TY - JOUR
T1 - Preclinical Alzheimer's disease and its outcome
T2 - A longitudinal cohort study
AU - Vos, Stephanie J.B.
AU - Xiong, Chengjie
AU - Visser, Pieter Jelle
AU - Jasielec, Mateusz S.
AU - Hassenstab, Jason
AU - Grant, Elizabeth A.
AU - Cairns, Nigel J.
AU - Morris, John C.
AU - Holtzman, David M.
AU - Fagan, Anne M.
N1 - Funding Information:
SJBV receives research support from the Center for Translational Molecular Medicine, project LeARN (grant 02N-01 ) and the EU/EFPIA Innovative Medicines Initiative Joint Undertaking, and received funds from Internationale Stichting Alzheimer Onderzoek to undertake this study. PJV has served as an advisory board member of Bristol-Myers Squibb and has received research grants from Bristol-Myers Squibb, the European Union's Sixth and Seventh Framework Programme, Life Sciences, Genomics, and Biotechnology for Health and Innovative Medicines Initiative Joint Undertaking (grant agreement number 115372 ), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme and European Federation of Pharmaceutical Industries and Associations companies, Diagenic Norway, and Innogenetics Belgium. JCM has participated or is participating in clinical trials of anti-dementia drugs sponsored by Janssen Immunotherapy and Pfizer; has served as a consultant for Eisai, Esteve, Janssen Alzheimer Immunotherapy Program, GlaxoSmithKline, Novartis, and Pfizer; receives research support from Eli Lilly/Avid Radiopharmaceuticals; and is funded by National Institutes of Health (NIH) grants P50-AG005681, P01-AG003991, P01-AG026276, and U19-AG032438 . DMH reports consulting for Bristol-Myers Squibb, AstraZeneca, and Genentech; is on the scientific advisory board of C2N Diagnostics; and receives research grant support from the NIH, Ellison Medical Foundation, Cure Alzheimer's Fund, Pfizer, AstraZeneca, C2N Diagnostics, and Integrated Diagnostics. AMF serves as an advisory board member for Roche and Eli Lilly. CX, MSJ, JH, EAG, and NJC declare that they have no conflicts of interest.
PY - 2013/10
Y1 - 2013/10
N2 - 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. Findings: 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). Interpretation: 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. Funding: 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.
AB - 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. Findings: 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). Interpretation: 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. Funding: 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.
UR - http://www.scopus.com/inward/record.url?scp=84884127276&partnerID=8YFLogxK
U2 - 10.1016/S1474-4422(13)70194-7
DO - 10.1016/S1474-4422(13)70194-7
M3 - Article
C2 - 24012374
AN - SCOPUS:84884127276
SN - 1474-4422
VL - 12
SP - 957
EP - 965
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 10
ER -