Menopause is associated with sharp declines in concentrations of circulating estrogens. Estrogen-containing hormone therapy initiated after about age 65 years increases dementia risk. Estrogen therapy should not be initiated after age 65 to prevent dementia or remediate cognitive aging.
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Action of Estrogens in the Aging Brain Dementia and Cognitive Aging
Menopause is associated with sharp declines in concentrations of circulating estrogens. Estrogen-containing hormone therapy initiated after about age 65 years increases dementia risk. Estrogen therapy should not be initiated after age 65 to prevent dementia or remediate cognitive aging.
Menopause is associated with sharp declines in concentrations of circulating estrogens. Estrogen-containing hormone therapy initiated after about age 65 years increases dementia risk. Estrogen therapy should not be initiated after age 65 to prevent dementia or remediate cognitive aging.
Action of estrogens in the aging brain: Dementia and cognitive aging
Victor W. Henderson Departments of Health Research and Policy (Epidemiology) and of Neurology and Neurological Sciences, Stanford University School of Medicine, 259 Campus Drive, Stanford, CA 94305-5405, USA a b s t r a c t a r t i c l e i n f o Article history: Received 25 July 2009 Received in revised form 20 October 2009 Accepted 2 November 2009 Available online 12 November 2009 Keywords: Aging Alzheimer's disease Cognition Dementia Estrogen Hormone therapy Background: Menopause is associated with sharp declines in concentrations of circulating estrogens. This change in hormone milieu has the potential to affect brain functions relevant to dementia and cognitive aging. Scope of review: Focused review of published results of randomized clinical trials of estrogen-containing hormone therapy for Alzheimer's disease treatment and dementia prevention, observational research on cognition across the menopause transition, and observational research on the association of hormone therapy and Alzheimer's disease risk. Major conclusions: Clinical trial evidence supports conclusions that estrogen therapy does not improve dementia symptoms in women with Alzheimer's disease and that estrogen-containing hormone therapy initiated after about age 65 years increases dementia risk. Hormone therapy begun in this older postmenopausal group does not ameliorate cognitive aging. Cognitive outcomes of midlife hormone exposures are less well studied. There is no strong indication of short-term cognitive benet of hormone use after natural menopause, but clinical trial data are sparse. Little research addresses midlife estrogen use after surgical menopause; limited clinical trial data imply short-term benet of prompt initiation at the time of oophorectomy. Whether exogenous estrogen exposures in the early postmenopause affect Alzheimer risk or cognitive aging much later in life is unanswered by available data. Observational results raise the possibility of long-term cognitive benet, but bias is a concern in interpreting these ndings. General signicance: Estrogen-containing hormone therapy should not be initiated after age 65 to prevent dementia or remediate cognitive aging. Further research is needed to understand short-term and long-term cognitive effects of estrogen exposures closer to the age of menopause. 2009 Elsevier B.V. All rights reserved. Estrogen receptorsestrogen receptor alpha and estrogen receptor betaare members of a nuclear receptor superfamily that includes receptors for androgen, progesterone, glucocorticoids, and miner- alocorticoids. Within mammalian brain, these receptors have delim- ited topographic distributions unique to each hormone. Estrogen receptor alpha, for example, is the predominant receptor subtype of cholinergic neurons in the basal forebrain, whereas estrogen receptor beta is more abundantly expressed in the hippocampus and cerebral cortex [1,2]. These receptors function as ligand-activated transcription factors that bind hormone response elements on the genome to modulate the expression of nearby target genes. In addition, putative G-protein-coupled estrogen receptors are associated with the plasma membrane, one role of which appears to be regulation of intracellular signaling cascades and mediation of rapid actions not involving genomic activation [3,4]. The brain is affected secondarily by estrogens acting on non-neural tissues, which in turn inuence normal and pathological processes within the central nervous system. Examples are estrogen effects on vascular