Alzheimer's Disease In Postmenopausal Women Research Articles

Estrogen signalling and Alzheimer's disease: Decoding molecular mechanisms for therapeutic breakthrough.

In females, Alzheimer's disease (AD) incidences increases as compared to males due to estrogen deficiency after menopause. Estrogen therapy is the mainstay therapy for menopause and associated complications. Estrogen, a hormone with multifaceted physiological functions, has been implicated in AD pathophysiology. Estrogen plays a crucial role in amyloid precursor protein (APP) processing and overall neuronal health by regulating various factors such as brain-derived neurotrophic factor (BDNF), intracellular calcium signalling, death domain-associated protein (Daxx) translocation, glutamatergic excitotoxicity, Voltage-Dependent Anion Channel, Insulin-Like Growth Factor 1 Receptor, estrogen-metabolising enzymes and apolipoprotein E (ApoE) protein polymorphisms. All these factors impact the physiology of postmenopausal women. Estrogen replacement therapies play an important treatment strategy to prevent AD after menopause. However, use of these therapies may lead to increased risks of breast cancer, venous thromboembolism and cardiovascular disease. Various therapeutic approaches have been used to mitigate the effects of estrogen on AD. These include hormone replacement therapy, Selective Estrogen Receptor Modulators (SERMs), Estrogen Receptor Beta (ERβ)-Selective Agonists, Transdermal Estrogen Delivery, Localised Estrogen Delivery, Combination Therapies, Estrogen Metabolism Modulation and Alternative Estrogenic Compounds like genistein from soy, a notable phytoestrogen from plant sources. However, mechanism via which these approaches modulate AD in postmenopausal women has not been explained earlier thoroughly. Present review will enlighten all the molecular mechanisms of estrogen and estrogen replacement therapies in AD. Along-with this, the association between estrogen, estrogen-metabolising enzymes and ApoE protein polymorphisms will also be discussed in postmenopausal AD.

Estrogen deficiency exacerbates learning and memory deficits associated with glucose metabolism disorder in APP/PS1 double transgenic female mice

Alterations in glucose metabolism occur in the brain in the early stage of Alzheimer's disease (AD), and menopausal women have more severe metabolic dysfunction and are more prone to dementia than men. Although estrogen deficiency-induced changes in glucose metabolism have been previously studied in animal models, their molecular mechanisms in AD remain elusive. To investigate this issue, double transgenic (APP/PS1) female mice were subjected to bilateral ovariectomy at 3 months of age and were sacrificed 1 week, 1 month and 3 months after surgery to simulate early, middle and late postmenopause, respectively. Our analysis demonstrated that estrogen deficiency exacerbates learning and memory deficits in this mouse model of postmenopause. Estrogen deficiency impairs the function of mitochondria in glucose metabolism. It is possible that the occurrence of AD is associated with the aberrant mitochondrial ERβ-mediated IGF-1/IGF-1R/GSK-3β signaling pathway. In this study, we established a potential mechanism for the increased risk of AD in postmenopausal women and proposed a therapeutic target for AD due to postmenopause.

Hormone Therapy and Effects on Sporadic Alzheimer's Disease in Postmenopausal Women: Importance of Nomenclature.

Numerous observational studies have suggested that hormone therapy (HT) might protect postmenopausal women against cognitive decline and Alzheimer's disease (AD). However, because of the significant disparity between results, especially those between observational and randomized controlled trials (RCT), this postulate remains unproven. A significant contributing factor to these inconsistencies is the loose use of the generic definitions of estrogens and progestogens with most studies not delineating the clear differences between non-endogenous and endogenously identical (bioidentical) hormones, their molecular binding affinities and actions, and resultant metabolites. This is highlighted by the generalized terminological use of HT, which is often used to encompass significantly disparate hormonal formulations without clear demarcation. This has impacted and continues to significantly influence interpretations of data, meta-analyses, observational studies, etc., relevant to AD. To progress forward and allow unbiased interpretation, it is no longer acceptable to group HT formulations together as a homogenous group. This will also allow differentiation between compounds that exhibit beneficial actions and those that do not and whether these effects are specific or generalized. The role of the endogenous hormones, 17 beta-oestradiol (E2) and progesterone (P4), in the development of sporadic AD in postmenopausal women is also examined.

