Complexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics
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Document de travail - Pré-publication
Résumé en anglais
Importance: 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 ...Lire la suite >
Importance: 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preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in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.< Réduire
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