Dementia In Postmenopausal Women Research Articles

Cholesterol Levels, Hormone Replacement Therapy, and Incident Dementia among Older Adult Women.

Previous studies revealed that hormone replacement therapy (HRT) probably has a protective effect for preventing dementia in post-menopausal women. However, the results were still controversial. The association between cholesterol levels and incident dementia in older women is not fully understood either. We conducted a retrospective analysis on a cohort of non-demented women aged older than 50 years, which was registered in the History-based Artificial Intelligence Clinical Dementia Diagnostic System database from September 2015 to August 2021. We followed this cohort longitudinally to examine the rates of conversion to dementia. Using a Cox regression model, we investigated the impact of the quartile of total cholesterol (TC) levels on incident dementia, adjusting for age, sex, education, neuropsychiatric symptoms, neuropsychological assessments, HRT, as well as various vascular risk factors and medications. We examined a cohort of 787 participants, comprising 539 (68.5%) individuals who did not develop dementia (non-converters). Among these non-converters, 68 individuals (12.6%) were treated with HRT. By contrast, there were 248 (31.5%) who did develop dementia (converters). Among the converters, 28 individuals (11.3%) were treated with HRT. The average follow-up durations were 2.9 ± 1.5 and 3.3 ± 1.6 years for non-converters and converters, respectively. Compared to the lowest quartile of TC levels (<153), the hazard ratios (HR) for converting to dementia were 0.61, 0.58, and 0.58 for the second (153-176), third (177-201), and highest (>201) quartiles, respectively (all p < 0.05). However, the low-density lipoprotein cholesterol (LDL-C) level and HRT did not alter the rate of conversion to dementia. In conclusion, the lowest quartile of TC increased incident dementia in post-menopausal women without dementia; however, HRT did not contribute to conversion to dementia. Some studies suggest that post-menopausal women who have reduced estrogen levels might have an increased risk of Alzheimer's disease if they also have high cholesterol. Nonetheless, the evidence is inconclusive, as not all studies support this finding. The "Lower LDL-C is better" strategy for preventing cardiac vascular disease should be re-examined for the possible serial adverse effects of new onset dementia due to very low cholesterol levels.

The Role of Estrogen Therapy as a Protective Factor for Alzheimer's Disease and Dementia in Postmenopausal Women: A Comprehensive Review of the Literature.

The complete cessation of menstruation for 12 months with associated vasomotor symptoms is termed menopause.Apart from playing a role in reproduction, estrogen significantly affects the central nervous system (CNS). Population-based studies highlighted a substantial difference in the prevalence of dementia between men and women, with Alzheimer-associated dementia being more prevalent in women, indicating that estrogen deficiency might be a risk factor for neurodegenerative diseases. Patients with dementia experience a progressive decline in neurocognitive function, beginning with short-term memory loss that progresses to long-term memory loss and the inability to perform everyday activities, leading ultimately to death.There is currently no cure for dementia, so preventing or slowing the disease's progression is paramount. Accordingly, researchers have widely studied the role of estrogen as a neuroprotective agent. Estrogen prevents dementia by augmenting Hippocampal and prefrontal cortex function, reducing neuroinflammation, preventing degradation of estrogen receptors, decreasing oxidative damage to the brain, and increasing cholinergic and serotonergic function. According to the window phase hypothesis, estrogen's effect on preventing dementia is more pronounced if therapy is started early, during the first five years of menopause.Other studies like The Woman's Health Initiative Memory Study (WHIMS) showed unfavorable effects of estrogen on the brain. This review aims to establish an understanding of the currently available data on estrogen's effect on neurodegeneration, namely, dementia and Alzheimer's disease.

Cognitive disorders and dementia in postmenopausal women

Cognitive dysfunction in postmenopausal women reduces their quality of life, social and family adaptation and can lead to complications such as dementia including Alzheimer's disease. Results of the studies on the potential of hormone replacement therapy in prevention of this group of disorders are controversial and require further investigation. However, following healthy lifestyle, certain diets as well as regular physical and mental activity can minimize the risks of dementia and ensure normal mental performance in old age.

