APOE4 rat model of Alzheimer’s disease: sex differences, genetic risk and diet

Abstract The strongest genetic risk factor for Alzheimer’s disease (AD) is the Ɛ4 allele of apolipoprotein E (ApoE ɛ4). A high fat diet also adds to the risk of dementia and AD. In addition, there are sex differences as women carriers have a higher risk of an earlier onset and rapid decline in memory than men. The present study looked at the effect of the genetic risk of ApoE ɛ4 together with a high fat/high fructose diet (HFD/HSD) on brain function in male and female rats using magnetic resonance imaging. We hypothesized female carriers would present with deficits in cognitive behavior together with changes in functional connectivity as compared to male carriers. Four-month-old wildtype and human ApoE ɛ4 knock-in (TGRA8960), male and female Sprague Dawley rats were put on a HFD/HSD for four months. Afterwards they were imaged for changes in function using resting state BOLD functional connectivity. Images were registered to, and analyzed, using a 3D MRI rat atlas providing site-specific data on 173 different brain areas. Resting state functional connectivity showed male wildtype had greater connectivity between areas involved in feeding and metabolism while there were no differences between female and male carriers and wildtype females. The data were unexpected. The genetic risk was overshadowed by the diet. Male wildtype rats were most sensitive to the HFD/HSD presenting with a deficit in cognitive performance with enhanced functional connectivity in neural circuitry associated with food consumption and metabolism.