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
基本信息
- 批准号:10607612
- 负责人:
- 金额:$ 7.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Abeta clearanceAccelerationAddressAdultAgeAgingAllelesAlzheimer disease detectionAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease riskAlzheimer’s disease biomarkerAmenorrheaApolipoproteinsAtrophicBehaviorBehavioralBiologicalBrainClinicalCognitionCognitiveComplexDataDevelopmentDiscriminationDiseaseDisease ProgressionDisparateEarly DiagnosisElderlyEmotionalEndocrineEstradiolEstrogen declineEstrogensExhibitsFemaleGenetic RiskGonadal Steroid HormonesHealthHippocampusHyperactivityImpaired cognitionInterventionLongevityMagnetic Resonance ImagingMeasuresMedialMediatingMemoryMenopauseMenstrual cycleMentorshipMethodsNeurobiologyNeurosecretory SystemsOutcomePathogenesisPathologyPerformancePerimenopausePhasePostmenopausePredispositionPremenopausePreventionProcessResearchResolutionRestRiskRisk FactorsSex DifferencesSignal TransductionStimulusSymptomsTemporal LobeTherapy trialTimeWorkage relatedaging brainapolipoprotein E-4brain healthcareercognitive performanceendophenotypeexperiencefunctional MRI scangenetic risk factorhealthy aginghormone therapyinnovationinsightmalemiddle ageneuroimagingneuroprotectionnormal agingnovel strategiespre-clinicalreproductivereproductive hormonereproductive senescencesalivary assaysexskillssupport networktraining opportunity
项目摘要
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
项目成果
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