High post-menopausal levels of the pituitary gonadotropin follicle-stimulating hormone (FSH) are strongly associated with the onset of Alzheimer's disease (AD). We have shown recently that FSH directly activates the hippocampal FSH receptors (FSHRs) to drive AD-like pathology and memory loss in mice. To unequivocally establish a role for FSH in memory loss, we depleted the Fshr on a 3xTg background and utilized Morris Water Maze to study deficits in spatial memory. 3xTg;Fshr+/+ mice displayed impaired spatial memory at 5 months of age. The loss of memory acquisition and retrieval were both rescued in 3xTg;Fshr-/- mice and, to a lesser extent, in 3xTg;Fshr+/- mice-documenting clear gene-dose-dependent prevention of spatial memory loss. Furthermore, at 5 and 8 months, sham-operated 3xTg;Fshr-/- mice showed better memory performance during the learning and/or retrieval phases, further suggesting that Fshr deletion prevents age-related progression of memory deficits. This prevention was not seen when mice were ovariectomized, except in the 8-month-old 3xTg;Fshr-/- mice. There was also a gene-dose-dependent reduction mainly in the amyloid β40 isoform in whole brain extracts. Finally, serum FSH levels <8 ng/mL in 16-month-old APP/PS1 mice were associated with better retrieval of spatial memory. Collectively, the data provide compelling genetic evidence for a protective effect of inhibiting FSH signaling on the progression of spatial memory deficits in mice and lay a firm foundation for the use of an FSH-blocking agent for the early prevention of memory loss in post-menopausal women.

Despite a well-known inverse association between education and dementia risk, the mediating mechanisms are not well understood. We explored how lifestyle and health risk factors across the life-course mediate the relationship between education and dementia among adults aged 70 + years. We included 7,655 participants with dementia diagnoses and education information, using a historical cohort design linking prospective exposure data across the life course from the HUNT4 70 + Study with registry data from Statistics Norway and earlier HUNT surveys. We conducted causal mediation analysis to assess the mediating roles of occupational characteristics, lifestyle factors (smoking, physical inactivity), and health risk factors (obesity, hypertension, diabetes, hearing impairment, cardiovascular diseases, LDL cholesterol, depression, anxiety) assessed during early, middle, and late adulthood in the relationship between education and dementia in later life. Participants with lower education were more likely to have dementia with odds ratios of 1.99, 1.88, 1.83 for the model's accounting exposure to mediators during early, middle, and late adulthood, respectively. These associations were partially mediated by the joint effect of health and lifestyle risk factors from early through late adulthood (mediated 11.55-19.50%). Health risk factors from early to late adulthood jointly mediated 6.85-13.06% of the effect of low education on dementia risk later in life. Additionally, lifestyle factors during middle and late adulthood jointly mediated 4.11-4.96% of the total effect of low education on dementia risk later in life. Educational differences in dementia risk can partly mediated by lifestyle and health factors across the life course. These findings suggest potential targets to address varying dementia risks linked to education levels.

The two-times higher prevalence of Alzheimer's disease (AD) in females versus males is well-known; however, there are also sex/gender differences in clinical presentation and diagnostic accuracy that are less examined but equally important to understand in terms of improving early detection, intervention and disease tracking in each sex/gender. This review explores how these disparities in clinical presentation manifest across the AD continuum, with a focus on the earlier stages of preclinical AD and mild cognitive impairment (MCI). We summarize evidence indicating that female's verbal memory advantage may mask early cognitive decline, leading to delayed MCI diagnosis and limiting opportunities for early intervention. Conversely, females demonstrate steeper cognitive decline at later disease stages compared to males. These patterns align with the cognitive reserve theory, suggesting female's verbal memory strength may act as a domain-specific resilience factor. Lastly, this review emphasizes the need for sex-sensitive diagnostic tools to improve early detection accuracy and equity in clinical practice.

Recent evidence suggests the experience of menopausal symptoms (i.e., perimenopausal symptoms) may be associated with cognitive and behavioural changes. We investigated these two relationships in a sample of postmenopausal females.

Cross-sectional observational study.

Participant data was collected from the Canadian Platform for Research Online to Investigate Health, Quality of Life, Cognition, Behaviour, Function, and Caregiving in Aging (CAN-PROTECT) study.

896 postmenopausal female participants.

Menopausal symptom burden was operationalized by summing the total number of recalled perimenopausal symptoms experienced. Cognitive function was measured using the Everyday Cognition (ECog-II) Scale, with higher scores reflecting greater severity. Mild Behavioral Impairment (MBI) was measured using the Mild Behavioral Impairment Checklist (MBI-C), with higher scores reflecting greater severity. A negative-binomial regression model examined the relationship between menopausal symptom burden and cognitive function, while a zero-inflated negative binomial regression model examined the relationship between menopausal symptom burden and MBI symptoms. Models adjusted for age, years of education, age of menopausal onset, type of menopause, and hormone therapy (HT). Age of menopausal onset and use of HT in the two associations were investigated with moderation analyses.

Greater menopausal symptom burden was associated with higher ECog-II total scores (b [95% confidence interval (CI)] = 5.37 [2.85, 7.97]) and higher MBI-C total scores (b [95% CI] = 6.09 [2.50, 9.80]). Use of HT did not significantly associate with ECog-II total scores (b [95% CI] = -10.98 [-25.33, 6.35]), however, HT was significantly associated with lower MBI-C total scores (b [95% CI] = -26.90 [-43.35, -5.67]).

