AbstractAlzheimer’s disease (AD) is a fatal cognitive disorder with proteinaceous brain deposits, neuroinflammation, cerebrovascular dysfunction, and extensive neuronal loss over time. AD is a multifactorial disease, and lifestyle factors, including diet, are likely associated with the development of AD pathology. Since obesity and diabetes are recognized as risk factors for AD, it might be predicted that a high-fat diet (HFD) would worsen AD pathology. However, modeling HFD-induced obesity in AD animal models has yielded inconclusive results. Some studies report a deleterious effect of HFD on Aβ accumulation, neuroinflammation, and cognitive function, while others report that HFD worsens memory without affecting AD brain pathology. Moreover, several studies report no major effect of HFD on AD-related phenotypes in mice, while other studies show that HFD might, in fact, be protective. The lack of a clear association between dietary fat consumption and AD-related pathology and cognitive function in AD mouse models might be explained by experimental variations, including AD mouse model, sex and age of the animals, composition of the HFD, and timeline of HFD consumption. In this review, we summarize recent studies that aimed at elucidating the effect of HFD-induced obesity on AD-related pathology in mice and provide an overview of the factors that may have contributed to the results reported in these studies. Based on the heterogeneity of these animal model studies and given that the human population itself is quite disparate, it is likely that people will benefit most from individualized nutritional plans based on their medical history and clinical profiles.