Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease
Open accessAbstract
Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10-9), MINK1 (chromosome 17, meta-p = 1.98 × 10-7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10-7 and closest gene = MYBPC3, meta-p = 5.62 × 10-8). In a large 'AD-by-proxy' cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.
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These loci have previously been identified as genome-wide significant for AD in recent single-trait AD GWAS.
“All of these loci are novel pleiotropic loci between AD and the respective cardiometabolic traits, but have previously been identified as genome-wide significant for AD in recent single-trait AD GWAS [4, 17, 31].”
From Multi-trait association studies discover pleiotropic loci between Alzheimer’s disease and cardiometabolic traits (2021) · cites this paper as [4]
The Results (page unavailable) link some loci to previously reported AD variants, including one in the CELF1 region. But the paper calls four AD-associated loci novel, and three did not reach genome-wide significance in its meta-analysis. It therefore does not support the claim that all the loci had previously been genome-wide significant in single-trait AD GWAS. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMany cardiometabolic traits are genetically correlated with one another.
“Due to the epidemiological correlation between AD and cardiometabolic traits, coupled with the fact that many cardiometabolic traits are genetically correlated with one another, additional broader-scale pleiotropic studies are warranted, and recently the field has begun to do so [4, 11].”
From Multi-trait association studies discover pleiotropic loci between Alzheimer’s disease and cardiometabolic traits (2021) · cites this paper as [4]
The biological mechanisms behind the positive epidemiological correlation between Alzheimer's disease and cardiometabolic traits are not well understood.
“Studies have consistently found a positive epidemiological correlation between Alzheimer’s disease (AD) and cardiometabolic traits, yet the biological mechanisms behind this correlation is not well understood [1–4].”
From Multi-trait association studies discover pleiotropic loci between Alzheimer’s disease and cardiometabolic traits (2021) · cites this paper as [4]
There is a positive epidemiological correlation between Alzheimer's disease and cardiometabolic traits.
“Studies have consistently found a positive epidemiological correlation between Alzheimer’s disease (AD) and cardiometabolic traits, yet the biological mechanisms behind this correlation is not well understood [1–4].”
From Multi-trait association studies discover pleiotropic loci between Alzheimer’s disease and cardiometabolic traits (2021) · cites this paper as [4]
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- Authors
- Broce, I. J., Tan, C. H., Fan, C. C., Jansen, I., Savage, J. E., Witoelar, A., Wen, N., Hess, C. P., Dillon, W. P., Glastonbury, C. M., Glymour, M., Yokoyama, J. S., Elahi, F. M., Rabinovici, G. D., Miller, B. L., Mormino, E. C., Sperling, R. A., Bennett, D. A., McEvoy, L. K., Brewer, J. B., Feldman, H. H., Hyman, B. T., Pericak-Vance, M., Haines, J. L., Farrer, L. A., Mayeux, R., Schellenberg, G. D., Yaffe, K., Sugrue, L. P., Dale, A. M., Posthuma, D., Andreassen, O. A., Karch, C. M., & Desikan, R. S.
- Affiliations
- University of California, San Francisco (US)
- Nanyang Technological University (SG)
- University of California San Diego (US)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- University of Oslo (NO)
- Washington University in St. Louis (US)
- Stanford Medicine (US)
- Brigham and Women's Hospital (US)
- Rush University Medical Center (US)
- Harvard University (US)
- Case Western Reserve University (US)
- Boston University (US)
- Columbia University (US)
- University of Pennsylvania (US)
- Corresponding author
- Broce, Iris J.
- Karch, Celeste M.
- Desikan, Rahul S.
- ORCID
- Broce, Iris J.
- Tan, Chin Hong
- Fan, Chun Chieh
- Jansen, Iris
- Savage, Jeanne E.
- Witoelar, Aree
- Wen, Natalie
- Hess, Christopher P.
- Dillon, William P.
- Glastonbury, Christine M.
- Glymour, Maria
- Yokoyama, Jennifer S.
- Elahi, Fanny M.
- Rabinovici, Gil D.
- Miller, Bruce L.
- Mormino, Elizabeth C.
- Sperling, Reisa A.
- Bennett, David A.
- McEvoy, Linda K.
- Feldman, Howard H.
- Hyman, Bradley T.
- Haines, Jonathan L.
- Farrer, Lindsay A.
- Mayeux, Richard
- Schellenberg, Gerard D.
- Yaffe, Kristine
- Sugrue, Leo P.
- Dale, Anders M.
- Andreassen, Ole A.
- Karch, Celeste M.
- Desikan, Rahul S.
- Venue
- Acta Neuropathologica
- Published
- 2018-11-09
- Volume
- 137
- Issue
- 2
- Pages
- 209-226
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC6358498
- OpenAlex
- W2899829198
- Cited by
- 140
- References
- 60
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 20 · 2023: 23 · 2022: 20 · 2021: 28 · 2020: 20 · 2019: 10 · 2018: 1
- FWCI
- 10.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- DR-NTU (Nanyang Technological University) (submittedVersion)
- VU Research Portal (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- National Institutes of Health (AG046374, K01AG049152)
- National Alzheimer's Coordinating Center
- Radiological Society of North America
- Foundation of the American Society of Neuroradiology
- Norges Forskningsråd (213837, 225989, 223273, 237250/EU JPND)
- South East Norway Health Authority
- Norwegian Health Association
- KG Jebsen Foundation
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, cardiovascular risk factors, genetic overlap, pleiotropy, plasma lipids, type 2 diabetes, coronary artery disease, body mass index, waist-to-hip ratio, apolipoprotein E, DDB2, novel genetic loci, postmortem gene expression, polygenic risk
- MeSH terms
- Aged, Aged, 80 and over, Alleles, Alzheimer Disease, Apolipoproteins E, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Female, Humans, Male, Middle Aged, Risk Factors, Cohort Studies, Genetic Predisposition to Disease, Genome-Wide Association Study
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