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Abstract

Objective

To determine whether years of education and the ε4 risk allele at APOE influence β-amyloid (Aβ) pathology similarly in asymptomatic individuals with a family history of sporadic Alzheimer disease (AD) and presymptomatic autosomal dominant AD mutation carriers.

Methods

We analyzed cross-sectional data from 106 asymptomatic individuals with a parental history of sporadic AD (PREVENT-AD cohort; age 67.28 ± 4.72 years) and 117 presymptomatic autosomal dominant AD mutation carriers (DIAN cohort; age 35.04 ± 9.43 years). All participants underwent structural MRI and Aβ-PET imaging. In each cohort we investigated the influence of years of education, APOE ε4 status, and their interaction on Aβ-PET.

Results

Asymptomatic individuals with a parental history of sporadic AD showed increased Aβ burden associated with APOE ε4 carriage and lower level of education, but no interaction between these. Presymptomatic mutation carriers of autosomal dominant AD showed no relation between APOE ε4 and Aβ burden, but increasing level of education was associated with reduced Aβ burden. The association between educational attainment and Aβ burden was similar in the 2 cohorts.

Conclusions

While the APOE ε4 allele confers increased tendency toward Aβ accumulation in sporadic AD only, protective environmental factors, like increased education, may promote brain resistance against Aβ pathology in both sporadic and autosomal dominant AD.

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Information & Authors

Information

Published In

Neurology®
Volume 95Number 11September 15, 2020
Pages: e1554-e1564
PubMed: 32759192

Publication History

Received: July 2, 2019
Accepted: March 23, 2020
Published online: August 5, 2020
Published in print: September 15, 2020

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Disclosure

The authors report no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.

Study Funding

This work was supported by 2 Canada Research Chairs (S.V., J.C.S.B.), a Canadian Institutes of Health Research project grant PJT-148963 (S.V.), a Canada Fund for Innovation (S.V.), an Alzheimer's Association Research Grant NIRG-397028 (S.V.), the Lemaire foundation (J.P., S.V.), the J.L. Levesque Foundation (J.P.), a joint Alzheimer Society of Canada and Brain Canada Research grant NIG-17-08 (S.V.), a StoP-AD fellowship (J.G.), a Quebec Bio-Imaging Network scholarship (J.G.), and a joint FRQ-S and Alzheimer Society of Canada scholarship (A.P.B.). PREVENT-AD was funded by a $13.5 million, 7-year public–private partnership using funds provided by McGill University, the Fonds de Recherche du Québec–Santé (FRQ-S), an unrestricted research grant from Pfizer Canada, the Levesque Foundation, the Douglas Hospital Research Centre and Foundation, the Government of Canada, the Canada Fund for Innovation, and Genome Quebec Innovation Center (J.C.S.B., J.P.). Data collection and sharing for this project was also supported by The Dominantly Inherited Alzheimer's Network (DIAN, U19AG032438) funded by the National Institute on Aging (NIA), the German Center for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), partial support by the Research and Development Grants for Dementia from Japan Agency for Medical Research and Development, AMED, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI).