Menopausal symptom burden is associated with poorer cognitive function and more MBI symptoms in mid- to late life. HT may help mitigate symptoms of MBI. These findings suggest that the experience of menopause may indicate susceptibility to cognitive and behavioural changes, both markers of dementia.

The benefits of estrogen treatment on cognition in middle-aged and older women are dependent on many factors, including the timing of treatment. Moreover, the potential interactive effects with other lifestyle factors, such as exercise, are poorly understood. In this study, we tested for lasting benefits of independent and combined treatment with estrogen and voluntary exercise initiated in midlife, using a rat model of menopause. Twelve-month-old, retired female breeders were bilaterally ovariectomized and received six weeks of 17β-estradiol (E2) treatment via subcutaneous implant, with or without access to running wheels. After E2 treatment, animals in the exercise groups had running wheel access for seven additional weeks, including a two-week period of cognitive and affective testing. Thereafter, hippocampal neuronal and cellular plasticity were assessed. E2 and exercise independently exerted effects on behavioral and cellular outcome measures. Transient E2 treatment enduringly increased motor output, lowered body weight, and increased behavioral plasticity. Exercise decreased total hippocampal microglia number and increased brain weight. No additive effects of exercise and E2 treatment were observed. E2 treatment may provide a means by which to enduringly increase physical activity in middle age, but combined E2 and exercise do not produce additive benefits on hippocampal behavioral or cellular plasticity.

Changes associated with Alzheimer's disease (AD) may have measurable effects on the retina, which may facilitate early detection due to the eye's accessibility. Retinal pathology and the regulation of serine racemase (SR) were investigated in the retinas of APP(SW)/PS1(∆E9) mice.

SR in the retinas and the content of D-serine in the aqueous humor were analyzed. The structure and function of the retina were assessed. Additionally, the regulation of SR in primary Müller cell cultures was investigated.

SR levels were significantly higher in the retinas of 18- and 24-month-old male APP/PS1 mice, whereas aqueous humor D-serine was lower in 24-month-old APP/PS1 male mice compared to wild-type (WT) mice. Neither Aβ nor 17β-estradiol increased SR, but the combination of both did in Müller cell cultures. In contrast, 17β-estradiol increased Srr mRNA in the cultures. At 8 months of age, male APP/PS1 mice began to display reduced b-wave amplitude in scotopic and photopic electroretinography (ERG) recordings, unlike female APP/PS1 mice. Although the retinal layer thickness in APP/PS1 mice did not differ from WT mice, there was overt apoptosis in the inner and outer nuclear layers of the APP/PS1 mice retinas.

The age- and sex-specific regulation of SR is correlated with the pathology of an AD retina. Because the time window for SR regulation and D-serine alteration occurs after photoreceptor dysfunction in the AD retinas, it has limited value as a detection biomarker but may be useful as a topographic biomarker for staging severity and monitoring drug interventions in the eye or central nervous system.

Deficits in memory, language, and other cognitive domains that impact an individual's ability to perform necessary tasks of daily living are symptoms of dementia, which is a major cause of death and disability in older adults. As the global population continues to age, deepening our understanding of dementia is crucial. Alzheimer's disease is the leading cause of dementia and accounts for between 60% and 80% of total dementia cases. Declines in episodic memory are considered a hallmark of Alzheimer's disease and occur early in disease progression. The cognitive effects of Alzheimer's disease differ from the cognitive changes expected in nonpathological or normal aging. While some cognitive changes are expected as a part of the aging processes, the declines in cognition associated with Alzheimer's disease are to a degree that the individual diagnosed with the disease is unable to function independently in activities of daily living. In this review, we will discuss how cognition is impacted by both normal and pathological aging, with a focus on Alzheimer's disease. We describe the progressive nature of Alzheimer's disease, as well as the effects of each stage of the disease on cognition.

We examined how symptoms across the mood spectrum relate to Alzheimer's disease (AD) biomarkers in older women at high risk for AD. Participants included 25 women aged 65+ with mild cognitive deficits and elevated AD genetic risk. The Profile of Mood States Questionnaire measured mood symptoms and a total mood disturbance (TMD) score. Tau burden in the meta-temporal region of interest was measured using MK-6240 Tau positron emission tomography (PET) imaging. A subset (n = 12) also had p-Tau181, and Aß40/42 levels measured in plasma. Higher TMD scores related to higher tau PET standardized uptake value ratio (SUVR). Greater negative mood symptoms correlated with higher tau PET SUVR, while greater vigor correlated with lower SUVR. Similar results were seen with plasma p-Tau181 levels, but not with Aβ40/42 levels. In conclusion, positive and negative mood symptoms related to tau pathology in older women at high risk for AD, highlighting a role of mental well-being in AD risk.

The risk of Alzheimer's disease (AD) and other dementias increases with greater global exposure to metabolic risks, making this a crucial public health issue. This study aimed to report the metabolism-attributable global burden of AD and other dementias from 1990 to 2021.

