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Background: Age is the biggest risk factor for Alzheimer's disease (AD) but being female also increases risk with ∼63% of AD patients being female. This sex difference could partly be explained by menopause‐related oestrogen deficiencies during ageing. Oestrogen is neuroprotective and it is highly probable this deficiency after the menopause affects neuronal survival and contributes to the onset of AD. Oestrogen receptors are found in mitochondria and evidence suggests that the neuroprotective effect of oestrogen involves supporting mitochondrial function. The clear link between mitochondrial dysfunction and the pathophysiology of AD suggests a decrease in the beneficial effects of oestrogen on mitochondrial function after the menopause would have serious consequences. We hypothesise that alterations in oestrogen, due to ageing and the menopause, affect mitochondrial function and contribute to the increased susceptibility of women to AD. Method: Levels of mitochondrial proteins, dynamin‐related protein‐1 (DRP‐1), mitofusin‐1/2 (Mfn1/2), mitochondrial dynamin‐like GTPase (OPA1) and the electron transport chain (ETC) complexes 1‐5, were measured using immunoblotting in frontal cortical brain samples from young (20‐36), middle‐aged (40‐53) and old (64‐99) men and women with no history of dementia and in AD patients (Braak stage 5/6, 69‐92 age). Result: In female AD brains a significant decrease was observed in Mnf1 and DRP‐1 compared to age‐matched females and in OPA1 in male AD compared to old male brains. Mnf2 and ETC complex 3 (cytochrome reductase) were significantly increased in female AD compared to male AD brains. DRP‐1 was significantly decreased in old males compared to middle‐aged males, while ETC complex 2 (succinate dehydrogenase) was significantly increased in old females compared to young females. Conclusion: We demonstrate for the first time age, sex and disease differences in the expression of proteins involved in various aspects of mitochondrial function including fusion, fission and energy production. These changes could underlie previous findings showing a range of mitochondrial abnormalities in AD brains and support the 'mitochondrial cascade hypothesis' that mitochondrial dysfunction is the primary event causing β‐amyloid deposition, synaptic degeneration, and NFT formation (Swerdlow et al., J. Alz. Dis. 2010 20:Suppl 2, 265‐79.). Our findings could partly explain female vulnerability to AD development. [ABSTRACT FROM AUTHOR]

Background: Emerging evidence suggests that experiencing specific symptoms during menopause can heighten risks of developing conditions which can impact lifespan and long‐term vitality including dementia, cardiovascular disease, psychiatric conditions and cancer. In addition, it is now recognised that, while women live on average about 5 years longer than men, they often have poorer health which could be linked to this increased risk. The aim of the present review was to assess past literature to understand how distinct menopausal symptom presentations can impact lifespan and propensity for developing life‐limiting conditions. Method: The following databases were searched: Google Scholar, EMBASE, MEDLINE, Cochrane Library, Scopus, PubMed, and Web of Science. Keys words aimed to capture factors relating to menopause, menopausal symptoms, mortality, and life limiting conditions such as Alzheimer's disease, dementia, cardiovascular disease, stroke, cancer, liver disease, and suicide susceptibility. Result: Findings suggested that cognitive symptoms experienced during menopause were related to heightened risks of developing Alzheimer's disease, mild cognitive impairment, dementia, and premature mortality. Vasomotor symptoms were related to increased risks of stroke and cardiovascular disease mortality. Psychological symptoms during the menopause transition were related to increased suicide risks and cardiovascular disease. Sleeping problems during menopause were related to heightened risks of cardiovascular mortality, cancer‐related mortality, and premature death from all causes. Conclusion: These findings warrant further investigation through robust analyses of public health data, to evaluate whether these outcomes are replicated within the general population. Should these findings endure, these outcomes suggest a need to improve the health of women during midlife, as doing so may prolong wellness in later life and also have consequences for socioeconomic costs. Furthermore, clarifying these associations may enable women and their health providers to recognise whether they are at risk of developing life‐limiting conditions, thus enhancing their vitality by increasing their likelihood of accessing preventative or early interventions and treatments. [ABSTRACT FROM AUTHOR]

