Relation of estrogen pathway genes to cognitive decline in elderly women and men

描述（由申请人提供）：这个以患者为导向的指导研究职业发展奖（K23）将为Sarah Janicki博士提供额外的教育和培训，使她成为认知能力下降和阿尔茨海默病（AD）激素介质的临床转化科学家。一个综合的多学科教学和实践培训计划已经制定，使Janicki博士能够实现以下目标：1)扩展她在衰老遗传流行病学先进方法方面的培训；2)学习和使用纵向数据分析技术；3)发展结构MRI数据的神经形态分析技术的专业知识；4)转变为独立的临床转化科学家。Janicki博士的培训项目得到了来自遗传学、流行病学、认知评估和阿尔茨海默病神经影像学方面的知名专家小组的坚定和热情的指导，并受益于优秀的智力环境、职业发展机会和大量的机构承诺。提出的研究计划的目的是确定雌激素生物合成途径基因变异对认知能力下降的贡献，并利用神经影像学分析来确定这些基因多态性影响不同种族老年男性和女性认知能力下降的潜在神经生物学途径。调查

DESCRIPTION (provided by applicant): This Mentored Patient-Oriented Research Career Development Award (K23) will provide additional education and training for Dr. Sarah Janicki to establish herself as a clinical translational scientist in the hormonal mediators of cognitive decline and Alzheimer's disease (AD). An integrated multidisciplinary didactic and practical training program has been developed to allow Dr. Janicki to accomplish the following goals: 1) extend her training in advanced methods in the genetic epidemiology of aging; 2) learn and use longitudinal data analytic techniques; 3) develop expertise in neuromorphometric analytic techniques of structural MRI data; 4) transition to an independent career as a clinical translational scientist. Dr. Janicki's training program is supported by committed and enthusiastic mentorship from a panel of renowned experts in the genetics, epidemiology, cognitive assessment and neuroimaging of AD, and benefits from an outstanding intellectual environment, opportunities for career growth, and substantial institutional commitment. The objectives of the proposed research plan are to determine the contribution of estrogen biosynthetic pathway gene variants to cognitive decline, and to employ neuroimaging analyses to determine the underlying neurobiological pathways through which polymorphisms in these genes affect cognitive decline in elderly men and women of different ethnicities. Investigations in the neuropathology, neuroimaging, and neuropsychological studies of AD suggest that it is an estrogen-sensitive disease. Many prior studies evaluating the effect of estrogen on cognitive decline and brain morphology in the elderly have used study populations receiving exogenous estrogen supplementation, since age-related declines in endogenous hormones do not allow accurate assessment of estrogen status. However, hormone replacement therapy may have different effects on brain morphology than does lifelong hormone exposure due to composition and administration late in life. This study uses variants in genes of known estrogen receptor and biosynthetic function (ESR1, ESR2, CYP17, CYP19, and HSD17B1) as instrumental variables to estimate the effects of single nucleotide polymorphisms (SNPs) on changes in neuropsychological cognitive assessments and structural brain outcomes. The study population includes elderly men and women from the Washington Heights-Inwood Community Aging Project (WHICAP) and the Alzheimer's disease Neuroimaging Initiative (ADNI). Confirmatory analyses of significant findings will be performed in the Rotterdam Study (RS). Exploratory aims will examine how the effects of estrogen SNPs may vary by ethnicity due to socioeconomic and cerebrovascular risk factors associated with risk for cognitive decline. This study will lay the groundwork for future R01 grant applications identifying mechanisms of hormone action that direct areas of intervention in AD. This application directly supports the National Institute on Aging's proposed mission to conduct genetic and biological research related to diseases associated with aging, its objective to understand health differences and inequities associated with race, ethnicity, and gender among older adults, and its stated commitment to foster the development of clinician scientists in aging.