Cross-Species Analyses Identify Dlgap2 as a Regulator of Age-Related Cognitive Decline and Alzheimer’s Dementia

Genetic mechanisms underlying age-related cognitive decline and dementia remain poorly understood. Here, we take advantage of the Diversity Outbred mouse population to utilize quantitative trait loci mapping and identify Dlgap2 as a positional candidate responsible for modifying working memory decline. To evaluate the translational relevance of this finding, we utilize longitudinal cognitive measures from human patients, RNA expression from post-mortem brain tissue, data from a genome-wide association study (GWAS) of Alzheimer’s dementia (AD), and GWAS results in African Americans. We find an association between Dlgap2 and AD phenotypes at the variant, gene and protein expression, and methylation levels. Lower cortical DLGAP2 expression is observed in AD and is associated with more plaques and tangles at autopsy and faster cognitive decline. Results will inform future studies aimed at investigating the cross-species role of Dlgap2 in regulating cognitive decline and highlight the benefit of using genetically diverse mice to prioritize novel candidates. [Display omitted] •Dlgap2 QTL associates with working memory decline in Diversity Outbred (DO) mice•DLGAP2 variants associate with AD by GWAS in human populations•DLGAP2 gene and protein expression are associated with cognitive decline in humans•Results highlight translational relevance of DO mice for studying complex traits Ouellette et al. identify Dlgap2 as a potential modifier of working memory in an aged Diversity Outbred (DO) mouse population. The cross-species significance of this finding is highlighted by the association between human DLGAP2 and Alzheimer’s disease phenotypes at the variant, gene expression, and methylation levels.