Several observational and longitudinal studies of healthy community-dwelling women suggest that women who use HRT (either unopposed estrogens or estrogens plus progestogen) may perform better on a broad spectrum of cognitive skills or may outperform nonusers on more discrete memory measures. Estrogen users showed significantly higher scores on verbal memory, verbal fluency, and visual memory and higher scores on the Modified Mini-Mental State Examination (3MS) compared with age-matched nonusers [7–10]. In a well-characterized aging cohort in Baltimore, women receiving estrogen performed significantly better than women who had never used estrogen on the Benton Visual Retention Test, a task that measures short-term non-verbal memory and drawing skills [11, 12]. In this study, estrogen users seemed resistant to age-associated declines in the test scores. Because CEE 0.625 mg was the most popular drug and dose used to treat postmenopausal women at the time these studies were undertaken, the vast majority of women who participated were taking CEE 0.625 mg.

The epidemiological data on the neuroprotective effects of estrogen-base therapy were reviewed by Leblanc and colleagues [13]; women who were symptomatic from the menopause had improvement in verbal memory, vigilance, reasoning, and motor speed when given HRT. The same meta-analysis of observational studies examining HRT and cognitive function also suggests a significant reduction in the risk of AD among women who have ever used HRT. In particular, the strongest evidence for an association between HRT and Alzheimer disease comes from two cohort studies: the Manhattan Study of Aging [14] and the Baltimore Longitudinal Study of Aging [12]. The two prospective cohort studies that reported a significantly reduced risk of AD in estrogen users are particularly compelling because they avoid both recall and prescribing practice bias. In the Italian Longitudinal Study on Aging, ERT was associated with a reduced prevalence of AD in 2816 women (OR, 0.24; 95 % CI, 0.07–0.77) [15]. Analysis of observational data from the Cache County Study [16] suggested a reduction in the risk of AD for past HRT users for 3–10 years. In the same study, the “excess” risk of AD when compared with age-equivalent men disappeared among women who received HRT for more than 10 years. However, like the longitudinal studies on estrogen use and cognition, these studies on ERT and the risk for AD show possible biases, which suggest caution in their interpretation. Nevertheless, their findings should be considered consistent in suggesting a protective effect of ERT with regard to the development of AD.

Recent randomized controlled trials (RCTs) of estrogens and cognition have better characterized postmenopausal subjects. Several RCT studies imply that women given estrogen outperformed placebo-treated women on a variety of psychometric measures, including choice reaction time, attention and concentration, distract ability, verbal memory, and abstract reasoning [17]. Sherwin has argued persuasively that estrogen-induced improvement is most apparent on tasks assessing the recall of verbal information, such as recalling details from a paragraph-length narrative [12]. In general, the magnitude of an estrogen effect in healthy women appears to be modest, but in some circumstances, such as surgical menopause, differences appear to be great enough to be clinically meaningful.

A major controversy has been launched during the past 2 years concerning the use of HRT in postmenopausal women [18, 19]. Recent findings from the Women’s Health Initiative Memory Study (WHIMS) indicated an increased risk in long-time postmenopausal women treated with CEE-MPA for diagnosis of probable dementia and mild cognitive impairment compared to placebo. In addition, in the same postmenopausal women aged 65 years or older recruited in the WHIMS, estrogen plus progestin did not improve cognitive function when compared to placebo. Therefore, findings from the estrogen-alone arm of WHIMS indicate that women aged 65 years or older treated with CEE had a slightly lower average cognitive function compared to women assigned to placebo. Moreover, in the same study, the incidence of dementia resulted higher in women receiving CEE-alone compared to the placebo group, but this negative trend did not reach statistical significance [20–23].

The discrepancy between the earlier, smaller RCTs and the WHIMS became apparent, and results from the WHIMS are attributed to the critical issue of the study design; the WHIMS findings do not address the possible role of HRT initiated before the age of 65 years. Group differences in pre-existing risk factors (hypertension, obesity, and diabetes) partly explain the increased rates of adverse vascular effects among women taking HRT [24]. Moreover WHIMS conclusions, like those of the earlier reports of WHI study, are related to the specific strength formulation of hormone therapy and not to different formulations or routes of administration. The oral HT used in WHIMS was either unopposed CEE or continuous combined CEE and medroxyprogesterone acetate. Previous reports suggest that medroxyprogesterone acetate counteracts the beneficial effects of estrogen [25]

The most persuasive explanation for the failure of WHIMS to find a beneficial effect of estrogen on cognition is that the women were too old at the time treatment was initiated for it to have had any protective effect. There are some suggestions that estrogens may be more protective against AD when used by younger postmenopausal women or when initiated at an earlier age.

The analysis of observational data from Cache County Study, suggesting a decreased risk of AD in older HRT user, might be viewed as predicting the WHIMS finding of dementia for women initiating after age 65, with benefit for older women with more typical pattern of past use at a younger age. These issues support the assumption on the presence of a critical period for HRT and related neuroprotection, already raised in the WHIMS accompanying editorial by Schneider [26]. Evidence to support the idea of a window of effectiveness for the initiation of HRT in order to protect against cognitive aging is also raised in the studies of Henderson [27] and Matthews et al. [28]. Similarly, evidence from animal studies indicates that the neuroprotective effects of estrogen and neuroprotection are based on a model of early therapy initiation after the menopause. The importance of timing of initiation of HT and cognitive function is evident in a review of randomized clinical trials of HT and verbal memory [29]. Six of six randomized clinical trials of estrogen therapy in young women demonstrate enhancements in verbal memory. On the contrary, two of two randomized clinical trials of combined oral estrogen and progestogen therapy in older women demonstrate neutral or detrimental effects on verbal memory [30, 31].

Bagger and colleagues demonstrated that women who received HRT in a placebo randomized controlled trials for 2–3 years in the early postmenopausal year have a reduced risk of cognitive impairment 5–15 years later.

In addition, MacLennan et al. present the results of a pilot study (REMEMBER study) examining the timing of initiation of HT on later cognitive function in a population-based study of 428 women. Early initiators of HT performed better than late initiators on the Mini-Mental State Examination and were faster than never-users on the Trail Making Test Part A [32, 33]. The final results from the more representative population-based study will address more consistent data on the “critical window hypothesis” for HRT.