endothelium and the immune system [5,6]. Menopause represents the permanent loss of ovarian follicles, which during a woman's reproductive years cyclically produce estrogens and progesterone. Menopause is thus associated with sharp declines in concentrations of circulating estradiol and estrone [7], the two primary ovarian estrogens, as well as progesterone. This change in endocrine milieu has the potential to affect a variety of brain functions during midlife and beyond. From animal models based on ovariectomy or on reproductive senescence, it is clear that estradiol can facilitate or enhance aspects of learning and memory [8-11]. Some types of memory are clearly not aided, however; striatal-dependent motor learning, for example, may be impeded by estradiol adminis- tration after ovariectomy [11]. There is great interest in whether reduced levels of sex hormones due to specically to menopause or, in the case of men, related more generally to ageaffect cognition. In the late nineteenth and early twentieth centuries, the clinical focus was on testosterone and cognitive function in older men [12]. Although a century later testosterone is now again a topical area of investigation, greater attention during the past decade and a half has been paid to estrogen and cognitive aging in women. This line of research was engendered by emerging interests during the 1970s and 1980s in menopause, climacteric symptoms, and women's health [13-15] and by parallel Biochimica et Biophysica Acta 1800 (2010) 10771083 Fax: +1 650 725 6951. E-mail address: vhenderson@stanford.edu. 0304-4165/$ see front matter 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.bbagen.2009.11.005 Contents lists available at ScienceDirect Biochimica et Biophysica Acta j our nal homepage: www. el sevi er. com/ l ocat e/ bbagen advances in the psychology and neurology of human sex differences [16,17]. The following sections consider effects of estrogens on severe cognitive decrement characteristic of dementia and on minor cognitive decrement associated with usual aging. 1. Dementia Dementia can be dened as major cognitive impairment, where cognitive decits interfere substantially with social or occupational function. The term implies decline from a premorbid level at which there were no functional limitations as well as the presence of an underlying pathobiological substrate. In the United States and Europe, Alzheimer's disease is by far the most common cause of dementia in old age [18,19]. In some Asian countries, vascular dementia may be more prevalent, although the reported higher frequency could be due to methodological differences in case ascertainment [20]. Overlapping pathologies (e.g., co-existing changes of both Alzheimer's disease and vascular disease) are increasingly recognized and may be more common than so-called pure cases [21]. Cognitive loss in Alzheimer's disease begins insidiously and progresses gradually over a period of years. It is rare before age 60 years and increases in incidence and prevalence into the ninth and tenth decades of life. A consistent early symptom reecting impairment in episodic memory is loss of the ability to recall recent events or recently encountered information [22]. Other cognitive skills are also affected, but typically less noticeably so, especially early in the disease course. Observations that women with Alzheimer's disease may have relatively greater difculty with cognitive skills sometimes viewed as female-advantaged (verbal uency, naming, verbal episodic memory) [23] led to inquiries on the relation between estrogen and this dementing disorder. Early observational studies revealed an associ- ation between a woman's use of estrogen-containing hormone therapy and a reduced risk of later developing Alzheimer's disease [24,25]. Subsequent case-control and cohort studies generally reinforced the view that estrogens used after menopause could reduce Alzheimer risk [26-34] (Table 1), with meta-analyses indicating signicant risk reductions in the range of 30 to 40 percent [35,36]. These clinical ndings were supported by strong biological plausibility. Estradiol facilitates hippocampal long-term potentiation [37] (a physiological process believed to be important in episodic memory formation) in awake ovariectomized rats and, similarly, it enhances long-term potentiation in hippocampal slice preparations derived from a transgenic mouse model of Alzheimer's disease [38]. Estradiol also reduces the formation of -amyloid [39] and hyperpho- sphorylated tau protein [40], key biochemical abnormalities in brains of