The benefits of estradiol on cognitive aging in rats are independent from its effects on cardiometabolic health

Research in preclinical models of menopause indicates that exogenously administered estrogens positively impact cognitive aging. However, clinical evidence indicates that the effects of estrogen therapy on cognition are inconsistent and may be modulated by pre-existing cardiometabolic conditions. The extent to which cardiometabolic health affects the cognitive outcomes of estrogen therapy remains unclear. This study aimed to determine whether variations in cardiometabolic health, both prior to and resulting from different estradiol treatment regimens, are related to the ability of estradiol to improve the cognitive aging trajectory in ovariectomized Long-Evans rats. Cognitive function and health status were assessed at 10 months of age after which rats were ovariectomized and administered vehicle or various estradiol treatments. Rats were assessed again at 18 (middle age) and 22 (old age) months. Cognition was evaluated using a spatial memory radial-maze task. Health status was determined through body composition (dual-energy X-ray absorptiometry), glucose tolerance testing, and blood pressure (tail-cuff plethysmography). Results demonstrated that both continuous ongoing estradiol treatment and a previous 40-day estradiol exposure (terminated long before testing) significantly improved the cognitive aging trajectory from middle to old age. However, only continuous estradiol treatment had positive impacts on health measures; previous estradiol treatment provided no benefits to aging cardiometabolic systems. In contrast, a delayed estradiol treatment (initiated months after ovariectomy) provided no benefits for cognition but provided health benefits. Results indicated that estradiol impacts on cognition in healthy aging rats are separate from and not secondary to its effects on cardiometabolic health.