Estrogens still represent an attractive therapeutic approach for Alzheimer's disease.

Estrogens still represent an attractive therapeutic approach for Alzheimer's disease.

CEREBROVASCULAR FUNCTION, COGNITION AND OVERALL WELL-BEING IN POSTMENOPAUSAL WOMEN ARE IMPROVED FOLLOWING REGULAR RESVERATROL SUPPLEMENTATION

Impairment of cerebrovascular function is evident after menopause, which may explain the heightened risk of dementia in postmenopausal women. We tested whether supplementation with resveratrol (a phytoestrogen) could improve their cerebrovascular function and cognitive performance and overall well-being. Eighty community dwelling postmenopausal women aged 45–85 years were randomised to take resveratrol (resVida™, 2 x 75 mg/day) or placebo for 14 weeks and changes in the following were assessed: cognitive tests for executive function, semantic, verbal and visuospatial working memory; transcranial Doppler ultrasound recording of percent increase of blood flow velocity in the middle cerebral artery to both cognitive testing and hypercapnia (breathing carbogen gas for 3 min), which assessed neurovascular coupling capacity and global vasodilatation respectively. Rating scales from self-reports of pain, sleep, menopausal symptoms, mood states and quality of life using Short-Form 36 were averaged to provide a composite score representing overall well-being. Compared to placebo, supplementation with resveratrol elicited 17% increases in cerebrovascular responsiveness (CVR) to both the hypercapnic (P=0.010) and cognitive stimuli (P=0.002). The latter was an overall response to the cognitive test battery. There were also increases in CVR to verbal memory (P=0.041) and in overall cognitive performance (p=0.020) that correlated with the enhancement of neurovascular coupling capacity (r=0.327, P=0.048). We also found a significant reduction in perception of pain (P<0.001), attributable to age-related osteoarthritis, and an improvement in overall well-being (P=0.008) following supplementation; both outcomes correlated with the treatment change in CVR to hypercapnia. Neither pain reduction nor boosting of overall well-being significantly correlated with the improvement of cognitive performance. This is the first demonstration that regular consumption of a modest dose of resveratrol can enhance cognition and overall well-being and reduce pain perception in postmenopausal women; all of which were partially attributed to enhancement of cerebrovascular function. Further investigation elucidating the underlying mechanisms involving circulatory function and age-related chronic pain is warranted. Our findings offer a promising new approach for reducing the heightened risk of accelerated cognitive decline in this population.

Clinical Evaluation of Effects of Chronic Resveratrol Supplementation on Cerebrovascular Function, Cognition, Mood, Physical Function and General Well-Being in Postmenopausal Women-Rationale and Study Design.

Background: This methodological paper presents both a scientific rationale and a methodological approach for investigating the effects of resveratrol supplementation on mood and cognitive performance in postmenopausal women. Postmenopausal women have an increased risk of cognitive decline and dementia, which may be at least partly due to loss of beneficial effects of estrogen on the cerebrovasculature. We hypothesise that resveratrol, a phytoestrogen, may counteract this risk by enhancing cerebrovascular function and improving regional blood flow in response to cognitive demands. A clinical trial was designed to test this hypothesis. Method: Healthy postmenopausal women were recruited to participate in a randomised, double-blind, placebo-controlled (parallel comparison) dietary intervention trial to evaluate the effects of resveratrol supplementation (75 mg twice daily) on cognition, cerebrovascular responsiveness to cognitive tasks and overall well-being. They performed the following tests at baseline and after 14 weeks of supplementation: Rey Auditory Verbal Learning Test, Cambridge Semantic Memory Battery, the Double Span and the Trail Making Task. Cerebrovascular function was assessed simultaneously by monitoring blood flow velocity in the middle cerebral arteries using transcranial Doppler ultrasound. Conclusion: This trial provides a model approach to demonstrate that, by optimising circulatory function in the brain, resveratrol and other vasoactive nutrients may enhance mood and cognition and ameliorate the risk of developing dementia in postmenopausal women and other at-risk populations.