Alzheimer patients. In addition, estradiol is neuroprotective in models of ischemia, oxidative stress, excitatory neurotoxicity, and apoptosis [41-43]; and it has tropic effects in promoting neurite growth and synapse formation [44,45]. Mitochondrial actions of estradiol enhance glycolytic metabolism in the brain [46]. Two lines of clinical research, however, have challenged the implication that estrogen-containing hormone therapy might have a therapeutic role with respect to Alzheimer risk. First, randomized trials of estrogens for women with mild-to-moderate symptoms of Alzheimer's disease generally failed to show improvement in dementia symptoms [47-50]. The largest of these found no between-group differences on most functional and cognitive compar- isons after 1 year of unopposed conjugated equine estrogens [48]. Second, an ancillary study of the Women's Health Initiative, the Women's Health Initiative Memory Study (WHIMS), showed that hormone therapy actually increased dementia risk [51]. WHIMS examined effects of a widely used oral hormone preparation on incident dementia in postmenopausal women age 65 to 79 years. Baseline cognitive assessment in this randomized controlled trial excluded women with pre-existing dementia. Participants were randomly assigned to receive conjugated equine estrogens (0.625 mg/day) or placebo. Women with a uterus in the estrogen group also received a progestogen (medroxyprogesterone acetate 2.5 mg/day) in a continuous combined formulation. During the course of the WHIMS trials, 61 women with a uterus and 47 women without a uterus developed dementia. For women with a uterus, the hazard ratio (a measure of relative risk) of developing dementia was doubled for women receiving the estrogen-progestogen formulation (2.05, 95% condence interval 1.2 to 3.5) [51]. For women who had undergone hysterectomy, the relative risk for women receiving estrogens alone was increased by half (hazard ratio 1.5, 95% condence interval 0.8 to 2.7) [52]. It is clear that in vitro effects vary among different estrogens (e.g., estradiol or estrone [53]) and different progestogens (e.g., progester- one or medroxyprogesterone acetate [54]), and clinical outcomes might be inuenced by these differences. However, hormone formulations used by women in observational studies of Alzheimer risk often contained the same estrogens and same progestogen selected for the Women's Health Initiative clinical trials. In WHIMS, Alzheimer's disease was the specic diagnosis in half of the dementia cases [52], but because of the small sample size separate results for Alzheimer's disease were not reported. Women who were older at the start of the WHIMS trials were signicantly more apt to become demented, regardless of treatment arm [52]. The same association was seen for women with lower cognitive test scores at the start of the trial [52], perhaps implying that some women diagnosed with dementia during the trial already had subclinical disease at trial onset. Consistent with most prior observational studies on hormone therapy and Alzheimer's disease risk [35,36], WHIMS participants who had used hormone therapy before enrolling in Women's Health Initiative studies were less likely to develop dementia during the WHIMS trial, regardless of treatment arm [34,52]. Interestingly, in a large clinical trial conducted among postmenopausal women with Table 1 Hormone therapy and Alzheimer's disease risk: observational studies in which information on hormone exposure was obtained before dementia onset. Study [Ref.] Source of exposure information Number of cases Number of controls Relative risk Condence interval Brenner et al [26] Pharmacy records a 107 120 1.1 0.6-1.8 Paganini-Hill and Henderson [27] Self-report 248 1193 0.65 0.5-0.9 Tang et al [28] Self-report 167 957 0.5 0.25-0.9 Kawas et al [29] Self-report 34 438 0.5 0.2-1.0 Waring et al [30] b Medical records 222 222 0.4 0.2-0.96 Roberts et al [33] b Medical records 245 245 1.1 0.6-1.9 Seshadri et al [31] Pharmacy records a 59 221 1.2 0.6-2.4 Zandi et al [32] Self-report 84 1866 0.6 0.4-0.96 WHIMS [34] c Self-report 53 7047 0.4 0.2-0.85 WHIMS= Women's Health Initiative Memory Study. a Pharmacy records for studies of Brenner et al [26] and Seshadri et al [31] were available from approximately the preceding decade. b Separate, independent Mayo Clinic case-control studies, with cases from 1980-1984 (Waring et al [30]) and 1985-1989 (Roberts et al [33]). c Hormone therapy increased dementia risk during WHIMS trials irrespective of prior hormone exposures [52]. 