APOE genotype affects metabolic and Alzheimer-related outcomes induced by Western diet in female EFAD mice

Abstract

Development of Alzheimer's disease (AD) is regulated by interactive effects of genetic and environmental risk factors. The most significant genetic risk factor for AD is the ε4 allele of apolipoprotein E (APOE4), which has been shown to exert greater AD risk in women. An important modifiable AD risk factor is obesity and its associated metabolic dysfunctions. Whether APOE genotype might interact with obesity in females to regulate AD pathogenesis is unclear. To investigate this issue, we studied the effects of Western diet (WD) on female EFAD mice, a transgenic mouse model of AD that includes human APOE alleles ε3 (E3FAD) and ε4 (E4FAD). EFAD mice were fed either control (10% fat, 7% sugar) or WD (45% fat, 17% sugar), and both metabolic and neuropathologic outcomes were determined. Although E4FAD mice generally exhibited poorer metabolic status at baseline, E3FAD mice showed greater diet-induced metabolic impairments. Similarly, E4FAD mice exhibited higher levels of AD-related pathology overall, but only E3FAD showed significant increases on select measures of β-amyloid pathology after exposure to WD. These data demonstrate a gene–environment interaction between APOE and obesogenic diets in females. Understanding how AD-promoting effects of obesity are modulated by genetic factors will foster the identification of at-risk populations and development of preventive interventions.—Christensen, A., Pike, C. J. APOE genotype affects metabolic and Alzheimer-related outcomes induced by Western diet in female EFAD mice. FASEB J. 33, 4054–4066 (2019). www.fasebj.org.