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.
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