The Global Burden of Disease Study (GBD) 2021 collected data on the number of deaths and disability-adjusted life-years (DALYs) related to AD and other dementias caused by metabolic risks, including high fasting plasma glucose (FPG) and high body mass index (BMI). The analysis assessed the disease burden and temporal patterns worldwide, examining data by region, country, level of social development, age group, and sex.

Globally, the count of AD and other dementia-related deaths due to metabolic risks grew from 98,608 to 399,824, a 4.1-fold increase. For dementias related to high FPG and high BMI, the age-standardized mortality rates (ASMR) and age-standardized DALY rate (ASDR) increased with age and were higher in females than in males. In 2021, the highest burden was observed in high-income North America. The ASMR and ASDR have grown worldwide between 1990 and 2021. The burden of metabolism-related AD and other dementias was positively correlated with the Socio-Demographic Index (SDI), with higher ASMR and ASDR in high SDI regions but showing more pronounced increases in low and low-middle SDI regions.

Metabolism-related global burden of AD and other dementias is increasing, particularly among women and in high-income regions. Targeted prevention programs for dementia should be developed, along with early interventions for risk factors.

Alzheimer's disease is partially characterized by the progressive accumulation of aggregated tau-containing neurofibrillary tangles. Although the association between accumulated tau, neurodegeneration, and cognitive decline is critical for disease understanding and clinical trial design, we still lack robust tools to predict individualized trajectories of tau accumulation. Our objective was to assess whether brain imaging biomarkers of flortaucipir-positron emission tomography (PET), in combination with clinical and genomic measures, could predict future pathological tau accumulation.

We quantified the disease profile of participants (N = 276) using a comprehensive set of descriptors, including clinical/demographic (age, diagnosis, amyloid status, sex, race, ethnicity), genetic (apolipoprotein E [APOE]-ε4), and flortaucipir-PET imaging measures (regional flortaucipir standardized uptake value ratio [SUVr] and comprehensive radiomic texture features extracted from Automated Anatomical Labeling template regions). We trained an AdaBoost machine learning algorithm in a 2:1 split train-test configuration to derive a prognostic index that (i) stratifies individualized brain regions including global (AD-signature region) and lobar regions (frontal, occipital, parietal, temporal) into stable/slow- and fast-progressors based on future tau accumulation, and (ii) forecasts individualized regional annualized-rate-of-change in flortaucipir-PET SUVr. Further, we developed an adaptive model incorporating flortaucipir-PET measurements from the baseline and intermediate timepoints to predict annualized-rate-of-change.

In binary classification for predicting stable/slow- versus fast-progressors, the area-under-the-receiver-operating-characteristic curve was 0.86 in the AD-signature region and 0.83, 0.82, 0.84, and 0.83 in frontal, occipital, parietal, and temporal regions, respectively. The trained models successfully predicted annualized-rate-of-change of flortaucipir-PET regional flortaucipir SUVr in AD-signature and lobar regions (Pearson-correlation [R]: AD-signature = 0.73; frontal = 0.73; occipital = 0.71; parietal = 0.70; temporal = 0.69). The models' performance in predicting annualized-rate-of-change slightly increased when imaging features from intermediate timepoints were used in the adaptive setting (R: AD-signature = 0.79; frontal = 0.87; occipital = 0.83; parietal = 0.74; temporal = 0.82).

Taken together, our results propose a robust approach to predict future tau accumulation that may improve the ability to enroll, stratify, and gauge efficacy in clinical trial participants.

Machine learning predicts the future rate of tau accumulation in Alzheimer's disease.Tau prediction in lobar/global regions benefits from diverse multimodal features.This prognostic index can serve as a sensitive tool for patient stratification.

While many risk factors are modifiable, there remains a compelling need for novel approaches to prevent cognitive impairment. We propose that unstable carotid plaque causes microemboli that, in turn, cause microinfarcts and other adverse pathophysiological cerebral processes, which individually do not manifest clinically but cumulatively manifest as cognitive decline and ultimately cognitive impairment. Animal models support multiple cerebral microemboli having adverse effects on cognition. By addressing the source for microembolization by endarterectomy or stenting, patients with high-grade atherosclerotic stenosis may have better cognitive outcomes. If our hypothesis is verified, then treatment of carotid plaque at elevated risk of generating cerebral microemboli would be effective in preserving cognition, regardless of whether the stenosis is high-grade or causing cerebral hemispheric hypoperfusion.

Dementia poses a growing global mental health impact, with variations in prevalence by gender, possibly influenced by reproductive factors. Ectopic pregnancy (EP), known for its association with cardiovascular diseases and depression, which are also predictors of dementia, prompted an exploration of their interplay.

Using Taiwan's National Health Insurance Research Database, this nationwide cohort study examined 53,096 individuals to investigate the link between EP and dementia. Covariates included age, insured premiums, comorbidity by Charlson Comorbidity Index revised by excluding dementia, level of care, and residence. Surgical approaches, number of EP episodes, and dementia subtypes were considered in outcomes analysis using Cox regression.

Among 13,274 women diagnosed with EP, 791 developed dementia over a 15-year follow-up, particularly vascular dementia. Adjusting for the covariates, the adjusted sub-distribution Hazard Ratio (asHR) with competing risks was 1.644 (95% CI, 1.394-2.053; p < 0.001). For patients with more than one episode, it was even higher (asHR=1.670 [95% CI, 1.419-2.092; p < 0.001]). Post-ectopic depression, prevalent in 62.2% within four weeks, was associated with a greater dementia risk compared to those without (asHR=1.702 [95% CI, 1.444-2.125; p<0.001] vs. asHR=1.551 [95%CI, 1.310-1.937; p<0.001]). Antidepressant treatments showed a partial protective effect, reducing the increased risk by 14.7%.

