{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T21:37:57Z","timestamp":1793828277903,"version":"4.6.1"},"reference-count":81,"publisher":"American Medical Association (AMA)","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential epidemiologic biases.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This study first examined the association of genetically determined WMH burden, stroke, and BP levels with Alzheimer disease (AD) in a 2-sample mendelian randomization (2SMR) framework. Second, using population-based studies (1979-2018) with prospective dementia surveillance, the genetic association of WMH, stroke, and BP with incident all-cause dementia was examined. Data analysis was performed from July 26, 2020, through July 24, 2022.<\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n Genetically determined WMH burden and BP levels, as well as genetic liability to stroke derived from genome-wide association studies (GWASs) in European ancestry populations.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n The association of genetic instruments for WMH, stroke, and BP with dementia was studied using GWASs of AD (defined clinically and additionally meta-analyzed including both clinically diagnosed AD and AD defined based on parental history [AD-meta]) for 2SMR and incident all-cause dementia for longitudinal analyses.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n In 2SMR (summary statistics\u2013based) analyses using AD GWASs with up to 75\u202f024 AD cases (mean [SD] age at AD onset, 75.5 [4.4] years; 56.9% women), larger WMH burden showed evidence for a causal association with increased risk of AD (odds ratio [OR], 1.43; 95% CI, 1.10-1.86;\n P<\/jats:italic>\n \u2009=\u2009.007, per unit increase in WMH risk alleles) and AD-meta (OR, 1.19; 95% CI, 1.06-1.34;\n P<\/jats:italic>\n \u2009=\u2009.008), after accounting for pulse pressure for the former. Blood pressure traits showed evidence for a protective association with AD, with evidence for confounding by shared genetic instruments. In the longitudinal (individual-level data) analyses involving 10\u202f699 incident all-cause dementia cases (mean [SD] age at dementia diagnosis, 74.4 [9.1] years; 55.4% women), no significant association was observed between larger WMH burden and incident all-cause dementia (hazard ratio [HR], 1.02; 95% CI, 1.00-1.04;\n P<\/jats:italic>\n \u2009=\u2009.07). Although all exposures were associated with mortality, with the strongest association observed for systolic BP (HR, 1.04; 95% CI, 1.03-1.06;\n P<\/jats:italic>\n \u2009=\u20091.9\u2009\u00d7\u200910\n \u221214<\/jats:sup>\n ), there was no evidence for selective survival bias during follow-up using illness-death models. In secondary analyses using polygenic scores, the association of genetic liability to stroke, but not genetically determined WMH, with dementia outcomes was attenuated after adjusting for interim stroke.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n These findings suggest that WMH is a primary vascular factor associated with dementia risk, emphasizing its significance in preventive strategies for dementia. Future studies are warranted to examine whether this finding can be generalized to non-European populations.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2024.12824","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T11:34:42Z","timestamp":1716377682000},"page":"e2412824","source":"Crossref","is-referenced-by-count":23,"title":["Genetic Complexities of Cerebral Small Vessel Disease, Blood Pressure, and Dementia"],"prefix":"10.1001","volume":"7","author":[{"given":"Muralidharan","family":"Sargurupremraj","sequence":"first","affiliation":[{"name":"Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France"},{"name":"Glenn Biggs Institute for Alzheimer\u2019s & Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aicha","family":"Soumar\u00e9","sequence":"additional","affiliation":[{"name":"Bordeaux 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France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria J.","family":"Knol","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiqi","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Public Health, Boston University and the National Heart, Lung, and Blood Institute Framingham Heart Study, Boston, Massachusetts"},{"name":"Department of Neurology, Boston University School of Medicine, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Public Health, Boston University and the National Heart, Lung, and Blood Institute Framingham Heart Study, Boston, Massachusetts"},{"name":"Department of Neurology, Boston University School of Medicine, Boston, 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Informatics Center, Washington University in St Louis, St Louis, Missouri"},{"name":"Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri"},{"name":"Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole","family":"Dufouil","sequence":"additional","affiliation":[{"name":"Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevi\u00e8ve","family":"Ch\u00eane","sequence":"additional","affiliation":[{"name":"Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France"},{"name":"Department of Public Health, CHU de Bordeaux, Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar L.","family":"Lopez","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania"},{"name":"Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce M.","family":"Psaty","sequence":"additional","affiliation":[{"name":"Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle"},{"name":"Department of Epidemiology, University of Washington, Seattle"},{"name":"Department of Health Systems and Population Health, University of Washington, Seattle"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Tzourio","sequence":"additional","affiliation":[{"name":"Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France"},{"name":"Department of Public Health, CHU de Bordeaux, Bordeaux, 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Arfan","family":"Ikram","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vilmundur","family":"Gudnason","sequence":"additional","affiliation":[{"name":"Icelandic Heart Association, Kopavogur, Iceland"},{"name":"Faculty of Medicine, University of Iceland, Reykjavik, Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Milani","sequence":"additional","affiliation":[{"name":"Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bendik S.","family":"Winsvold","sequence":"additional","affiliation":[{"name":"Division of Clinical Neuroscience, Department of Research and Innovation, Oslo University Hospital, Oslo, Norway"},{"name":"K. 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