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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 \u03b54 allele of apolipoprotein E (<jats:italic>APOE<\/jats:italic>4). 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<jats:italic>APOE<\/jats:italic>4 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 (DIO) in the EFAD mouse model, which combines familial AD transgenes with human<jats:italic>APOE<\/jats:italic>3 or<jats:italic>APOE<\/jats:italic>4. 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 DIO were similar in E3FAD and E4FAD mice. Importantly, our data showed a significant interaction between diet and<jats:italic>APOE<\/jats:italic>genotype on AD-related outcomes in which Western diet was associated with robust increases in amyloid deposits, \u03b2-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<jats:italic>APOE<\/jats:italic>genotype.<\/jats:p>","DOI":"10.1523\/eneuro.0077-17.2017","type":"journal-article","created":{"date-parts":[[2017,6,13]],"date-time":"2017-06-13T00:30:34Z","timestamp":1497313834000},"page":"ENEURO.0077-17.2017","source":"Crossref","is-referenced-by-count":74,"title":["Obesity Accelerates Alzheimer-Related Pathology in<i>APOE4<\/i>but not<i>APOE3<\/i>Mice"],"prefix":"10.1523","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7365-0176","authenticated-orcid":false,"given":"V. 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