Estrogen Declines with Menopause: Impacts on the Medial Temporal Lobe Network and Emotional Memory in Aging Females at Genetic Risk for Alzheimer’s Disease

雌激素随更年期下降：对有阿尔茨海默病遗传风险的老年女性内侧颞叶网络和情绪记忆的影响

• 批准号: 10607612
• 负责人: Hannah Ballard
• 金额: $ 7.32万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-16 至 2026-03-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607612
• 关键词: Abeta clearance; Acceleration; Address; Adult; Age; Aging; Alleles; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amenorrhea; Apolipoproteins; Atrophic; Behavior; Behavioral; Biological; Brain; Clinical; Cognition; Cognitive; Complex; Data; Development; Discrimination; Disease; Disease Progression; Disparate; Early Diagnosis; Elderly; Emotional; Endocrine; Estradiol; Estrogen decline; Estrogens; Exhibits; Female; Genetic Risk; Gonadal Steroid Hormones; Health; Hippocampus; Hyperactivity; Impaired cognition; Intervention; Longevity; Magnetic Resonance Imaging; Measures; Medial; Mediating; Memory; Menopause; Menstrual cycle; Mentorship; Methods; Neurobiology; Neurosecretory Systems; Outcome; Pathogenesis; Pathology; Performance; Perimenopause; Phase; Postmenopause; Predisposition; Premenopause; Prevention; Process; Research; Resolution; Rest; Risk; Risk Factors; Sex Differences; Signal Transduction; Stimulus; Symptoms; Temporal Lobe; Therapy trial; Time; Work; age related; aging brain; apolipoprotein E-4; brain health; career; cognitive performance; endophenotype; experience; functional MRI scan; genetic risk factor; healthy aging; hormone therapy; innovation; insight; male; middle age; neuroimaging; neuroprotection; normal aging; novel strategies; pre-clinical; reproductive; reproductive hormone; reproductive senescence; salivary assay; sex; skills; support network; training opportunity

Project Summary Relative to males, females exhibit greater cognitive decline and are more severely impacted by age-related disease (e.g., Alzheimer’s disease (AD)). The impact of AD risk factors such as the apolipoprotein E4 (ApoE4) allele, accumulation of AD biomarkers, and cognitive impairment with AD is more pronounced in females and does not simply reflect their greater longevity. The reasons for these sex differences remains unclear, thus, it is important to probe the biological underpinnings of sex distinctions in the aging brain. Menopause may contribute to the disproportionate impact of aging on females as it is accompanied by a large decrease in estrogens, which have neuroprotective effects on brain health and cognition. Notably, AD pathology begins to develop decades before clinical symptom onset, and this preclinical phase of AD overlaps with the menopausal transition during mid-life (late 40s-early 50s). Thus, the depletion of estrogen with menopause may increase female susceptibility to AD pathogenesis. In fact, changes in reproductive hormones have been associated with increased risk for developing AD and poor memory function. The medial temporal lobe (MTL) network, which is important for memory, is dysfunctional in aging and AD. Deficits in emotional memory are observed with the menopausal transition and early development of AD pathology. Moreover, early changes in emotional memory brain networks, including the MTL, have been discovered in preclinical AD and are the first to accumulate AD pathology. Given substantial evidence of interactions between menopause and early AD, interrogating the linkage between reproductive aging and AD risk is critical for uncovering sex-specific factors involved in age-related disease and creating novel approaches to treatment or prevention. However, work on the impact of menopause in aging females is lacking, especially in the context of genetic risk for AD. To address these gaps, the proposed project will examine the effect of estrogen decline with menopause on MTL network dynamics and emotional memory in cognitively normal females at risk for AD (e.g., ApoE4+). Aim 1 will establish the relationship between estrogen levels and AD risk in aging females, Aim 2 will quantify the impact of estrogen on MTL network connectivity in aging females at risk for AD, and Aim 3 will determine the effect of estrogen on MTL activation and emotional memory in females at risk for AD. Together, the proposed work will provide important new insight into the biological mechanisms underlying sex differences in AD. Examining the impact of menopause in cognitively normal aging during the same timeframe that AD pathology begins could provide a novel approach towards the early detection of AD. These aims will offer many training opportunities for the applicant, who will gain proficiency in complex neuroimaging analyses, enhanced statistical skills, application of aging research towards disease states (e.g., AD), and valuable mentorship experience. The training opportunities facilitated by this work will accelerate the applicant’s transition to an independent career focused on sex differences in aging outcomes.

项目总结