Abstract
Hippocampal sclerosis of aging (HS-Aging) is a common neurodegenerative condition associated with dementia. To learn more about genetic risk of HS-Aging pathology, we tested gene-based associations of the ABCC9 gene, which was reported to be associated with HS-Aging pathology in previous studies. Genetic data were obtained from the Alzheimer’s Disease Genetics Consortium (ADGC), linked to autopsy-derived neuropathological outcomes from the National Alzheimer’s Coordinating Center (NACC). Of 3,730 subjects with both genotype and autopsy information available to us, those who died at age 60 years or older were included in this study. After applying inclusion/exclusion criteria and quality control filtering, data from 3,251 participants of European ancestry were used in the analyses. Of the 3,251 subjects included in the study, 271 (8.3%) were identified as a HS-Aging case. The ABCC9 gene was significantly associated with HS-Aging when assuming a recessive mode of inheritance. For sensitivity analysis, we confirmed the same results even in people aged 80 years or older at death. The significant gene-based association between ABCC9 and HS-Aging appeared to be driven by a region in which significant haplotype-based associations were found. We further tested the haplotypes as an expression quantitative trait locus (eQTL) using two different public-access brain gene expression databases. The HS-Aging pathology protective ABCC9 haplotype was associated with decreased ABCC9 expression, and the results were consistent in two independent datasets. The gain-of-function haplotype in the ABCC9 gene was protective for HS-Aging in older people.