Depressive Symptoms and Longitudinal Changes in Cognition

Elevated depressive symptoms (DS) are associated with incident mild cognitive impairment and probable dementia in postmenopausal women. We examined the association of elevated DS with domain-specific cognitive changes and the moderating role of cardiovascular risk factor severity and cardiovascular disease (CVD). A total of 2221 elderly women who participated in the Women's Health Initiative Study of Cognitive Aging were separated into those with (N = 204) and without (N = 2017) elevated DS. The DS and multidomain cognitive outcomes were measured annually for an average follow-up of 5.04 years. Women with elevated DS showed baseline multidomain cognitive deficits but longitudinal declines in global cognition only. Persistent DS was related to greater global cognition, verbal knowledge and fluency, and memory declines. Significant DS-CVD interactions were observed cross-sectionally (but not longitudinally) for figural memory and fine motor speed. Future studies should investigate the role of nonvascular mechanisms linking DS and cognitive decline.

Endogenous and Exogenous Estrogen, Cognitive Function, and Dementia in Postmenopausal Women: Evidence from Epidemiologic Studies and Clinical Trials

There are more than 200 published scientific papers showing that estrogen has favorable effects on brain tissue and physiology in cell culture and animal models including non-human primates. The biological plausibility for a neuroprotective estrogen effect is overwhelming. However, most studies of endogenous estrogen and cognitive decline or dementia in women fail to show protection, and some suggest harm. Failure to find any consistent association might reflect the limitations of a single time of estrogen assay or poor assay sensitivity. More than half of the observational studies of hormone therapy suggest benefit. Nearly all long-term clinical trials fail to show benefit, and the longer trials tend to show harm. Failure to adequately adjust for self-selection of healthier and wealthier women and publication bias could account for some, or all, of the protective effect attributed to estrogen in observational studies. Overall, the evidence does not convincingly support the prescription of early or late postmenopausal estrogen therapy to preserve cognitive function or prevent dementia.

A Prospective Study of the Effect of Hypertension and Baseline Blood Pressure on Cognitive Decline and Dementia in Postmenopausal Women: The Women's Health Initiative Memory Study

To examine the relationship between baseline hypertension, blood pressure, and the development of cognitive decline in participants in the Women's Health Initiative Memory Study (WHIMS). Prospective analyses. Thirty-nine centers. Seven thousand one hundred forty-nine women aged 65 and older. The Modified Mini-Mental State Examination (3MS) was used to assess global cognitive functioning. Participants who scored below pre-established cutpoints were scheduled for more-extensive neurocognitive assessments. Results from these assessments were centrally adjudicated. The mean age of this group of 7,149 participants at baseline was 71.0 +/- 3.8, and the mean 3MS score was 95.2 +/- 4.3. During a mean follow-up period of 4.5 years, women without hypertension tended to have slightly higher 3MS scores than women with hypertension (P=.001), but the difference was not seen after adjustment for covariates (P=.17). Women with hypertension also appeared to be at greater risk for probable dementia or mild cognitive impairment (MCI) (hazard ratio=1.35, 95% confidence interval=1.07-1.70, P=.01), although when potential cofounders were accounted for, this association was no longer significant (P=.06). Hypertension and high blood pressure at baseline were not independently associated with MCI or probable dementia over time in older, cognitively intact, postmenopausal women enrolled in WHIMS after other potential confounders were taken into account. These analyses should not be viewed as discouraging appropriate medical treatment for hypertension.

