title: 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.
authors.affiliation: Departments of Neurology and Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Massimo S
authors.initials: MS
authors.lastname: Fiandaca
authors.affiliation: Clinical Research Branch, Intramural Research Program, National Institute on Aging, Baltimore, MD, USA.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Kapogiannis
authors.affiliation: Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Mapstone
authors.affiliation: Department of Neurology, Memory and Aging Center, UCSF Medical Center, San Francisco, CA, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Boxer
authors.affiliation: Clinical Research Branch, Intramural Research Program, National Institute on Aging, Baltimore, MD, USA.
authors.forename: Erez
authors.initials: E
authors.lastname: Eitan
authors.affiliation: Department of Medicine, UCSF Medical Center and the Jewish Home of San Francisco, San Francisco, CA, USA.
authors.forename: Janice B
authors.initials: JB
authors.lastname: Schwartz
authors.affiliation: Department of Neurology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Abner
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Departments of Neurology and Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Federoff
authors.affiliation: Department of Neurology, Memory and Aging Center, UCSF Medical Center, San Francisco, CA, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Department of Medicine, UCSF Medical Center and the Jewish Home of San Francisco, San Francisco, CA, USA. Electronic address: edward.goetzl@ucsf.edu.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Goetzl
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood* / Q000145:classification; D016229:Amyloid beta-Peptides / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D016002:Discriminant Analysis; D004797:Enzyme-Linked Immunosorbent Assay; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D057180:Frontotemporal Dementia / Q000097:blood* / Q000145:classification; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood*; D010766:Phosphorylation; D062706:Prodromal Symptoms; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013997:Time Factors; D016875:tau Proteins / Q000097:blood*
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; C054369:MAPT protein, human; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
keywords: Aβ1–42; Biomarkers; Neural exosomes; P-Tau; Preclinical AD