Authors

Affiliations & Disclosures

Julie Gonneaud, PhD
From the Department of Psychiatry (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), McGill University; Douglas Mental Health University Institute (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), StoP-AD Centre, Montreal, Canada; Knight Alzheimer's Disease Research Center (T.L.S.B., J.C.M., R.J.B.); and Washington University School of Medicine (T.L.S.B., J.C.M., R.J.B.), St. Louis, MO.
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.
NONE
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.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Christophe Bedetti, MSc
From the Department of Psychiatry (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), McGill University; Douglas Mental Health University Institute (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), StoP-AD Centre, Montreal, Canada; Knight Alzheimer's Disease Research Center (T.L.S.B., J.C.M., R.J.B.); and Washington University School of Medicine (T.L.S.B., J.C.M., R.J.B.), St. Louis, MO.
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.
NONE
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.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Alexa Pichet Binette, MSc
From the Department of Psychiatry (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), McGill University; Douglas Mental Health University Institute (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), StoP-AD Centre, Montreal, Canada; Knight Alzheimer's Disease Research Center (T.L.S.B., J.C.M., R.J.B.); and Washington University School of Medicine (T.L.S.B., J.C.M., R.J.B.), St. Louis, MO.
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.
NONE
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.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Tammie L.S. Benzinger, MD, PhD
From the Department of Psychiatry (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), McGill University; Douglas Mental Health University Institute (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), StoP-AD Centre, Montreal, Canada; Knight Alzheimer's Disease Research Center (T.L.S.B., J.C.M., R.J.B.); and Washington University School of Medicine (T.L.S.B., J.C.M., R.J.B.), St. Louis, MO.
Disclosure
Scientific Advisory Boards:
1.
(1) Advisory board, Eisai
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
(1) Radiologic Society of North America, travel to grant review (2) Alzheimer's Association International Convention (AAIC) 2017, 2018, 2019, 2020 travel (invited speaker)
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
Unpaid consulting, ADMDx, Siemens, Eli Lilly, Eisai.
Speakers' Bureaus:
1.
Biogen
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
(1) Investigator initiated research grants, Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly). Support for the research projects only, no personal compensation or salary support. (2) Roche - participation as site investigator in clinical trials (3) Biogen - participation as site investigator in clinical trials (4) J&J - participation as site investigator in clinical trials (5) Lilly - participation as site investigator in clinical trials (7) Eisai- participation as site investigator in clinical trials
Research Support, Government Entities:
1.
(1) NIH funded research
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
(1) Barnes-Jewish Hospital Foundation (2) Foundation for the ASNR (3) Hope Center (4) 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
John C. Morris, MD
From the Department of Psychiatry (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), McGill University; Douglas Mental Health University Institute (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), StoP-AD Centre, Montreal, Canada; Knight Alzheimer's Disease Research Center (T.L.S.B., J.C.M., R.J.B.); and Washington University School of Medicine (T.L.S.B., J.C.M., R.J.B.), St. Louis, MO.
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.
NONE
Research Support, Government Entities:
1.
National Institute on Aging grants P50AG005681; P01AG003991; P01AG026276; UF1AG032438
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.
1. Clinical Dementia Rating assessment tool (pharma-sponsored clinical trials of investigational drugs for Alzheimer disease 2. AD8 assessment tool (pharma-sponsored clinical trials of investigational drugs for Alzheimer disease)
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
