How women’s reproductive life-history relates to cognitive decline and neuropathology in Alzheimer’s disease and related dementias

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PROJECT SUMMARY There is a critical need to understand conditions across the lifespan that may contribute to sex and gender differences in Alzheimer’s disease and related dementias (ADRD) etiologies. We focus on reproductive history, the most fundamental contributor to sex-specific health effects. Pregnancy and lactation are sensitive periods of plasticity for human mothers as well as other mammals. During these life phases, permanent, re-organizing effects transpire in various physiological systems, including the brain. Therefore, it is plausible that women’s reproductive patterns modify the risks and mechanisms involved in neuropathogenesis across the lifespan. We are galvanized by pilot results that both pregnancy and breastfeeding provided protection against women’s ADRD onset as well as evidence of motherhood-related neurocognitive benefits in animal systems and human postpartum neuroimaging studies. We capitalize on our trans-disciplinary perspective. Our project is cost- efficient in utilizing available data and resources from an NIA-funded, large cohort study. We will analyze data collected from 7,479 post-menopausal women age 65+ who participated in the Women’s Health Initiative (WHI) Memory Study (WHIMS) and from the subset of 2,304 women in the WHI Study of Cognitive Aging (WHISCA). We will also conduct new measurements of brain atrophy in existing MRI images that were collected from the subset of 1,403 women in the WHIMS-MRI study. We will use a highly sensitive, voxel-wise approach that is powerful for visualizing sub-regional patterns of disease-related atrophy. Aim 1 will examine how women’s history of pregnancy relates to ADRD classification, verbal memory, hippocampal ischemic volume, and atrophy using voxel-wise approaches to measure cortical gray matter thickness and subcortical gray matter density. Aim 2 will examine how women’s history of breastfeeding relates to the same list of ADRD-related pathology outcomes. Both aims will test the interaction of APOE-ε4 carrier status. The ε4 allele is associated with miscarriage, reduced fertility, and weaker estrogenic neuroprotection compared to ε3 and ε2, in addition to its association with enhanced AD risk in some demographic groups. We predict that pregnancy-related and breastfeeding-related ADRD resilience will be weaker in ε4 carriers. Also, we suspect reproductive history could potentially exert differential effects on etiological pathways involved in different forms of dementia. Therefore, we will conduct exploratory analyses stratifying the cohort by global ischemia. After this project, we plan to pursue an R01 to examine endocrine, immune, cardiovascular, and metabolic biomechanisms, working towards designing clinical risk assessment tools. This project is responsive to the Notice of Special Interest: Sex and Gender Differences in AD/ADRD which invites proposals on life course factors e.g., reproductive history, and sex-specific risk factors, e.g., pregnancy. We address NIA’s ADRD Research Implementation Milestones 1.I to “identify critical periods of life and critical lifestyle and other parameters with respect to cognitive impairment and dementia prevention” and 1.B to “employ a life-course approach” examining “information on early life exposures/events.”