How Studies of the Serotonin System inMacaque Models of Menopause Relate toAlzheimer's Disease1.

Serotonin plays a key role in mood or affect, and dysfunction of the serotonin system has been linked to depression in humans and animal models. Depression appears prior to or coincident with overt symptoms of Alzheimer's disease (AD) in about 50% of patients, and some experts consider it a risk factor for the development of AD. In addition, AD is more prevalent in women, who also show increased incidence of depression. Indeed, it has been proposed that mechanisms underlying depression overlap the mechanisms thought to hasten AD. Women undergo ovarian failure and cessation of ovarian steroid production in middle age and the postmenopausal period correlates with an increase in the onset of depression and AD. This laboratory has examined the many actions of ovarian steroids in the serotonin system of non-human primates using a rhesus macaque model of surgical menopause with short or long-term estradiol (E) or estradiol plus progesterone (E+P) replacement therapy. In this mini-review, we present a brief synopsis of the relevant literature concerning AD, depression, and serotonin. We also present some of our data on serotonin neuron viability, the involvement of the caspase-independent pathway, and apoptosis-inducing factor in serotonin-neuron viability, as well as gene expression related to neurodegeneration and neuron viability in serotonin neurons from adult and aged surgical menopausal macaques. We show that ovarian steroids, particularly E, are crucial for serotonin neuron function and health. In the absence of E, serotonin neurons are endangered and deteriorating toward apoptosis. The possibility that this scenario may proceed or accompany AD in postmenopausal women seems likely.

Alzheimer disease in post-menopausal women: Intervene in the critical window period

Alzheimer disease (AD) is a crippling neurodegenerative disorder. It is more common in females after menopause. Estrogen probably has a protective role in cognitive decline. Large amount of research has been carried out to see the benefits of hormone replacement therapy with regards to Alzheimer still its neuroprotective effect is not established. Recent studies suggest a reduced risk of AD and improved cognitive functioning of post-menopausal women who used 17 β-estradiol in the critical period. Use of 17 β-estradiol in young and healthy post-menopausal women yields the maximum benefit when the neurons are intact or neuronal stress has just started. Hence intervention in the critical period is key in the prevention or delay of AD in post-menopausal women.

Androgen receptor gene and sex-specific Alzheimer's disease

Women are at a 2-fold risk of developing late-onset Alzheimer's disease (AD) (onset at 65 years of age or older) compared with men. During perimenopausal years, women undergo hormonal changes that are accompanied by metabolic, cardiovascular, and inflammatory changes. These all together have been suggested as risk factors for late-onset AD. However, not all perimenopausal women develop AD; we hypothesize that certain genetic factors might underlie the increased susceptibility for developing AD in postmenopausal women. We investigated the Androgen Receptor gene (AR) in a clinical cohort of male and female AD patients and normal control subjects by sequencing all coding exons and evaluating the length and distribution of the CAG repeat in exon 1. We could not establish a correlation between the repeat length, sex, and the disease status, nor did we identify possible pathogenic variants. AR is located on the X chromosome; to assess its role in AD, X-inactivation patterns will need to be studied to directly correlate the actual expressed repeat length to a possible sex-specific phenotypic effect.

Progesterone and Estrogen Regulate Alzheimer-Like Neuropathology in Female 3xTg-AD Mice