From the Department of Psychiatry (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), McGill University; Douglas Mental Health University Institute (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), StoP-AD Centre, Montreal, Canada; Knight Alzheimer's Disease Research Center (T.L.S.B., J.C.M., R.J.B.); and Washington University School of Medicine (T.L.S.B., J.C.M., R.J.B.), St. Louis, MO.
Disclosure
Scientific Advisory Boards:
1.
(1) C2N Diagnostics, present (2) World Dementia Council, 2018
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
(1) Salk Institute for Biological Studies - Adler Meeting - travel. (2) Rainwater Foundation - Tau Consortium - travel (3) Alzheimer's Association - travel (4) Roche - travel and honoraria (5) AC Immune - travel and honoraria (6) American Neurological Association - travel (7) Eisai - honoraria
Editorial Boards:
1.
(1) The Journal for the Prevention of Alzheimer Disease, Editorial Board 2014-present
Patents:
1.
(1)Holtzman, DM, Bateman, RJ, Kim, J, inventors; Washington University in St. Louis, assignee. Methods for measuring the metabolism of CNS derived biomolecules in vivo. US Patent Application 12/267,974. June 4, 2009. (2)Bateman, RJ, Holtzman, DM, inventors; The Washington University, assignee. Fluctuations in Amyloid Beta as a Biomarker for Alzheimer’s Disease. US Patent Application PCT/US2008/086529. June 18, 2009. (3) Bateman, RJ, Wildsmith, KR, Dobrowolska, J, Munsell, L,Mawuenyega, K, inventors; The Washington University, assignee. Methods for simultaneously measuring the in vivo metabolism of two or more isoforms of a biomolecule. US Patent Application PCT/US2009/064146. May 20, 2010. US Patent Application 13/129,036. December 1, 2011. (4) Bateman, RJ, Holtzman, DM, inventors; The Washington University, assignee. Methods for Measuring the Metabolism of Neurally Derived Biomolecules in Vivo. US Patent 7,892,845. October 2, 2008. US Patent 8,232,107. July 31, 2012 US Patent Application 14/224,993. July 17, 2014. (5) Bateman, RJ, Holtzman, DM, Mawuenyega, K, inventors; The Washington University, assignee. Methods of determining amyloid beta turnover in blood. US Patent Application PCT/US2011/037754. June 26, 2012. US Patent Application 13/699,497. May 9, 2013. (6) Bateman, RJ, Mawuenyega, K, Ovod, V, Bareiss, A, Kasten, T, Holtzman, DM, inventors; The Washington University, assignee. Methods for Detecting Amyloid Beta Amyloidosis. US Patent Application PCT/US2016/0178646. US Patent Application 15/057,694. June 23, 2016 (7)Bateman, RJ, Patterson, BW, Elbert, DL, inventors; Washington University, assignee. Methods of Diagnosing Amyloid Pathologies Using Analysis of Amyloid-Beta Enrichment Kinetics. US Patent Application PCT/US2013/071042. May 30, 2014. (8) Bateman, RJ, inventor; Washington University, assignee. Plasma Based Methods for Detecting CNS Amyloid Deposition. US Patent Application 62/492,718. May 1, 2017. US Patent Application 62/515,294. June 5, 2017.
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
(1) Washington University School of Medicine Charles F. and Joanne Knight Distinguished Professor of Neurology, 2012-present (2) A4, Site Principal Investigator, 2014 to present (3) Washington University School of Medicine, Professor of Neurology, 2015 (4) Dominantly Inherited Alzheimer’s Network Trials Unit (DIAN-TU), Director, 2011-Present (5) Dominantly Inherited Alzheimer's Network (DIAN), Director, 2013-present
Consultancies:
1.
(1) Roche (2) AC Immmune (3) Eisai
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
(1) Eli Lilly (2) Roche (3) Janssen (4) DIAN Pharmaceutical Consortium (Biogen, Eisai, Lilly/Avid, Roche/Genentech, United Neuroscience, Janssen) (5) Abbvie (6) Avid (7) Biogen
Research Support, Government Entities:
1.
(1) NIH R01AG053798, Advisor, 2017-present (2) NIH R01NS095773, PI, 2016-present (3) NIH/NIA U01AG042791, PI, 2013-present (4) NIH/NIA R01AG046179, PI, 2014-present (5) NIH/NIA UF1AG032438, PI, 2008-present (6) NIH R01AG053267, PI, 2017-present (7) NIH U19AG010483, Site PI, 2012-present (8) NIH R01AG061900(R01NS065667), PI, 2008-present (9) NIH U01AG059798, Co-Investigator, 2018-present
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
(1) BrightFocus Foundation (2) Cure Alzheimer's Fund (3) Association for Frontotemporal Degeneration (4) Rainwater Foundation (5) Alzheimer's Association (6) GHR Foundation (7) Anonymous Foundation
Stock/stock Options/board of Directors Compensation:
1.
C2N Diagnostics
License Fee Payments, Technology or Inventions:
1.
C2N Diagnostics, Washington University
