Neuronal changes arise early in the perimenopausal transition and HIIT did not improve recognition memory when initiated in menopause. Highlights: The menopausal decline in ovarian estrogen production increases the risk of Alzheimer's disease (AD). The chronological development of this connection is not well defined because of the lack of animal models that recapitulate the time course of menopause. 4-vinylcyclohexene diepoxide (VCD)-induced ovarian failure provides a model that simulates the average human experience in the transition from perimenopause to menopause. We demonstrate that cognitive and biochemical effects related to AD pathology are present from the earliest available timepoint in perimenopause in VCD mice. This work highlights the importance of examining the time course in the progression to menopause and the use of VCD as a model to investigate changes in the brain.

Female mice were injected with VCD for 15 days. Novel object recognition tests (NORT) were conducted during (perimenopause) and after (menopause) ovarian failure (n = 7). HIIT was initiated in menopause and mice underwent NORT testing after 2 and 8 weeks of HIIT (n = 5).

VCD mice had a lower discrimination index, and lower SNAP25 and NeuN expression in perimenopause. HIIT did not recover memory in VCD mice.