Estrogen depletion in postmenopausal women is a significant risk factor for the development of Alzheimer's disease (AD), and estrogen-based hormone therapy may reduce this risk. However, the effects of progesterone both alone and in combination with estrogen on AD neuropathology remain unknown. In this study, we used the triple transgenic mouse model of AD (3xTg-AD) to investigate the individual and combined effects of estrogen and progesterone on beta-amyloid (Abeta) accumulation, tau hyperphosphorylation, and hippocampal-dependent behavioral impairments. In gonadally intact female 3xTg-AD mice, AD-like neuropathology was apparent by 3 months of age and progressively increased through age 12 months, a time course that was paralleled by behavioral impairment. Ovariectomy-induced depletion of sex steroid hormones in adult female 3xTg-AD mice significantly increased Abeta accumulation and worsened memory performance. Treatment of ovariectomized 3xTg-AD mice with estrogen, but not progesterone, prevented these effects. When estrogen and progesterone were administered in combination, progesterone blocked the beneficial effect of estrogen on Abeta accumulation but not on behavioral performance. Interestingly, progesterone significantly reduced tau hyperphosphorylation when administered both alone and in combination with estrogen. These results demonstrate that estrogen and progesterone independently and interactively regulate AD-like neuropathology and suggest that an optimized hormone therapy may be useful in reducing the risk of AD in postmenopausal women.

Estrogen, β‐Amyloid Metabolism/Trafficking, and Alzheimer's Disease

Estrogen plays key regulatory roles in a variety of biological actions besides its classic function as a sex hormone. Recently, estrogen has been linked to neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). Several lines of evidence support the notion that brain estrogen exerts neuroprotective effects against various types of neurotoxicity in different cellular and animal models. Despite some controversies, estrogen replacement therapy (ERT) at an early stage, especially when given prior to menopause, has been shown to reduce the risk of AD in postmenopausal women. In addition, multiple lines of evidence have proven the neuroprotective effects of estrogen, such as enhancing neurotrophin signaling and synaptic activities pertinent to memory functions and protecting neurons against oxidative injuries and beta-amyloid toxicity; the latter is widely accepted as the prime culprit known to trigger the pathogenesis of AD. Here we will summarize our findings that estrogen decreased generation and secretion of beta-amyloid peptides in cultured cells and primary neurons and that administration of estrogen in estrogen-deprived mice reversed the elevated levels of brain Abeta. We will also discuss the molecular and cellular mechanisms underlying estrogen's effects on Abeta metabolism, which is highlighted by our demonstration that estrogen increases intracellular trafficking of beta-amyloid precursor protein (betaAPP) and hence reduces maximal Abeta generation within the trans-Golgi network (TGN), a subcellular compartment in which APP is known to be cleaved by the secretase enzymes to generate Abeta.

Postmenopausal Estrogen Therapy and Alzheimer Disease: Overall Negative Findings

An inverse association between estrogen therapy (ET) and Alzheimer disease (AD) has been reported in some, but not in all studies. We investigated the association between ET and AD in postmenopausal women using a population-based case-control design. Women who developed AD from 1985 through 1989 in Rochester, MN (cases, n=264) were individually matched by age (+/-1 y) to control women free of dementia from the same population (controls, n=264). ET exposure (>/=6 mo after menopause) was ascertained by abstracting the complete medical records archived in the records-linkage system of the Rochester Epidemiology Project. The frequency of ET use was similar in cases (11.4%) and controls [10.6%; odds ratio=1.10; 95% confidence interval (CI)=0.63-1.93]. However, cases who used ET had a suggestive trend for an earlier age at start of ET compared with controls (median, 49.0 vs. 50.5 y; P=0.06). Although smoking (ever vs. never) was not associated with AD overall, we observed an interaction between smoking and ET. The odds ratio of AD in ET users was 4.55 (95% CI=1.33-15.53) among smokers, but was 0.68 (95% CI=0.35-1.32) among never-smokers (P for interaction=0.01). Our findings do not confirm a significant association between ET and AD overall; however, the possible interaction with smoking deserves further study.

Mood and Memory

Women are at a 2-fold risk of developing late-onset Alzheimer's disease (AD) (onset at 65 years of age or older) compared with men. During perimenopausal years, women undergo hormonal changes that are accompanied by metabolic, cardiovascular, and inflammatory changes. These all together have been suggested as risk factors for late-onset AD. However, not all perimenopausal women develop AD; we hypothesize that certain genetic factors might underlie the increased susceptibility for developing AD in postmenopausal women. We investigated the Androgen Receptor gene (AR) in a clinical cohort of male and female AD patients and normal control subjects by sequencing all coding exons and evaluating the length and distribution of the CAG repeat in exon 1. We could not establish a correlation between the repeat length, sex, and the disease status, nor did we identify possible pathogenic variants. AR is located on the X chromosome; to assess its role in AD, X-inactivation patterns will need to be studied to directly correlate the actual expressed repeat length to a possible sex-specific phenotypic effect.