An EP history is linked to an earlier onset and a higher risk of overall dementia, VaD in particular, in a dose dependent manner, regardless of surgical intervention and stroke. Post-ectopic depression exacerbates dementia risk, while antidepressants offer partial protection. These findings underscore the potential benefit of screening and treating depression in women following EPs.

Dementia is a gradual and ongoing cognitive decline due to damage to nerve cells in the brain. This meta-analysis aimed to assess the potential relationship between regional anesthesia (RA) and the risk of dementia.

Electronic databases including Embase, Medline, Google Scholar, and Cochrane Library were searched for studies investigating the association between RA and dementia risk from inception to March 2022. The primary outcome was the risk of dementia in patients who underwent RA (RA group) and those who received general anesthesia (GA group). Secondary outcomes included identifying other potential risk factors for dementia and comparing dementia risk between individuals receiving RA and those not receiving surgery/anesthesia (placebo group).

Eight cohort studies published between 2014 and 2023 were included in this analysis. A meta-analysis of the available data demonstrated no differences in baseline characteristics and morbidities (i.e., age, male proportion, hypertension, diabetes, depression, and severe comorbidities) between the RA and GA groups (all p > 0.05). Initial analysis revealed that the risk of dementia was higher in the GA group than in the RA group (HR = 1.81, 95% CI = 1.29-2.55, p = 0.007, I 2 = 99%, five studies). However, when a study featuring a relatively younger population was excluded from the sensitivity analysis, the results showed a similar risk of dementia (HR, 1.17; p = 0.13) between the GA and RA groups. The pooled results revealed no difference in dementia risk between the RA and placebo groups (HR = 1.2, 95% CI = 0.69-2.07, p = 0.52, I 2 = 68%, three studies). Sensitivity analysis revealed that the evidence was not stable, suggesting that limited datasets precluded strong conclusions on this outcome. Anxiety, stroke history, hypertension, diabetes, hyperlipidemia, and diabetes are potential predictors of dementia.

Our results emphasize that, while RA could be protective against dementia risk compared to GA, the association between the type of anesthesia and dementia risk might vary among different age groups. Owing to the significant prevalence of dementia among older people and their surgical needs, further investigations are warranted to clarify the association between dementia risk and regional anesthesia.Systematic review registration: https://www.crd.york.ac.uk/prospero/, CRD42023411324.

Background/Objectives: Metabolic syndrome (MS) is a constellation of several cardiometabolic risk factors. We investigated sex disparity in the associations between MS and cognitive impairment using cross-sectional data from Taiwan Biobank. Methods: We determined the associations of MS and its five components with cognitive impairment (mini-mental state examination, MMSE < 24) and the five domains of MMSE using logistic regression analyses. Results: A total of 7399 men and 11,546 women were included, and MS was significantly associated with cognitive impairment only in women (adjusted OR 1.48, 95% CI 1.29-1.71, p = 0.001) (p for interaction 0.005). In women, the association with MS was significant in orientation (adjusted OR 1.21, 95% CI 1.07-1.37, p = 0.003), memory (adjusted OR 1.12, 95% CI 1.01-1.25, p = 0.034) and design copying (adjusted OR 1.41, 95% CI 1.23-1.62, p = 0.001) (p value for interaction 0.039, 0.023, and 0.093, respectively). Among the components of MS, a large waist circumference (adjusted OR 1.25, 95% CI 1.08-1.46, p = 0.003), high fasting glucose (adjusted OR 1.16, 95% CI 1.00-1.34, p = 0.046), and low HDL cholesterol (adjusted OR 1.16, 95% CI 1.00-1.34, p = 0.049) were significantly associated with cognitive impairment in women. Conclusions: Our findings suggest that sex has a significant influence on the association between MS and cognitive dysfunction, especially in orientation and memory.