1078 V.W. Henderson / Biochimica et Biophysica Acta 1800 (2010) 10771083 osteoporosis, higher doses of raloxifene, a selective estrogen receptor modulator, reduced the incidence of mild cognitive impairment and dementia [55]. 1.1. Reconciling apparent differences between results of the WHIMS trial and results of observational research In trying to understand WHIMS results in the context of prior research on Alzheimer risk, at least two points should be considered [56]: bias and external validity. First, observational studies of hormone therapy probably have provided biased estimates of Alzheimer risk reduction. Exposure misclassication is a concern in studies where information on hormone use is collected retrospec- tively, after the onset of dementia. Where hormone usage was based on self-report before dementia diagnosis, women who were cogni- tively impaired at baselineand thus more likely to be diagnosed with frank dementia latermay have underreported prior usage compared to women without cognitive impairment at baseline [57]. Further, prior users of hormone therapy may be healthier than women who never used hormone therapy [58], and healthy life style practices unrelated to hormone use may have contributed to protective associations. On the other hand, it should be considered that women in the WHIMS clinical trials differed from women in observational studies, and WHIMS ndings might not generalize to women ineligible to participate in the clinical trials. A key difference was the age at which women initiated and used hormone therapy [56]. Because hormone therapy is most often used around the time of menopause for vasomotor symptoms, hormone use in observational studies more often than not occurred at a relatively young age. In contrast, WHIMS trial participants were at least 65 years of age at the time of randomization to study medication. Is this difference in timing relevant? There is indirect support for an interaction based on age or based on timing of hormone initiation. Estrogen effects on atherosclerosis progression, as an example, may vary according to a woman's age or the length of time since menopause. Earlier hormone use may retard atherosclerosis; later use in the presence of pre-existing atheroscle- rosis may promote adverse outcomes [5,59-61]. However, the clinical import of timing with respect to coronary heart disease has been challenged [62]. Some have speculated that estrogen effects on Alzheimer risk might also vary, depending on whether hormones are initiated or used during some critical period dened by young age or close proximity to menopause. In a Danish follow-up study, middle-age participants in three randomized trials of hormone therapy for osteoporosis prevention were assessed after a mean interval of 11 years. Women originally randomized to hormone therapy were signicantly less likely to have cognitive impairment at follow-up than women assigned to placebo [63]. These results suggest a cognitive protective effect of short-term midlife hormone therapy over a decade later. This inference is additionally supported by observations in one case-control study that hormone therapy was associated with reductions in Alzheimer risk only among younger postmenopausal women, where hormone use necessarily occurred at a younger age [64], and observations in a prospective cohort study that current hormone usein contrast to past usewas not linked to reduced risk [32]. Based on evidence discussed above, it remains at present unclear whether use of estrogens during the menopausal transition or early postmenopause affects Alzheimer risk and, if so, whether the effect is protective (as suggested by some observational research ndings) or harmful (as extrapolated from WHIMS clinical trial ndings). 2. Cognitive aging Beginning in midlife or earlier, decrements are apparent in many areas of cognitive function [65], and the term cognitive aging is often used to describe this age-related phenomenon. By convention, when the threshold for dementia is reached, one is no longer dealing with cognitive aging. The concept of cognitive aging also excludes forms of mild cognitive impairment (MCI, [66]), usually viewed as a transi- tional stage between normal and dementia, representing very early clinical manifestations of a dementing disorder such as Alzheimer's disease. Although unitary explanatory factors, such as slowed neural processing or impaired working memory, have been invoked to account for cognitive aging, it is more likely that multiple processes are involved [67]. The trajectory of cognitive aging is variable [68], and