Skip to main content
Advertisement
  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Specialty Sites
    • Equity, Diversity, and Inclusion
    • Innovations in Care Delivery
    • Without Borders
  • Collections
    • Topics A-Z
    • Residents & Fellows
    • Infographics
    • Patient Pages
    • Null Hypothesis
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center

Advanced Search

Main menu

  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Specialty Sites
    • Equity, Diversity, and Inclusion
    • Innovations in Care Delivery
    • Without Borders
  • Collections
    • Topics A-Z
    • Residents & Fellows
    • Infographics
    • Patient Pages
    • Null Hypothesis
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center
  • Home
  • Articles
  • Issues

User menu

  • My Alerts
  • Log in

Search

  • Advanced search
Neurology Genetics
Home
A peer-reviewed clinical and translational neurology open access journal
  • My Alerts
  • Log in
Site Logo
  • Home
  • Articles
  • Issues

Share

February 2018; 4 (1) ArticleOpen Access

Alzheimer risk loci and associated neuropathology in a population-based study (Vantaa 85+)

Mira Mäkelä, Karri Kaivola, Miko Valori, Anders Paetau, Tuomo Polvikoski, Andrew B. Singleton, Bryan J. Traynor, David J. Stone, Terhi Peuralinna, Pentti J. Tienari, Maarit Tanskanen, Liisa Myllykangas
First published January 18, 2018, DOI: https://doi.org/10.1212/NXG.0000000000000211
Mira Mäkelä
From the Department of Pathology (M.M., A.E.P., M.T., L.M.), University of Helsinki, and Helsinki University Hospital, Finland; Molecular Neurology (K.K., M.V., T. Peuralinna, P.J.T.), Research Programs Unit, University of Helsinki, and Department of Neurology, Helsinki University Hospital, Finland; Institute of Neuroscience (T. Polvikoski), Newcastle University, United Kingdom; Laboratory of Neurogenetics (A.B.S., B.J.T.), National Institutes on Aging, NIH, Bethesda, MD; and Merck Research Laboratories (D.J.S.), Merck & Co., Inc., West Point, PA, USA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Karri Kaivola
From the Department of Pathology (M.M., A.E.P., M.T., L.M.), University of Helsinki, and Helsinki University Hospital, Finland; Molecular Neurology (K.K., M.V., T. Peuralinna, P.J.T.), Research Programs Unit, University of Helsinki, and Department of Neurology, Helsinki University Hospital, Finland; Institute of Neuroscience (T. Polvikoski), Newcastle University, United Kingdom; Laboratory of Neurogenetics (A.B.S., B.J.T.), National Institutes on Aging, NIH, Bethesda, MD; and Merck Research Laboratories (D.J.S.), Merck & Co., Inc., West Point, PA, USA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Miko Valori
From the Department of Pathology (M.M., A.E.P., M.T., L.M.), University of Helsinki, and Helsinki University Hospital, Finland; Molecular Neurology (K.K., M.V., T. Peuralinna, P.J.T.), Research Programs Unit, University of Helsinki, and Department of Neurology, Helsinki University Hospital, Finland; Institute of Neuroscience (T. Polvikoski), Newcastle University, United Kingdom; Laboratory of Neurogenetics (A.B.S., B.J.T.), National Institutes on Aging, NIH, Bethesda, MD; and Merck Research Laboratories (D.J.S.), Merck & Co., Inc., West Point, PA, USA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anders Paetau
From the Department of Pathology (M.M., A.E.P., M.T., L.M.), University of Helsinki, and Helsinki University Hospital, Finland; Molecular Neurology (K.K., M.V., T. Peuralinna, P.J.T.), Research Programs Unit, University of Helsinki, and Department of Neurology, Helsinki University Hospital, Finland; Institute of Neuroscience (T. Polvikoski), Newcastle University, United Kingdom; Laboratory of Neurogenetics (A.B.S., B.J.T.), National Institutes on Aging, NIH, Bethesda, MD; and Merck Research Laboratories (D.J.S.), Merck & Co., Inc., West Point, PA, USA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tuomo Polvikoski
From the Department of Pathology (M.M., A.E.P., M.T., L.M.), University of Helsinki, and Helsinki University Hospital, Finland; Molecular Neurology (K.K., M.V., T. Peuralinna, P.J.T.), Research Programs Unit, University of Helsinki, and Department of Neurology, Helsinki University Hospital, Finland; Institute of Neuroscience (T. Polvikoski), Newcastle University, United Kingdom; Laboratory of Neurogenetics (A.B.S., B.J.T.), National Institutes on Aging, NIH, Bethesda, MD; and Merck Research Laboratories (D.J.S.), Merck & Co., Inc., West Point, PA, USA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrew B. Singleton