Royalty Payments, Technology or Inventions:
1.
C2N Diagnostics, Washington University
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Judes Poirier, PhD, MD (Hon)
From the Department of Psychiatry (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), McGill University; Douglas Mental Health University Institute (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), StoP-AD Centre, Montreal, Canada; Knight Alzheimer's Disease Research Center (T.L.S.B., J.C.M., R.J.B.); and Washington University School of Medicine (T.L.S.B., J.C.M., R.J.B.), St. Louis, MO.
Disclosure
Scientific Advisory Boards:
1.
1) Fondation Alzheimer (France)
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
1) NYU, Speaker, Symposium on Alzheimer, honorarium.
Editorial Boards:
1.
Journal of Alzheimer's Disease, Associate Editor, 2017- 2019
Patents:
1.
NONE
Publishing Royalties:
1.
Young and Centanarian, Trécarré (Canada), 2017 Alzheimer's Disease: The Complete Guide, 2012 La Maladie d'Alzheimer : Trécarré, (Canada), 2020
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.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
J.L. Levesque Foundation
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
John C.S. Breitner, MD, MPH
From the Department of Psychiatry (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), McGill University; Douglas Mental Health University Institute (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), StoP-AD Centre, Montreal, Canada; Knight Alzheimer's Disease Research Center (T.L.S.B., J.C.M., R.J.B.); and Washington University School of Medicine (T.L.S.B., J.C.M., R.J.B.), St. Louis, MO.
Disclosure
Scientific Advisory Boards:
1.
(1) Mayo Clinic Studies on Aging, Scientific Advisory Board(NIH-funded program)(2) Data and Safety Monitoring Board, SPRINT-MIND clinicaltrial (NIA / NHLBI sponsor)(3) Chair, DSMB, for MTI biotech Phase 1 trial
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Receive occasional honoraria for industry-sponsored talks
Editorial Boards:
1.
Alzheimer's Disease and Associated Disorders, EditorialBoard, 2003 - present;PLOS-One, Academics, 2009 - present;Alzheimer's and Dementia, Editorial Board, 2007 - present;
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.
Research Support (gift) from Pfizer Canada
Research Support, Government Entities:
1.
(1) Fonds de Recherche du Quebec - SantePI 2012-2015CIHR 2019-
Research Support, Academic Entities:
1.
(1) Program support from McGill University Faculty of Medicine
Research Support, Foundations and Societies:
1.
(2) Research support from the Douglas Hospital Research Centre and the Douglas Hospital Foundation.
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
From the Department of Psychiatry (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), McGill University; Douglas Mental Health University Institute (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), StoP-AD Centre, Montreal, Canada; Knight Alzheimer's Disease Research Center (T.L.S.B., J.C.M., R.J.B.); and Washington University School of Medicine (T.L.S.B., J.C.M., R.J.B.), St. Louis, MO.
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.
NONE
Research Support, Government Entities:
1.
Canadian Institutes of Health Research, post-doctoral fellowship, 02/12 to 01/15
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
for the DIAN Study Group and the PREVENT-AD Research Group
From the Department of Psychiatry (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), McGill University; Douglas Mental Health University Institute (J.G., C.B., A.P.B., J.P., J.C.S.B., S.V.), StoP-AD Centre, Montreal, Canada; Knight Alzheimer's Disease Research Center (T.L.S.B., J.C.M., R.J.B.); and Washington University School of Medicine (T.L.S.B., J.C.M., R.J.B.), St. Louis, MO.

Notes

Correspondence Dr. Villeneuve [email protected] or Dr. Gonneaud [email protected]
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
PREVENT-AD Research Group and DIAN Study Group coinvestigators are listed at links.lww.com/WNL/B169.
Data used in preparation of this article were obtained from the Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) program (douglas.research.mcgill.ca/stop-ad-centre), data release 5.0 (November 30, 2017). A complete listing of PREVENT-AD Research Group members can be found in the online data supplement and in the PREVENT-AD database: preventad.loris.ca/acknowledgements/acknowledgements.php?date=[2018-04-30].

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