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

妇女健康倡议（WHI）随机、安慰剂对照的激素治疗（HT）临床试验旨在验证结合马雌激素单独（CEE- alone）或与醋酸甲羟孕酮（CEE+MPA）联合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，该研究包括平行安慰剂对照随机临床试验，分别在子宫切除或子宫切除术后妇女中使用0.625 mg/天CEE治疗和不使用2.5 mg/天MPA。WHIMS研究了CEE单独和CEE+MPA对65岁及以上女性可能发生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认知衰老研究（WHISCA）是WHIMS的一项辅助研究，旨在研究HT对无痴呆女性特定领域认知功能的影响。WHISCA在14个WHIMS站点招募了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对认知改变率的影响，随机化后调整时间。WHIMS CEE+MPA试验比原计划（2002年7月）提前终止，原因是主要WHI试验的风险-收益对比不利。随后，WHI cee单独试验也提前终止（2004年2月）。WHIMS试验的结果显示，CEE-单独或CEE+MPA会增加65岁及以上女性患痴呆的风险，并对全球认知产生不利影响。HT也被证明会增加65岁及以上女性临床中风的风险。WHISCA的初步研究结果显示，与安慰剂相比，CEE + MPA对言语记忆有负向影响（p < 0.01），对图形记忆有正向影响（p = 0.012）。这些效果只有在长期治疗后才明显。CEE + MPA对积极情绪、消极情绪或抑郁症状无显著影响。这些发现表明，HT可能在不同的认知领域有不同的影响。在既往子宫切除术的妇女中，CEE单独试验的结果显示，CEE单独试验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跟踪。

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.