Abstract
BACKGROUND: Preclinical prediction of Alzheimer disease (AD) is important and critical to effective intervention. Plasma levels of amyloid-β (Aβ) peptides have been a principal focus of the growing literature on blood-based biomarkers, but studies to date have varied in design, assay methods, and sample size, making it difficult to readily interpret the overall data. OBJECTIVE: To conduct a systematic review and meta-analysis of relevant prospective studies to determine whether plasma amyloid-β levels may predict development of dementia, AD, and cognitive decline. DESIGN: We searched prospective studies published between 1995 and 2011 indexed in the MEDLINE, EMBASE, and PsycINFO databases. Selected studies included those measuring at least 1 relevant plasma amyloid-β species (Aβ(40), Aβ(42), or Aβ(42):Aβ(40) ratio) and reporting an effect estimate for dementia, AD, or cognitive change. MAIN OUTCOME MEASURES: Using a standardized extraction form, appropriate study parameters on subject information, exposure, and outcome were extracted. Random effects models were used to generate summary risk ratios and 95% confidence intervals comparing the bottom vs top quantiles for each plasma measure. RESULTS: Thirteen studies with a total of 10 303 subjects met inclusion criteria for meta-analysis. Lower Aβ(42):Aβ(40) ratios were significantly associated with development of AD (summary risk ratio, 1.60; 95% CI, 1.04-2.46; P = .03) and dementia (risk ratio, 1.67; 95% CI, 1.02-2.75; P = .04). Significant heterogeneity was found for both summary estimates, which could not be explained by participants' age, sex distribution, the study's follow-up time, or year of publication. Plasma levels of Aβ(40) and Aβ(42) alone were not significantly associated with either outcome. CONCLUSIONS: Overall, the literature indicates that plasma Aβ(42):Aβ(40) ratios predict development of AD and dementia. However, significant heterogeneity in the meta-analysis underlines the need for substantial further investigation of plasma amyloid-β levels as a preclinical biomarker.