Females are disproportionately affected by dementia due to Alzheimer's disease. Despite a similar amyloid-β (Aβ) load, a higher load of neurofibrillary tangles (NFTs) is seen in females than males. Previous literature has proposed that Aβ and phosphorylated-tau (p-tau) synergism accelerates tau tangle formation, yet the effect of biological sex in this process has been overlooked. In this observational study, we examined longitudinal neuroimaging data from the TRIAD and ADNI cohorts from Canada and USA, respectively. We assessed 457 participants across the clinical spectrum of Alzheimer's disease. All participants underwent baseline multimodal imaging assessment, including MRI and PET, with radioligands targeting Aβ plaques and tau tangles, respectively. CSF data were also collected. Follow-up imaging assessments were conducted at 1- and 2-year intervals for the TRIAD cohort and 1-, 2- and 4-year intervals for the ADNI cohort. The upstream pathological events contributing to faster tau progression in females were investigated-specifically, whether the contribution of Aβ and p-tau synergism to accelerated tau tangle formation is modulated by biological sex. We hypothesized that cortical Aβ predisposes tau phosphorylation and tangle accumulation in a sex-specific manner. Findings revealed that Aβ-positive females presented higher CSF p-tau181 concentrations compared with Aβ-positive males in both the TRIAD (P = 0.04, Cohen's d = 0.51) and ADNI (P = 0.027, Cohen's d = 0.41) cohorts. In addition, Aβ-positive females presented faster NFT accumulation compared with their male counterparts (TRIAD: P = 0.026, Cohen's d = 0.52; ADNI: P = 0.049, Cohen's d = 1.14). Finally, the triple interaction between female sex, Aβ and CSF p-tau181 was revealed as a significant predictor of accelerated tau accumulation at the 2-year follow-up visit (Braak I: P = 0.0067, t = 2.81; Braak III: P = 0.017, t = 2.45; Braak IV: P = 0.002, t = 3.17; Braak V: P = 0.006, t = 2.88; Braak VI: P = 0.0049, t = 2.93). Overall, we report sex-specific modulation of cortical Aβ in tau phosphorylation, consequently facilitating faster NFT progression in female individuals over time. This presents important clinical implications and suggests that early intervention that targets Aβ plaques and tau phosphorylation may be a promising therapeutic strategy in females to prevent the further accumulation and spread of tau aggregates.

Huntington's disease is a rare autosomal dominant disorder presenting with chorea, rigidity, hypo-/akinesia, cognitive decline, and psychiatric disturbances. Numerous risk factors have been defined in the onset of this disease. However, the number of CAG repeats in the genes are the most crucial factor rendering patients susceptible to the disease. Studies have shown significant differences in onset and disease presentation among the sexes, which prompts analysis of the impact of different sexes on disease etiology and progression. This article therefore discusses the evidence-based role of sex in aspects of symptomatology, pathogenesis, biomarkers, progression, and prognosis of Huntington's disease, with a secondary review of sex-linked differences in Alzheimer's and Parkinson's disease.

Considering that the combination of dasatinib and quercetin (D + Q) demonstrated a neuroprotective action, as well as that females experience a decline in hormonal levels during aging and this is linked to increased susceptibility to Alzheimer's disease, in this study we evaluated the effect of D + Q on inflammatory and oxidative stress markers and on acetylcholinesterase and Na+, K+-ATPase activities in brain of female mice.

Female C57BL/6 mice were divided in Control and D (5 mg/kg) + Q (50 mg/kg) treated. Treatment was administered via gavage for three consecutive days every two weeks starting at 30 days of age. The animals were euthanized at 6 months of age and at 14 months of age.

Results indicate an increase in reactive species (RS), thiol content and lipid peroxidation followed by a reduction in nitrite levels and superoxide dismutase, catalase and glutathione S-transferase activity in the brain of control animals with age. D+Q protected against age-associated increase in RS and catalase activity reduction. Acetylcholinesterase activity was increased, while Na+, K+-ATPase activity was reduced at 14 months of age and D+Q prevented this reduction.

These data demonstrate that D+Q can protect against age-associated neurochemical alterations in the female brain.

Despite evidence from preclinical studies suggesting estrogen's neuroprotective effects, the use of menopausal hormone therapy (MHT) to support cognitive function remains controversial.

We used random-effect meta-analysis and multi-level meta-regression to derive pooled standardized mean difference (SMD) and 95% confidence intervals (C.I.) from 34 randomized controlled trials, including 14,914 treated and 12,679 placebo participants.

Associations between MHT and cognitive function in some domains and tests of interest varied by formulation and treatment timing. While MHT had no overall effects on cognitive domain scores, treatment for surgical menopause, mostly estrogen-only therapy, improved global cognition (SMD=1.575, 95% CI 0.228, 2.921; P=0.043) compared to placebo. When initiated specifically in midlife or close to menopause onset, estrogen therapy was associated with improved verbal memory (SMD=0.394, 95% CI 0.014, 0.774; P=0.046), while late-life initiation had no effects. Overall, estrogen-progestogen therapy for spontaneous menopause was associated with a decline in Mini Mental State Exam (MMSE) scores as compared to placebo, with most studies administering treatment in a late-life population (SMD=-1.853, 95% CI -2.974, -0.733; P = 0.030). In analysis of timing of initiation, estrogen-progestogen therapy had no significant effects in midlife but was associated with improved verbal memory in late-life (P = 0.049). Duration of treatment >1 year was associated with worsening in visual memory as compared to shorter duration. Analysis of individual cognitive tests yielded more variable results of positive and negative effects associated with MHT.

These findings suggest time-dependent effects of MHT on certain aspects of cognition, with variations based on formulation and timing of initiation, underscoring the need for further research with larger samples and more homogeneous study designs.

