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Original Investigation
July 15, 2019

Association of Extracellular Vesicle Biomarkers With Alzheimer Disease in the Baltimore Longitudinal Study of Aging

Author Affiliations
  • 1Laboratory of Clinical Investigations, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
  • 2Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
  • 3Laboratory of Behavioral Neuroscience, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
  • 4Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 5Department of Medicine, University of California, San Francisco
  • 6Jewish Home of San Francisco, San Francisco, California
JAMA Neurol. Published online July 15, 2019. doi:10.1001/jamaneurol.2019.2462
Key Points

Question  Can blood extracellular vesicle biomarkers diagnose Alzheimer disease at the preclinical and clinical stages?

Findings  In a large case-control study examining 887 longitudinal samples from 128 Baltimore Longitudinal Study of Aging participants (split into training and test sets), combining extracellular vesicle biomarkers predicted Alzheimer disease with high discrimination accuracy and specificity about 4 years before symptom onset; individual biomarkers were associated with cognitive performance. Biomarkers were further validated in a case-control cohort from Johns Hopkins.

Meaning  Further development of extracellular vesicle biomarkers may establish them as a blood test for Alzheimer disease.

Abstract

Importance  Blood biomarkers able to diagnose Alzheimer disease (AD) at the preclinical stage would enable trial enrollment when the disease is potentially reversible. Plasma neuronal-enriched extracellular vesicles (nEVs) of patients with AD were reported to exhibit elevated levels of phosphorylated (p) tau, Aβ42, and phosphorylated insulin receptor substrate 1 (IRS-1).

Objective  To validate nEV biomarkers as AD predictors.

Design, Setting, Participants  This case-control study included longitudinal plasma samples from cognitively normal participants in the Baltimore Longitudinal Study of Aging (BLSA) cohort who developed AD up to January 2015 and age- and sex-matched controls who remained cognitively normal over a similar length of follow-up. Repeated samples were blindly analyzed over 1 year from participants with clinical AD and controls from the Johns Hopkins Alzheimer Disease Research Center (JHADRC). Data were collected from September 2016 to January 2018. Analyses were conducted in March 2019.

Main Outcomes and Measures  Neuronal-enriched extracellular vesicles were immunoprecipitated; tau, Aβ42, and IRS-1 biomarkers were quantified by immunoassays; and nEV concentration and diameter were determined by nanoparticle tracking analysis. Levels and longitudinal trajectories of nEV biomarkers between participants with future AD and control participants were compared.

Results  Overall, 887 longitudinal plasma samples from 128 BLSA participants who eventually developed AD and 222 age and sex-matched controls who remained cognitively normal were analyzed. Participants were followed up (from earliest sample to AD symptom onset) for a mean (SD) of 3.5 (2.31) years (range, 0-9.73 years). Overall, 161 participants were included in the training set, and 80 were in the test set. Participants in the BLSA cohort with future AD (mean [SD] age, 79.09 [7.02] years; 68 women [53.13%]) had longitudinally higher p-tau181, p-tau231, pSer312-IRS-1, pY-IRS-1, and nEV diameter than controls (mean [SD] age, 76.2 [7.36] years; 110 women [50.45%]) but had similar Aβ42, total tau, TSG101, and nEV concentration. In the training BLSA set, a model combining preclinical longitudinal data achieved 89.6% area under curve (AUC), 81.8% sensitivity, and 85.8% specificity for predicting AD. The model was validated in the test BLSA set (80% AUC, 55.6% sensitivity, 88.7% specificity). Preclinical levels of nEV biomarkers were associated with cognitive performance. In addition, 128 repeated samples over 1 year from 64 JHADRC participants with clinical AD and controls were analyzed. In the JHADRC cohort (35 participants with AD: mean [SD] age, 74.03 [8.73] years; 18 women [51.43%] and 29 controls: mean [SD] age, 72.14 [7.86] years; 23 women [79.31%]), nEV biomarkers achieved discrimination with 98.9% AUC, 100% sensitivity, and 94.7% specificity in the training set and 76.7% AUC, 91.7% sensitivity, and 60% specificity in the test set.

Conclusions and Relevance  We validated nEV biomarker candidates and further demonstrated that their preclinical longitudinal trajectories can predict AD diagnosis. These findings motivate further development of nEV biomarkers toward a clinical blood test for AD.

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