{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T08:56:37Z","timestamp":1774688197663,"version":"3.50.1"},"reference-count":49,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,9,22]],"date-time":"2023-09-22T00:00:00Z","timestamp":1695340800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG065477"],"award-info":[{"award-number":["R01AG065477"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG070488"],"award-info":[{"award-number":["R01AG070488"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) and cardiovascular traits might share underlying causes. We sought to identify clusters of cardiovascular traits that share genetic factors with AD. We conducted a univariate exome-wide association study and pair-wise pleiotropic analysis focused on AD and 16 cardiovascular traits\u20146 diseases and 10 cardio-metabolic risk factors\u2014for 188,260 UK biobank participants. Our analysis pinpointed nine genetic markers in the APOE gene region and four loci mapped to the CDK11, OBP2B, TPM1, and SMARCA4 genes, which demonstrated associations with AD at p \u2264 5 \u00d7 10\u22124 and pleiotropic associations at p \u2264 5 \u00d7 10\u22128. Using hierarchical cluster analysis, we grouped the phenotypes from these pleiotropic associations into seven clusters. Lipids were divided into three clusters: low-density lipoprotein and total cholesterol, high-density lipoprotein cholesterol, and triglycerides. This split might differentiate the lipid-related mechanisms of AD. The clustering of body mass index (BMI) with weight but not height indicates that weight defines BMI-AD pleiotropy. The remaining two clusters included (i) coronary heart disease and myocardial infarction; and (ii) hypertension, diabetes mellitus (DM), systolic and diastolic blood pressure. We found that all AD protective alleles were associated with larger weight and higher DM risk. Three of the four (75%) clusters of traits, which were significantly correlated with AD, demonstrated antagonistic genetic heterogeneity, characterized by different directions of the genetic associations and trait correlations. Our findings suggest that shared genetic factors between AD and cardiovascular traits mostly affect them in an antagonistic manner.<\/jats:p>","DOI":"10.3390\/genes14101834","type":"journal-article","created":{"date-parts":[[2023,9,22]],"date-time":"2023-09-22T03:44:42Z","timestamp":1695354282000},"page":"1834","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Exome-Wide Association Study Identified Clusters of Pleiotropic Genetic Associations with Alzheimer\u2019s Disease and Thirteen Cardiovascular Traits"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6730-7320","authenticated-orcid":false,"given":"Yury","family":"Loika","sequence":"first","affiliation":[{"name":"Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27708, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Loiko","sequence":"additional","affiliation":[{"name":"Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27708, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina","family":"Culminskaya","sequence":"additional","affiliation":[{"name":"Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27708, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0205-8228","authenticated-orcid":false,"given":"Alexander M.","family":"Kulminski","sequence":"additional","affiliation":[{"name":"Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27708, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1002\/alz.12638","article-title":"2022 Alzheimer\u2019s disease facts and figures","volume":"18","author":"Gaugler","year":"2022","journal-title":"Alzheimers Dement."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Malik, R., Kalra, S., Bhatia, S., Harrasi, A.A., Singh, G., Mohan, S., Makeen, H.A., Albratty, M., Meraya, A., and Bahar, B. (2022). Overview of therapeutic targets in management of dementia. Biomed. Pharmacother., 152.","DOI":"10.1016\/j.biopha.2022.113168"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1007\/s40265-023-01858-9","article-title":"Anti-Amyloid Monoclonal Antibodies are Transformative Treatments that Redefine Alzheimer\u2019s Disease Therapeutics","volume":"83","author":"Cummings","year":"2023","journal-title":"Drugs"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e13122","DOI":"10.1111\/bpa.13122","article-title":"Hypothesis review: Alzheimer\u2019s overture guidelines","volume":"33","author":"Ferrer","year":"2023","journal-title":"Brain Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1124\/pharmrev.121.000400","article-title":"Targeting Systemic Innate Immune Cells as a Therapeutic Avenue for Alzheimer Disease","volume":"74","author":"Pons","year":"2022","journal-title":"Pharmacol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"370","DOI":"10.3389\/fnagi.2019.00370","article-title":"Revealing a Novel Landscape of the Association Between Blood Lipid Levels and Alzheimer\u2019s Disease: A Meta-Analysis of a Case-Control Study","volume":"11","author":"Tang","year":"2019","journal-title":"Front. Aging Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"215","DOI":"10.3233\/JAD-160826","article-title":"Updating the Evidence on the Association between Serum Cholesterol and Risk of Late-Life Dementia: Review and Meta-Analysis","volume":"56","author":"Anstey","year":"2017","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/alz.12641","article-title":"Midlife lipid and glucose levels are associated with Alzheimer\u2019s