From the Rush Alzheimer's Disease Center (S.O., J.Y., L.Y., D.B., W.B., S.T., F.G., Y.W., J.A.S., D.A.B.), Rush University Medical Center, Chicago; Departments of Neurological Sciences (S.O., J.Y., L.Y., S.T., J.A.S., D.A.B.) and Internal Medicine (F.G.), Rush University Medical Center, Chicago, IL; Department of Epidemiology (J.Z.), University of Florida, Gainesville; Center for Translational & Computational Neuroimmunology (P.L.D.J.), Department of Neurology, Columbia University Irving Medical Center, New York; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (P.L.D.J.), Columbia University Irving Medical Center, New York, New York; and Department of Pathology (J.A.S.), Rush University Medical Center, Chicago, IL.
Neurology. 2023 Apr 4;100(14):e1474-e1487. doi: 10.1212/WNL.0000000000206833. Epub 2023 Jan 25.
Lifetime risk of Alzheimer disease (AD) dementia is twofold higher in women compared with men, and low estrogen levels in postmenopause have been suggested as a possible contributor. We examined 3 (, , and ) variants in association with AD traits as an indirect method to test the association between estrogen and AD in women. Although the study focus was on women, in a comparison, we separately examined molecular variants in men.
Participants were followed for an average of 10 years in one of the 2 longitudinal clinical pathologic studies of aging. Global cognition was assessed using a composite score derived from 19 neuropsychological tests' scores. Postmortem pathologic assessment included examination of 3 AD (amyloid-β and tau tangles determined by immunohistochemistry, and a global AD pathology score derived from diffuse and neurotic plaques and neurofibrillary tangle count) and 8 non-AD pathology indices. molecular genomic variants included genotyping and examining DNA methylation and RNA expression in brain regions including the dorsolateral prefrontal cortex (DLPFC) that are major players in cognition and often have AD pathology.
The mean age of women (N = 1711) at baseline was 78.0 (SD = 7.7) years. In women, molecular variants had the most consistent associations with AD traits. DNA methylation was associated with cognitive decline, tau tangle density, and global AD pathology score. RNA expression in DLPFC was related to cognitive decline and tau tangle density. Other associations included associations of and sequence variants and DNA methylation with cognition. RNA expressions in DLPFC of genes involved in signaling mechanisms of activated ERs were also associated with cognitive decline and tau tangle density in women. In men (N = 651, average age at baseline: 77.4 [SD = 7.3]), there were less robust associations between molecular genomic variants and AD cognitive and pathologic traits. No consistent association was seen between molecular genomic variations and non-AD pathologies in either of the sexes.
DNA methylation and RNA expression, and to some extent polymorphisms, were associated with AD cognitive and pathologic traits in women, and to a lesser extent in men.
女性患阿尔茨海默病（AD）痴呆的终身风险是男性的两倍，绝经后雌激素水平较低被认为是一个可能的原因。我们研究了 3 个（ 、 和 ）变体与 AD 特征的关联，作为间接方法来测试女性中雌激素与 AD 之间的关联。虽然该研究的重点是女性，但在比较中，我们分别检查了男性的 分子变体。
参与者在衰老的 2 项纵向临床病理研究之一中平均随访 10 年。使用 19 项神经心理学测试分数的综合得分来评估整体认知。死后病理评估包括通过免疫组织化学检查 3 种 AD（淀粉样β和 tau 缠结）和源自弥漫性和神经原性斑块和神经纤维缠结计数的全球 AD 病理评分）和 8 种非 AD 病理指数。 分子基因组变体包括基因分型以及检查大脑区域（包括背外侧前额叶皮层，DLPFC）的 DNA 甲基化和 RNA 表达，这些区域是认知的主要参与者，并且通常具有 AD 病理。
女性（N = 1711）基线时的平均年龄为 78.0（SD = 7.7）岁。在女性中， 分子变体与 AD 特征最一致相关。DNA 甲基化与认知能力下降、tau 缠结密度和全球 AD 病理评分相关。DLPFC 的 RNA 表达与认知能力下降和 tau 缠结密度相关。其他关联包括 和 序列变体和 DNA 甲基化与认知的关联。参与激活 ERs 的信号转导机制的基因的 DLPFC 中的 RNA 表达也与女性的认知能力下降和 tau 缠结密度相关。在男性（N = 651，基线时的平均年龄为 77.4[SD = 7.3]）中， 分子基因组变体与 AD 认知和病理特征之间的关联较弱。在两性中均未观察到 分子基因组变异与非 AD 病理学之间的一致关联。
DNA 甲基化和 RNA 表达，在一定程度上 多态性，与女性的 AD 认知和病理特征相关，在男性中的相关性较小。
