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

Special Report: Neuropsychiatry

During and after menopause,many women report impairmentsin cognitive functioning.One of the most controversial issues inmedicine today is the decision toprescribe hormone therapy for womenas a way to mitigate the physical andcognitive symptoms of menopause.There is some evidence that estrogentherapy (ET) results in the maintenanceof a premenopausal level of cognitivefunctioning^1-4 and may reduce the riskof Alzheimer disease (AD).^5-8 Withmany in the baby boom generation nowwell into menopause, this issue will beof increasing importance in the comingyears.

Contrasting results

Studies examining the difference inhormone levels in postmenopausalwomen with and without AD yieldcontrasting results. While one studyfound women with AD to have significantlylower estradiol levels than healthy controls,⁹ suggesting a possiblerelationship between estrogen andthe risk of AD, another study found nosignificant difference in estradiol levelsbetween these 2 groups and no correlationbetween cognitive performanceand hormone levels.¹⁰

Women appear to be at higher riskfor AD than men, particularly if theycarry the APOE4 allele.¹¹ Furthermore,certain estrogen receptor 1 polymorphismsappear to be associated withthe risk of cognitive impairment.¹² Estrogen reduces neuronal generationof β-amyloid peptides, which may causea delay in the onset of AD.¹³

There is considerable epidemiologicevidence from both prospectiveand case-control studies that estrogenuse in postmenopausal women maydecrease the risk of the developmentand/or expression of AD,^5-8,14,15 with anoverall odds ratio of 0.66,16 but not allstudies have found this.¹⁷ ET alone mayimprove cognitive functioning in femaleAD patients.¹⁸ However, other trials ofestrogen alone as a therapy for mild tomoderate AD have had equivocal results, showing no significant effecton cognitive measures of long-termprogression,^19-21 suggesting that estrogenalone cannot significantly preventprogression of an already establisheddisease.

ET may, however, be helpful incognitive decline resulting from normalaging, as opposed to reversing orpreventing established AD pathologyspecifically. Some of the most consistentevidence for a direct effect ofestrogen on cognitive function is fromstudies of surgically menopausalwomen.

Sherwin²² studied women after totalabdominal hysterectomy/bilateral salpingo-oophorectomy with randomassignment to estrogen or placebo for3 months and found that the treatedgroup showed preservation of verbalmemory, while the placebo groupshowed a significant decline. These datawere confirmed in a study showing that,for 3 months after this surgery, estrogen-treated women showed eitherimprovement in or preservation ofverbal learning and memory performance,while placebo-treated womenshowed a decline.²³

In a naturalistic study, women whoreceived estrogen after surgical menopausehad better preserved verbal memoryand constructional ability thanwomen not receiving estrogen.²⁴ In addition,2 studies showed that ET specificallyimproves attentional functions,compared with placebo treatment.^4,25

While these studies have shownpositive effects of ET on cognition, anumber of studies showed no benefit.^26-30 Also, there are conflicting data regardingthe ability of estrogen to protectagainst dementia. Recent findings fromthe Women's Health Initiative (WHI)and Women's Health Initiative MemoryStudy (WHIMS) have called into questionthe ability of hormone therapy todecrease the risk of dementia. TheWHIMS found that the risk of dementiain women taking estrogen alone orestrogen and progesterone was twicethat 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 andprogesterone, no benefit for cognitionwas seen after 4 years of follow-up.³⁴

Weighing factors

Many factors need to be taken intoaccount before drawing conclusionsregarding the effects of gonadal steroidson dementia and cognition in these studies.First, many of the dementia diagnoseswere related to vascular disease.³⁵ This is also consistent with other findingsfrom the WHI study showing thatthere is an increased risk of stroke forolder women taking estrogen and progesterone.Second, women who tookpart in the WHI/WHIMS were older(65 years minimum) than those forwhom estrogen is prescribed for thetreatment of menopausal symptoms.

Third, the combination of conjugatedequine estrogen (CEE) and medroxyprogesteroneacetate (MPA) used in theWHI study may not be the optimal hormonecombination for showing cognitiveimprovements. Animal studies haveshown that estradiol leads to an increasein hippocampal choline acetyltransferaselevels³⁶ while CEE plus MPA leads todecreases in choline acetyltransferaseand acetylcholinesterase in the basalforebrain.³⁷ Taken together with theevidence that the basal forebrain cholinergicsystem plays an important role incognition, long-term use of the CEE plusMPA regimen might negatively impactcognition and perhaps even lead todementia.³⁸

Fourth, the WHIMS estrogen plusprogesterone arm was terminatedprematurely at 4.2 years of follow-upand the estrogen-alone arm was terminatedat 5.4 years of follow-up. The abilityto examine possible preventiveeffects of the hormones on AD wastherefore limited, because it may takeup to 10 years for the disease to manifest.⁸ Thus, the question of whethergonadal steroids have a role in preventingAD has not yet been determinedfrom the WHI/WHIMS.³⁹ The role ofestrogen and progesterone in the preservationof normal cognitive functioninghas also not been determined in thesestudies. Therefore, prospective andsome longitudinal studies indicate beneficialeffects of estrogen replacementon cognitive functioning of postmenopausalwomen.

