GWAS identifies genetic factors associated with severity of cerebral amyloid angiopathy pathology

Abstract

AbstractBackgroundCerebral amyloid angiopathy (CAA) commonly co‐occurs with Alzheimer’s disease (AD) pathologies, leading to an increased risk and severity of cognitive decline. While CAA is known to impact cognitive impairment, the genetics of CAA are not well understood, and most previous sample sizes have been small. To address this gap, we conducted a genome‐wide association study (GWAS) of CAA pathology to identify genetic factors that are associated with this understudied AD‐related amyloidosis.MethodWe utilized data from 6,038 autopsied and genotyped individuals from the National Alzheimer’s Coordinating Centers (NACC) who were evaluated for CAA pathology upon autopsy. Participants were age 50+ at death and non‐Hispanic white. Genetic data were available from SNP arrays imputed to TOPMed and analyses were conducted only on common variants (MAF >0.01). GWAS performed ordinal logistic regression to determine the effects of genetic variants on CAA pathology (coded as 0, none; 1, mild; 2, moderate; 3, severe). Models adjusted for sex, age at death, and the first three genetic principal components (PC‐AiR; GENESIS; R v4.2). We then meta‐analyzed across the cohorts (METAL).ResultWe observed genome‐wide significant associations with CAA severity at established AD loci, including APOE (top SNP: rs429358, MAF = 0.155, P = 1.6E−86) and BIN1 (top SNP: rs6733839, MAF = 0.397, P = 3.9E−08). We observed a novel association with CAA pathology on chromosome 9 (top SNP: rs10908023, MAF = 0.258, P = 4.3E−11).ConclusionThis is the largest study to date aimed at identifying genetics factors associated with CAA pathology. Our findings offer new insights into the genetics of CAA, a common player in the AD landscape. We acknowledge the need for a larger dataset and are now expanding the study by sample size and by including additional ADRD phenotypes to gain a better understanding of the full spectrum AD/ADRD. Continuing to uncover the genetic underpinnings of CAA could potentially help us think about AD treatment in new ways and mitigate the negative side‐effects of brain swelling and bleeding that have been observed in recent clinical trials.