many even among the oldest old remain cognitively competent [69]. A decline in episodic memory performance may precede the clinical diagnosis of Alzheimer's disease, but episodic memory is among the cognitive domains impactedalbeit more modestlyby usual aging as well. In the clinical setting, this form of memory is tested by tasks that require exposures to new material (e.g., a list of words or a paragraph-length story) followed by conscious recollec- tion of this material. Almost all studies of estrogen and aging have included memory tasks; other cognitive domains have been assessed less reliably. Many women complain of forgetfulness or poor memory around the time of the menopausal transition [70]. Forgetfulness, however, is a common symptom at any age, and serum estradiol levels at midlife are unrelated to memory performance or performance in other cognitive domains [71-73]. Moreover, observational ndings from well-characterized midlife cohorts suggest that natural menopause does not lead to measurable change in midlife cognition [71,72,74,75] (Table 2). However, there is some suggestion that learning may be less Table 2 Objective cognitive outcomes across the natural menopause transition a . Study [Ref.] Cohort description Number Mean age Memory Other cognitive scores Henderson et al [71] Population-based, Melbourne, Australia 326 57 years NS Fuh et al [75] Population-based, Kinmen, Taiwan 495 48 years NS Most NS b Kok et al [74] Population-based, United Kingdom birth cohort 997 53 years NS Slower search speed c Herlitz et al [72] Population-based, Umea, Sweden 242 49 years NS NS Luetters et al [73] d Ethnically-diverse convenience sample, United States 1657 50 years NS NS Greendale [76] d Ethnically-diverse convenience sample, United States 2362 46 years NS e NS e NS= non-signicant probability pN 0.05. a Includes cross-sectional and longitudinal analyses. b Lower verbal uency for women transitioning to perimenopause compared to premenopause; no differences on digit span forward or backward, or on Trail Making Test, Part A or B. c Trend for slower visual search on a letter cancellation task across pre-peri-and postmenopausal groups, with lower scores in the postmenopause. d Women in Leutters et al [73] represent a subset of women in the sample of Greendale et al [76]. e No differences based on menopause transition stage. Non-signicant (0.05b pb 0.1) trend for lower rate of improvement on verbal recall scores across annual visits for women in early and late perimenopausebut not postmenopausecompared to premenopause. Non-signicant trend for lower rate of improvement on processing speed (Symbol Digit Modality Test) for women in late perimenopause compared to premenopause. 1079 V.W. Henderson / Biochimica et Biophysica Acta 1800 (2010) 10771083 efcient during the uctuating hormonal milieu of the perimeno- pause in comparison to the premenopause or postmenopause [76]. During midlife, memory complaints often appear more closely related to mood than to objective memory decits [77]. 2.1. Cognitive aging: clinical trials in women below age 65 There is a growing experimental literature on cognitive effects of menopausal hormone therapy. This literature is more substantial for older postmenopausal women than for women closer to the age of menopause, where smaller studies of estrogen-containing hormone therapy have often lacked statistical power to detect important cognitive effects. Most trials conducted among midlife women have not reported signicant treatment effects [78], a nding predicted on the basis of observational studies of the natural menopause transition [71-75] (Table 2). The largest clinical trial of younger postmeno- pausal women randomized 180 volunteers 45 to 55 years of age [79] (Table 3). Participants had undergone natural menopause, and active treatment was with conjugated equine estrogens combined with medroxyprogesterone acetate. Findings at 4 months revealed no signicant benet on tests of episodic memory or other cognitive abilities. 