Searching for Methods to Detect, Prevent, and Treat Alzheimer’s Disease

Searching for Methods to Detect, Prevent, and Treat Alzheimer’s Disease

Long-term melatonin or 17β-estradiol supplementation alleviates oxidative stress in ovariectomized adult rats

Melatonin is an endogenously generated potent antioxidant. Our previous results indicated that melatonin improved learning and memory deficits in the transgenic mouse model of Alzheimer's disease (AD) and ovariectomized (OVX) rats by improving cholinergic nerve system dysfunction, preventing apoptosis. In this study we aim to investigate the antioxidative effects of melatonin or estradiol in the brains of ovariectomized rats. OVX Sprague-Dawley rats received daily injections of melatonin (5, 10, or 20 mg/kg), 17β-estradiol (80 μg/kg), or sesame oil for 16 weeks. We found an increase in brain mitochondrial thiobarbituric acid-reactive substances (TBARS) levels, a decrease in mitochondrial glutathione (GSH) content as well as mitochondrial superoxide dismutase (SOD) activity and upregulation of the apoptotic-related factors, such as Bax, Caspase-3, and Prostate apoptosis response-4 (Par-4) in the frontal cortex of OVX rats. In addition to oxidative stress, OVX also caused decreased activities of mitochondrial respiration complex I and complex IV, which implicated mitochondrial dysfunction. Melatonin or 17β-estradiol antagonized the detrimental effects induced by OVX. Furthermore, immunohistochemistry results revealed that the abnormal upregulation of the apoptotic related factor such as Bax, Caspase-3, and (Par-4) greatly reduced expression after melatonin or 17β-estradiol supplement action. These findings demonstrate the important effects of melatonin or 17β-estradiol on postmenopausal neuropathy and support the potential application of melatonin in the treatment of dementia in postmenopausal women. Early, long-term melatonin application is a promising strategy which could potentially be applied in a clinical setting.

Oestrogen plus progestin increased risk of stroke and probable dementia in postmenopausal women

(2003) JAMA 289, 2673; Wassertheil-Smoller S, Hendrix SL, Limacher M, et al. . Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial....

Estrogen plus progestin increased risk for stroke and probable dementia in postmenopausal women

Estrogen plus progestin increased risk for stroke and probable dementia in postmenopausal women

Oestrogen plus progestin doubles the risk of dementia in post-menopausal women

Shumaker S, Legault C, Rapp S et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the women’s health initiative memory study: a...

Estrogens, selective estrogen receptor modulators, and dementia: what is the evidence?

At least 10% of people aged 65 or older have some form of cognitive impairment, increasing to around 50% by age 85. Several studies have suggested that estrogen may improve cognitive function or prevent the development of dementia, but other studies have not shown a benefit, and results from large randomized trials are lacking. Fortunately, further trials are currently being conducted. With the recognition that selective estrogen receptor modulators (SERMs) have differential tissue-dependent effects on estrogen receptor function, there is recent interest in the effects of raloxifene, tamoxifen, and other SERMs on cognition. In this paper, the current state of knowledge of the role of estrogen for preventing dementia in postmenopausal women will be reviewed. In addition, the status of ongoing and recently completed trials of estrogen and SERMs on cognitive function or on Alzheimer's disease severity will be summarized.

Reproductive period and risk of dementia in postmenopausal women.

