Basic Science and Pathogenesis

Genome-wide association studies (GWAS) have identified over 1,000 blood pressure (BP) loci and over 80 Alzheimer's disease (AD) loci. Considering BP is an AD risk factor, identifying pleiotropy in BP and cognitive performance may indicate mechanistic links between BP and AD.

GWAS for pleiotropy in four BP variables-systolic (SBP), diastolic (DBP), mean arterial (MAP), pulse pressure (PP)-and co-calibrated scores for cognitive domains (executive function, language, memory) were performed using generalized linear mixed models and 116,075 longitudinal measures from 25,726 participants of clinic-based and prospective cohorts. Pleiotropy GWAS was conducted using PLACO to estimate SNP's main effect, SNP×age interaction, and their joint effect on pleiotropy. Effects of genome-wide significant (GWS) pleiotropic SNPs on cognition as direct or mediated through BP were evaluated using Mendelian randomization. Potential contribution of genes in top-ranked pleiotropic loci to cognitive resilience was assessed by comparing their expression in brain tissue from pathologically confirmed AD cases with and without clinical symptoms.

Pleiotropy GWAS identified GWS associations with APOE and 11 novel loci. GWS pleiotropy was identified for SBP and language with SNPs in JPH2 (P_Joint=6.09×10^-9) and GATA3 (P_G×Age=1.42×10^-8) in the total sample and with RTN4 (P_G×Age=1.49×10^-8) in prospective cohorts. GWS pleiotropy was observed for PP and language with ADAMTS3 (P_G=2.37×10^-8) in clinic-based cohorts. ULK2 was pleiotropic for DBP and executive function (P_Joint=2.85×10^-8) in prospective cohorts. In the total sample, PAX2 (P_G×Age=4.22×10^-8) and LOC105371656 (P_G×Age=1.75×10^-8) had GWS pleiotropy for MAP paired with executive function and language, respectively, and SUFU was pleiotropic for DBP and language (P_G=2.10×10^-8). LINC02946 was associated with memory paired with SBP (P_G×Age=3.47×10^-8) in clinic-based cohorts. GWS pleiotropy was found in prospective cohorts for PP and memory with SORBS2 (P_G=2.33×10^-8) and for DBP and memory with LOC100128993 (P_G×Age=2.81×10^-8). Five of the GWS pleiotropic loci influence cognition directly. Genes at six pleiotropic loci were differentially expressed between pathologically confirmed AD cases with and without clinical symptoms.

Our results provide insight into the underlying mechanisms of BP and AD. Ongoing efforts to harmonize BP and cognitive measures across several cohorts will improve the power of discovering, replicating, and generalizing novel associations with pleiotropic loci.