Identification of Genetic Loci and Sex Differences Associated with Amyloid Burden Using the AD‐BXD Mouse Population

AbstractBackgroundIn light of the rising prevalence of both diet‐induced obesity and Alzheimer’s Disease (AD) in the developed world, the influence of a high‐fat diet (HFD) on AD progression was investigated. Beta‐amyloid 1‐42 (Aβ42), in particular, was examined as little is known about the extent to which an individual’s genetics, sex, and diet determine the onset and progression of this classic AD neuropathology.MethodAD‐BXD mice were generated by crossing female 5XFAD mice to male members of the BXD reference panel (Neuner, et al. 2019). Cortical Aβ42 levels were quantified (ELISA) from four hundred and twenty‐two mice (235 female, 187 male) across 52 AD‐BXD strains fed either a 6kcal% extruded control diet (n = 227) or 45kcal% HFD (n = 195) at 10 weeks of age until 3, 6, or 14 months old.ResultWhile a 45kcal% HFD did not alter cortical Aβ42 levels in 5XFAD mice relative to control diet, there was a main effect of genetic background (strain) and sex. Specifically, wide variation in cortical Aβ42 was observed across the AD‐BXD mouse population that was highly heritable (h2≈0.9), and females displayed greater Aβ42 levels than males. Quantitative trait locus (QTL) mapping revealed significant genetic loci associated with increased amyloid burden with aging, indicating sequence differences on chromosomes (Chr) 19 and X that may underlie the observed sex differences when age was included as covariates. Furthermore, we identified several missense mutations within our Chr 19 QTL that could explain differences in Aβ42 phenotype, and expression QTL analysis is underway to identify putative regulatory variants of cortical amyloid burden.ConclusionWe found that genetic factors, strain and sex, are key determinants of cortical amyloid burden – but not diet (environmental factor) suggesting involvement of other regulators/pathways in eliciting cognitive decline in AD‐BXD mouse population (Dunn et. al., AAIC 2021) Resolving genetic modifiers of amyloid burden located on Chr 19 and X may reveal novel targets for anti‐amyloid therapeutics and provide a possible mechanistic explanation for why females (XX) are at a higher risk for developing AD than males (XY).