Sex-Dependent Progression of Alzheimer’s Disease Pathologies in a 3xTg AD Mouse Model Exposed to an Adolescent High Fat Diet

Metabolic disease is one of many factors that increases the risk for Alzheimer’s disease (AD). However this risk is age dependent. A high BMI in mid life increases your risk for AD, but a high BMI in late life decreasing this risk. Yet, there is a gap in knowledge on how obesity starting in early adolescence impacts AD onset. We hypothesized that the onset of AD pathologies, such as vascular decline and hyperglycemia, will present in both male and female 3xtg mice fed a high fat diet earlier then compared to low fat controls. In our study, we exposed male and female 3xtg and WT mice, at ~21 days to either a 10% low fat diet (LFD) or a 60% high fat diet (HFD) to further explore the connection between age, metabolic disease, and AD. Cerebral blood flux and glucose tolerance testing was conducted at 5 months and 9 months to track the progression of the disease in both a young adult time-point (5M) and an early middle age time-point (9M). We saw that at 5M female 3xtg mice on a HFD showed an extreme metabolic dysfunction, yet no deficits were detected in vascular health. The male 3xtg HFD group at the 5M timepoint showed metabolic dysfunction and vascular decline. Both male and female 3xTg HFD groups showed continued metabolic impairment at 9M. The WT F HFD group showed lower global cerebral blood flux values relative to the WT F LFD. However, the 3xTg F HFD had higher levels of global flux compared to the 3xTg LFD, indicating a possible protective effect. We aim to further explore these sex-dependents differences seen within AD, metabolic disease, and age to allow for a better understanding of the disease as a whole. R01 NS117754 T32 AG052375 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.