Variations in menopause etiologies, from surgical manipulation to a natural transition, can impact cognition in both healthy and neurodegenerative aging. Although abundant research has demonstrated impacts from surgical versus transitional menopause, such as variations in timing of menopause, both variations in initiation of menopause and length of time since menopause, but not all avenues have been systematically evaluated. Further, assessments of variations in hormone therapies have demonstrated marked outcomes on the brain and cognition in different menopause etiologies, and results can differ depending on type of hormone, combination of hormones, dose, route of administration, among other factors, in regard to healthy aging. Further, the impact of the endocrine system on neurodegenerative disease is multifaceted. Research has highlighted that the endocrine system not only impacts neurodegeneration, such as in Alzheimer’s disease (AD), but that fluctuations in the endocrine system might be strong mediators in disease prevalence and progression. This dissertation seeks to understand how factors such as menopause etiology, biological sex, and hormone therapy impact normative and neurodegenerative aging. Assessments in a rat model of normal aging of progestogen-based hormone therapy given during the transition to menopause demonstrated attenuation of impairment seen with transitional menopause that was working memory specific. In evaluating a rat model of AD, there were distinct trends in neuropathology and associated cognitive changes in males and females with and without gonadal hormone deprivation. Further, assessment of transitional menopause in this AD model yielded an interaction between follicular depletion and genotype for neuropathology that was not present in cognitive assessments. Together, these dissertation chapters highlight that there are a multitude of factors to consider when evaluating effects of menopause and that these variations in experience underscore a need for personalized medicine when selecting therapeutic targets for healthy and neurodegenerative aging that includes consideration of overall hormone milieu and menopause history. Further, these data suggest that the inclusion of males and females in the study of AD-related factors is crucial for understanding disease progression.

The experience of menopause, typically occurring in midlife, can be markedly diverse, with surgical or transitional onset that results in alterations in circulating ovarian hormones and reproductive cyclicity. Such diverse experiences can coincide with the onset of symptoms and indications that impact long-term health outcomes. Indeed, prior work has shown that various facets of the menopausal experience can modulate later cardiovascular, immune, cognitive, and affective risks, making menopause a critical timepoint during aging. While clinical research provides great insight into numerous variables of interest, preclinical research can extend insights into these areas more directly by probing putative mechanisms driving long-term health risks as well as systematic assessment of therapeutic interventions. Reproductive senescence in the female rat differs from that of humans, as ovarian hormone decline and follicular depletion are less pronounced at midlife in the rodent. With advances in rodent modeling, preclinical researchers can probe questions pertaining to age and menopause independently, facilitating systematic exploration of factors affecting aging. This dissertation explores the impact of chronological aging, menopause etiology, and reproductive hormone alterations using a multidisciplinary approach, evaluating numerous dimensions of behavioral and physiological changes including immunology, endocrinology, and behavioral neuroscience. Assessments of chronological aging, both in normal aging and neurodegenerative rodent models, showed that patterns of memory decline differ by memory type, with midlife highlighted as a unique timepoint for learning and memory changes. Using several distinct rodent models of menopause in conjunction with a novel preclinical hysterectomy model, differences in cognitive and physiological profiles were observed. Notably, these effects depended upon age at surgery and ovarian status. Finally, evaluations of hormone therapy which were mapped on to variants of clinically-relevant menopause models provided further context into the patterns of nuanced cognitive effects revealed within the clinical literature. Collectively, these dissertation chapters delineate a myriad of factors to consider when evaluating cognitive and physiological outcomes associated with menopause. Maximizing communication and collaboration across preclinical and clinical realms of menopause research will best leverage and facilitate translational outcomes. Such exchanges will ultimately create a framework to propel the understanding of hormone-brain-cognition relationships, optimizing care for women at midlife and beyond.