From the Department of Pathology (M.M., A.E.P., M.T., L.M.), University of Helsinki, and Helsinki University Hospital, Finland; Molecular Neurology (K.K., M.V., T. Peuralinna, P.J.T.), Research Programs Unit, University of Helsinki, and Department of Neurology, Helsinki University Hospital, Finland; Institute of Neuroscience (T. Polvikoski), Newcastle University, United Kingdom; Laboratory of Neurogenetics (A.B.S., B.J.T.), National Institutes on Aging, NIH, Bethesda, MD; and Merck Research Laboratories (D.J.S.), Merck & Co., Inc., West Point, PA, USA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bryan J. Traynor
From the Department of Pathology (M.M., A.E.P., M.T., L.M.), University of Helsinki, and Helsinki University Hospital, Finland; Molecular Neurology (K.K., M.V., T. Peuralinna, P.J.T.), Research Programs Unit, University of Helsinki, and Department of Neurology, Helsinki University Hospital, Finland; Institute of Neuroscience (T. Polvikoski), Newcastle University, United Kingdom; Laboratory of Neurogenetics (A.B.S., B.J.T.), National Institutes on Aging, NIH, Bethesda, MD; and Merck Research Laboratories (D.J.S.), Merck & Co., Inc., West Point, PA, USA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David J. Stone
From the Department of Pathology (M.M., A.E.P., M.T., L.M.), University of Helsinki, and Helsinki University Hospital, Finland; Molecular Neurology (K.K., M.V., T. Peuralinna, P.J.T.), Research Programs Unit, University of Helsinki, and Department of Neurology, Helsinki University Hospital, Finland; Institute of Neuroscience (T. Polvikoski), Newcastle University, United Kingdom; Laboratory of Neurogenetics (A.B.S., B.J.T.), National Institutes on Aging, NIH, Bethesda, MD; and Merck Research Laboratories (D.J.S.), Merck & Co., Inc., West Point, PA, USA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Terhi Peuralinna
From the Department of Pathology (M.M., A.E.P., M.T., L.M.), University of Helsinki, and Helsinki University Hospital, Finland; Molecular Neurology (K.K., M.V., T. Peuralinna, P.J.T.), Research Programs Unit, University of Helsinki, and Department of Neurology, Helsinki University Hospital, Finland; Institute of Neuroscience (T. Polvikoski), Newcastle University, United Kingdom; Laboratory of Neurogenetics (A.B.S., B.J.T.), National Institutes on Aging, NIH, Bethesda, MD; and Merck Research Laboratories (D.J.S.), Merck & Co., Inc., West Point, PA, USA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pentti J. Tienari
From the Department of Pathology (M.M., A.E.P., M.T., L.M.), University of Helsinki, and Helsinki University Hospital, Finland; Molecular Neurology (K.K., M.V., T. Peuralinna, P.J.T.), Research Programs Unit, University of Helsinki, and Department of Neurology, Helsinki University Hospital, Finland; Institute of Neuroscience (T. Polvikoski), Newcastle University, United Kingdom; Laboratory of Neurogenetics (A.B.S., B.J.T.), National Institutes on Aging, NIH, Bethesda, MD; and Merck Research Laboratories (D.J.S.), Merck & Co., Inc., West Point, PA, USA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maarit Tanskanen
From the Department of Pathology (M.M., A.E.P., M.T., L.M.), University of Helsinki, and Helsinki University Hospital, Finland; Molecular Neurology (K.K., M.V., T. Peuralinna, P.J.T.), Research Programs Unit, University of Helsinki, and Department of Neurology, Helsinki University Hospital, Finland; Institute of Neuroscience (T. Polvikoski), Newcastle University, United Kingdom; Laboratory of Neurogenetics (A.B.S., B.J.T.), National Institutes on Aging, NIH, Bethesda, MD; and Merck Research Laboratories (D.J.S.), Merck & Co., Inc., West Point, PA, USA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Liisa Myllykangas
From the Department of Pathology (M.M., A.E.P., M.T., L.M.), University of Helsinki, and Helsinki University Hospital, Finland; Molecular Neurology (K.K., M.V., T. Peuralinna, P.J.T.), Research Programs Unit, University of Helsinki, and Department of Neurology, Helsinki University Hospital, Finland; Institute of Neuroscience (T. Polvikoski), Newcastle University, United Kingdom; Laboratory of Neurogenetics (A.B.S., B.J.T.), National Institutes on Aging, NIH, Bethesda, MD; and Merck Research Laboratories (D.J.S.), Merck & Co., Inc., West Point, PA, USA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Full PDF
Citation
Alzheimer risk loci and associated neuropathology in a population-based study (Vantaa 85+)
Mira Mäkelä, Karri Kaivola, Miko Valori, Anders Paetau, Tuomo Polvikoski, Andrew B. Singleton, Bryan J. Traynor, David J. Stone, Terhi Peuralinna, Pentti J. Tienari, Maarit Tanskanen, Liisa Myllykangas
Neurol Genet Feb 2018, 4 (1) e211; DOI: 10.1212/NXG.0000000000000211

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Permissions

Make Comment

See Comments

Downloads
618

Share

  • Article
  • Figures & Data
  • Info & Disclosures
Loading

Abstract

Objective To test the association of distinct neuropathologic features of Alzheimer disease (AD) with risk loci identified in genome-wide association studies.

