Women's Health Initiative Memory Study Extension: Alzheimer's Disease and Related Dementia, Cognitive Decline and Resilience

妇女健康倡议（WHI）激素治疗（HT）的随机、安慰剂对照临床试验旨在检验单独使用结合马雌激素（CEE）或与醋酸甲羟孕酮（CEE+MPA）联合使用可保护绝经后妇女免受心脏病发展的假设。WHI记忆研究（WHIMS）是WHI试验的一项辅助研究，该研究包括在子宫切除或子宫切除后的女性中分别进行的0.625 mg/d CEE治疗（联合或不联合2.5 mg/d MPA）的平行安慰剂对照随机临床试验。WHIMS研究了CEE单独和CEE+MPA对65岁及以上女性可能痴呆和轻度认知障碍风险的影响，以及这些治疗对整体认知功能的影响。WHI认知老化研究（WHISCA）是WHIMS的辅助研究，旨在研究HT对非痴呆女性特定领域认知功能的影响。WHISCA在14个WHIMS研究中心招募了2305名女性，分布在两个平行试验中。WHISCA在WHI随机化后平均3年开始，主要结局是HT对认知变化率的影响，根据随机化后的时间进行调整。WHIMS CEE+MPA试验因主要WHI试验中的不良风险-获益特征而提前终止（2002年7月）。随后，WHI CEE单独试验也提前终止（2004年2月）。WHIMS试验的结果表明，单独使用CEE或CEE+MPA会增加老年痴呆症的风险，并对65岁或以上女性的整体认知产生不利影响。HT也被证明会增加65岁及以上女性临床中风的风险。WHISCA研究结果的初步报告显示，与安慰剂相比，CEE + MPA对文字记忆有负面影响（p < 0.01），随着时间的推移，对图形记忆有积极影响的趋势（p = 0.012）。这些效果只有在长期治疗后才明显。CEE + MPA没有显着影响积极情绪，消极情绪，或抑郁症状。这些发现表明HT可能对不同的认知领域产生不同的影响。在既往子宫切除术的女性中进行的CEE单独试验的结果显示，CEE单独治疗不会随着时间的推移影响特定领域的认知功能。 WHIMS研究的参与者继续通过电话认知评估进行随访。 WHIMS研究套件由维克森林大学进行，该大学也是WHI东南区域中心的所在地。在最初的WHIMS队列（WHIMS扩展研究）中，通过电话评估继续进行随访认知评估，直到2021年，电话评估的经验对于在COVID 19大流行期间过渡到远程评估的其他队列非常宝贵。 WHIMS队列中丰富的认知、成像和其他数据的可用性继续作为包括年轻研究者在内的几个小组新方向的基础。 这些分析包括与认知障碍风险和认知轨迹的遗传和表观遗传关联，颗粒空气污染对认知，情感和大脑结果的影响，以及进一步调查即使在存在APOE e4遗传风险等位基因的情况下也能促进认知恢复力的因素。 空气污染与大脑和认知结果之间的关联的调查，包括方法学考虑）由JC Chen和他在南加州大学的同事领导，并且在过去的一年中继续成为特别活跃的调查领域（Petkus等人，2022，Younan等人，2022; Wang等人，2022年）。 我们继续作为合作者，使用WHIMS数据为这些新项目提供投入。 最近NIA IRP和维克森林研究人员之间的合作研究集中在携带APOE e4风险等位基因但即使达到80岁也不会发生认知障碍的女性身上。 在先前发表的研究（Hayden等人，2019年），我们研究了可能预测老年人完整认知功能的潜在人口统计学，医学和社会因素，尽管携带APOE e4。 一般来说，较高的基线认知功能和较好的一般健康特征预示着较好的晚年认知。 在过去的一年里，我们研究的一个主要重点是调查APOE e4逃逸者认知弹性的生物学基础。我们已经完成了在20世纪90年代中期WHI基线收集的生物标本的测定，并正在评估蛋白质组学，代谢组学和阿尔茨海默病生物标志物，包括ABeta 40，ABeta 42和总tau蛋白在1625名妇女。对这些血浆生物标志物作为APOE基因型和认知状态的函数的分析正在进行中，并将告知我们即使面对APOE e4风险等位基因也能理解认知弹性的生物学。

The Womens Health Initiative (WHI) randomized, placebo-controlled clinical trials of hormone therapy (HT) were designed to test the hypothesis that conjugated equine estrogens alone (CEE-Alone) or in combination with medroxyprogesterone acetate (CEE+MPA) protected postmenopausal women against the development of heart disease. The WHI Memory Study (WHIMS) was an ancillary study to the WHI trials, which consisted of parallel placebo-controlled randomized clinical trials of 0.625 mg/day CEE therapy with and without 2.5 mg/day MPA in women with a uterus or post-hysterectomy, respectively. WHIMS investigated the effect of CEE-Alone and CEE+MPA on risk for probable dementia and mild cognitive impairment in women age 65 and older, as well as the effects of these treatments on global cognitive function. The WHI Study of Cognitive Aging (WHISCA), an ancillary study to WHIMS, was developed to investigate the effects of HT on domain-specific cognitive function in women without dementia. WHISCA enrolled 2305 women at 14 of the WHIMS sites, distributed across the two parallel trials. WHISCA was initiated on average 3 years after WHI randomization and the primary outcome was the effect of HT on rates of cognitive change, adjusted for time since randomization. The WHIMS CEE+MPA trial terminated earlier than planned (July, 2002) due to an adverse risk-to-benefit profile in the main WHI trial. Subsequently, the WHI CEE-Alone Trial also was terminated early (February, 2004). Results from the WHIMS trials showed that CEE-Alone or CEE+MPA increase the risk of dementia and have adverse effects on global cognition in