Hormones and dementia - a comparative study of hormonal impairment in post-menopausal women, with and without dementia.

Women seem to be more vulnerable to dementia, particularly Alzheimer's disease (AD), than men. There is controversy among studies correlating estrogen deficit to cognitive impairment. Because of the sudden drop of estrogens in menopause, this hormonal deficit could represent one of the risk factors for the larger incidence and prevalence of AD in post-menopausal women. We therefore wanted to find out if post-menopausal women with dementia, or even in a prior stage, mild cognitive impairment (MCI), would have a more significant deficit of estrogens than post-menopausal women without dementia, or any other type of cognitive problem. The aim of this study was to detect possible differences of the sex hormone levels among post-menopausal women, simultaneously affected by MCI or dementia, in comparison with a control group without cognitive impairment. A small, multicenter, prospective study was performed on 82 post-menopausal women (41 cases, 41 controls), aged 45-81 years, to investigate their sex hormone balance. The diagnosis of dementia was made according to ICD 9 or 10 and DSM III-R or IV appropriate to the time interval. The diagnosis of probable AD followed the NINCDS-ADRDA criteria. MCI met the Paquid-study criteria. Blood was analyzed in qualified centers for LH, FSH, and 17-beta-estradiol. All women went through a thorough psychiatric examination and those with a suspected hormonal impairment were examined by a gynecologist. 15 cases (36.6%) had impaired hormonal function, compared with 8 controls (19.5%). Of the 15 cases with hormonal impairment, 9 had MCI. These preliminary data stress a considerable difference between the sex hormone status of these two populations, showing a tendency towards a more accentuated estrogen deficit linked to cognitive deficit. Enlarging the sample and following the evolution could bring more interesting data.

Postmenopausal Estrogen Therapy (ET) and Alzheimer's Disease (AD): Effect modificiation by smoking

To investigate the association between ET and AD in postmenopausal women using a population-based case-control study design. Case patients were all postmenopausal women who developed AD from 1985–1989 in Rochester, MN (n = 277). One control subject from the same population and free of dementia was matched to each case patient by age (± 1 year; n = 277). Estrogen exposure was defined as any form of estrogen (oral, parenteral, topical, suppository) used for at least 6 months after the onset of menopause and before the year of onset of AD (or corresponding year in matched control subject). A history of ET, duration of use, and cumulative dose was ascertained by a detailed review of the complete medical records archived in the records linkage system of the Rochester Epidemiology Project. Among women with natural menopause, the frequency of ET use (≥6 months) was similar in AD cases (11.6%) and controls (14.3%; OR = 0.80; 95% CI = 0.45 to 1.41). However, among women treated with ET, cases had an earlier age at start of treatment (median = 50 versus 53 years; p = 0.05), and a shorter lag time between menopause and initiation of ET (median = 1 years versus 4 years; p = 0.11) than controls. Smoking (ever vs. never) was not associated with the risk of AD overall; however, we observed an interaction between smoking and ET. The OR for AD in ET users was 1.93 (95% CI = 0.65 to 5.74) among smokers, but was 0.54 (95% CI = 0.27 to 1.09) in non-smokers (p value for interaction = 0.06). For women who never smoked, the inverse association of ET with AD reached statistical significance for duration of ET longer than 3 years (OR = 0.33; 95% CI = 0.12 to 0.95). The possible interaction with smoking was also observed with cumulative dose of ET. Although we failed to show a significant overall association between ET and AD, our findings suggest that early ET use may predict AD in postmenopausal women. In addition, our findings suggest that ET may be protective for AD in women who have never been smokers.

