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Genetics, diet, and sex interact to modulate cognitive decline in Alzheimer’s disease
Author(s) -
Dunn Amy R.,
O'Connell Kristen M.S.,
Kaczorowski Catherine C.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.043779
Subject(s) - disease , cognition , cognitive decline , population , alzheimer's disease , cognitive aging , hippocampus , biology , working memory , psychology , neuroscience , gerontology , genetics , medicine , dementia , environmental health
Background Alzheimer’s disease (AD) etiology is complex, with disease risk and progression mediated by individual genetic and environmental factors. Additionally, there are significant sex differences in aging, brain metabolism, and AD risk. This complexity adds challenges to understanding disease mechanisms and developing treatment strategies that will be effective across the AD population; human studies have been limited in understanding these interacting effects due to human genome complexity and difficulty controlling environmental factors, such as diet. Method We recently developed a population of genetically diverse mice carrying the 5XFAD transgene (AD‐BXDs; Neuner, et al. 2019). Because they model human genetic heterogeneity, AD‐BXDs are ideally suited to investigate translationally‐relevant gene‐environment and sex interactions. Here, we used AD‐BXDs to determine how genetics, diet, and sex interact to modify AD‐related symptoms. We fed a chronic 45% high fat diet (HFD) starting at ∼2.5mo of age to 39 strains of AD‐BXDs and nontransgenic littermates (Ntg‐BXD). We monitored hippocampus‐dependent cognitive function using y‐maze (working memory) and contextual fear conditioning (short‐ and long‐term memory) across their lifespan. Result Gene‐by‐diet interactions accounted for a significant proportion of variance in cognitive phenotypes across the population of AD‐BXDs and Ntg‐BXDs, and the effect of HFD differed depending on sex. We saw a protective effect of HFD in female AD mice on working memory through middle age that was not seen in male mice. By 14mo, female Ntg – but not AD – mice on HFD experienced significantly worse cognitive decline than those on chow—an effect that again was not seen in males. Conclusion Our results suggest that diet affects AD risk and progression differentially based on sex and genetic background: intriguingly, HFD may be protective in female AD mice while being detrimental to cognitive function in “normal” aging. These findings in the AD‐BXDs demonstrate individual variation in how diet affects AD risk and cognitive aging, and that the mechanisms underlying this variation are ripe for discovery. Future analyses will build upon these data to identify genetic and molecular targets contributing to AD pathogenesis sensitized by sex and HFD that may be exploited to delay, prevent or treat AD.