Overall, we found significant yet modest adverse associations between HT use and decline over 4 years in general cognitive performance, as measured by the TICS, verbal memory and attention. These results were consistent with the findings of the WHI. Most women in our study who were current users of HT were estrogen only users who had initiated use close to the time of menopause; we observed that early initiation of hormone was associated with worse rates of decline. Thus, there was no support for the “window hypothesis” for cognitive benefits in our data. However, we observed a suggestion that adverse effects of HT may be focused among those with the apolipoprotein e4 allele that warrants further study.
This study is an extended longitudinal follow-up study to a previous longitudinal investigation(Kang et al., 2004
). It is worth noting the differences in the findings between the original publication and this follow-up study. The first study had 2 years of follow-up with two assessments, whereas this study had 4 years of follow-up with 3 assessments; differences in the results could be either due to methodological issues such as statistical variation, measurement error (i.e., more errors are inherent with more assessments), learning bias (i.e., the first study was likely more affected by learning than this study) or true biological changes in effects that are reflected in changes in associations with time. However, there are important similarities in the results of these two studies, and these results should be emphasized as they are more robust. First, neither the earlier study nor this study observed that the associations with postmenopausal hormone use in relation to cognitive decline were protective in nature. In fact, the directions of most associations were consistent with adverse relations: the first study observed that the adverse associations were significant with current use with long-term duration, whereas this present study found significant adverse association with any current use. Secondly, neither the earlier study nor this study provide support for the hypothesis that current use of postmenopausal hormones with early initiation may be beneficial for delaying cognitive decline. The first study found a significant increased risk of cognitive decline among women who were current users who initiated at older ages and a null association with current use with initiation early in the menopausal transition, whereas the present study observed significant adverse associations with early initiation. Finally, neither the earlier study nor this study found significant interactions between current hormone therapy use and apolipoprotein e4 allele on risk. However, this study found that current hormone users who were also apolipoprotein e4 positive had the worst rate of decline in the TICS and the rate was significantly worse than never users who were non-carriers, which merits further study in a larger study.
Our study has unique strengths. The majority of existing observational studies began their collection of hormone data in participants aged 65 years and older. Thus, there may be greater opportunity for misclassification HT use history, especially use near menopause, since women would have to recall hormone use from 15 or more years in the past. In particular, recall may be especially biased in those with latent dementia. In contrast, our detailed and prospective collection of data on hormones from 1976, beginning at or near menopause, minimizes the possibility for differential misclassification of HT use over time. In addition, the prospective data collection since menopause would minimize random misclassification, and enhance our overall ability to detect effects. Moreover, in our population of health professionals, all with access to healthcare and health knowledge, opportunities for confounding by HT may be minimized. Indeed, we found relatively few differences in characteristics of women who used and did not use HT. In addition, for other outcomes we have examined in the Nurses’ Health Study cohort (e.g., stroke, pulmonary embolism, heart disease, breast cancer and colon cancer), we have found relations with HT consistent with those reported in randomized clinical trials,(Grodstein et al., 2003
) suggesting lack of important confounding.
Although experimental data suggest that estrogen positively affects neurotransmitter systems, improves synaptic properties of neurons, and increases blood flow and activation in the brain,(Fillit, 2002
; Henderson, 2000
) HT also modestly increases risk of stroke in our cohort(Grodstein et al., 2008
) and in the WHI,(Wassertheil-Smoller et al., 2003
) and elevated levels of C-reactive protein,(Cushman et al., 1999
) an inflammatory marker (both stroke and inflammation are associated with cognitive decline). In addition, the WHI reported that HT decreased brain volume.(Resnick et al., 2009b
Many large-scale observational epidemiologic studies have examined HT use in relation to cognitive decline, and the results have been inconsistent. Several clinical trials of 2–3 years duration
in various populations of women have reported no effects of HT on cognitive function (Almeida et al., 2006
; Pefanco et al., 2007
; Resnick et al., 2009a
; Viscoli et al., 2005
; Yaffe et al., 2006
). In a study of 1,800 women(Carlson et al., 2001
), HT was related to significantly less decline on the MMSE over three years compared with non-use (difference in rate of change for hormone users vs. non-users=0·75, p<0·05), after adjustment for confounding; findings were similar for past and current use. In several studies, particularly population-based studies with great variation in socioeconomic status,(Fillenbaum et al., 2001
; Yaffe et al., 2000
) adjustment for confounding reversed or substantially attenuated any apparent cognitive benefits of hormone use. Consistent with our studies, in the Rotterdam Scan Study,(den Heijer et al., 2003
) where most women were not on HT, higher levels of endogenous plasma estradiol were related to significantly smaller hippocampal volume, as well as poorer memory performance.
