Metabolic Shifts Precede Cognitive Decline in the Male hAß‐KI Alzheimer's Mouse Model

A major barrier in AD research is the lack of animals that recapitulate sporadic AD, which accounts for most human cases. Recently, a novel mouse model (hAβ‐KI) was developed by introducing a three‐point mutation that humanizes the beta‐amyloid peptide. These mice exhibit age‐dependent cognitive decline and beta‐amyloid accumulation. However, limited research has been conducted related to AD risk factors and sex‐specific responses in this model. Male and female control and hAß‐KI mice were assessed at ages 4, 8, 10, 12 and 15 months. Body composition (bone mineral density, lean and fat mass) and metabolic function (respiratory exchange rate, energy expenditure, and activity levels) were evaluated, in addition to insulin tolerance testing (ITT). An open field test (OFT) was performed to evaluate anxiety‐like behaviors, and novel object location (NOLT) and recognition tests (NORT) were conducted to measure cognitive impairment at endpoint. With aging, the male hAß‐KI mice exhibited increased body and fat mass %, decreased lean mass %, decreased activity, and impaired glucose handling prior to confirmed cognitive impairment by NORT and NOLT. In contrast, the female hAß‐KI did not display similar differences compared to controls. These findings support the utility of this model as a valuable tool for investigating systemic risk factors related to sporadic AD, and the absence of similar differences in the females highlights the importance of considering sex as a variable in AD pathology.