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

女性的生殖生活史与阿尔茨海默病和相关痴呆症的认知能力下降和神经病理学有何关系

• 批准号: 10740751
• 负责人: Molly Maurer Fox
• 金额: $ 21.72万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740751
• 关键词: Address; Adopted; Affect; Age; Alleles; Alzheimer' s disease related dementia; Amyloid beta-Protein Precursor; Anatomy; Animals; Anthropology; Assessment tool; Atrophic; Attenuated; Biological; Biological Markers; Biology; Birth; Brain; Breast Feeding; California; Cardiovascular system; Classification; Cognitive; Cognitive aging; Cohort Studies; Data; Data Sources; Dementia; Dependence; Detection; Disease; Elderly; Endocrine; Etiology; European ancestry; Event; Exhibits; Fertility; Funding; Genetic Polymorphism; Geriatric Psychiatry; Gravidity; Health; Hippocampus; Hormones; Human; Image; Immune; Impaired cognition; Interview; Ischemia; Lactation; Life; Life Cycle Stages; Life Style; Link; Longevity; Magnetic Resonance Imaging; Mammals; Measurement; Measures; Memory; Metabolic; Methodology; Methods; Modeling; Mothers; Neurocognitive; Neurologic; Neuropathogenesis; Neurosciences; Outcome; Participant; Pathogenesis; Pathology; Pathway interactions; Pattern; Phase; Phenotype; Physiological; Physiology; Pilot Projects; Population; Populations at Risk; Postmenopause; Postpartum Period; Pregnancy; Pregnancy Histories; Prevention; Process; Proxy; Recording of previous events; Reproductive History; Research; Resources; Risk; Risk Assessment; Risk Factors; Rodent; Role; Sample Size; Sex Differences; Spontaneous abortion; Statistical Methods; Structure; System; Testing; Thick; Time; Verbal Learning; Visualization; Woman; Women' s Health; Work; adjudication; age related; apolipoprotein E-4; carrier status; cerebral atrophy; child bearing; clinical diagnosis; clinical risk; cohort; cost efficient; critical period; dementia risk; density; design; disorder risk; early life exposure; empowerment; epidemiology study; estrogenic; experience; follow-up; gender difference; glucose metabolism; gray matter; high risk; hormone therapy; human old age (65+); improved; interest; ischemic lesion; life history; lipid metabolism; malignant breast neoplasm; men; middle age; morphometry; motherhood; neuroimaging; neuropathology; neuroprotection; novel; parity; pregnancy failure; pregnant; proband; programs; protective effect; recruit; reproductive; resilience; resilience factor; secondary analysis; sex; verbal

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.”

项目摘要 有一个关键的需要，以了解整个生命周期的条件，可能有助于性和性别 阿尔茨海默病和相关痴呆（ADRD）病因的差异。我们关注的是生殖史， 对特定性别的健康影响的最基本的贡献者。妊娠期和哺乳期是 对人类母亲和其他哺乳动物的可塑性。在这些生命阶段，永久的，重新组织 影响在包括大脑在内的各种生理系统中发生。因此，有理由认为，女性的 生殖模式改变了整个生命周期中神经发病机制的风险和机制。我们 试验结果表明，怀孕和母乳喂养都能保护妇女免受 ADRD发作以及动物系统和人类中母性相关神经认知益处的证据 产后神经影像学研究。我们利用我们的跨学科视角。我们的项目是成本- 有效利用来自NIA资助的大型队列研究的可用数据和资源。我们将分析数据 从7,479名65岁以上的绝经后妇女中收集，这些妇女参加了妇女健康倡议（WHI） 记忆研究（WHIMS）和WHI认知老化研究（WHISCA）中的2，304名女性的子集。 我们还将在现有的MRI图像中对脑萎缩进行新的测量，这些图像是从 WHIMS-MRI研究中的1，403名女性的子集。我们将使用一种高度敏感的体素方法， 对于可视化疾病相关萎缩的次区域模式是强大的。目标1将考察女性的历史 与ADRD分类、言语记忆、海马缺血体积和萎缩有关。 体素方式的方法来测量皮质灰质厚度和皮质下灰质密度。目标2将 检查妇女的母乳喂养史与ADRD相关病理结果的相同列表之间的关系。 这两个目标都将测试APOE-ε4携带者状态的相互作用。ε4等位基因与流产有关， 与ε3和ε2相比，雌激素性神经保护作用较弱，此外， 在某些人口统计学群体中增加AD风险。我们预测怀孕和哺乳相关的 在ε4载波中，ADRD弹性将较弱。同时，我们怀疑生育史可能会 对不同形式痴呆症的病因学途径的不同影响。因此，我们将进行 通过全脑缺血对队列进行分层的探索性分析。在这个项目之后，我们计划追求R 01， 研究内分泌，免疫，心血管和代谢生物力学，致力于设计临床 风险评估工具。该项目是响应特别关注的通知：性别和性别差异 在AD/ADRD中，邀请关于生命过程因素的建议，例如，生殖史和性别特异性风险因素， 例如，在一个实施例中，怀孕我们提出NIA的ADRD研究实施计划1.I，以“确定 生活和关键的生活方式和其他参数方面的认知障碍和痴呆症的预防”， 1.B“采用生命过程方法”，审查“关于生命早期接触/事件的信息”。