In recent years, it has been proposed that the timing of initiation of HT might be important, and that there may be a ‘critical window of opportunity’ for HT initiation for beneficial effects of estrogen in the brain. There are several lines of suggestive evidence from animal studies, observational studies and trials for this hypothesis. Early initiation of estradiol improved the cognitive performance of female rats after ovariectomy, but not when there was delay.(Gibbs and Gabor, 2003
; Markowska and Savonenko, 2002
) In humans, the Cache Study found that when HT was initiated near menopause, use was inversely associated with risk of Alzheimer’s disease, but current hormone use initiated within the recent 10 years past was associated with elevated risk(Zandi et al., 2002
); however, these data were based on very few women who reported initiation near menopause. In contrast, Petitti et al,(Petitti et al., 2008
) in an observational study utilizing a prescription database, found no suggestion that HT initiation near menopause was related to a decreased risk of dementia at older ages. Additionally, in the WHI data, there was no significant interaction by timing of initiation (p=0.31).(Espeland et al., 2004
) Although we observed a suggestion of increased risk of substantial decline, which appeared focused among late initiators, in our previous report of cognitive decline over two years,(Kang et al., 2004
) in the present analyses, with longer follow-up and greater power, these relations were no longer observed. In addition, neither the Nurses’ Health Study, nor the Women’s Health Initiative, have reported that the timing of HT initiation influences risk of stroke.(Grodstein et al., 2008
, Prentice et al., 2009
Interestingly, there are several lines of evidence indicating that apolipoprotein E e4 allele may interact with estrogen status. For example, in apolipoprotein E e4 transgenic mice, females demonstrated greater cognitive impairment than males.(Raber et al., 1998
) Estrogen is known to modulate the expression of apolipoprotein E, and estradiol promotes synaptogenesis in response to injury via an apolipoprotein E -dependent mechanism.(Stone et al., 1998
) However, estradiol had no such effect in the absence of apolipoprotein E or in the presence of apolipoprotein E e4.(Struble et al., 2008
) In humans, the Cardiovascular Health Study found a significant interaction (p=0.04) between apolipoprotein E e4, estrogen use and cognitive decline, where estrogen use was significantly inversely associated with cognitive decline in women without apolipoprotein E e4, (RR = 0.59; 95% CI, 0.36, 0.99) but was non-significantly adversely associated among women positive for e4 (RR = 1.33; 95% CI, 0.74, 2.42).(Yaffe et al., 2000
) In the same study, when internal carotid wall thickness, which was a significant predictor of cognitive decline, was examined, a similar interaction was observed, supporting the biologic plausibility of this interaction.(Yaffe et al., 2000
) Our results also suggested the presence of such effect modification by apolipoprotein E e4, and this interaction clearly deserves further investigation.
Limitations of our study should be considered. Hormone use was self-reported. However, we believe any errors to be minimal since validation studies of many self-reported exposures in this cohort of registered nurses have proven their reports to be highly accurate, (Colditz et al., 1987
; Willett et al., 1983
) and since detailed information on hormone use was collected from participants every two years beginning at or near menopause. Misclassification of HT would likely have been random given the generally high cognitive functioning and may have led us to slightly underestimate associations. Because this was an ongoing follow-up study, we were able to assess the associations with cognitive change over 3–4 years by HT use status and initiation. However, we were unable to assess acute changes in cognition related to HT use. However, we were unable to assess the acute or short term changes in cognition. Our relatively homogenous population of aging female nurses comprises a select group of highly educated women and thus our findings should be interpreted in the context of our population characteristics. Finally, loss-to-follow-up is a potential source of bias in prospective studies; yet we maintained 92% follow-up, which did not vary by hormone use, making it unlikely that there was major bias.
Overall, HT was related to modestly worse general cognitive function and verbal memory, irrespective of the timing of initiation. However, any adverse effects of hormones on cognition appeared to be focused on women with an apolipoprotein E e4 allele, and this interaction clearly warrants further investigation.