Elsevier

The Lancet Neurology

Volume 12, Issue 10, October 2013, Pages 957-965
The Lancet Neurology

Articles
Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study

https://doi.org/10.1016/S1474-4422(13)70194-7Get rights and content

Summary

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.

Introduction

Alzheimer's disease (AD) starts with a preclinical phase in which AD neuropathological abnormalities begin to accumulate but cognitive ability is normal.1, 2, 3 Now that biomarkers for AD have become available, identification of preclinical AD in vivo in cognitively normal individuals is possible.4 Information regarding the occurrence and outcome of preclinical AD is crucial for the understanding of AD pathophysiology and the design of secondary prevention trials.

Research criteria for preclinical AD have been proposed by the Preclinical Working Group of the National Institute on Aging (NIA) and Alzheimer's Association (AA).5 The NIA-AA criteria for preclinical AD propose ordered stages for cognitively normal individuals with abnormal amyloid markers (stage 1), abnormal amyloid and neuronal injury markers (stage 2), and abnormal amyloid and neuronal injury markers and subtle cognitive changes (stage 3).5 In a 2012 study in which structural and amyloid imaging markers were used to categorise individuals according to these stages,6 the rate of short-term (1 year) progression to mild cognitive impairment (MCI) or dementia increased with advancing preclinical AD stage.

The aim of this study was to identify the prevalence and long-term outcome of preclinical AD according to these criteria in a cohort of cognitively normal individuals. We used CSF markers to define NIA-AA preclinical AD stages and assessed the long-term cognitive and mortality outcomes of participants in each stage. We also tested whether the proportion and cognitive outcome of preclinical AD were affected by age or APOE genotype.

Section snippets

Participants

Participants were cognitively normal community-dwelling volunteers enrolled between June, 1998, and September, 2011, in longitudinal studies of memory and ageing at the Knight Alzheimer's Disease Research Center (KADRC) of the Washington University School of Medicine (St Louis, MO, USA). Details of recruitment and assessment methods for these participants have been published.7 Participants in the KADRC cohort were living independently in the community at study entry and underwent annual

Results

Table 1 lists demographics and baseline characteristics. 129 of 311 (41%) participants were classified in the normal group, 47 (15%) as stage 1, 36 (12%) as stage 2, 13 (4%) as stage 3, 72 (23%) as being in the SNAP group, and 14 (5%) remained unclassified. The appendix shows the distribution of participants across the stages. MMSE and memory scores were lower in stage 3 than in the other groups (table 1). Preclinical AD (stage 1–3) was more prevalent in individuals older than 72 years (median

Discussion

In this study, we show that preclinical AD can be defined by CSF markers, is common in individuals aged at least 65 years, and is associated with an increased risk of cognitive decline, progression to CDR at least 0·5, symptomatic AD, and mortality (panel 2).

31% of participants in our cohort had preclinical AD (stages 1–3), which is consistent with findings from clinicopathological studies1, 2, 3 and the population-based Mayo Clinic Study of Aging (MCSA), which used imaging measures (appendix).

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