Neurobiological Consequences of Long-Term Estrogen Therapy

Postmenopausal women demonstrate an increased incidence of Alzheimer's disease (AD). Epidemiological evidence suggests that estrogen replacement therapy (ERT) may reduce the risk or delay the onset of AD, yet recent clinical trials found no cognitive benefits of ERT in women with mild to moderate AD. This review suggests that the timing of estrogen administration may explain these conflicting results. Chronic administration has neurobiological consequences that can affect neural and immune function, but a therapy designed to mimic the natural cycle of fluctuating hormones may more effectively slow the progression of AD in postmenopausal women.

The Role of Hormone Replacement Therapy in the Prevention of Alzheimer Disease

Alzheimer disease (AD) is the most common form of dementia among the elderly. A higher prevalence of AD in women than in men suggests a link between gonadal hormone levels and AD. Increasing evidence supports a role for estrogen in brain regions involved in learning and memory and in the protection and regulation of cholinergic neurons, which degenerate in AD. Despite the lack of consensus, many studies indicate that hormone replacement therapy may decrease the risk for or delay the onset of AD in postmenopausal women. Recent trials have suggested that estrogen treatment may have no significant effect on the clinical course of AD in elderly women with the disease. Thus, the role of estrogen therapy seems to be confined to primary rather than secondary prevention of AD. Ongoing clinical studies may help to determine the role of estrogen in the cognitive function of postmenopausal women and in the prevention of AD.

Estrogen Replacement Therapy for Alzheimer Disease in Postmenopausal Women

Estrogen Replacement Therapy for Alzheimer Disease in Postmenopausal Women

Estrogen replacement therapy for Alzheimer disease in postmenopausal women.

To evaluate the clinical utility of oral conjugated equine estrogen in postmenopausal women with Alzheimer disease. Literature was identified through MEDLINE (1997-January 2002). Key search terms included Alzheimer disease, estrogen replacement therapy, and treatment. Estrogen has been identified as a neuroprotective agent with possible application in degenerative disorders. Observational studies have demonstrated an association between estrogen replacement therapy and decreased incidence of Alzheimer disease. Two recent, controlled clinical trials have evaluated the role of oral conjugated estrogen in the treatment of Alzheimer disease. Clinical trials indicate that oral conjugated equine estrogen is not an effective treatment for Alzheimer disease in postmenopausal women.

Ovariectomy and 17beta-estradiol modulate the levels of Alzheimer's amyloid beta peptides in brain.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of aggregated forms of the 40- and 42-amino acid Abeta peptides (Abeta40 and Abeta42). Estrogen replacement therapy (ERT) in postmenopausal women is associated with decreased risk for AD and/or delay in disease onset. The mechanism by which estrogen exerts this neuroprotective effect is elusive. 17beta-estradiol (E2) was shown to reduce the release of Abeta peptides by primary neuronal cultures of murine and human origin. To test whether estrogen can modulate the metabolism of Abeta peptides in vivo, four experimental sets of guinea pigs were used: intact animals, ovariectomized animals, and ovariectomized animals that received E2 at two different doses. Ovariectomy was associated with a 1.5-fold average increase in total brain Abeta levels as compared to intact controls. E2 treatment significantly reversed the ovariectomy-induced increase in brain Abeta levels. The high-dose E2 treatment did not lead to further decrease in brain Abeta beyond the one observed with the low-dose E2 treatment. Our results infer that cessation of ovarian estrogen production in postmenopausal women might facilitate Abeta deposition by increasing the local concentrations of Abeta40 and Abeta42 peptides in brain and suggest that modulation of Abeta metabolism may be one of the ways by which ERT prevents and/or delays the onset of AD in postmenopausal women.

Testosterone reduces neuronal secretion of Alzheimer's beta-amyloid peptides.