2.2. Cognitive aging: clinical trials in women age 65 and older Clinical trial ndings on cognitive outcomes among women in the early postmenopause are limited. Trial data are ampler for women in the late postmenopause [78]. Results in this older age group provide no evidence for cognitive improvement from late initiation or use of hormone therapy. Indeed, there are some hints of cognitive harmafter several years of use [80] associated with reduced brain volume [81]. However, the magnitude of mean decrement on neuropsychological tests, when detected at all, is probably too small to be clinically apparent. In the WHIMS trials discussed above with respect to dementia outcomes, scores on a modied version of the Mini-Mental State examination, a test of global cognition, were slightly lower among women randomized to hormone therapy after treatment durations averaging 4.2 years (women with a uterus [82]) or 5.4 years (women without a uterus [83]). Mean differences between treatment groups were about a quarter of a point on a 100-point scale (effect size of approximately 0.05). These small differences were further attenuated after women with incident dementia, MCI, or stroke were excluded [83]. An ancillary study in the WHIMS cohort found the combined estrogen-progestogen preparation slightly improved mem- ory for a visual design but slightly impaired memory for a list of words [80] (Table 3). Cognitive abilities have been assessed in other fairly large clinical trials in this age group, with mean treatment durations as long as 4 years. Two such trials focused on women with known vascular disease, either coronary heart disease [84] or stroke or transient ischemic attack [85] (Table 3). Active treatment used conjugated equine estrogens with medroxyprogesterone acetate [84] or oral estradiol [85]. Two other large trials involved women believed to be healthy. In these studies, active treatment was with oral estradiol [86] or very low-dose transdermal estradiol [87] (Table 3). None of these trials demonstrated improvements in memory, and none suggested overall cognitive benet or harm. 2.3. Is surgical menopause different? Natural menopause occurs at a mean age of 51 years [88], and fewer than 2% of women experience menopause after age 55 [89]. In the United States, hysterectomy is the second most common major surgery among women ages 18 to 44 years, surpassed only by cesarean section. By age 54 years, 28% of women have undergone hysterectomy [90]. Bilateral oophorectomy is performed at the time of hysterectomy somewhat more than half of the time [91]. Surgical menopause begins abruptly after bilateral oophorectomy performed during a woman's reproductive years which, by denition, occurs before the age that natural menopause would have otherwise occurred. Cognitive consequences of surgical menopausewhere the ovarian production of estrogens and progesterone, as well as androgens, ceases abruptlymay differ from those of natural meno- pause occurring at a later age. Surgical menopause, for example, has been linked with heightened risk of late-life cognitive impairment [92] and Alzheimer's disease [93], but it is also reported not to be related to cognitive function later in life [94]. Few clinical trials have assessed cognitive effects of estrogens in surgically menopausal women. Signicant cognitive benet is reported from two very small trials [95,96]. In these, participating women were relatively young (mean ages of 45 and 48 years), and therapy was initiated immediately after surgery. Supportive ndings fromthe same investigative group come froma trial conducted among even younger women (mean age 34 years) treated with a gonado- tropin-releasing hormone agonist to suppress ovarian function [97]. In this study, women began oral conjugated estrogens or placebo after 3 months, while continuing to receive the gonadotropin-releasing hormone agonist. Cognitive testing 2 months later showed signi- cantly better test scores in the estrogen group, although cognitive Table 3 Hormone therapy and objective cognitive outcomes in women without dementia: large randomized placebo-controlled trials a . Trial Reproductive stage b Menopause type b Number Mean age Duration Memory Other cognitive scores Grady et al [84] Late Both 1063 67 years 4 years NS Most NS c Rapp et al [82] d Late Natural 4381 6579 years e 4 years NS Espeland et al [83] d Late Surgical 2808 6579 years e 5 years NS Viscoli et al [85] Late Both 461 70 years 3 years NS NS Almeida et al [86] Late Surgical 115 74 years 5 months NS NS Resnick et al [80] d Late Natural 1416 71 years 4 years Variable f NS Yaffe et al [87] Late Natural 417 67 years 2 years NS NS Maki et al [79] Early Natural 180 52 years 4 months NS NS NS= non-signicant probability, pN0.05. a Restricted to randomized placebo-controlled trials in postmenopausal women without dementia, sample size of at least 100, duration of at least 1 month, and objective measures of cognitive outcomes. b Early=early postmenopause [104], Late=late postmenopause [104], Natural =natural menopause, Surgical =surgical menopause based on hysterectomy status, Both=natural and surgical menopause. c Better verbal uency in placebo group; no differences for global cognition, naming, or executive function (Trail Making Test, Part B). d Women's Health Initiative Memory Study of women with [80, 82] or without [83] a uterus. Rapp et al. [82] and Espeland et al. [83] report global cognition on the Modied Mini- Mental State examination. Resnick et al. [80] report more detailed cognitive analyses on a subset of women with a uterus; these women are included in the sample of Rapp et al. [82]. See text for details. e Age range; mean ages not stated. f Based on annual rates of change, verbal memory was better in placebo group, and nonverbal memory was better in hormone group. 