Alzheimer's disease (AD) is a major progressive neurodegenerative disorder of the aging population. High post-menopausal levels of the pituitary gonadotropin follicle-stimulating hormone (FSH) are strongly associated with the onset of AD, and we have shown recently that FSH directly activates the hippocampal Fshr to drive AD-like pathology and memory loss in mice. To establish a role for FSH in memory loss, we used female 3xTg;Fshr+/+, 3xTg;Fshr+/- and 3xTg;Fshr-/- mice that were either left unoperated or underwent sham surgery or ovariectomy at 8 weeks of age. Unoperated and sham-operated 3xTg;Fshr-/- mice were implanted with 17β-estradiol pellets to normalize estradiol levels. Morris Water Maze and Novel Object Recognition behavioral tests were performed to study deficits in spatial and recognition memory, respectively, and to examine the effects of Fshr depletion. 3xTg;Fshr+/+ mice displayed impaired spatial memory at 5 months of age; both the acquisition and retrieval of the memory were ameliorated in 3xTg;Fshr-/- mice and, to a lesser extent, in 3xTg;Fshr+/- mice- -thus documenting a clear gene-dose-dependent prevention of hippocampal-dependent spatial memory impairment. At 5 and 10 months, sham-operated 3xTg;Fshr-/- mice showed better memory performance during the acquasition and/or retrieval phases, suggesting that Fshr deletion prevented the progression of spatial memory deficits with age. However, this prevention was not seen when mice were ovariectomized, except in the 10-month-old 3xTg;Fshr-/- mice. In the Novel Object Recognition test performed at 10 months, all groups of mice, except ovariectomized 3xTg;Fshr-/- mice showed a loss of recognition memory. Consistent with the neurobehavioral data, there was a gene-dose-dependent reduction mainly in the amyloid β40 isoform in whole brain extracts. Finally, serum FSH levels < 8 ng/mL in 16-month-old APP/PS1 mice were associated with better retrieval of spatial memory. Collectively, the data provide compelling genetic evidence for a protective effect of inhibiting FSH signaling on the progression of spatial and recognition memory deficits in mice, and lay a firm foundation for the use of an FSH-blocking agent for the early prevention of cognitive decline in postmenopausal women.

Magnesium is an essential nutrient required to maintain brain health throughout life, and adequate magnesium intake is positively associated with cognitive performance in older adults. However, sex differences in magnesium metabolism have not been adequately assessed in humans.

We investigated sex differences in the effect of dietary magnesium intake and the risk of different types of cognitive impairment in older Chinese adults.

We collected and assessed dietary data and cognitive function status in people aged 55 years and older in northern China who participated in the Community Cohort Study of Nervous System Diseases from 2018 to 2019 to explore the relationship between dietary magnesium intake and the risk of each type of mild cognitive impairment (MCI) in sex-specific cohorts of older adults.

The study included 612 people: 260 (42.5%) men and 352 (57.5%) women. Logistic regression results showed that for the total sample and women's sample, high dietary magnesium intake reduced the risk of amnestic MCI (ORtotal = 0.300; ORwomen = 0.190) and multidomain amnestic MCI (ORtotal = 0.225; ORwomen = 0.145). The results of restricted cubic spline analysis showed that the risk of amnestic MCI (ptotal = 0.0193; pwomen = 0.0351) and multidomain amnestic MCI (ptotal = 0.0089; pwomen = 0.0096) in the total sample and women's sample gradually decreased with increasing dietary magnesium intake.

The results suggest that adequate magnesium intake may have a preventive effect against the risk of MCI in older women.

Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and prion disease, are characterized by the conversion of normally soluble proteins or peptides into aggregated amyloidal fibrils. These diseases result in the permanent loss of specific types of neurons, making them incurable and devastating. Research on animal models of memory problems mentioned in this article contributes to our knowledge of brain health and functionality. Neurodegenerative disorders, which often lead to cognitive impairment and dementia, are becoming more prevalent as global life expectancy increases. These diseases cause severe neurological impairment and neuronal death, making them highly debilitating. Exploring and understanding these complex diseases offer significant insights into the fundamental processes essential for maintaining brain health. Exploring the intricate mechanisms underlying neurodegenerative diseases not only holds promise for potential treatments but also enhances our understanding of fundamental brain health and functionality. By unraveling the complexities of these disorders, researchers can pave the way for advancements in diagnosis, treatment, and ultimately, improving the lives of individuals affected by neurodegenerative diseases.

The increase in the incidence of dementia over the last century correlates strongly with the increases in post-reproductive lifespan during this time. As post-reproductive lifespan continues to increase it is likely that the incidence of dementia will also increase unless therapies are developed to prevent, slow or cure dementia. A growing body of evidence implicates age-related endocrine dyscrasia and the length of time that the brain is subjected to this endocrine dyscrasia, as a key causal event leading to the cognitive decline associated with aging and Alzheimer's disease (AD), the major form of dementia in our society. In particular, the elevations in circulating gonadotropins, resulting from the loss of gonadal sex hormone production with menopause and andropause, appear central to the development of AD neuropathology and cognitive decline. This is supported by numerous cell biology, preclinical animal, and epidemiological studies, as well as human clinical studies where suppression of circulating luteinizing hormone and/or follicle-stimulating hormone with either gonadotropin-releasing hormone analogues, or via physiological hormone replacement therapy, has been demonstrated to halt or significantly slow cognitive decline in those with AD. This review provides an overview of past and present studies demonstrating the importance of hypothalamic-pituitary-gonadal hormone balance for normal cognitive functioning, and how targeting age-related endocrine dyscrasia with hormone rebalancing strategies provides an alternative treatment route for those with AD.

There is renewed interest in whether sex differences in dementia risk exist, and what influence social and biological factors have.

To review evidence from the Cognitive Function and Ageing Studies (CFAS), a multi-center population-representative cohort study in the UK; focusing on dementia and cognition, incorporating findings on participants' health and social circumstances.