Introduction: Depression in Alzheimer's disease (AD) is difficult to treat and our preliminary data in care homes, captured from electronic medicines administration records (eMAR) suggested that residents with AD were receiving multiple psychotropic drugs. We are investigating the psychotropic burden of AD residents to determine whether treatment is appropriate. We report here demographic characteristics of all care home residents. Methods: Secondary cross‐sectional, pseudonymised data for residents in care homes were collected by eMAR from 2014‐2020. SQLPRO Studio was used to interrogate the database and mediations were classified using the BNF. Residents with archived records, aged >105 years, with unclear gender or stopped medication status were excluded. Results: 9060 residents living in 310 care homes across the UK were included. 29% and 71% were male and female, respectively. 38% were 'youngest‐old' (65 ‐ 85 years) with 62% 'oldest‐old' (85 ‐ 105 years). The mean number of active medications per resident was 10.36 (SD 4.9). 'Youngest‐old' males and females had 11.11 (SD 5.2) and 10.54 (SD 5.1) active medications, respectively versus 10.56 (SD 4.9) and 9.99 (SD 4.7) active medications in the Oldest‐old. The top three classes of active mediations were for the nervous (28%), gastrointestinal (19%) and cardiovascular (14%) systems. For the nervous system, the largest classes were analgesics (44%) and antidepressants (17%). Residents administered psychotropic medications were 30.5% male and 69.5% female with 44.5% for 'youngest‐old' and 55.5% for 'oldest‐old' residents. The medications comprised antidepressants (48.7%), antipsychotics (13.8%) and anxiolytics (6.5%). The mean number of active psychotropic medications per resident was 1.54 (SD 0.794). Conclusions: Most care home residents were female and 'oldest‐old' agreeing with the 2011 census and showing the study population is representative of care home residents. Nervous system medications were the largest class with antidepressants the highest psychotropic class and largely prescribed to the female 'oldest‐old'. [ABSTRACT FROM AUTHOR]

The cleavage of amyloid precursor protein (APP) by β- and γ-secretases results in the production of amyloid-β (Aβ) in Alzheimer's disease. We raised two monoclonal antibodies, 2B3 and 2B12, that recognize the β-secretase cleavage site on APP but not Aβ. We hypothesized that these antibodies would reduce Aβ levels via steric hindrance of β-secretase. Both antibodies decreased extracellular Aβ levels from astrocytoma cells, but 2B3 was more potent than 2B12. Levels of soluble sAPPα from the nonamyloidogenic α-secretase pathway and intracellular APP were not affected by either antibody nor were there any effects on cell viability. 2B3 exhibited a higher affinity for APP than 2B12 and its epitope appeared to span the cleavage site, whereas 2B12 bound slightly upstream. Both of these factors probably contribute to its greater effect on Aβ levels. After 60 min incubation at pH 4.0, most 2B3 and 2B12 remained bound to their antigen, suggesting that the antibodies will remain bound to APP in the acidic endosomes where β-secretase cleavage probably occurs. Only 2B3 and 2B12, but not control antibodies, inhibited the cleavage of sAPPα by β-secretase in a cell-free assay where the effects of antibody internalization and intracellular degradation were excluded. 2B3 virtually abolished this cleavage. In addition, levels of C-terminal APP fragments, generated following β-secretase cleavage (βCTF), were significantly reduced in cells after incubation with 2B3. These results strongly suggest that anti-cleavage site IgGs can generically reduce Aβ levels via inhibition of β-secretase by steric hindrance and may provide a novel alternative therapy for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Age is the biggest risk factor for Alzheimer's disease (AD) with cases doubling every 5 years after 65 years. Increased risk is also associated with being female. This gender difference in AD incidence could be partly explained by menopause‐related hormone deficiencies during ageing. Clinical studies concluded that the age when hormone replacement therapy was started, especially after the menopause, was critical in delaying AD development. Deposition of b‐amyloid (Ab) in the hippocampus and cortex is the key pathological feature in AD. Much evidence has demonstrated that oestrogen activation of oestrogen receptors (ER) in neurones decreases Ab accumulation and antagonizes its cytotoxic effects in AD. ERb is an ER subtype highly expressed in the nervous system. In vivo studies reported that ERb activation reduces the cytotoxic effect of Ab through the Akt pathway and improves learning and memory capacity in AD models. However, this finding has not yet been investigated in the clinic. We hypothesised that the increased risk of AD in women could be partly explained by alterations in the levels of oestrogen, its receptors and downstream signalling pathways in the female brain during ageing affecting the expression of AD biomarkers. Method: Levels of ERb, phosphorylated and total Akt, APP, its secretases and metabolites were measured using immunoblotting and ELISA in frontal cortical brain samples from young (20‐30), middle‐aged (45‐55) and old (70‐90) men and women with no history of dementia. Result: In female brains significant age‐related increases in APP and the secretases were observed but were not seen in male samples. bCTF and the Aβ42:40 ratio also showed age‐related increases only in women. Aβ42 levels were higher in elderly female samples compared to male. In contrast, significant age‐related increases in ERb and pAkt:total Akt were only seen in male samples. Conclusion: We demonstrate for the first time a sex difference in the expression of AD biomarkers with ageing with a novel age‐related increase in APP in the ageing female brain. The increase in ERb expression in male but not female samples could result in a neuroprotective effect against Aβ cytotoxicity. Our findings could partly explain female vulnerability for AD development. [ABSTRACT FROM AUTHOR]