Alzheimer’s disease (AD) is a neurodegenerative disease characterized by a set of progressively appearing pathologies. Accumulation of hyperphosphorylated tau (p-tau) and tau-derived tangles (NFTs) are major hallmarks of the disease. It has long been suspected that the accumulation of p-tau may begin already during the prodromal stages of AD, preceding overt cognitive decline. Preventative interventions during this early window may offer the greatest potential for disease modification. Rodent models remain indispensable in AD research, providing valuable insights into the complex mechanisms underlying the pathology. But a limitation with rodents is that they are largely resistant to formation of p-tau and NFTs. As a result, many have employed strategies to artificially express human and/or mutated forms of p-tau in rodent models. However, the insights gained from these approaches remain limited, as it has proven challenging to distinguish genuine disease-relevant mechanisms from artifacts caused by the overexpression of a foreign protein. This project aims to (I) Use anesthesia to induce endogenous p-tau in McGill-R-Thy1-APP transgenic rats and wild-type Wistar rats, and (II) investigate the effects of high-intensity interval training (HIIT) on such endogenous p-tau. HIIT interventions will be applied in both acute and chronic paradigms to assess their potential in mitigating p-tau and ameliorating cognitive deficits. This project may provide valuable insights into non-pharmacological strategies for preventing or slowing the development of AD, with implications for at-risk populations, including older adults exposed to repeated anesthesia.