After identifying all CFAS publications, the results of all sex-stratified primary analyses of CFAS data were narratively reviewed.

Of 337 publications, 94 report results by sex (including null findings), which are summarized by theme: dementia epidemiology, cognition, mental health, health expectancy, social context and biological resource (including neuropathology).

Where differences are found they most commonly favor men; however, greater mortality in men may confound associations with age-related outcomes. This 'survival bias' may explain findings of greater risk of dementia and faster cognitive decline in women. Age-specific dementia incidence was similar between sexes, although reduced incidence across study generations was more pronounced in men. Mood disorders were more prevalent in women, but adjusting for disability and deprivation attenuated the association. Prominent findings from other cohorts that women have more Alzheimer's disease pathology and greater risk of dementia from the Apolipoprotein E ɛ4 allele were not observed, warranting further investigation. The 'male-female health-survival paradox' is demonstrated whereby women live longer but with more comorbidity and disability. Examining why health expectancies changed differently over two decades for each sex (interacting with deprivation) may inform population interventions to improve cognitive, mental and physical health in later life.

Although the Clinical Dementia Rating (CDR) scale was originally developed to stage Alzheimer's dementia (AD), it is now used globally for various types of dementia. The aim of this study was to investigate the characteristic pattern of CDR domains and its association with neuropsychological findings and activities of daily living (ADL) in patients with vascular dementia (VaD) and patients with AD.

We recruited very mild to mild VaD and AD patients who were age-matched among the first visitors to a dementia clinic. All subjects underwent a standardized clinical interview, physical and neurological examinations, and laboratory tests, including brain magnetic resonance imaging, according to the protocol of the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease assessment battery.

A total of 105 pairs of VaD and AD patients participated in this study. Although the adjusted scores on Korean version of the Mini-Mental State Examination were similar between the two groups, the VaD patients performed better on the Boston Naming Test, Word List Memory, Word List Recall, Word List Recognition, and Constructional Recall Test. However, the scores on global CDR, CDR sum of boxes, and ADL-related CDR domains were higher in VaD patients than in AD patients (p<0.001). The VaD patients also showed poor performances on the Disability Assessment for Dementia Scale, Frontal Assessment Battery, Executive Clock Drawing Task, and Stroop tests.

Despite similar general cognitive function and better memory function, patients with VaD tend to be staged as severer dementia on the CDR scale than patients with AD because of more impaired ADL associated with executive dysfunction.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease characterized by cognitive and behavioral changes in older adults. Emerging evidence suggests poor oral health is associated with AD, but there is a lack of large-scale clinical studies demonstrating this link. Herein, we used the TriNetX database to generate clinical cohorts and assess the risk of AD and survival among >30 million de-identified subjects with normal oral health (n = 31,418,814) and poor oral health (n = 1,232,751). There was a greater than two-fold increase in AD risk in the poor oral health cohort compared to the normal oral health group (risk ratio (RR): 2.363, (95% confidence interval: 2.326, 2.401)). To reduce potential bias, we performed retrospective propensity score matching for age, gender, and multiple laboratory measures. After matching, the cohorts had no significant differences in survival probability. Furthermore, when comparing multiple oral conditions, diseases related to tooth loss were the most significant risk factor for AD (RR: 3.186, (95% CI: 3.007, 3.376)). Our results suggest that oral health may be important in AD risk, regardless of age, gender, or laboratory measures. However, more large-scale cohort studies are necessary to validate these findings and further evaluate links between oral health and AD.

Despite a large preclinical literature demonstrating neuroprotective effects of estrogen, use of menopausal hormone therapy (HT) for Alzheimer's disease (AD) risk reduction has been controversial. Herein, we conducted a systematic review and meta-analysis of HT effects on AD and dementia risk.

Our systematic search yielded 6 RCT reports (21,065 treated and 20,997 placebo participants) and 45 observational reports (768,866 patient cases and 5.5 million controls). We used fixed and random effect meta-analysis to derive pooled relative risk (RR) and 95% confidence intervals (C.I.) from these studies.

Randomized controlled trials conducted in postmenopausal women ages 65 and older show an increased risk of dementia with HT use compared with placebo [RR = 1.38, 95% C.I. 1.16-1.64, p < 0.001], driven by estrogen-plus-progestogen therapy (EPT) [RR = 1.64, 95% C.I. 1.20-2.25, p = 0.002] and no significant effects of estrogen-only therapy (ET) [RR = 1.19, 95% C.I. 0.92-1.54, p = 0.18]. Conversely, observational studies indicate a reduced risk of AD [RR = 0.78, 95% C.I. 0.64-0.95, p = 0.013] and all-cause dementia [RR = .81, 95% C.I. 0.70-0.94, p = 0.007] with HT use, with protective effects noted with ET [RR = 0.86, 95% C.I. 0.77-0.95, p = 0.002] but not with EPT [RR = 0.910, 95% C.I. 0.775-1.069, p = 0.251]. Stratified analysis of pooled estimates indicates a 32% reduced risk of dementia with midlife ET [RR = 0.685, 95% C.I. 0.513-0.915, p = 0.010] and non-significant reductions with midlife EPT [RR = 0.775, 95% C.I. 0.474-1.266, p = 0.309]. Late-life HT use was associated with increased risk, albeit not significant [EPT: RR = 1.323, 95% C.I. 0.979-1.789, p = 0.069; ET: RR = 1.066, 95% C.I. 0.996-1.140, p = 0.066].

