Identification of preclinical Alzheimer's disease by a profile of pathogenic proteins in neurally derived blood exosomes: A case-control study

Alzheimers Dement. 2015 Jun;11(6):600-7.e1. doi: 10.1016/j.jalz.2014.06.008. Epub 2014 Aug 15.


Background: Proteins pathogenic in Alzheimer's disease (AD) were extracted from neurally derived blood exosomes and quantified to develop biomarkers for the staging of sporadic AD.

Methods: Blood exosomes obtained at one time-point from patients with AD (n = 57) or frontotemporal dementia (FTD) (n = 16), and at two time-points from others (n = 24) when cognitively normal and 1 to 10 years later when diagnosed with AD were enriched for neural sources by immunoabsorption. AD-pathogenic exosomal proteins were extracted and quantified by enzyme-linked immunosorbent assays.

Results: Mean exosomal levels of total tau, P-T181-tau, P-S396-tau, and amyloid β 1-42 (Aβ1-42) for AD and levels of P-T181-tau and Aβ1-42 for FTD were significantly higher than for case-controls. Step-wise discriminant modeling incorporated P-T181-tau, P-S396-tau, and Aβ1-42 in AD, but only P-T181-tau in FTD. Classification of 96.4% of AD patients and 87.5% of FTD patients was correct. In 24 AD patients, exosomal levels of P-S396-tau, P-T181-tau, and Aβ1-42 were significantly higher than for controls both 1 to 10 years before and when diagnosed with AD.

Conclusions: Levels of P-S396-tau, P-T181-tau, and Aβ1-42 in extracts of neurally derived blood exosomes predict the development of AD up to 10 years before clinical onset.

Keywords: Aβ1–42; Biomarkers; Neural exosomes; P-Tau; Preclinical AD.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / blood*
  • Alzheimer Disease / classification
  • Amyloid beta-Peptides / blood*
  • Biomarkers / blood
  • Case-Control Studies
  • Cross-Sectional Studies
  • Discriminant Analysis
  • Enzyme-Linked Immunosorbent Assay
  • Exosomes / metabolism*
  • Female
  • Frontotemporal Dementia / blood*
  • Frontotemporal Dementia / classification
  • Humans
  • Male
  • Middle Aged
  • Peptide Fragments / blood*
  • Phosphorylation
  • Prodromal Symptoms
  • Retrospective Studies
  • Severity of Illness Index
  • Time Factors
  • tau Proteins / blood*


  • Amyloid beta-Peptides
  • Biomarkers
  • MAPT protein, human
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • tau Proteins