Methods Vantaa 85+ is a population-based study that includes 601 participants aged ≥85 years, of which 256 were neuropathologically examined. We analyzed 29 AD risk loci in addition to APOE ε4, which was studied separately and used as a covariate. Genotyping was performed using a single nucleotide polymorphism (SNP) array (341 variants) and imputation (6,038 variants). Participants with Consortium to Establish a Registry for Alzheimer Disease (CERAD) (neuritic Aβ plaques) scores 0 (n = 65) vs score M + F (n = 171) and Braak (neurofibrillary tangle pathology) stages 0–II (n = 74) vs stages IV–VI (n = 119), and with capillary Aβ (CapAβ, n = 77) vs without (n = 179) were compared. Cerebral amyloid angiopathy (CAA) percentage was analyzed as a continuous variable.

Results Altogether, 24 of the 29 loci were associated (at p < 0.05) with one or more AD-related neuropathologic features in either SNP array or imputation data. Fifteen loci associated with CERAD score, smallest p = 0.0002122, odds ratio (OR) 2.67 (1.58–4.49) at MEF2C locus. Fifteen loci associated with Braak stage, smallest p = 0.004372, OR 0.31 (0.14–0.69) at GAB2 locus. Twenty loci associated with CAA, smallest p = 7.17E-07, β 14.4 (8.88–20) at CR1 locus. Fifteen loci associated with CapAβ smallest p = 0.002594, OR 0.54 (0.37–0.81) at HLA-DRB1 locus. Certain loci associated with specific neuropathologic features. CASS4, CLU, and ZCWPW1 associated only with CAA, while TREM2 and HLA-DRB5 associated only with CapAβ.

Conclusions AD risk loci differ in their association with neuropathologic features, and we show for the first time distinct risk loci for CAA and CapAβ.

Glossary

Aβ=
amyloid-β;
AD=
Alzheimer disease;
APOE=
apolipoprotein E;
CAA=
cerebral amyloid angiopathy;
CapAβ=
capillary Aβ;
CERAD=
Consortium to Establish a Registry for Alzheimer Disease;
Chr9 region=
chromosome 9 region;
CI=
confidence interval;
GWAS=
genome-wide association study;
IHC=
immunohistochemistry;
LOAD=
late-onset Alzheimer disease;
OR=
odds ratio;
SNP=
single nucleotide polymorphism

Footnotes

  • ↵* These authors contributed equally to this work.

  • Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.

  • The Article Processing Charge was funded by the University of Helsinki (funded by Academy of Finland).

  • Received May 13, 2017.
  • Accepted in final form November 26, 2017.
  • Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

View Full Text

Letters: Rapid online correspondence

No comments have been published for this article.
Comment

NOTE: All contributors' disclosures must be entered and current in our database before comments can be posted. Enter and update disclosures at http://submit.ng.neurology.org. Exception: replies to comments concerning an article you originally authored do not require updated disclosures.

  • Stay timely. Submit only on articles published within the last 8 weeks.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • 200 words maximum.
  • 5 references maximum. Reference 1 must be the article on which you are commenting.
  • 5 authors maximum. Exception: replies can include all original authors of the article.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Letters

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Letters Submission Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
  • Article
    • Abstract
    • Glossary
    • Methods
    • Results
    • Discussion
    • Author contributions
    • Study funding
    • Disclosure
    • Acknowledgment
    • Footnotes
    • References
  • Figures & Data
  • Info & Disclosures

Related Articles

  • No related articles found.

Topics Discussed

  • Alzheimer's disease
  • Cohort studies

Alert Me

  • Alert me when eletters are published
Advertisement
Neurology Genetics: 7 (2)

Articles

  • Articles
  • Issues
  • Popular Articles

About

  • About the Journals
  • Ethics Policies
  • Editors & Editorial Board
  • Contact Us
  • Advertise

Submit

  • Author Center
  • Submit a Manuscript
  • Information for Reviewers
  • AAN Guidelines
  • Permissions

Subscribers

  • Subscribe
  • Sign up for eAlerts
  • RSS Feed
Site Logo
  • Visit neurology Template on Facebook
  • Follow neurology Template on Twitter
  • Visit Neurology on YouTube
  • Neurology
  • Neurology: Clinical Practice
  • Neurology: Genetics
  • Neurology: Neuroimmunology & Neuroinflammation
  • AAN.com
  • AANnews
  • Continuum
  • Brain & Life
  • Neurology Today

Wolters Kluwer Logo

Neurology: Genetics | Online ISSN: 2376-7839

© 2021 American Academy of Neurology

  • Privacy Policy
  • Feedback
  • Advertise