Exogenous estrogen use may lower risk of dementia in postmenopausal women. A relationship between long-term exposure to endogenous estrogens and incident dementia has been hypothesized but not studied. To determine whether a longer reproductive period, as an indicator of longer exposure to endogenous estrogens, is associated with lower risk of dementia and Alzheimer disease (AD) in women who have natural menopause. The Rotterdam Study, a population-based prospective cohort study conducted in the Netherlands. A total of 3601 women aged 55 years or older who did not have dementia at baseline (1990-1993) and had information on age at menarche, age at menopause, and type of menopause. Participants were reexamined in 1993-1994 and 1997-1999 and were continuously monitored for development of dementia. Incidence of dementia, based on Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria, and AD, based on National Institute of Neurological Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria, compared by quartiles of reproductive period among women with natural menopause. During 21 046 person-years of follow-up (median follow-up, 6.3 years), 199 women developed dementia, including 159 who developed AD. After adjusting for age, dementia was not clearly associated with length of reproductive period. However, after adjusting for multiple covariates, women with natural menopause and more reproductive years had an increased risk of dementia (adjusted rate ratio [RR] for women with >39 reproductive years [highest quartile] compared with <34 reproductive years [lowest quartile], 1.78; 95% confidence interval [CI], 1.12-2.84). The adjusted RR per year of increase was 1.04 (95% CI, 1.01-1.08). For risk of AD, the adjusted RRs were 1.51 (95% CI, 0.91-2.50) and 1.03 (95% CI, 1.00-1.07), respectively. Risk of dementia associated with a longer reproductive period was most pronounced in APOE epsilon4 carriers (adjusted RR for >39 reproductive years compared with <34 reproductive years, 4.20 [95% CI, 1.97-8.92] for dementia and 3.42 [95% CI, 1.51-7.75] for AD), whereas in noncarriers, no clear association with dementia or AD was observed. Our findings do not support the hypothesis that a longer reproductive period reduces risk of dementia in women who have natural menopause.

Oestrogen and the cholinergic hypothesis: implications for oestrogen replacement therapy in postmenopausal women.

Cholinergic deficits in the basal forebrain, hippocampus and cortex are thought to contribute to the risk and severity of cognitive decline associated with ageing and Alzheimer's disease. Work in our laboratory has demonstrated that in rats, basal forebrain cholinergic neurons are affected by physiological fluctuations in circulating oestrogen and progesterone, and that long-term loss of ovarian function produces decreases in cholinergic parameters and nerve growth factor receptor (trkA) mRNA beyond the effects of normal ageing. Conversely, short-term treatment with oestrogen or oestrogen plus progesterone produces increases in cholinergic parameters and trkA, as well as increases in potassium-stimulated acetylcholine release, that are consistent with an increase in basal forebrain cholinergic function. These findings are consistent with recent studies showing the ability of oestrogen and progesterone replacement to enhance spatial memory and reduce performance deficits associated with hippocampal cholinergic impairment. We hypothesize that similar effects of the ovarian hormones on basal forebrain cholinergic neurons in humans may contribute to the effects of hormone replacement on cognitive processes that have recently been described, and to the ability of oestrogen replacement to reduce the risk and severity of Alzheimer's-related dementia in postmenopausal women.

Vascular actions of estrogen and Alzheimer's disease.

Women are two to three times more likely to develop late-onset Alzheimer's disease (AD) than age-matched men. A large number of observational reports and a few randomized clinical trials have indicated that estrogen replacement therapy (ERT) may retard the development and severity of dementia in postmenopausal women. A chronic inflammatory reaction mediated by abnormal deposition of proteins such as amyloid-beta (A beta) is central to the pathology of AD. We investigated the effect of low doses of conjugated estrogen (Premarin) in an animal model of A beta-induced vascular disruption and inflammatory reaction. Estrogen prevented vascular deposition of A beta, endothelial and vessel wall disruption with plasma leakage, platelet and mast cell activation, and characteristic features of an inflammatory reaction: adhesion and transmigration of leukocytes. The beneficial effect was lost when estrogen treatment was discontinued. This novel protective effect of estrogen against A beta-induced vascular dysfunction may contribute to the therapeutic efficacy of estrogen in AD and coronary vascular disease.

