Polygenic impact of common genetic risk loci for Alzheimer's disease on cerebral blood flow in young individuals

Abstract

Genome-wide association studies (GWAS) show that many common alleles confer risk for developing Alzheimer's disease (AD). These risk loci may contribute to MRI alterations in young individuals, preceding the clinical manifestations of AD. Prior evidence identifies vascular dysregulation as the earliest marker of disease progression. However, it remains unclear whether cerebrovascular function (measured via grey-matter cerebral blood flow (gmCBF)) is altered in young individuals with increased AD genetic risk. We establish relationships between gmCBF with APOE and AD polygenic risk score in a young cohort (N = 75; aged: 19-32). Genetic risk was assessed via a) possessing at least one copy of the APOE ɛ4 allele and b) a polygenic risk score (AD-PRS) estimated from AD-GWAS. We observed a reduction in gmCBF in APOE ɛ4 carriers and a negative relationship between AD-PRS and gmCBF. We further found regional reductions in gmCBF in individuals with higher AD-PRS across the frontal cortex (P_FWE < 0.05). Our findings suggest that a larger burden of AD common genetic risk alleles is associated with attenuated cerebrovascular function, during young adulthood. These results suggest that cerebral vasculature is a mechanism by which AD risk alleles confer susceptibility.

Figure 1

Results for both the APOE status group difference in gmCBF and the association between AD-PRS and gmCBF. (a) Total gmCBF (grey matter cerebral blood flow) stratified by presence of APOE ε4 isoform; (b) association between gmCBF and AD-PRS. R² and p-values estimated from linear regression, controlling for age, gender, GMV and PRS (in (a)) or APOE (in (b)). (c) Reflects the individual contributions to gmCBF for all SNPs within the AD-PRS (N_SNPS = 17), controlling for covariates. CIs = confidence intervals.

Figure 2

Voxel wide analysis of gmCBF for AD-PRS. Regional association between gmCBF and AD-PRS across all grey matter. All clusters that remain (red-yellow) reflect voxels that survived correction across the whole brain (using threshold free cluster enhancement) with permutation testing (N = 5000) (P_FWE < 0.05). Color-bar represents regional t-statistic.

Figure 3

Average gmCBF maps. Top. A mean gmCBF map of all participants within the sample (N = 75). Middle. Mean gmCBF for APOE ɛ4− group (N = 54). Below. Mean gmCBF for APOE ɛ4+ group (N = 21). Colorbar represents regional gmCBF (ml/min/100 g).