Alzheimer's disease (AD) is characterized by the age-related deposition of beta-amyloid (Abeta) 40/42 peptide aggregates in vulnerable brain regions. Multiple levels of evidence implicate a central role for Abeta in the pathophysiology of AD. Abeta peptides are generated by the regulated cleavage of an approximately 700-aa Abeta precursor protein (betaAPP). Full-length betaAPP can undergo proteolytic cleavage either within the Abeta domain to generate secreted sbetaAPPalpha or at the N- and C-terminal domain(s) of Abeta to generate amyloidogenic Abeta peptides. Several epidemiological studies have reported that estrogen replacement therapy protects against the development of AD in postmenopausal women. We previously reported that treating cultured neurons with 17beta-estradiol reduced the secretion of Abeta40/42 peptides, suggesting that estrogen replacement therapy may protect women against the development of AD by regulating betaAPP metabolism. Increasing evidence indicates that testosterone, especially bioavailable testosterone, decreases with age in older men and in postmenopausal women. We report here that treatment with testosterone increases the secretion of the nonamyloidogenic APP fragment, sbetaAPPalpha, and decreases the secretion of Abeta peptides from N2a cells and rat primary cerebrocortical neurons. These results raise the possibility that testosterone supplementation in elderly men may be protective in the treatment of AD.

17?-Estradiol attenuates oxidative impairment of synaptic Na+/K+-ATPase activity, glucose transport, and glutamate transport induced by amyloid ?-peptide and iron

Synapse loss, deposits of amyloid beta-peptide (Abeta), impaired energy metabolism, and cognitive deficits are defining features of Alzheimer's disease (AD). Estrogen replacement therapy reduces the risk of developing AD in postmenopausal women. Because synapses are likely sites for initiation of neurodegenerative cascades in AD, we tested the hypothesis that estrogens act directly on synapses to suppress oxidative impairment of membrane transport systems. Exposure of rat cortical synaptosomes to Abeta25-35 (Abeta) and FeSO4 induced membrane lipid peroxidation and impaired the function of the plasma membrane Na+/K+-ATPase, glutamate transporter, and glucose transporter. Pretreatment of synaptosomes with 17beta-estradiol or estriol largely prevented impairment of Na+/K+-ATPase activity, glutamate transport, and glucose transport; other steroids were relatively ineffective. 17Beta-estradiol suppressed membrane lipid peroxidation induced by Abeta and FeSO4, but did not prevent impairment of membrane transport systems by 4-hydroxynonenal (a toxic lipid peroxidation product), suggesting that an antioxidant property of 17beta-estradiol was responsible for its protective effects. By suppressing membrane lipid peroxidation in synaptic membranes, estrogens may prevent impairment of transport systems that maintain ion homeostasis and energy metabolism, and thereby forestall excitotoxic synaptic degeneration and neuronal loss in disorders such as AD and ischemic stroke.

Estrogen Replacement Therapy and Risk of Alzheimer Disease

With Alzheimer disease emerging as a major public health problem, the identification of factors that might prevent this disease are important. Estrogen loss associated with menopause may contribute to the development of Alzheimer disease. To evaluate the effects of different estrogen preparations, varying dosages of estrogen, and duration of estrogen replacement therapy on the risk of Alzheimer disease in postmenopausal women. A case-control study nested within a prospective cohort study of residents of Leisure World Laguna Hills, a retirement community in Southern California. The cohort comprised 8877 women who were first mailed a health survey in 1981. Of the 3760 female cohort members who died between 1981 and 1995, 248 women with Alzheimer disease or other dementia diagnoses likely to represent Alzheimer disease (senile dementia, dementia, or senility) mentioned on the death certificate were identified. Five controls were individually matched to each case according to year of death and year of birth (+/- 1 year). The risk of Alzheimer disease and related dementia was significantly reduced in estrogen users compared with nonusers (odds ratio, 0.65; 95% confidence interval, 0.49-0.88). The risk was reduced for both oral and nonoral (i.e., injections and/or creams) routes of administration. The risk decreased significantly with both increasing dosages (P = .01) and increasing duration (P = .01) of oral therapy with conjugated equine estrogen, the most commonly used estrogen preparation. Within each dose category, the risk decreased with increasing duration of therapy, with the lowest observed risk in long-term users who received high doses (odds ratio, 0.48; 95% confidence interval, 0.19-1.17). This study suggests that estrogen replacement therapy may be useful for preventing or delaying the onset of Alzheimer disease in postmenopausal women.