We report new results from the CCS on the relationship between HT use and incident AD. Our findings extend earlier findings by inclusion of up to 7 years of additional follow-up and more detailed data on the timing, duration, and type of HT. Consistent with the hypothesis of a critical window around the time of menopause during which HT may protect against AD, we observed a 30% reduction in AD risk in HT users who initiated treatment within 5 years after menopause. This reduction was greater with sustained use of 10 years or more. We saw no differences in these associations with use of opposed vs unopposed. If HT was initiated later, there was no such association and there was some suggestion that opposed HT was associated with increased AD risk if initiated shortly before the study's baseline.
The nature of the relationship between HT and AD risk remains controversial. Although findings of previous observational studies have not always been consistent, 2 meta-analyses estimated the risk reduction at 29% to 44%.23,24
By contrast, the randomized WHIMS6,7
found that HT use was associated with a significant increase in dementia risk. The divergence of results between observational and randomized studies has been a source of puzzlement. One explanation posits existence of a critical time window around menopause during which HT is protective. Many observational studies might capture this association but the WHIMS trial, which enrolled women older than 65 years, would not.8
Our original report from the CCS5
provided limited evidence in support of the critical window hypothesis. It noted that reduction in AD risk was greatest with prior HT use, whereas current HT users showed reduced risk only if the duration of treatment was for more than 10 years. Presumably, the last group included some women who had initiated treatment around the time of menopause. At the time, we were unable to test this notion directly, but a large subsequent retrospective study provided further circumstantial evidence in support of it,25
showing an inverse association between HT and AD risk for younger women who used HT near the time of menopause but not for older women who used HT at other times. More recently, a large prospective study found that women who used HT only in midlife had a 26% lower risk of dementia compared with nonusers.26
The CCS findings reported here show point estimates (0.74) for AD risk with HT initiated around menopause (i.e., in midlife) that are nearly identical to those of the last study.
We also found a suggestive increase in AD risk associated with HT initiated later in life, i.e., close to the CCS baseline when all participants were 65 years or older (average age at study entry was approximately 75 years). This increase was similar to findings from a recent large prospective study26
and the WHIMS trial. Interestingly, our finding of an increase specific to opposed HT also echoed the results of the WHIMS trial, which found that the increase in AD risk was greater with opposed (HR 2.05; 95% CI 1.21–3.48) than with unopposed treatment (HR 1.49; 95% CI 0.83–2.66).
Our study has several limitations. Women who used HT may have differed from nonusers in ways that explain their lower AD risk. For example, women who took HT were younger and better educated, younger at menopause, and had fewer live births. Control on these and other potential confounders in our analyses may have been incomplete, or there may have been other unmeasured characteristics that we did not consider. We note, however, that adjustment for potential measured confounders that might be associated with HT use or AD risk did not change the present results meaningfully. Alternatively, HT initiated around menopause could have increased mortality among women who were more vulnerable to develop AD in later life, thus creating a misleading impression of reduced risk in these women. This explanation seems unlikely given that mortality during the follow-up interval was lower, if anything, among HT users, including in particular those who initiated HT within 5 years of menopause (data not shown). There was also a significantly longer lag between age at menopause and baseline for nonusers compared with users. AD events among women occurring during this period of time might be undetected by the current study, potentially biasing the results. However, one might expect a greater number of events undetected among nonusers given their longer lag time, tending to bias the results toward a lower AD risk among nonusers. This is the opposite of what we found. Finally, the observed inverse association might reflect recall bias if women who developed AD during the follow-up interval had experienced prodromal memory problems that made them less likely to report HT use decades earlier, around menopause (note that 37 women had a nondementia cognitive impairment at the baseline visit). To explore this possibility, we repeated our analyses after controlling for baseline 3MS as a measure of cognitive status, but results were virtually identical (data not shown).
Our study also has several strengths. It is one of only a few studies with sufficient data to examine the long-term relationship between HT use around menopause and subsequent AD risk decades later. Although our results were similar to the aforementioned recent observational study,26
the latter was limited by its reliance on clinical databases of patient encounters with community-based physicians for case identification. Instead, we used standardized methods of case detection based on direct contact and validated for research purposes.20,27,28
Our study was also differentiated by availability of specific data on the timing and type of HT used, whereas others (e.g., reference 26
) could only contrast “midlife” vs “late-life” use. Our study's reliance on a relatively homogeneous population in rural Utah might conceivably limit the generalizability of our findings, but there are also strengths in comparisons conducted within restricted populations that offer reduced chance of selection or other biases producing spurious results.
Whereas HT was once thought to offer promise for AD prevention, the WHIMS trial cast serious doubts on its utility and effectively discouraged continued research in this area. Importantly, however, the results reported here add to a nascent body of findings suggesting that HT may have neuroprotective effects that depend on when it is initiated. Our findings therefore provide a rationale for continued research into the varied effects of HT. Practical concerns make it unlikely that new randomized trials of HT can examine the timing effects of HT (because of the long periods of follow-up necessary to properly test the critical window hypothesis). Such trials could also raise ethical concerns, given the current view that HT use would pose confirmed risks to trial participants. We suggest that other forms of new evidence will be needed before findings such as the current CCS results should reasonably result in any clinical recommendation of HT use for the prevention of AD.29