women aged 65 years or older. HT also has been shown to increase the risk of clinical stroke in women 65 years and older. The initial report of WHISCA findings showed that CEE + MPA had a negative impact on verbal memory (p < 0.01) and a trend to a positive impact on figural memory (p = 0.012) over time compared with placebo. These effects were evident only after long-term therapy. CEE + MPA did not significantly influence positive affect, negative affect, or depressive symptoms. These findings suggest that HT may have different effects across different cognitive domains. The findings from the CEE-Alone Trial in women with prior hysterectomy who were randomized to CEE or placebo show that CEE alone did not affect domain-specific cognitive function over time. Participants in the WHIMS studies continue to be followed through telephone cognitive assessments. The WHIMS Suite of Studies is conducted by Wake Forest University, which is also the site for the Southeast Regional Center for WHI. Follow-up cognitive evaluations continued through telephone assessments in the original WHIMS cohort (WHIMS extension study) through 2021, and this experience with telephone assessments was invaluable to other cohorts who transitioned to remote assessments during the COVID19 pandemic. The availability of rich cognitive, imaging and other data in the WHIMS cohort continues to serve as the basis for new directions by several groups, including young investigators. These analyses include genetic and epigenetic associations with risk for cognitive impairment and with cognitive trajectories, effects of particulate air pollution on cognitive, affective and brain outcomes, and further investigation of factors that promote cognitive resilience even in the presence of the APOE e4 genetic risk allele. Investigations of associations between air pollution and brain and cognitive outcomes, including methodological considerations) have been led by JC Chen and his colleagues at the University of Southern California and have continued to be a particularly active area of investigation over the last year (Petkus et al., 2022, Younan et al., 2022; Wang et al., 2022). We continue to serve as collaborators, providing input into these novel projects using WHIMS data. Recent collaborative studies between a number of NIA IRP and Wake Forest investigators focus on women who carry the APOE e4 risk allele but do not develop cognitive impairment despite reaching age 80. In a prior published study (Hayden et al., 2019), we examined potential demographic, medical and social factors that might predict intact cognitive function in old age despite carriage of an APOE e4. In general, higher baseline cognitive function and better general health characteristics predicted better late-life cognition. A major focus of our studies over the last year has been the investigation of the biologic underpinnings of cognitive resilience in APOE e4 escapees. We have completed assays of biospecimens collected at WHI baseline in the mid-1990s and are evaluating proteomic, metabolomic and Alzheimers Disease biomarkers, including ABeta 40, ABeta 42 and total tau in 1625 women. Analyses of these plasma biomarkers as a function of APOE genotype and cognitive status are ongoing and will inform our understand of the biology of cognitive resilience even in the face of the APOE e4 risk alleles.