title: Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease.
abstract: OBJECTIVE
  Diverse autolysosomal proteins were quantified in neurally derived blood exosomes from patients with Alzheimer disease (AD) and controls to investigate disordered neuronal autophagy.
  
  
  METHODS
  Blood exosomes obtained once from patients with AD (n = 26) or frontotemporal dementia (n = 16), other patients with AD (n = 20) both when cognitively normal and 1 to 10 years later when diagnosed, and case controls were enriched for neural sources by anti-human L1CAM antibody immunoabsorption. Extracted exosomal proteins were quantified by ELISAs and normalized with the CD81 exosomal marker.
  
  
  RESULTS
  Mean exosomal levels of cathepsin D, lysosome-associated membrane protein 1 (LAMP-1), and ubiquitinylated proteins were significantly higher and of heat-shock protein 70 significantly lower for AD than controls in cross-sectional studies (p ≤ 0.0005). Levels of cathepsin D, LAMP-1, and ubiquitinylated protein also were significantly higher for patients with AD than for patients with frontotemporal dementia (p ≤ 0.006). Step-wise discriminant modeling of the protein levels correctly classified 100% of patients with AD. Exosomal levels of all proteins were similarly significantly different from those of matched controls in 20 patients 1 to 10 years before and at diagnosis of AD (p ≤ 0.0003).
  
  
  CONCLUSIONS
  Levels of autolysosomal proteins in neurally derived blood exosomes distinguish patients with AD from case controls and appear to reflect the pathology of AD up to 10 years before clinical onset. These preliminary results confirm in living patients with AD the early appearance of neuronal lysosomal dysfunction and suggest that these proteins may be useful biomarkers in large prospective studies.
authors.affiliation: From the Department of Medicine (E.J.G.), UCSF Medical Center and the Jewish Home of San Francisco; Memory and Aging Center (A.B., B.L.M.), Department of Neurology, UCSF Medical Center, San Francisco; Departments of Medicine and Bioengineering (J.B.S.), UCSF and the Jewish Home of San Francisco, CA; Sanders-Brown Center on Aging (E.L.A.), University of Kentucky, Lexington; Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN; and Intramural Research Program (D.K.), National Institute on Aging, Baltimore, MD. edward.goetzl@ucsf.edu.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Goetzl
authors.affiliation: From the Department of Medicine (E.J.G.), UCSF Medical Center and the Jewish Home of San Francisco; Memory and Aging Center (A.B., B.L.M.), Department of Neurology, UCSF Medical Center, San Francisco; Departments of Medicine and Bioengineering (J.B.S.), UCSF and the Jewish Home of San Francisco, CA; Sanders-Brown Center on Aging (E.L.A.), University of Kentucky, Lexington; Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN; and Intramural Research Program (D.K.), National Institute on Aging, Baltimore, MD.
authors.forename: Adam
authors.initials: A
authors.lastname: Boxer
authors.affiliation: From the Department of Medicine (E.J.G.), UCSF Medical Center and the Jewish Home of San Francisco; Memory and Aging Center (A.B., B.L.M.), Department of Neurology, UCSF Medical Center, San Francisco; Departments of Medicine and Bioengineering (J.B.S.), UCSF and the Jewish Home of San Francisco, CA; Sanders-Brown Center on Aging (E.L.A.), University of Kentucky, Lexington; Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN; and Intramural Research Program (D.K.), National Institute on Aging, Baltimore, MD.
authors.forename: Janice B
authors.initials: JB
authors.lastname: Schwartz
authors.affiliation: From the Department of Medicine (E.J.G.), UCSF Medical Center and the Jewish Home of San Francisco; Memory and Aging Center (A.B., B.L.M.), Department of Neurology, UCSF Medical Center, San Francisco; Departments of Medicine and Bioengineering (J.B.S.), UCSF and the Jewish Home of San Francisco, CA; Sanders-Brown Center on Aging (E.L.A.), University of Kentucky, Lexington; Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN; and Intramural Research Program (D.K.), National Institute on Aging, Baltimore, MD.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Abner
authors.affiliation: From the Department of Medicine (E.J.G.), UCSF Medical Center and the Jewish Home of San Francisco; Memory and Aging Center (A.B., B.L.M.), Department of Neurology, UCSF Medical Center, San Francisco; Departments of Medicine and Bioengineering (J.B.S.), UCSF and the Jewish Home of San Francisco, CA; Sanders-Brown Center on Aging (E.L.A.), University of Kentucky, Lexington; Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN; and Intramural Research Program (D.K.), National Institute on Aging, Baltimore, MD.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: From the Department of Medicine (E.J.G.), UCSF Medical Center and the Jewish Home of San Francisco; Memory and Aging Center (A.B., B.L.M.), Department of Neurology, UCSF Medical Center, San Francisco; Departments of Medicine and Bioengineering (J.B.S.), UCSF and the Jewish Home of San Francisco, CA; Sanders-Brown Center on Aging (E.L.A.), University of Kentucky, Lexington; Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN; and Intramural Research Program (D.K.), National Institute on Aging, Baltimore, MD.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: From the Department of Medicine (E.J.G.), UCSF Medical Center and the Jewish Home of San Francisco; Memory and Aging Center (A.B., B.L.M.), Department of Neurology, UCSF Medical Center, San Francisco; Departments of Medicine and Bioengineering (J.B.S.), UCSF and the Jewish Home of San Francisco, CA; Sanders-Brown Center on Aging (E.L.A.), University of Kentucky, Lexington; Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN; and Intramural Research Program (D.K.), National Institute on Aging, Baltimore, MD.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Kapogiannis
mesh_terms: D000544:Alzheimer Disease / Q000097:blood* / Q000175:diagnosis*; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002402:Cathepsin D / Q000097:blood; D003430:Cross-Sectional Studies; D042241:Early Diagnosis; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D057180:Frontotemporal Dementia / Q000097:blood / Q000175:diagnosis; D006801:Humans; D008137:Longitudinal Studies; D051907:Lysosomal Membrane Proteins / Q000097:blood; D008297:Male; D009474:Neurons / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D012189:Retrospective Studies; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D015415:Biomarkers; D002402:Cathepsin D; D051907:Lysosomal Membrane Proteins; D011506:Proteins; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C018589:lysosomal proteins; C533922:CTSD protein, human