner T, Andreasson U, Gobom J, Zetterberg H, Kobold U, Portelius E, Blennow K, IFCC Scientific Division Working Group on CSF proteins. Mass spectrometry-based candidate reference measurement procedure for quantification of amyloid-β in cerebrospinal fluid. Clin Chem. 2014 Jul;60(7):987-94. Epub 2014 May 19 PubMed.
Further Reading
News
- Not Sexy but Oh-So-Important: Committee Blesses Way to Measure CSF Aβ
- More Accurate Ways to Measure CSF Aβ Debut
Risk variants in ABCA7 and MS4A6A
[Copyright 2011 Macmillan Publishers Ltd.]
GERAD+ study design. (From Hollingworth et al., 2011.)
[Copyright 2011 Macmillan Publishers Ltd.]
Results of the GERAD+ study. Odds ratios for the reported SNPs on the right. (From Hollingworth et al., 2011.)
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Primary Papers
- Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, Abraham R, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Jones N, Stretton A, Thomas C, Richards A, Ivanov D, Widdowson C, Chapman J, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Beaumont H, Warden D, Wilcock G, Love S, Kehoe PG, Hooper NM, Vardy ER, Hardy J, Mead S, Fox NC, Rossor M, Collinge J, Maier W, Jessen F, Rüther E, Schürmann B, Heun R, Kölsch H, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Gallacher J, Hüll M, Rujescu D, Giegling I, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Pankratz VS, Sando SB, Aasly JO, Barcikowska M, Wszolek ZK, Dickson DW, Graff-Radford NR, Petersen RC, , van Duijn CM, Breteler MM, Ikram MA, DeStefano AL, Fitzpatrick AL, Lopez O, Launer LJ, Seshadri S, Berr C, Campion D, Epelbaum J, Dartigues JF, Tzourio C, Alpérovitch A, Lathrop M, Feulner TM, Friedrich P, Riehle C, Krawczak M, Schreiber S, Mayhaus M, Nicolhaus S, Wagenpfeil S, Steinberg S, Stefansson H, Stefansson K, Snædal J, Björnsson S, Jonsson PV, Chouraki V, Genier-Boley B, Hiltunen M, Soininen H, Combarros O, Zelenika D, Delepine M, Bullido MJ, Pasquier F, Mateo I, Frank-Garcia A, Porcellini E, Hanon O, Coto E, Alvarez V, Bosco P, Siciliano G, Mancuso M, Panza F, Solfrizzi V, Nacmias B, Sorbi S, Bossù P, Piccardi P, Arosio B, Annoni G, Seripa D, Pilotto A, Scarpini E, Galimberti D, Brice A, Hannequin D, Licastro F, Jones L, Holmans PA, Jonsson T, Riemenschneider M, Morgan K, Younkin SG, Owen MJ, O'Donovan M, Amouyel P, Williams J. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet. 2011 May;43(5):429-35. PubMed.
Further Reading
News
- Large Genetic Analysis Pays Off With New AD Risk Genes
Semagacestat fails in Phase 3
Primary Links
- Semagacestat