The Role of Estrogen in the Development of Age-Related Cognitive Impairment and Dementia

While these studies have shown positive effects of ET on cognition, a number of studies showed no benefit.^26-30 Also, there are conflicting data regarding the ability of estrogen to protect against dementia. Recent findings from the Women's Health Initiative (WHI) and Women's Health Initiative Memory Study (WHIMS) have called into question the ability of hormone therapy to decrease the risk of dementia. The WHIMS found that the risk of dementia in women taking estrogen alone or estrogen and progesterone(Drug information on progesterone) was twice that of women in the placebo group.^31,32 In addition, in women with dementia, no overall cognitive benefit was seen.³³ In another study also using estrogen and progesterone, no benefit for cognition was seen after 4 years of follow-up.³⁴

Many factors need to be taken into account before drawing conclusions regarding the effects of gonadal steroids on dementia and cognition in these studies. First, many of the dementia diagnoses were related to vascular disease.³⁵ This is also consistent with other findings from the WHI study showing that there is an increased risk of stroke for older women taking estrogen and progesterone. Second, women who took part in the WHI/WHIMS were older (65 years minimum) than those for whom estrogen is prescribed for the treatment of menopausal symptoms.

Third, the combination of conjugated equine estrogen (CEE) and medroxyprogesterone(Drug information on medroxyprogesterone) acetate (MPA) used in the WHI study may not be the optimal hormone combination for showing cognitive improvements. Animal studies have shown that estradiol(Drug information on estradiol) leads to an increase in hippocampal choline acetyltransferase levels³⁶ while CEE plus MPA leads to decreases in choline acetyltransferase and acetylcholinesterase in the basal forebrain.³⁷ Taken together with the evidence that the basal forebrain cholinergic system plays an important role in cognition, long-term use of the CEE plus MPA regimen might negatively impact cognition and perhaps even lead to dementia.³⁸

Fourth, the WHIMS estrogen plus progesterone arm was terminated prematurely at 4.2 years of follow-up and the estrogen-alone arm was terminated at 5.4 years of follow-up. The ability to examine possible preventive effects of the hormones on AD was therefore limited, because it may take up to 10 years for the disease to manifest.⁸ Thus, the question of whether gonadal steroids have a role in preventing AD has not yet been determined from the WHI/WHIMS.³⁹ The role of estrogen and progesterone in the preservation of normal cognitive functioning has also not been determined in these studies. Therefore, prospective and some longitudinal studies indicate beneficial effects of estrogen replacement on cognitive functioning of postmenopausal women.

It is critical to understand the role of estrogen in the brain and the effects of menopause on cognition in nondemented postmenopausal women. The type of hormone, length of treatment, side effects (Table), method of administration, and age of starting therapy all need to be taken into account to address the effects of hormone therapy on cognition. The next step in elucidating the effects of estrogen on cognitive functioning is to determine the mechanism by which estrogen is acting in the brain. Evidence from the animal literature and preliminary evidence from the human literature implicates the cholinergic system as the critical neurotransmitter system influenced by estrogen treatment and withdrawal. In one study with AD patients, estrogen administration appeared to enhance the effect of the anticholinesterase tacrine(Drug information on tacrine) (Cognex) in AD.⁴⁰ Such data are supportive of a positive effect of estrogen on cholinergic systems. Estrogen has been shown to modulate cholinergic neurotransmission in the brain.⁴¹

A number of studies have investigated the interaction of estrogen and the cholinergic system and its effects on cognitive performance in animals. Tinkler and Voytko have shown that estrogen modulates attentional performance in primates through its interaction with the cholinergic system. After ovariectomy, monkeys were impaired during invalid cues in an attention task. This impairment was lessened after ET and not after placebo.⁴³ Importantly, monkeys on ET did not show any improvement in simple reaction time.

This supports the conclusion that the estrogen effect is specific to attentional processes and not simply an overall speeding of performance. Voytko⁴³ also showed that scopolamine impaired performance on the attention task but not the memory task during estrogen administration. Thus, estrogen uses the muscarinic cholinergic system to influence visuospatial attention.⁴²

Thus far, only one experimental study in women has examined the interaction of estrogen and the cholinergic system and the effects of this interaction on cognition.⁴⁴ We employed a model of the estrogen-cholinergic system interaction with which we examined the effects of 3 months of estrogen treatment on cognitive task performance after anticholinergic drug challenge. In this study, the anticholinergic drugs impaired performance across all domains of cognition. However, 3 months of estrogen treatment significantly attenuated the anticholinergic-induced impairment in attention tasks and other tasks with a speeded component, suggesting a beneficial effect on cholinergic system activity/integrity.