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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.

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Supplementary Material

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Information & Authors

Information

Published In

Neurology®
Volume 85Number 1July 7, 2015
Pages: 40-47
PubMed: 26062630

Publication History

Received: October 3, 2014
Accepted: January 29, 2015
Published online: June 10, 2015
Published in print: July 7, 2015

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Disclosure

E. Goetzl has filed a provisional application with the US Patent Office for the platform and methodologies described in this report; he was a founder of Nanosomix, but now only receives from them support for purchasing laboratory supplies. A. Boxer declares that outside the submitted studies he has grants from NIH/NIA, grants from Tau Research Consortium, grants from Corticobasal Degeneration Solutions, grants, personal fees, and nonfinancial 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, and grants from Eli Lilly. J. Schwartz and E. Abner report no disclosures relevant to the manuscript. R. Petersen is chair of the Data Monitoring Committee, Pfizer, Inc., and Janssen Alzheimer Immunotherapy, and a consultant for Merck, Inc., Roche, Inc., and Genentech, Inc. B. Miller and D. Kapogiannis report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.

Study Funding

Intramural Research Program of the National Institute on Aging (NIA; D.K.), UK ADC P30, AG028383 (E.L.A.), and an unrestricted grant for method development from NanoSomiX, Inc. (E.J.G.).

Authors

Affiliations & Disclosures

Edward J. Goetzl, MD
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.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
(1) The FASEB J., Associate Editor, 1995-present
Patents:
1.
(1) Use of immunoabsorption to isolate organ-specific exosomes for analyses of proteins.
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
(1) Nanosomix, Inc., occasional uncompensated scientific advice
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
(1) Nanosomix, Inc. provided some support for research supplies only; they did not influence the area or direction of the research and were not in any way involved in preparing this publication.
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
(1) Nanosomix, Inc., minimal stock, 2014 only and before the subject study of this paper was conceived and work was begun.
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Adam Boxer, MD, PhD
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.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
I have received funding for travel from the International Society for CNS Clinical Trials Methodology and the Movement Disorders Society
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
Iperion, Isis, Merck
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
I received research support from Allon, Avid, BMS, C2N, Cortice, Forum, Genentech, Janssen, Pfizer, Eli Lilly and TauRx for conducting clinical trials or biomarker studies.
Research Support, Government Entities:
1.
NIH: U54NS092089 (PI), R01AG031278 (PI), R01AG038791 (PI), U54R01AG032306 (co-I), R01AG022983 (Co-I)
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
The Tau Research Consortium, the Bluefield Project to Cure Frontotemporal Dementia and the Alzheimer's Association.
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Janice B. Schwartz, MD
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.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
Trends in Cardiovascular Medicine,Associate Editor, 2014
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NIA/NIH, R21 AG 041660, 2012-2015 Principal Investigator, Optimizing vitamin D in the elderly.
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
Spouse 1) Cardiokinetics, Inc 2) Catheter Robotics, Inc
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Erin L. Abner, PhD
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.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Alltech Life Sciences
Research Support, Government Entities:
1.
(1) NIA P30 AG028383, Co-investigator, 2006-present (2) NIA R01 AG019241, Co-investigator, 2006-present (3) NIA R01 AG038651, Co-investigator, 2011-present (4) NIH R01 NR014189, Co-investigator, 2013-present (5) NIH R01 HD064993, Co-investigator, 2013-present
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Ronald C. Petersen, MD, PhD
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.
Disclosure
Scientific Advisory Boards:
1.
(1) Pfizer, Inc., Chair, Data Monitoring Committee; (2) Janssen Alzheimer Immunotherapy, Chair, Data Monitoring Committee
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
Mild Cognitive Impairment,Oxford University Press, 2003
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
(1) Roche Incorporated, (2) Merck, (3) Genentech
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
National Institute on Aging: U01-AG006786 (PI) (1986-present) P50-AG016574 (PI) (1990-present) R01-AG011378 (Co-I) U01-AG024904 (Co-I)
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Bruce L. Miller, MD
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.
Disclosure
Scientific Advisory Boards:
1.
(1) Scientific Advisor - Tau Consortium (2) Medical Advisor - The John Douglas French Foundation (3) Director - The Larry Hillblom Foundation (4) SAB Nat'l Institute for Health Research in Dememtia (UK) (5) FasterCures A Center of the Milken Institute (6) Tangled Bank Studios
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
1. Neurocase, Editor 2. Cambridge University Press 3. Guilford Pulbications, Inc.
Patents:
1.
NONE
Publishing Royalties:
1.
Behavioral Neurology of Dementia, Cambridge 2009 Handbook of Neurology, Elsevier 2009 The Human Frontal Lobes, Guilford, 2008
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
1. NIA P50 AG23501 PI, (2004-) 2. NIA P01 AG19724 PI, (2002-) 3. NIA P50 AG16573 PI, (2003-) 4. CMS 1C1CMS331346-01-00 PI, (2013 -)
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Dimitrios Kapogiannis, MD
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.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
(1) Aging Research Reviews, member of editorial Board and Guest Editor, 2013 - now (2) npj Aging and Mechanisms of Disease, member of editorial Board, 2014 - now
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
Intramural Research Program of the National Institute on Aging, National Institutes of Health
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE

Notes

Correspondence to Dr. Goetzl: [email protected]
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

Author Contributions

E.J.G. developed analytical methodology, performed laboratory bench work, analyzed data, wrote and edited manuscript. A.B. evaluated patients, analyzed data, edited manuscript. J.B.S. analyzed data, wrote and edited manuscript. E.L.A. evaluated patients, analyzed data, edited manuscript. R.C.P. evaluated patients, analyzed data, edited manuscript. B.L.M. evaluated patients, analyzed data, edited manuscript. D.K. evaluated patients, analyzed data, performed statistical analyses, edited manuscript.

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