Alzheimer Disease candidate variants are associated with cerebral amyloid angiopathy

AbstractBackgroundThe hallmark lesions of Alzheimer Disease (AD) include tangles and plaques; however, these seldom appear alone. Lesions of AD‐related dementias such as vascular dementias and Lewy body dementias often co‐occur with AD. These co‐occurring lesions and total lesion burden are associated with a higher likelihood of dementia and severe cognitive impairment. Even amongst other lesions, cerebral amyloid angiopathy (CAA) presents a strong risk for more severe cognitive impairment. CAA also shows moderate correlations to AD (rho = 0.31), suggesting that CAA pathology could present an underlying or related process of AD pathology. We hypothesize that there is a genetic overlap between CAA and AD and therefore we investigate the influence of known AD genes on CAA.MethodData come from 3,495 autopsied individuals with neuropathology and array data from the National Alzheimer’s Coordinating Centers (NACC). CAA was measured according to NACC neuropathology form guidelines. We used ordinal logistic regression to model APOE genotype and 22 other known AD variants with CAA severity while adjusting for sex, age at death, and AD pathology. For the 22 other known AD variants, we tested the lead variants reported by Kunkle et al. and labeled by closest gene. We modeled APOE by carrier status and genotype.ResultWe confirmed associations for APOE with CAA severity, when modeling APOE as e4 dosage (OR=2.34, p<0.001) or by genotype (e3/e4: OR=1.96, p<0.001; e4/e4: OR=5.76, p<0.001). However, we did not see a significant association between CAA severity and APOEe2 carriers, as others have reported. Association persisted when including AD pathology terms in the model, even when extending to interaction‐based models. Genetic variations in 7 of the 22 known AD genes (BIN1, HLA‐DRB1, TREM2, CLU, PICALM, SORL1, SLC24A4) showed significant associations with CAA while accounting for AD pathology.ConclusionWe confirmed strong associations of APOEe4 with CAA in a large clinical population. We modeled other known AD genes and 7 of them showed significant associations with CAA, demonstrating genetic overlap between AD and CAA pathologies. This study suggests that there is genetic overlap between CAA and AD pathology that could point to shared disease mechanisms for the targeting and treatment of AD.