1080 V.W. Henderson / Biochimica et Biophysica Acta 1800 (2010) 10771083 benet was restricted to verbal memory performance [97]. This nding of domain-specic cognitive improvement is consistent with results in surgically menopausal women [96]. Other trials of surgically menopausal women found no cognitive improvement [80,82,86,98,99], including trials conducted as part of the Women's Health Initiative [80,82]. Surgical menopause in these negative trials was dened by hysterectomy status and not oopho- rectomy status, and only one of thesea 3-month crossover trial of 62 Finish women [98]involved primarily midlife women. Verbal memory was not assessed in this trial [98]. Similar issues are raised by early menopause induced by irradiation or adjuvant cancer chemotherapy. Cognitive complaints, which are common in this clinical setting, undoubtedly have multiple determinants. Treatment-induced menopause may be associated with short-term cognitive decits [100], although potential consequences of early menopause are difcult to disambiguate from those of therapy per se. Among breast cancer survivors, tamoxifen, a selective estrogen receptor modulator, and aromatase inhibitors such as anastrozole, exemestane, and letrozole raise particular concerns. It is not clear, however, that resultant hormonal changes substantially impact cognitive skills, at least in the short-term [101,102], although data remain sparse and much remains to be determined. 3. Estrogens, dementia, and cognitive aging: a summing up Despite convincing demonstration that estrogens affect brain tissues and brain processes in ways expected to reduce dementia risk and improve the course of cognitive aging, clinical ndings have been disappointing. There are, of course, important differences between in vitro and in vivo laboratory models and clinical practice. A major issue is the question of timing: are estrogen effectsfor example, on key biochemical perturbations of Alzheimer's disease [39,40]modied by use during a so-called critical window dened by age or temporal propinquity to menopause [56]? One clinical trial (WHIMS) indicates that hormones increase dementia rate [51]; many (but not all) observational studies imply that hormones reduce the rate of Alzheimer's disease (Table 1). Major differences in ages at time of hormone exposures (at least 65 years of age for women in WHIMS, but generally much younger in observational studies), lend credence to this view. If correct, this nding begs the important question of mechanism by which the hormone effect is modied by age. Some of the apparent discrepancy between research ndings might also be ascribed to competing risks. Whereas some estrogenic effects on the vasculature are clearly protective [5,60,61], other actions are harmful. Estrogens have complex, competing effects on pathways involved in inammation, thrombosis and thrombolysis, brinolysis, and the formation and rupture of atherosclerotic vascular plaques. Because the clinical manifestations of Alzheimer neuropa- thology depend in part on the presence or absence of vascular disease and other brain pathology [21], the net cognitive outcome is not easily predicted from short-term laboratory experiments in models that at best only approximate the human situation. It is important to appreciate that some clinical issues now appear to be resolved, thanks to new clinical research informed by basic laboratory investigation. This was not the case a decade ago. It now seems apparent that starting estrogen-containing hormone therapy in women with Alzheimer's disease probably does not benet dementia symptoms, and hormone initiation after about age 65 years increases rather than reduces dementia risk. Further, hormones, when used over periods of up to several years, do not provide net benet to cognitive aging in this older age group (Table 3). 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