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 with no effect on other cognitive domains. In addition, 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 WHISCA and WHIMS studies continue to be followed through telephone cognitive assessments as they pass through the risk period for cognitive decline. The WHIMS Suite of Studies also included cognitive follow-up of women in the WHIMS-Younger (WHIMS-Y) study, who were randomized to hormone therapy through the WHI when aged 50-54 years. The WHIMS-Y study tested the hypothesis that hormone therapy around the time of the menopause may benefit cognitive function later in life. Initial results from the WHIMS-Y study were based on 1326 postmenopausal women studied with a validated telephone cognitive assessment battery an average of 7.2 years after the trials ended, when women had a mean age of 67.2 years. The initial report included the first two administrations of the cognitive battery and showed neither harm nor benefit of early post-menopausal HT on later cognitive function. 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 continue through telephone assessments in the original WHIMS cohort (WHIMS extension study). The WHIMS-Y study has concluded as sufficient data were obtained in this cohort to test the study hypotheses. In addition to ongoing evaluations in the current WHIMS extension cohort, analysis of existing data continues. These analyses include genetic associations with risk for cognitive impairment and with cognitive trajectories, effects of particulate air pollution on cognitive, affective and brain outcomes, development of an MRI-based Alzheimers Disease Progression Score, relationship between cognitive reserve and cognitive and brain outcomes, and determination of factors that promote cognitive resilience even in the presence of the APOE e4 genetic risk allele. In one recent study, the joint effects of hearing loss (HL) and HT were investigated in relation to global cognitive decline and increased risk of incident cognitive impairment in 7,220 WHIMS participants. Linear mixed effects models were used to analyze rate of change in global cognition. Accelerated failure time models were used to evaluate time to incident cognitive impairment, stratified by HT. Within the CEE-Alone trial, observed adverse effects of CEE-Alone on change in global cognition did not differ by HL, and estimated joint effects of HL and CEE-Alone were not associated with incident cognitive impairment. Within the CEE+MPA trial, HL did not independently accelerate time to cognitive impairment, but the adverse effect of CEE+MPA on global cognitive decline was heightened in older women with HL. Thus, HL may accentuate the adverse effect of CEE+MPA on global cognitive decline, not incident cognitive impairment, among postmenopausal women on HT. In a second recent paper, we examined potential sociodemographic predictors of cognitive resilience in unimpaired older WHIMS women who carry the APOE e4 risk allele by comparing them to non-carriers and APOE e4+ women who developed cognitive impairment before age 80. Among 5,716 women, APOE e4 carriers and noncarriers were compared using logistic regression, co-varying for treatment, demographics, lifestyle, cardiovascular and physical function, well-being, and self-rated general health. Among 557 APOE e4+ women, those who survived to age 80+ without cognitive impairment had higher baseline self-rated general health and cognitive scores than those who developed cognitive impairment before age 80. Among women who survived to 80+ without cognitive impairment, more APOE e4+ women had a history of high total cholesterol (p=0.003) and LDL cholesterol. There were no differences in hypertension, diabetes, or other vascular risk factors in APOE e4+ women compared with non-carriers. These findings highlight the importance of baseline cognitive function, and general health for late-life cognition among e4+ women. While sociodemographic and selected health factors did not distinguish APOE e4 escapees, we are continuing to pursue biologic factors which may predict women who survive to old age (80+) and remain cognitively healthy, cognitive resilience. Biospecimens obtained at WHI baseline from 1625 women will be used to conduct studies of insulin resistance, proteomics, metabolomics and auto-antibody profiles in APOE e4 escapees in comparison to those who develop cognitive impairment and in comparison to women with the APOE e3/e3 genotype.
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