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

Abstract

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.

Conflict of interest statement

Conflicts of interest: Only two authors report possible conflicts of interest. Dr. Boxer delares grants from NIH / NIA, grants from Tau Research Consortium, grants from Corticobasal Degeneration Solutions, grants, personal fees and non-financial support from Archer Biosciences, grants from Allon Therapeutics, personal fees from Acetylon, personal fees from Ipierian, grants from Genentech, grants from Bristol Myers Squibb, grants from TauRx, grants from Alzheimer’s Association, grants from Bluefield Project to Cure FTD, grants from Association for Frontotemporal Degeneration, grants from Alzheimer’s Drug Discovery Foundation, grants from EnVivo, grants from C2N Diagnostics, grants from Pfizer, grants from Eli Lilly, outside the submitted work. Dr. Goetzl has filed a provisional application with the U.S. Patent Office for the platform and methodologies described in this report.

Copyright © 2015 The Alzheimer's Association. All rights reserved.

Figures

Fig. 1

Levels of proteins in blood exosomes of patients with AD, FTD and cognitively normal matched case-controls (AC, FTC). The horizontal line in each cluster here and in Fig. 2 depicts the mean for that set.

Fig. 2

Sequential levels of proteins in blood exosomes of patients with AD measured first at a time of normal cognition (preclinical, AP) and later at the time of development of aMCI or dementia (AD).