Estrogen and Basal Forebrain Cholinergic Neurons: Implications for Brain Aging and Alzheimer's Disease-Related Cognitive Decline

Recent studies suggest that estrogen replacement therapy can reduce the risk and severity of Alzheimer's disease (AD)-related dementia in postmenopausal women. Many different mechanisms by which estrogen therapy may help to reduce the risk and severity of AD-related pathophysiology have been proposed. Recent animal studies suggest that one way in which estrogen replacement may help to reduce cognitive deficits associated with aging and AD is by enhancing the functional status of cholinergic projections to the hippocampus and cortex. Here we review the evidence that estrogen is important in the maintenance of cholinergic neurons projecting to the hippocampus and cortex and that estrogen replacement can enhance the functional status of these neurons, as well as reduce cognitive deficits associated with muscarinic cholinergic impairment. Based on these studies, we conclude that, in animals, short-term treatment with physiological levels of estrogen, or estrogen and progesterone, has significant positive effects on cholinergic neurons in the medial septum and nucleus basalis magnocellularis and on their projections to the hippocampus and cortex. We hypothesize that similar effects in humans may help delay the decline in basal forebrain cholinergic function associated with aging and AD and thereby reduce the risk and severity of AD-related dementia in postmenopausal women.

Impairment of Basal Forebrain Cholinergic Neurons Associated with Aging and Long-Term Loss of Ovarian Function

Recent studies suggest that women are at greater risk for Alzheimer's disease than men and that estrogen replacement can help to reduce the risk and severity of Alzheimer's-related dementia in postmenopausal women. We have hypothesized that the increased risk for Alzheimer's-related dementia is due, in part, to the loss of ovarian function in postmenopausal women and to the effects that decreased levels of ovarian hormones have on basal forebrain cholinergic function. In the present study, the effects of aging and ovariectomy on cholinergic neurons in the rat basal forebrain were examined to determine (1) whether aging differentially affects cholinergic neurons in the basal forebrain of males vs females, and (2) whether long-term loss of ovarian function produces deficits in basal forebrain cholinergic function beyond those associated with aging and sex. In part I of the study, gonadally intact male and female rats were sacrificed at 13, 19, and 25 months of age and the effects of aging on cholinergic neurons in the medial septum (MS) and nucleus basalis magnocellularis (NBM) were compared. In part II of the study, female rats were ovariectomized at 13 months of age and then sacrificed 3 and 6 months later along with gonadally intact, age-matched controls. Adjacent sections through the MS and NBM were processed for either immunocytochemical detection of choline acetyltransferase (ChAT) and p75NTR-like immunoreactivity or forin situhybridization detection and quantification of ChAT and trkA mRNA. Results from part I revealed no significant effects of age on the relative size or density of cholinergic neurons in the MS and NBM of gonadally intact animals. Likewise, no significant effects on the relative numbers of cholinergic neurons expressing p75NTR protein were detected. However, a significant decrease in trkA mRNA was detected in the MS of gonadally intact females, but not males, between 13 and 25 months of age. No significant effects of aging on ChAT mRNA were detected. Results from part II revealed significant decreases in both ChAT and trkA mRNA in the MS and NBM of female rats sacrificed 6 months, but not 3 months, following ovariectomy relative to age-matched, gonadally intact controls. Short-term estrogen replacement initiated 6 months following ovariectomy and administered for 3 days prior to sacrifice partially restored ChAT mRNA levels in the MS and trkA mRNA levels in the NBM. These findings suggest that ovarian hormones play a role in maintaining normal levels of ChAT and trkA expression in the MS and NBM. The fact that ChAT mRNA was decreased in the MS and NBM at 6 months following ovariectomy suggests that long-term loss of ovarian function produces a decrease in the functional status of basal forebrain cholinergic neurons projecting to the hippocampus and cortex. In addition, we hypothesize that the decreases in trkA mRNA detected both in the MS as a function of aging, and in the MS and NBM in response to ovariectomy, reflect decreases in the production of high affinity nerve growth factor (NGF) receptors, and a decrease in the responsiveness of the cholinergic neurons to endogenous NGF. This, in turn, may increase the susceptibility of the cholinergic neurons to the effects of aging and disease and thereby contribute to basal forebrain cholinergic decline. We conclude that long-term loss of ovarian function combined with aging has a negative impact on basal forebrain cholinergic neurons. These effects may contribute to the risk and severity of cognitive decline associated with aging and Alzheimer's disease in postmenopausal women.