disease","volume":"19","author":"Zhang","year":"2023","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s13195-021-00773-z","article-title":"Multi-trait association studies discover pleiotropic loci between Alzheimer\u2019s disease and cardiometabolic traits","volume":"13","author":"Bone","year":"2021","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s00401-018-1928-6","article-title":"Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer\u2019s disease","volume":"137","author":"Broce","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1212\/01.wnl.0000172914.08967.dc","article-title":"Aggregation of vascular risk factors and risk of incident Alzheimer disease","volume":"65","author":"Luchsinger","year":"2005","journal-title":"Neurology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1001\/archneur.62.10.1556","article-title":"Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease","volume":"62","author":"Kivipelto","year":"2005","journal-title":"Arch. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.3233\/JAD-221025","article-title":"Signatures of Neuropsychological Test Results in the Long Life Family Study: A Cluster Analysis","volume":"93","author":"Xiang","year":"2023","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9121","DOI":"10.1073\/pnas.132656399","article-title":"Cluster analysis of gene expression dynamics","volume":"99","author":"Ramoni","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"275","DOI":"10.3233\/JAD-140276","article-title":"Neuropsychological criteria for mild cognitive impairment improves diagnostic precision, biomarker associations, and progression rates","volume":"42","author":"Bondi","year":"2014","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.jalz.2018.12.009","article-title":"Early versus late MCI: Improved MCI staging using a neuropsychological approach","volume":"15","author":"Edmonds","year":"2019","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1017\/S1355617716000199","article-title":"Neuropsychological Criteria for Mild Cognitive Impairment and Dementia Risk in the Framingham Heart Study","volume":"22","author":"Jak","year":"2016","journal-title":"J. Int. Neuropsychol. Soc."},{"key":"ref_18","first-page":"e210003","article-title":"Genetic Association Studies of Age-Related Traits: New Perspectives","volume":"3","author":"Kulminski","year":"2021","journal-title":"Adv. Geriatr. Med. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1002\/gepi.22497","article-title":"Genetic heterogeneity: Challenges, impacts, and methods through an associative lens","volume":"46","author":"Woodward","year":"2022","journal-title":"Genet. Epidemiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1093\/ageing\/afv151","article-title":"The risk of overweight\/obesity in mid-life and late life for the development of dementia: A systematic review and meta-analysis of longitudinal studies","volume":"45","author":"Pedditzi","year":"2016","journal-title":"Age Ageing"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"201","DOI":"10.3233\/JAD-130698","article-title":"Midlife and late-life body mass index and late-life dementia: Results from a prospective population-based cohort","volume":"38","author":"Tolppanen","year":"2014","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"433","DOI":"10.3389\/fgene.2019.00433","article-title":"Pleiotropic Meta-Analysis of Age-Related Phenotypes Addressing Evolutionary Uncertainty in Their Molecular Mechanisms","volume":"10","author":"Kulminski","year":"2019","journal-title":"Front. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"492","DOI":"10.18632\/aging.101407","article-title":"Strong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes","volume":"10","author":"Kulminski","year":"2018","journal-title":"Aging"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1093\/gerona\/glz225","article-title":"Quantitative and Qualitative Role of Antagonistic Heterogeneity in Genetics of Blood Lipids","volume":"75","author":"Kulminski","year":"2020","journal-title":"J. Gerontol. Ser. A Biol. Sci. Med. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1007\/s11357-021-00458-3","article-title":"Mediation of the APOE associations with Alzheimer\u2019s and coronary heart diseases through body mass index and lipids","volume":"44","author":"Loika","year":"2022","journal-title":"GeroScience"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/s11357-021-00484-1","article-title":"Pleiotropic predisposition to Alzheimer\u2019s disease and educational attainment: Insights from the summary statistics analysis","volume":"44","author":"Kulminski","year":"2022","journal-title":"GeroScience"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.3233\/JAD-230397","article-title":"Prevailing Antagonistic Risks in Pleiotropic Associations with Alzheimer\u2019s Disease and Diabetes","volume":"94","author":"Kulminski","year":"2023","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Sudlow, C., Gallacher, J., Allen, N., Beral, V., Burton, P., Danesh, J., Downey, P., Elliott, P., Green, J., and Landray, M. (2015). UK biobank: An open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med., 12.","DOI":"10.1371\/journal.pmed.1001779"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","article-title":"The UK Biobank resource with deep phenotyping and genomic data","volume":"562","author":"Bycroft","year":"2018","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1038\/s41588-021-00885-0","article-title":"Advancing human genetics research and drug discovery through exome sequencing of the UK Biobank","volume":"53","author":"Szustakowski","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_31","unstructured":"Fisher, R.A.S. (1970). Statistical Methods for Research Workers, Oliver and Boyd. [14th ed.]