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

National Institute On Aging

Investigators

Linked publications & trials

Abstract

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 was 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 an active area of investigation over the last year (e.g. Petkus 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. In addition, the measures generated in this recent project of markers of cognitive resilience have been used in a study of the relation between proteomic indicators of an inflammatory diet and future cognitive impairment (Duggan et al., 2023). Olink proteomics in 1528 WHIMS participants identified a group of immune related proteins (CXCL10, CCL3, HGF, OPG, CDCP1, NFATC3, ITGA11) that were related to future cognitive impairment over a 14-year follow-up period. Several of these inflammatory diet proteins correlated with plasma AD biomarkers of neurodegeneration and neurodegeneration and were also associated with dementia risk in 2 external cohorts.