These findings support renewed research interest in evaluating midlife estrogen therapy for AD risk reduction.

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.

Alzheimer's disease (AD) is the most common form of dementia, and both the incidence of this disease and its associated cognitive decline disproportionally effect women. While the etiology of AD is unknown, recent work has demonstrated that the balance of excitatory and inhibitory activity across the brain may serve as a strong predictor of cognitive impairments in AD. Across the cortex, the most prominent source of inhibitory signalling is from a class of parvalbumin-expressing interneurons (PV+). In this mini-review, the impacts of sex- and age-related factors on the function of PV+ neurons are examined within the context of vulnerability to AD pathology. These primary factors of influence include changes in brain metabolism, circulating sex hormone levels, and inflammatory response. In addition to positing the increased vulnerability of PV+ neurons to dysfunction in AD, this mini-review highlights the critical importance of presenting sex stratified data in the study of AD.

Women are more vulnerable to Alzheimer's disease (AD) than men. The entorhinal cortex (EC) is one of the earliest structures affected in AD. We identified in cognitively intact elderly different molecular changes in the EC in relation to age.

Changes in 12 characteristic molecules in relation to age were determined by quantitative immunohistochemistry or in situ hybridization in the EC. They were arbitrarily grouped into sex steroid-related molecules, markers of neuronal activity, neurotransmitter-related molecules, and cholinergic activity-related molecules.

The changes in molecules indicated increasing local estrogenic and neuronal activity accompanied by a higher and faster hyperphosphorylated tau accumulation in women's EC in relation to age, versus a mainly stable local estrogenic/androgenic and neuronal activity in men's EC.

EC employs a different neurobiological strategy in women and men to maintain cognitive function, which seems to be accompanied by an earlier start of AD in women.

Local estrogen system is activated with age only in women's entorhinal cortex (EC). EC neuronal activity increased with age only in elderly women with intact cognition. Men and women have different molecular strategies to retain cognition with aging. P-tau accumulation in the EC was higher and faster in cognitively intact elderly women.

Alzheimer's disease (AD) is considered as one of the leading causes of death among people over the age of 70 that is characterized by memory degradation and language impairment. Due to language dysfunction observed in individuals with AD patients, the speech-based methods offer non-invasive, convenient, and cost-effective solutions for the automatic detection of AD. This paper systematically reviews the technologies to detect the onset of AD from spontaneous speech, including data collection, feature extraction and classification. First the paper formulates the task of automatic detection of AD and describes the process of data collection. Then, feature extractors from speech data and transcripts are reviewed, which mainly contains acoustic features from speech and linguistic features from text. Especially, general handcrafted features and deep embedding features are organized from different modalities. Additionally, this paper summarizes optimization strategies for AD detection systems. Finally, the paper addresses challenges related to data size, model explainability, reliability and multimodality fusion, and discusses potential research directions based on these challenges.

Clinical studies and experimental data together support a role for pituitary gonadotropins, including luteinizing hormone (LH), otherwise considered solely as fertility hormones, in age-related cognitive decline. Furthermore, rising levels of LH in post-menopausal women have been implicated in the high prevalence of mood disorders. This study was designed to examine the effect of deficient LH signaling on both cognitive and emotional behavior in 12-month-old Lhcgr-/- mice. For this, we established and validated a battery of five tests, including Dark-Light Box (DLB), Y-Maze Spontaneous Alternation, Novel Object Recognition (NOR), and contextual and cued Fear Conditioning (FCT) tests. We found that 12-month-old female wild type mice display a prominent anxiety phenotype on DLB and FCT. This phenotype was not seen in 12-month-old female Lhcgr-/- mice, indicating full phenotypic rescue. Furthermore, there was no effect of LHCGR depletion on recognition memory or working spatial memory on NOR and Y-maze testing, respectively, in 12-month-old mice, notwithstanding the absence of a basal phenotype in wild type littermates. The latter data do not exclude an effect of LH on cognition documented in previous studies. Finally, 12-month-old male mice and 3-month-old male and female mice did not consistently display deficits on any test. The data collectively document, for the first time, that loss of LH signaling reverses age-related emotional disturbances, a prelude to future targeted therapies that block LH action.

Sex differences in dementia risk, and risk factor (RF) associations with dementia, remain uncertain across diverse ethno-regional groups.

A total of 29,850 participants (58% women) from 21 cohorts across six continents were included in an individual participant data meta-analysis. Sex-specific hazard ratios (HRs), and women-to-men ratio of hazard ratios (RHRs) for associations between RFs and all-cause dementia were derived from mixed-effect Cox models.

Incident dementia occurred in 2089 (66% women) participants over 4.6 years (median). Women had higher dementia risk (HR, 1.12 [1.02, 1.23]) than men, particularly in low- and lower-middle-income economies. Associations between longer education and former alcohol use with dementia risk (RHR, 1.01 [1.00, 1.03] per year, and 0.55 [0.38, 0.79], respectively) were stronger for men than women; otherwise, there were no discernible sex differences in other RFs.

Dementia risk was higher in women than men, with possible variations by country-level income settings, but most RFs appear to work similarly in women and men.