."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"i185","DOI":"10.1093\/bioinformatics\/btu273","article-title":"GRASP: Analysis of genotype-phenotype results from 1390 genome-wide association studies and corresponding open access database","volume":"30","author":"Leslie","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"D977","DOI":"10.1093\/nar\/gkac1010","article-title":"The NHGRI-EBI GWAS Catalog: Knowledgebase and deposition resource","volume":"51","author":"Sollis","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"359","DOI":"10.2478\/s11658-011-0011-2","article-title":"Mislocalization of CDK11\/PITSLRE, a regulator of the G2\/M phase of the cell cycle, in Alzheimer disease","volume":"16","author":"Bajic","year":"2011","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2953","DOI":"10.1007\/s10571-023-01341-9","article-title":"CDK10, CDK11, FOXO1, and FOXO3 Gene Expression in Alzheimer\u2019s Disease Encephalic Samples","volume":"43","author":"Fredi","year":"2023","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/onc.2012.535","article-title":"CHK2 kinase promotes pre-mRNA splicing via phosphorylating CDK11(p110)","volume":"33","author":"Choi","year":"2014","journal-title":"Oncogene"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2654","DOI":"10.1021\/pr400008f","article-title":"Global analysis of phosphorylation of tau by the checkpoint kinases Chk1 and Chk2 in vitro","volume":"12","author":"Mendoza","year":"2013","journal-title":"J. Proteome Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"284","DOI":"10.4161\/bioa.1.6.19336","article-title":"TPM3 and TPM4 gene products segregate to the postsynaptic region of central nervous system synapses","volume":"1","author":"Guven","year":"2011","journal-title":"Bioarchitecture"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Pelucchi, S., Stringhi, R., and Marcello, E. (2020). Dendritic Spines in Alzheimer\u2019s Disease: How the Actin Cytoskeleton Contributes to Synaptic Failure. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030908"},{"key":"ref_40","first-page":"291","article-title":"Immunochemical demonstration of tropomyosin in the neurofibrillary pathology of Alzheimer\u2019s disease","volume":"137","author":"Galloway","year":"1990","journal-title":"Am. J. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.jprot.2017.12.018","article-title":"Gender-related increase of tropomyosin-1 abundance in platelets of Alzheimer\u2019s disease and mild cognitive impairment patients","volume":"178","author":"Reumiller","year":"2018","journal-title":"J. Proteom."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.neuint.2012.12.001","article-title":"Alzheimer disease periventricular white matter lesions exhibit specific proteomic profile alterations","volume":"62","author":"Castano","year":"2013","journal-title":"Neurochem. Int."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.yjmcc.2017.03.006","article-title":"Tropomyosin 1: Multiple roles in the developing heart and in the formation of congenital heart defects","volume":"106","author":"England","year":"2017","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3330","DOI":"10.1073\/pnas.76.7.3330","article-title":"Receptor-mediated endocytosis: Insights from the lipoprotein receptor system","volume":"76","author":"Brown","year":"1979","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"8404","DOI":"10.1038\/s41598-022-12391-2","article-title":"Genome-wide association of polygenic risk extremes for Alzheimer\u2019s disease in the UK Biobank","volume":"12","author":"Gouveia","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"112702","DOI":"10.1016\/j.physbeh.2019.112702","article-title":"Associations of olfactory dysfunction with anthropometric and cardiometabolic measures: Findings from the 2013\u20132014 national health and nutrition examination survey (NHANES)","volume":"215","author":"Gallo","year":"2020","journal-title":"Physiol. Behav."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3249","DOI":"10.18632\/aging.204665","article-title":"Exogenous exposures shape genetic predisposition to lipids, Alzheimer\u2019s, and coronary heart disease in the MLXIPL gene locus","volume":"15","author":"Loika","year":"2023","journal-title":"Aging"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.mam.2015.06.006","article-title":"Shared genetic etiology underlying Alzheimer\u2019s disease and type 2 diabetes","volume":"43\u201344","author":"Hao","year":"2015","journal-title":"Mol. Asp. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/S1474-4422(22)00395-7","article-title":"Diabetes and Alzheimer\u2019s disease: Shared genetic susceptibility?","volume":"21","author":"Hardy","year":"2022","journal-title":"Lancet Neurol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/10\/1834\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:55:40Z","timestamp":1760129740000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/10\/1834"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,22]]},"references-count":49,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["genes14101834"],"URL":"https:\/\/doi.org\/10.3390\/genes14101834","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,22]]}}}