title: Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study.
abstract: BACKGROUND
  New research criteria for preclinical Alzheimer's disease have been proposed, which include stages for cognitively normal individuals with abnormal amyloid markers (stage 1), abnormal amyloid and neuronal injury markers (stage 2), or abnormal amyloid and neuronal injury markers and subtle cognitive changes (stage 3). We aimed to investigate the prevalence and long-term outcome of preclinical Alzheimer's disease according to these criteria.
  
  
  METHODS
  Participants were cognitively normal (clinical dementia rating [CDR]=0) community-dwelling volunteers aged at least 65 years who were enrolled between 1998 and 2011 at the Washington University School of Medicine (MO, USA). CSF amyloid-β1-42 and tau concentrations and a memory composite score were used to classify participants as normal (both markers normal), preclinical Alzheimer's disease stage 1-3, or suspected non-Alzheimer pathophysiology (SNAP, abnormal injury marker without abnormal amyloid marker). The primary outcome was the proportion of participants in each preclinical AD stage. Secondary outcomes included progression to CDR at least 0·5, symptomatic Alzheimer's disease (score of at least 0·5 for memory and at least one other domain and cognitive impairments deemed to be due to Alzheimer's disease), and mortality. We undertook survival analyses using subdistribution and standard Cox hazards models and linear mixed models.
  
  
  RESULTS
  Of 311 participants, 129 (41%) were classed as normal, 47 (15%) as stage 1, 36 (12%) as stage 2, 13 (4%) as stage 3, 72 (23%) as SNAP, and 14 (5%) remained unclassified. The 5-year progression rate to CDR at least 0·5, symptomatic Alzheimer's disease was 2% for participants classed as normal, 11% for stage 1, 26% for stage 2, 56% for stage 3, and 5% for SNAP. Compared with individuals classed as normal, participants with preclinical Alzheimer's disease had an increased risk of death after adjusting for covariates (hazard ratio 6·2, 95% CI 1·1-35·0; p=0·040).
  
  
  CONCLUSIONS
  Preclinical Alzheimer's disease is common in cognitively normal elderly people and is associated with future cognitive decline and mortality. Thus, preclinical Alzheimer's disease could be an important target for therapeutic intervention.
  
  
  BACKGROUND
  National Institute of Aging of the National Institutes of Health (P01-AG003991, P50-AG05681, P01-AG02676), Internationale Stichting Alzheimer Onderzoek, the Center for Translational Molecular Medicine project LeARN, the EU/EFPIA Innovative Medicines Initiative Joint Undertaking, and the Charles and Joanne Knight Alzheimer Research Initiative.
authors.affiliation: Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, Netherlands. Electronic address: s.vos@maastrichtuniversity.nl.
authors.forename: Stephanie Jb
authors.initials: SJ
authors.lastname: Vos
authors.forename: Chengjie
authors.initials: C
authors.lastname: Xiong
authors.forename: Pieter Jelle
authors.initials: PJ
authors.lastname: Visser
authors.forename: Mateusz S
authors.initials: MS
authors.lastname: Jasielec
authors.forename: Jason
authors.initials: J
authors.lastname: Hassenstab
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Grant
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology* / Q000401:mortality / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D001057:Apolipoproteins E / Q000235:genetics; D001921:Brain / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D061212:Memory, Episodic; D008875:Middle Aged; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D015995:Prevalence; D062706:Prodromal Symptoms; D011569:Psychiatric Status Rating Scales; D012720:Severity of Illness Index; D016019:Survival Analysis; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins