11 The Effects of Estrogens on Cognition and Alzheimer’s Dementia Tony Edwin and Uriel Halbreich

Introduction Several lines of evidence suggest that mood and behavior effects of estrogen reflect the direct action of this hormone on neurons and other components of the central nervous system (CNS). Elements within the CNS that are responsive to estrogens encompass structural neuronal systems, blood flow, energy delivery and utilization, dendrite activity, neurotransmitters, and neuromodulators as well as intraneuronal and other processes. Estrogens readily cross the blood-brain barrier where they interact with nuclear estrogen receptors present in neuronal populations from different brain regions and with membrane-bound receptors (Sherwin 1997; Kawata 1995). Estrogen modulates growth proteins specifically associated with axonal elongation (Shugrue and Dorsa 1993), enhances the outgrowth or nerve processes in cultured neurons (ToranAllerand 1984), and promotes the formation of dendrite spines and synapses (Chung et al. 1988). The viability of in vitro cultures of differentiated amygdala (Arimatsu and Hatamaka 1986) or hypothalamic (Faivre-Bauman et al. 1981) neurons is prolonged by the addition of estrogen. Neurite outgrowth in the developing brain is stimulated by estrogens (Toran-Allerand 1993). Dendritic growth is stimulated by estrogen and is responsive to the hormonal fluctuations along the estrous cycle (McEwen et al. 1997). The physiological relevance of some of these estrogen effects is suggested by enhanced long-term potentiation (Warren et al. 1995), in parallel with increased synapse formation in the CA1 region of the hippocampus (Woolley and McEwen 1993) during the proestrus (high-estrogen) phase of the rat estrus cycle. Estrogen influences several neurotransmitter systems, including those using acetylcholine (Singh et al. 1994), norepinephrine (Sar and Stumpf 1981), serotonin (Kendall et al. 1981), dopamine (Toran-Allerand 1984), and other neurotransmitters.

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Cholinergic and noradrenergic neurons from the basal forebrain, noradrenergic neurons from the brain stem locus caeruleus, and serotonergic neurons from the midbrain regions are all substantially affected by estrogens (Coyle et al. 1983). Estrogen’s interactions with the cholinergic systems are especially noteworthy in the context of this chapter. Cholinergic mechanisms are critically involved in attentional processes, learning, and memory: cognitive functions that are critically affected by Alzheimer’s disease (AD) (Bartus et al. 1981). Basal forebrain cholinergic neurons possess nuclear receptors for estrogen and low-affinity receptors for nerve growth factor (Torran-Allerand et al. 1992). Nerve growth factor prevents atrophy of cholinergic neurons after experimental injury (Hefti et al. 1993), and estrogens may regulate or modulate neurotrophins (Sorabji et al. 1994). Even though the hippocampus contains few estrogen and progestin receptors, this structure displays a robust response to exposure to exogenous estrogen and progestin treatment and to endogenous ovarian steroids during the natural estrous cycle (Toran-Allerand 1984). This first became apparent with the finding of cyclic variations in the threshold of the dorsal hippocampus to elicitation of seizures, with the greatest sensitivity occurring during proestrus (Terasawa and Timiras 1968). Morphologic studies indicate that estrogen induces dendritic spines and new synapses in the venteromedial hypothalamus of the female rat but also increases density of dendritic spines on pyramidal neurons in the hippocampus (McEwen and Woolley 1994). Spine density also changes cyclically during the estrus cycle of the female rat. These findings indicate that synapses are formed and broken down rapidly during the natural reproductive cycle. It is of significance that several gender differences in brain development are regulated by estrogen. In the CAl region of males, estrogen treatment fails to induce as great a number of spine synapses as in females, but blockade at birth of the aromatization of testosterone to estradiol in male neonates increases the number of spine synapses induced by estrogen treatment in adulthood (Wong and Moss 1992). This suggests that the responsiveness of the hippocampus to estrogenic regulation of synapse formation is defeminized in males by the neonatal actions of testosterone. Ovarian steroids regulate the midbrain serotonergic system by mechanisms as yet undefined. Estrogen increases serotonergic post-

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synaptic responsivity (Rosencrans 1970) and increases both the number of serotonergic receptors and neurotransmitter uptake (Rosencrans 1970). Estrogen also increases 5-hydroxytryptamine (5-HT) synthesis and 5-HTlA levels; it upregulates 5-HT1 receptors and downregulates 5-HT2 receptors. It decreases monoamine oxidase activity (Chakravorthy and Halbreich 1997) and increases the responsitivity of postsynaptic receptors to stimulation with the serotonergic agonist mCPP (Halbreich et al. 1995. The cumulative effect of estrogen on serotonergic function is as a 5-HT agonist (Kahn and Halbreich 1999).

Estrogen and Human Cognition Sex differences in brain structure and brain function including cognition are believed to result from differential exposure of men and women to sex hormones during fetal life (Chung et al. 1988). On average, men excel in spatial and quantitative abilities and in gross motor strength, whereas women excel in verbal abilities, in perceptual speed and accuracy, and in fine motor skills (Jarvik 1975). It is important to note, however, that the magnitude of the sex differences in test performance is modest and ranges between 0.25 and 1.0 standard deviations (SD) from normative scores (Chung et al. 1988). Sex differences in specific cognitive abilities in healthy men and women are probably due to prenatal influences on brain organization. This information can be extrapolated from studies of individuals affected by genetic syndromes that altered, in some manner, the concentration of gonadal hormones to which the fetuses were exposed, such as in congenital adrenal hyperplasia (CAH) (Chung et al. 1988). Fetuses with CAH are exposed to high levels of adrenal androgen production because of their adrenocorticotropic hormone (ACTH) levels. Predictably, women with CAH have a lower verbal IQ score (Perlman 1973), increased spatial abilities (Resnik et al. 1986), and an increased frequency of specific learning disabilities (dyscalculia) (Nass and Baker 1991) compared to their unaffected sisters. It may be inferred from this finding that the prenatal hormonal environment influences gender differences in certain cognitive functions. Studies of short-term verbal memory in humans indicate that estrogens have beneficial effects in women whose

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estrogen levels have been reduced by various means (e.g., physiological postmenopausal status or “medical menopause” by administration of gonadotropin-releasing hormone [GnRH] analogues] (Sherwin 1994; Sherwin and Tulandi 1996). An increased estrogen level in women has also been associated with better performance on tests of fine motor skills and somewhat poorer performance on tests of spatial recognition (Hampson and Kimura 1988). The selective deterioration of some cognitive functions in menopausal women might suggest an association with low levels of estrogen and not age per se. Several cognitive functions such as delayed recall, visual reproduction, digit span, as well as spatial ability and attention span or visual memory are probably not improved with estrogen replacement therapy (ERT). Since the early 1950s, it has been suggested that estrogen’s influence might be diversified and may depend on the cognitive construct studied (Caldwell and Watson 1952). In most of the cases, when various tests of memory were studied, a positive effect of estrogen was reported (Hackman and Galbraith 1976; Campbell and Whitehead 1977; Fedor-Freybergh 1977; Phillips and Sherwin 1992). However, this improvement is not generalized. For example, some women who had improved immediate recall and association learning in response to estradiol (Phillips and Sherwin 1992) did not show improvement of delayed recall, visual reproduction, or digit span. This was demonstrated by Kampen and Sherwin (1994), who found that verbal memory improved, whereas spatial ability and attention span did not. In a classic study, Sherwin and Phillips (1990) tested estrogen’s effect on cognition in premenopausal women who underwent total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) for benign disease. They administered the Paragraph Recall Test (for verbal memory) to women having a normal estradiol level before undergoing surgery. This assessment was repeated after the surgical procedure, when women were randomly assigned to receive intramuscular androgen, combined estrogen – androgen, estrogen, or placebo for 3 months. Sherwin and Phillips found that women receiving any of the single or combination hormone treatments following the ovariectomy had at least maintained their baseline paragraph recall scores, whereas those women receiving placebo after removal of their uterus and ovaries had a statistically significant decrease in scores. From these results, Sherwin and

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Phillips then undertook a similar comparison with a more comprehensive battery of neuropsychologic tests. Their findings indicate a significant decrease in paired association scores, tests for memory, and capacity to form new associations in women on placebo who maintained baseline levels in the paragraph recall test. However, women who received estrogen scored higher than at baseline. Two studies failed to find any effects of estrogen on memory in postmenopausal women. Ditkoff and colleagues (Ditkoff et al. 1991) administered either 0.625 mg conjugated equine estrogen (CEE), 1.25 mg CEE, or placebo to postmenopausal women who had a previous TAH and who were not experiencing vasomotor symptoms. After 3 months of treatment, there were no within- or between-group differences in scores on the digit symbol or the digit span subtests of the Wechsler Adult Intelligence Scale, which were the only cognitive tests administered. Barret-Connor and Kritz-Silverstein (1993) administered a comprehensive battery of neuropsychologic tests to 800 women between the ages of 65 and 95 years who were in the Rancho Bernado cohort assembled in 1972–1974 to study heart disease risk factors. Almost half of this upper middle class cohort had used estrogen at some point after the menopause and one third were current users. Women who had used estrogen for at least 20 years had higher scores on the category fluency test, whereas those who were past users had significantly higher scores on the mini-mental state examination. However, no differences were found between the performance of past users, current users, or those who had never used estrogen in other tests of verbal memory or tests of visual memory. In a more recent study to determine whether endogenous hormone levels predict cognitive function in older women, BarrettConnor and Goodman-Gruen (1999) evaluated cognitive function in 393 community-dwelling women aged 55–89 years who were not using replacement estrogen. It was found that in these older women, higher endogenous estrogen levels were not associated with significantly better performance on any cognitive function test administered. Our own studies (Halbreich et al. 1993; Halbreich 1995; 1997) with an extensive battery of cognitive tests showed improvement in complex integrative cognitive tasks that require integration of several cognitive constructs, such as recognition, interpretation, decision making, eye-hand coordination, and reaction. We also found positive effects of estrogen on several short-term memory functions,

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but not on tests of manual dexterity, visuospatial and verbal abilities, indicating a selective task-dependent effect of estrogen on cognition (Halbreich 1995).

Estrogen and Dementia of the Alzheimer’s Type Dementia of the Alzheimer’s type (DAT) is precipitated by a combination of genetic vulnerability and environmental and biological processes. Many of these mechanisms are influenced by estrogen. A genetic disposition is widely accepted. Aside from advanced age, the most consistently identified risk factor is a family history of dementia. An individual’s risk for developing AD is more than doubled when a parent or sibling is demented, and the risk estimate is even greater for two or more affected first-degree relatives (Pericak-Vance and Haines 1995). With respect to early-onset AD, it now appears that the illness can be attributed to point mutations in the chromosome 14 gene encoding a cell-membrane-spanning protein of uncertain function, referred to as presenilin-1. Less common are point mutations in the chromosome 1 gene for a homologous protein (presenilin-2) or the chromosome 21 gene for the amyloid precursor protein (Henderson 1997). These autosomal-dominant defects show virtually complete age-dependent penetrance and share similar clinical and pathologic phenotypes. In contrast, late-onset AD is infrequently associated with recognized mutations, but the risk for dementia in this older age group is strongly influenced by the polymorphism of apolipoprotein E (ApoE4), a plasma lipoprotein constituent encoded by chromosome 19. The observation that many identical twins are discordant for AD (Toran-Allerand 1984; Nee et al. 1987; Small et al. 1993) implies the existence of environmental factors or a multifactorial model leading to late-onset AD. Accumulating evidence suggests that for women, one such exogenous risk factor is postmenopausal estrogen deprivation. The insidious onset and progressive decline in mental and cognitive functions characterize DAT. It is more prevalent in women than in men (up to three times) (Jorm et al. 1987), even when adjusted for age. Although there is a genetic predisposition to DAT, environmental factors play an important role in the actual manifestation of the disorder, and some other risk factors have been identified (Jorm

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et al. 1987; Birge 1997). Some of these risk factors have been shown to be more prevalent among women and to be influenced by estrogen. They include female gender itself, hysterectomy, hip fracture, hypertension, myocardial infarction, diabetes, hypothyroidism, and increased hematocrit (Birge 1997) as well as depression. Therefore, it appears logical that the lack of estrogen would be implicated in increasing the risk for DAT and that ERT would be suggested as a preventive and treatment modality. So far, most of the evidence for a positive influence of ERT on DAT is derived from epidemiological studies showing a lower incidence of DAT in women who received ERT (Birge 1994; Henderson et al. 1994; Mortel and Meyer 1995; Lerner et al. 1995) as compared to those who did not. Thus, the use of ERT has been shown to reduce the relative risk (odds ratio) of developing DAT by about 0.5 (Paganini-Hill and Henderson 1996; Brenner et al. 1994; Morrison et al. 1996; Caldwell 1954) in most, but not all studies. The demonstration of dose and duration effects of ERT on the rate of DAT reinforces the credibility of the epidemiological data. Women who received higher doses of estrogen for longer times had lower risks for developing DAT (Paganini-Hill et al. 1996). Actual prospective treatment trials with estrogen in patients with dementia and specifically with DAT are still scarce, even though they date back to the early 1950s (Kantor et al. 1973). Nonetheless, their positive results are quite consistent (Birge 1997; Fillit et al. 1986; Honjo et al. 1989; Okhura et al. 1995; Schneider et al. 1996; Halbreich 1997). Available epidemiological studies have examined AD risk when information on postmenopausal estrogen use was collected mostly retrospectively before the presumptive onset of dementia symptoms. The Leisure World retirement community cohort in southern California was established by a postal survey in 1981 (Paganini-Hill and Henderson 1994). Detailed information on hormone use in this upper middle-class population was collected from each female participant at the time of enrollment, and death certificates have subsequently been obtained for virtually all deceased cohort members. From the records of 2,529 female cohort members who died before 1993, Paganini-Hill and Henderson (1994) identified diagnoses of AD and other diagnoses believed likely to represent AD. Estrogen users in this nested case-control study had about a 30% lower risk of developing AD or related diseases (odds ratio, 0.69; 95% CI, 0.49–1.03).

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Morrison and coworkers (Morrison et al. 1996) identified 38 incident cases of AD from among 472 older women participating in the Baltimore Longitudinal Study of Aging. The use of oral and transdermal estrogen therapy was documented prospectively and, after adjusting for education, the relative risk of developing AD among “ever-users” of postmenopausal estrogen as compared to “neverusers” was reduced by over one half (odds ratio, 0.44; 95% CI, 0.20–0.97). Tang and colleagues (Tang et al. 1996) examined information on oral estrogen use for 1,124 cognitively intact older women. In this community-based northern Manhattan cohort, 167 incident cases of AD were identified over a follow-up period of 1–5 years. Postmenopausal use of oral estrogens was reported by 6% of women with AD and 16% of other cohort members. Among estrogen users, the risk of AD was reduced by 60% (odds ratio, 0.40; 95% CI, 0.22-0.85), and the age at onset of AD was significantly higher among estrogen users who became demented than never-users who became demented. However, in another case-control study derived from a large health maintenance organization population in the Puget Sound area of Washington state, Brenner and colleagues (Brenner et al. 1994) compared estrogen exposure between 107 incident cases of AD and 120 control subjects, who were frequency matched for age. They failed to confirm an association with postmenopausal ERT (everversus never-use as documented by computerized pharmacy records; odds ratio, 1.10; CI, 0.6–1.8). In a retrospective longitudinal study, Costa and Reus (1999) assessed cognitive functioning in female estrogen users and non-estrogen users (n = 3,128). It was found that at baseline, estrogen users had significantly lower rates of DAT diagnoses than non-estrogen users. ERT was significantly associated with higher cognitive functioning at baseline and at 1-year follow-up. Asthana and Craft (1999) evaluated the cognitive effects of transdermal estrogen in a small sample of postmenopausal women with DAT during an 8-week treatment period. The salutary effects of estrogen on cognition were observed after the first week of treatment, and started to diminish when treatment was terminated. Enhancement of verbal memory was positively correlated with plasma levels of estradiol. In addition, the authors suggest that several markers of neuroendocrine activity may serve to index the magnitude of estrogen-induced facilitation on cognition.

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The advantages are further supported by Henderson’s finding that the effects of HRT were dose and duration dependent: Women on a higher dose (1.25 mg of conjugated estrogen) had less relative risk for DAT than women who had not received ERT. Women who received HRT for more than 7 years had less relative risk for DAT than women who were treated for under 1 year. The hormone’s biological effects support the epidemiological and clinical reports on the efficacy of ERT for prevention and treatment of DAT. It has already been mentioned here that estrogen, which crosses the blood–brain barrier, has genomic intracellular signal transduction effects. It also has neurostructural effects on dendrites and axons as well as synapse level effects on several related neurotransmitters, especially acetylcholine and 5-HAT as well as cation channels. Therefore, the future of ERT for prevention of the deterioration of cognitive functioning and dementia is suggested to be quite certainly positive (Van Duijn and Hofman 1992). It is still unknown, however, whether estrogen would be effective as a treatment once DAT has developed. An important mechanism of estrogen’s improvement of cognitive function in women with DAT is the effect of the hormone on blood flow. The role of vascular dysfunction in the pathogenesis of dementia is now being revisited as a consequence of our greater ability to assess cerebral blood flow through advances in neuroimaging. Increasing evidence suggests that estrogen replacement could not only prevent the development of vascular disorder but also improve blood flow in women with existing vascular disorders (Mendelsohn and Karas 1999). These effects of estrogen are believed to be mediated through its direct effects on the endothelium and vasomotor function, specifically, the inhibition of the vasoconstrictor endothelin (Polderman et al. 1993) and the stimulation of the vasodilator endothelium-derived relaxing factor (van Buren et al. 1992). In postmenopausal women, estrogens administration increases cardiac output and systemic arterial blood flow, including internal carotid artery blood flow and cerebral blood flow (Ohkura et al. 1994). Because of the probable role of vascular disease in the pathogenesis of DAT and estrogen’s effect on cerebral blood flow, estrogen replacement is an attractive adjuvant for the treatment and prevention of DAT. Addition of estrogen to in vitro cultures of neurons results in stimulation of neurite outgrowth and promotion of neuron viability

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(Arimatsu and Hatamak 1986). These effects are replicated in live experimental animal models. Estrogen may attenuate neuronal injury related to its effects on the metabolism of the amyloid protein (APP). APP is expressed during neuronal injury (Regland and Gottfries 1992). Deposition of β-amyloid in brain parenchyma is a distinctive feature of the neuropathology of AD but also occurs to a lesser extent in normal aging (Armstrong 1995). In an estrogenreceptor-containing cell culture system, 17β-estradiol at physiological concentrations increases the secretory metabolism of the soluble fragment of APP without increasing intracellular levels of APP. Therefore, estrogen may favorably modify the processing of APP, thereby reducing the accumulation of the neurotoxic β-amyloid fragment (Birge 1997).

Conclusions Although the hypothesis that postmenopausal ERT favorably affects a women’s risk for developing AD is attractive, the issue is far from being settled. With regard to biological credibility, much remains to be done in terms of understanding how potentially relevant estrogen actions might affect the pathogenesis or progression of AD. Evidence favoring the estrogen hypothesis has been strengthened by recent experimental and epidemiological findings. However, even in positive epidemiological studies, the effects are moderate and the possibility that undetected selection or observation biases account for the reported associations cannot be excluded. Because a number of demographic features and lifestyles choices distinguish estrogen users from non-users (Hemminki et al. 1993; Derby et al. 1995), confounding of the estrogen–AD association by other unidentified variables must also be considered. Hogervorst and colleagues (Hogervorst et al. 1999) recently reported that the design and type of memory tests could explain the controversial results of studies on the effect of HRT on cognitive function. Furthermore, the authors suggested that HRT has a global activating effect, rather than a specific direct effect on cognitive function. Consistency of findings in future cohorts would strengthen an inferred causal link between estrogen replacement and a lowered risk for AD. More convincing evidence would come from adequately powered, randomized, placebo-controlled, primary intervention

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trials, such as the one through the Women’s Health Initiative of the National Institutes of Health (Henderson 1997). However, given the distressing high prevalence of AD among older women and the exorbitant social and economic costs associated with this disorder, a true risk reduction in the order of one third to one half, as suggested by several recent analytical studies, would be of tremendous public significance. Even a delay of 5–10 years in onset of DAT will have a high impact on prevalence and public health consequences. Preliminary evidence from the use of Selective Estrogen Receptor Modulators (SERMs) such as Raloxifene, which has estrogen-like properties on hippocampal choline acetyltransferase (ChAT) in vivo, suggests that they exert a beneficial effect on cholinergic transmission without producing peripheral stimulation of breast and uterine tissue (Wu and Glinn 1999). The significance of this effect on cognitive function needs to be further explored.

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