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Complexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics

dc.rights.licenseopenen_US
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorSARGURUPREMRAJ, Muralidharan
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorSOUMARE, Aicha
dc.contributor.authorBIS, Joshua C
dc.contributor.authorSURAKKA, Ida
dc.contributor.authorJURGENSON, Tuuli
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorJOLY, Pierre
dc.contributor.authorKNOL, Maria J
dc.contributor.authorWANG, Ruiqi
dc.contributor.authorYANG, Qiong
dc.contributor.authorSATIZABAL, Claudia L
dc.contributor.authorGUDJONSSON, Alexander
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorMISHRA, Aniket
dc.contributor.authorBOUTELOUP, Vincent
dc.contributor.authorPHUAH, Chia-Ling
dc.contributor.authorVAN DUIJN, Cornelia M
dc.contributor.authorCRUCHAGA, Carlos
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorDUFOUIL, Carole
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorCHENE, Genevieve
dc.contributor.authorLOPEZ, Oscar
dc.contributor.authorPSATY, Bruce M
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorTZOURIO, Christophe
dc.contributor.authorAMOUYEL, Philippe
dc.contributor.authorADAMS, Hieab H
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorJACQMIN-GADDA, Helene
dc.contributor.authorIKRAM, Mohammad Arfan
dc.contributor.authorGUDNASON, Vilmundur
dc.contributor.authorMILANI, Lili
dc.contributor.authorWINSVOLD, Bendik S
dc.contributor.authorHVEEM, Kristian
dc.contributor.authorMATTHEWS, Paul M
dc.contributor.authorLONGSTRETH, W T
dc.contributor.authorSESHADRI, Sudha
dc.contributor.authorLAUNER, Lenore J
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorDEBETTE, Stephanie
dc.date.accessioned2023-12-19T08:42:41Z
dc.date.available2023-12-19T08:42:41Z
dc.date.created2023-08-13
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/186716
dc.description.abstractEnImportance: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear. Objective: To disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist. To account for potential epidemiological biases inherent to late-onset conditions like dementia. Design, Setting, and Participants: This study first explored the association of genetically determined WMH, BP levels and stroke risk with AD using summary-level data from large genome-wide association studies (GWASs) in a two-sample Mendelian randomization (MR) framework. Second, leveraging individual-level data from large longitudinal population-based cohorts and biobanks with prospective dementia surveillance, the association of weighted genetic risk scores (wGRSs) for WMH, BP, and stroke with incident all-cause-dementia was explored using Cox-proportional hazard and multi-state models. The data analysis was performed from July 26, 2020, through July 24, 2022. Exposures: Genetically determined levels of WMH volume and BP (systolic, diastolic and pulse blood pressures) and genetic liability to stroke. Main outcomes and measures: The summary-level MR analyses focused on the outcomes from GWAS of clinically diagnosed AD (n-cases=21,982) and GWAS additionally including self-reported parental history of dementia as a proxy for AD diagnosis (ADmeta, n- It is made available under a CC-BY-NC-ND 4.0 International license . perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in medRxiv preprint doi: https://doi.org/10.1101/2023.08.08.23293761; this version posted August 13, 2023. The copyright holder for this cases=53,042). For the longitudinal analyses, individual-level data of 157,698 participants with 10,699 incident all-cause-dementia were studied, exploring AD, vascular or mixed dementia in secondary analyses. Results: In the two-sample MR analyses, WMH showed strong evidence for a causal association with increased risk of ADmeta (OR, 1.16; 95%CI:1.05-1.28; P=.003) and AD (OR, 1.28; 95%CI:1.07-1.53; P=.008), after accounting for genetically determined pulse pressure for the latter. Genetically predicted BP traits showed evidence for a protective association with both clinically defined AD and ADmeta, with evidence for confounding by shared genetic instruments. In longitudinal analyses the wGRSs for WMH, but not BP or stroke, showed suggestive association with incident all-cause-dementia (HR, 1.02; 95%CI:1.00-1.04; P=.06). BP and stroke wGRSs were strongly associated with mortality but there was no evidence for selective survival bias during follow-up. In secondary analyses, polygenic scores with more liberal instrument definition showed association of both WMH and stroke with all-causedementia, AD, and vascular or mixed dementia; associations of stroke, but not WMH, with dementia outcomes were markedly attenuated after adjusting for interim stroke. Conclusion: These findings provide converging evidence that WMH is a leading vascular contributor to dementia risk, which may better capture the brain damage caused by BP (and other etiologies) than BP itself and should be targeted in priority for dementia prevention in the population.
dc.language.isoENen_US
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/us/*
dc.title.enComplexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics
dc.typeDocument de travail - Pré-publicationen_US
dc.identifier.doi10.1101/2023.08.08.23293761en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed37790435en_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - UMR 1219en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.teamELEANOR_BPHen_US
bordeaux.teamAHEAD_BPHen_US
bordeaux.teamBIOSTAT_BPHen_US
bordeaux.teamHEALTHY_BPHen_US
hal.identifierhal-04352450
hal.version1
hal.date.transferred2023-12-19T08:42:45Z
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exporttrue
dc.rights.ccPas de Licence CCen_US
bordeaux.subtypePrepublication/Preprinten_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.au=SARGURUPREMRAJ,%20Muralidharan&SOUMARE,%20Aicha&BIS,%20Joshua%20C&SURAKKA,%20Ida&JURGENSON,%20Tuuli&rft.genre=preprint


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