PT - JOURNAL ARTICLE AU - V. Alexandra Moser AU - Christian J. Pike TI - Obesity Accelerates Alzheimer-Related Pathology in <em>APOE4</em> but Not <em>APOE3</em> Mice AID - 10.1523/ENEURO.0077-17.2017 DP - 2017 Jun 12 TA - eneuro PG - ENEURO.0077-17.2017 4099 - http://www.eneuro.org/content/early/2017/06/12/ENEURO.0077-17.2017.short 4100 - http://www.eneuro.org/content/early/2017/06/12/ENEURO.0077-17.2017.full AB - Alzheimer’s disease (AD) risk is modified by both genetic and environmental risk factors, which are believed to interact to cooperatively modify pathogenesis. Although numerous genetic and environmental risk factors for AD have been identified, relatively little is known about potential gene-environment interactions in regulating disease risk. The strongest genetic risk factor for late-onset AD is the ε4 allele of apolipoprotein E (APOE4). An important modifiable risk factor for AD is obesity, which has been shown to increase AD risk in humans and accelerate development of AD-related pathology in rodent models. Potential interactions between APOE4 and obesity are suggested by the literature but have not been thoroughly investigated. In the current study, we evaluated this relationship by studying the effects of diet-induced obesity in the EFAD mouse model, which combines familial AD transgenes with human APOE3 or APOE4. Male E3FAD and E4FAD mice were maintained for 12 weeks on either a control diet or a western diet high in saturated fat and sugars. We observed that metabolic outcomes of diet-induced obesity were similar in E3FAD and E4FAD mice. Importantly, our data showed a significant interaction between diet and APOE genotype on AD-related outcomes in which western diet was associated with robust increases in amyloid deposits, β-amyloid burden and glial activation in E4FAD but not in E3FAD mice. These findings demonstrate an important gene-environment interaction in an AD mouse model that suggests that AD risk associated with obesity is strongly influenced by APOE genotype.Significance Statement APOE4 is the strongest genetic risk factor for Alzheimer’s disease, but not all APOE4 carriers will develop the disease suggesting that APOE genotype interacts with other factors to modulate Alzheimer’s risk. Here we show that diet-induced obesity interacts with APOE4 genotype to increase Alzheimer’s-like pathology in an Alzheimer’s transgenic mouse model that contains human APOE3 versus APOE4 isoforms. Interestingly, mice with APOE3 do not show diet-induced increases in pathology, suggesting that the adverse effects of obesity on Alzheimer’s risk may be limited to APOE4 carriers. These findings identify an important gene-environment interaction that may have significant impact for understanding Alzheimer’s risk and etiology and promoting development of targeted therapeutic approaches that incorporate both obesity and APOE genotype.