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Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study
Open accessAbstract
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.
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“Attempts to quantify the duration of AD should be age-specific, because age imposes the greatest risk for both dementia and mortality, and take into account APOE genotype, sex, and cerebrospinal fluid (CSF) tau levels [4, 6, 10-12].”
From Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype (2019) · cites this paper as [12]
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“Initial studies in this emerging area have identified subgroups of older adults with subtle cognitive decline that do not conform to expected patterns and investigators have designated them as Suspected Non-Alzheimer Pathology (SNAP) and Unclassified groups [51, 52].”
From Neuropsychological Criteria for Mild Cognitive Impairment Improves Diagnostic Precision, Biomarker Associations, and Progression Rates (2014) · cites this paper as [52]
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“The rate of cognitive decline is significantly greater for cognitively impaired and CU individuals who have abnormalities in both an amyloid biomarker and a second biomarker type (which could be CSF T-tau or P-tau, atrophy, or hypometabolism) in comparison to individuals who have neither or only one of these biomarker abnormalities [30–35,39,40,42–45].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [32]
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“However, the combination of an abnormal MRI, CSF T-tau, or FDG PET study with an abnormal amyloid biomarker provides much more powerful prediction of future cognitive decline [30–35,39,40,42–45] than an abnormal amyloid study alone.”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [32]
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“longitudinal studies have demonstrated that soluble p-tau and t-tau are increased already in preclinical disease (e.g., no cognitive impairment but evidence of AD pathology).5,6”
From Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease (2022) · cites this paper as [5]
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“(3) By contrast, the additional presence of a biomarker of tau pathology is associated with a more rapid progression to clinical AD (Vos et al, 2013 Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study).”
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Metadata
- Authors
- Vos, S. J., Xiong, C., Visser, P. J., Jasielec, M. S., Hassenstab, J., Grant, E. A., Cairns, N. J., Morris, J. C., Holtzman, D. M., & Fagan, A. M.
- Affiliations
- Maastricht University (NL)
- Washington University in St. Louis (US)
- Corresponding author
- Vos, Stephanie JB
- Fagan, Anne M
- ORCID
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 12
- Issue
- 10
- Pages
- 957-965
- ISSN
- 1474-4422 (ISSN-L)
- PMC
- PMC3904678
- OpenAlex
- W2096063777
- Cited by
- 564
- References
- 45
- Citations by year
- 2026: 20 · 2025: 37 · 2024: 30 · 2023: 17 · 2022: 40 · 2021: 39 · 2020: 45 · 2019: 54 · 2018: 63 · 2017: 54 · 2016: 53 · 2015: 52 · 2014: 52 · 2013: 7
- FWCI
- 38.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Neurology (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- PubMed Central (acceptedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Mayo Clinic
- Center for Translational Molecular Medicine
- National Institute on Aging (P 50 AG05681, P50AG005681, P01AG003991, U19AG032438, P01-AG02676, P01AG026276)
- National Institute of Diabetes and Digestive and Kidney Diseases (K23DK094982)
- National Institute of Neurological Disorders and Stroke (P30NS057105)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Oncology › Cancer-related cognitive impairment studies
- Keywords
- preclinical Alzheimer's disease, amyloid-beta 42, tau protein, cerebrospinal fluid biomarkers, cognitive decline, conversion to dementia, mortality, prevalence, cognitively normal elderly, Alzheimer's disease staging, community-dwelling older adults
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Brain, Female, Humans, Longitudinal Studies, Male, Middle Aged, Neuropsychological Tests, Peptide Fragments, Psychiatric Status Rating Scales, Severity of Illness Index, Prevalence, Survival Analysis, Amyloid beta-Peptides, tau Proteins, Disease Progression, Memory, Episodic, Prodromal Symptoms
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