Abstract
Cerebral amyloid angiopathy (CAA) contributes to accelerated cognitive decline in Alzheimer’s disease (AD) dementia and is a common finding at autopsy. The APOEε4 allele and male sex have previously been reported to associate with increased CAA in AD. To inform biomarker and therapeutic target discovery, we aimed to identify additional genetic risk factors and biological pathways involved in this vascular component of AD etiology. We present a genome-wide association study of CAA pathology in AD cases and report sex- and APOE-stratified assessment of this phenotype. Genome-wide genotypes were collected from 853 neuropathology-confirmed AD cases scored for CAA across five brain regions, and imputed to the Haplotype Reference Consortium panel. Key variables and genome-wide genotypes were tested for association with CAA in all individuals and in sex and APOEε4 stratified subsets. Pathway enrichment was run for each of the genetic analyses. Implicated loci were further investigated for functional consequences using brain transcriptome data from 1,186 samples representing seven brain regions profiled as part of the AMP-AD consortium. We confirmed association of male sex, AD neuropathology and APOEε4 with increased CAA, and identified a novel locus, LINC-PINT, associated with lower CAA amongst APOEε4-negative individuals (rs10234094-C, beta = −3.70 [95% CI −0.49—−0.24]; p = 1.63E-08). Transcriptome profiling revealed higher LINC-PINT expression levels in AD cases, and association of rs10234094-C with altered LINC-PINT splicing. Pathway analysis indicates variation in genes involved in neuronal health and function are linked to CAA in AD patients. Further studies in additional and diverse cohorts are needed to assess broader translation of our findings.
Highlights
Alzheimer’s disease (AD), the most common form of dementia affecting the elderly, is definitively diagnosed at autopsy by the presence of both extracellular amyloidReddy et al acta neuropathol commun (2021) 9:93Cerebral amyloid angiopathy (CAA) at autopsy [12, 44]
Cerebral amyloid angiopathy associates with sex, APOEε4 and AD neuropathology A total of 821 neuropathologically confirmed AD cases from the Mayo Clinic Brain bank that were scored for CAA and passed genetic data quality control (Additional file 1: Figure S1) were included in this study
Genome-wide significant association was identified at a novel locus, LINC-PINT—rs10234094, with lower CAA in APOEε4 negative AD cases
Summary
Alzheimer’s disease (AD), the most common form of dementia affecting the elderly, is definitively diagnosed at autopsy by the presence of both extracellular amyloidReddy et al acta neuropathol commun (2021) 9:93CAA at autopsy [12, 44]. A genomewide association study (GWAS) identified significant association at the APOE locus [7], and pleiotropy analysis with ADNC (NP and NFT) nominated novel loci [14]. This prior work focused on combined assessment of both AD cases and controls, and a dichotomous or ordinal CAA phenotype. Enrichment strategies leveraging the full spectrum of genome-wide association results can identify biological pathways that may play a role in disease regardless of whether individual variants achieve genome-wide significance (GWS); these approaches have not yet been reported for CAA GWAS. The genetic architecture underlying risk for CAA in AD cases, and in the context of sex and APOEε4 genotype, is yet to be established
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