Genetic Complexities of Cerebral Small Vessel Disease, Blood Pressure, and Dementia

Abstract

Importance: Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain.

Objective: 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.

Design, setting, and participants: 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.

Exposures: 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.

Main outcomes and measures: 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.

Results: In 2SMR (summary statistics-based) analyses using AD GWASs with up to 75 024 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; P = .007, per unit increase in WMH risk alleles) and AD-meta (OR, 1.19; 95% CI, 1.06-1.34; P = .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 10 699 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; P = .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; P = 1.9 × 10-14), 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.

Conclusions: 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.

Figure 1.. Study Design

Analyses on summary-level data: In step 1, we used the standard inverse variance weighting method to estimate causal effects between each exposure and Alzheimer disease (AD) or AD-meta with parental history of dementia. Steps 2 and 3 addressed potential pleiotropic effects confounding the initial causal estimates using MR-RAPS, weighted-median and mode-based methods. ACD indicates all-cause dementia; BP, blood pressure; CHARGE, Cohorts for Heart and Aging Research in Genomic Epidemiology; DBP, diastolic blood pressure; EBB, Estonian Biobank; EUR, European population; GWAS, genome-wide association study; HUNT, Trøndelag Health Study; LD, linkage disequilibrium; PGS, polygenic profile score; PP, pulse pressure; SBP, systolic blood pressure; SNP, single-nucleotide polymorphism; UKBB, UK Biobank; and WMH, white matter hyperintensity. ^aIn step 4, we compared the causal model with the sharing model using MR-CAUSE. The risk factor–outcome associations favoring the causal model (change in expected log pointwise posterior density [ΔELPD] >0; see Methods) were validated in step 5 using multivariable mendelian randomization (MVMR). ^bAssociation analyses in a subset of CHARGE cohorts (Three-City study, Ages Gene/Environment Susceptibility study).

Figure 2.. Mendelian Randomization Results of Vascular Risk Factors With Alzheimer Disease (AD)

Point estimates and 95% CIs from the inverse variance weighted (IVW) method, along with the P value for the IVW and MR-Egger intercept, are shown. The causal estimates are scaled to represent a 1-SD change for the continuous exposures and per 1-unit higher log odds for binary exposures. DBP indicates diastolic blood pressure; OR, odds ratio; PP, pulse pressure; SBP, systolic blood pressure; and WMH, white matter hyperintensity.

Figure 3.. Multivariable Mendelian Randomization (MVMR) Along With the Univariable Mendelian Randomization (MR) for Alzheimer Disease (AD) as the Outcome

Univariable MR and MVMR results are shown, and the association P values are shown on the far right. The causal estimates are scaled to represent a 1-SD change for the continuous exposures and per 1-unit higher log odds for binary exposures. DBP indicates diastolic blood pressure; OR, odds ratio; PP, pulse pressure; SBP, systolic blood pressure; and WMH, white matter hyperintensity.

Figure 4.. Meta-Analysis Results of Risk Factor–Weighted Genetic Risk Scores (per SD Increase) With Incident All-Cause Dementia

Primary analysis: Cox proportional hazards regression model adjusted for sex, principal components of population stratification, study-specific criteria, and educational level. Sensitivity analysis I: Cox proportional hazards regression model adjusted for sex, principal components of population stratification, study-specific criteria. Sensitivity analysis II: prevalent stroke excluded and the Cox proportional hazards regression model adjusted for sex, principal components of population stratification, study-specific criteria, and interim stroke status. Association P values are shown on the far right. DBP indicates diastolic blood pressure; OR, odds ratio; PP, pulse pressure; SBP, systolic blood pressure; and WMH, white matter hyperintensity.