The cholinergic system

It is critical to understand the role ofestrogen in the brain and the effects ofmenopause on cognition in nondementedpostmenopausal women. Thetype of hormone, length of treatment,side effects (Table), method of administration,and age of starting therapy allneed to be taken into account to addressthe effects of hormone therapy on cognition.The next step in elucidating theeffects of estrogen on cognitive functioningis to determine the mechanismby which estrogen is acting in the brain.Evidence from the animal literature andpreliminary evidence from the humanliterature implicates the cholinergicsystem as the critical neurotransmittersystem influenced by estrogen treatmentand withdrawal.In one study with AD patients, estrogenadministration appeared to enhancethe effect of the anticholinesterasetacrine (Cognex) in AD.⁴⁰ Such dataare supportive of a positive effect ofestrogen on cholinergic systems.Estrogen has been shown to modulatecholinergic neurotransmission in thebrain.⁴¹

A number of studies have investigatedthe interaction of estrogen andthe cholinergic system and its effectson 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 theestrogen effect is specific to attentionalprocesses and not simply an overallspeeding of performance. Voytko⁴³ alsoshowed that scopolamine impairedperformance on the attention task butnot the memory task during estrogenadministration. Thus, estrogen uses themuscarinic cholinergic system to influencevisuospatial attention.⁴²

Thus far, only one experimental studyin women has examined the interactionof estrogen and the cholinergic systemand the effects of this interaction oncognition.⁴⁴ We employed a model ofthe estrogen-cholinergic system interactionwith which we examined theeffects of 3 months of estrogen treatmenton cognitive task performanceafter anticholinergic drug challenge.In this study, the anticholinergic drugsimpaired performance across all domainsof cognition. However, 3 monthsof estrogen treatment significantly attenuatedthe anticholinergic-inducedimpairment in attention tasks and othertasks with a speeded component, suggestinga beneficial effect on cholinergicsystem activity/integrity.

These results support the findingsfrom the primate literature showing thatestrogen and the cholinergic systeminteract to affect attentional performance.⁴² These findings further supportthe proposal that estrogen may preservecognitive functions by acting throughthe cholinergic system as well as addingto the evidence showing that estrogentreatment after menopause may be beneficial for cognition. The estrogencholinergicsystem link has implicationsfor the ability of estrogen to beuseful in the prevention or treatment ofAD. Many epidemiologic and someexperimental studies support the use ofestrogen for the maintenance of premenopausallevels of cognitive functioningin healthy older women and thepossibility of prevention of AD.

Summary

While evidence is conflicting, estrogencannot be recommended for thetreatment of dementia but may have arole in preserving cognitive functioningin older women. Estrogen may havea dementia-prevention effect aftermenopause based on epidemiologicstudies (not primary prevention studies),but this is not an approved indication.At this point, the off-labelprescribing of estrogen for cognitivedecline in the absence of dementia isnot a routine clinical practice and shouldbe regarded as appropriate only withinthe context of a research study. Estrogenmay be used in late-stage dementia totreat aggressive or sexually disinhibitedbehavior,⁴⁵ but this would not beconsidered a routine use in dementiapatients.

Estrogen use after menopause hasbeen linked to increased risk of venousthrombosis, and this risk increases withage and years of estrogen treatment.⁴⁶ Therefore, if estrogen were to be usedfor the prevention of cognitive impairment,it may have to be started early(during or soon after menopause) andcontinued only until the risk of vascularand thrombolytic complicationsrelated to estrogen use begins to rise,possibly in the seventh decade.

Variables such as the type of estrogen,the method of administration, andthe timing of ET relative to the menopausetransition may affect the successof estrogen in preserving cognition andwill require further research to resolve.Also, the role of progesterone remainsto be investigated. Evidence from ourlaboratory strongly suggests that beneficialeffects of estrogen on cognitionmay be acting through salutary interactionswith the brain cholinergicsystem, the same system that is responsiblefor the cognitive loss in AD.

Dr Dumas is a postdoctoral fellow at the ClinicalNeuroscience Research Unit in the departmentof psychiatry at the University of Vermont inBurlington. She acknowledges project supportfrom the National Institute on Aging.
Ms Salerno is a research associate at theClinical Neuroscience Research Unit in thedepartment of psychiatry at the University ofVermont in Burlington. She has no conflictsto report regarding the subject matter of thisarticle.
Dr Newhouse is the director of the ClinicalNeuroscience Research Unit and FunctionalBrain Imaging Program in the department ofpsychiatry at the University of Vermont inBurlington. He acknowledges project supportfrom the National Institute on Aging and theNational Center for Research Resources.

References:

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