Genetic overlap between vascular pathologies and Alzheimer's dementia and potential causal mechanisms

Abstract

Introduction: We sought to examine the genetic overlap between vascular pathologies and Alzheimer's disease (AD) dementia, and the potential mediating role of vascular pathologies between AD-related genetic variants and late-life cognition.

Methods: For 2907 stroke-free older individuals, we examined the association of polygenic risk scores for AD dementia (ADPRSs) with vascular pathologies and with cognition. Mediation analyses addressed whether association between ADPRSs and cognition was mediated by a vascular pathology.

Results: ADPRSs were associated with lobar cerebral microbleeds, white matter lesion load, and coronary artery calcification, mostly explained by single nucleotide polymorphisms in the 19q13 region. The effect of ADPRSs on cognition was partially but significantly mediated by cerebral microbleeds, white matter lesions, and coronary artery calcification.

Discussion: Our findings provide evidence for genetic overlap, mostly due to apolipoprotein E (APOE) gene, between vascular pathologies and AD dementia. The association between AD polygenic risk and late-life cognition is mediated in part via effects on vascular pathologies.

Keywords: Alzheimer's dementia; Causal mediation; Cerebral microbleeds; Cognitive impairment; Coronary calcification; Polygenic risk score; White matter lesions.

Figure 1.. Pair-wise polygenic association analyses between GW-ADPRS and (A) cognition scores, (B) vascular pathologies

We derived genome-wide PRS for AD dementia using ADGC GWAS as the discovery sample with three different P-value thresholds (PT used to select training set SNPs: 0.0001, 0.001, and 0.01) and apply them to (A) Z-score of the composite memory or global cognition score; and (B) each of the markers of vascular pathologies. Age and sex were included as covariates in the association analyses. Each pair is shown on the x-axis and the proportion of variance explained for each phenotype (estimated via partial correlation R²) on the y-axis. Unadjusted P-values are shown on the top of the bars if < 0.05. An asterisk indicates Bonferroni-corrected P-value < 0.05.

Figure 2.. Sensitivity analyses of unmeasured confounding for the relationship between 19q13-ADPRS and memory score mediated by (A) CMB, (B) WML, or (C) CAC

Figure 2 presents how the PM would change if unmeasured confounding of a specified direction and magnitude is allowed for in the mediation relationship between 19q13-ADPRS, vascular markers, and memory score. Detailed results of sensitivity analyses of unmeasured confounding for all other mediation analyses are described in Supplementary Results, Table S1, and Figure S3. A: predictor; 19q13-ADPRS M: mediator; (A) CMB, (B) WML, or (C) CAC Y: outcome; memory score The y-axis is the proportion mediated The x-axis, denoted by rho, is the degree of hypothetical unmeasured confounding, estimated by the size of the correlation between the residuals in the equation predicting M and the equation predicting Y. The larger the absolute value of rho, the stronger the confounding. The solid curve shows the estimated proportion mediated for different values of the correlation between the residuals in equations. The shaded part of the plot represents the 95% intervals surrounding the mediated effect. The x-intercept represents the value of rho at which proportion mediated equals to 0. The horizontal broken line denotes the proportion mediated without considering unmeasured confounding. When rho is equal to zero, the reported proportion mediated is the same as that we estimated in the mediation analysis without considering unmeasured confounding. For other values of rho, the proportion mediated is calculated under different levels of unobserved confounding. When rho<0, which means there is unmeasured confounding associated with better cognition and less severe vascular pathology or unmeasured confounding associated with poorer cognition and more severe vascular pathology (seemly more likely), our estimated PMs would underestimate the true mediation effects of vascular pathologies.