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Female longevity is observed in humans and much of the animal kingdom, but its causes remain elusive. Using a genetic manipulation that generates XX and XY mice, each with either ovaries or testes, we show that the female XX sex chromosome complement increases survival during aging in male and female mice. In combination with ovaries, it also extends lifespan. Understanding causes of sex‐based differences in aging could lead to new pathways to counter age‐induced decline in both sexes.

Sex and gender—biological and social constructs—significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding the interplay of these factors is central to understanding resilience and resistance mechanisms explaining maintained cognitive function and reduced pathology accumulation in aging and AD. In this narrative review, the ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach to provide the foundations and recommendations for future research into sex‐ and gender‐specific drivers of resilience, including a sex/gender‐oriented review of risk factors, genetics, AD and non‐AD pathologies, brain structure and function, and animal research. We urge the field to adopt a sex/gender‐aware approach to resilience to advance our understanding of the intricate interplay of biological and social determinants and consider sex/gender‐specific resilience throughout disease stages. Highlights Sex differences in resilience to cognitive decline vary by age and cognitive status. Initial evidence supports sex‐specific distinctions in brain pathology. Findings suggest sex differences in the impact of pathology on cognition. There is a sex‐specific change in resilience in the transition to clinical stages. Gender and sex factors warrant study: modifiable, immune, inflammatory, and vascular.

Dena B. Dubal is a physician–scientist and the endowed chair in aging and neurodegenerative disease in the neurology department at the University of California, San Francisco. She has received awards from the National Institutes of Health and American Federation for Aging Research.

Accumulation of hyperphosphorylated tau in the entorhinal cortex (EC) is one of the earliest pathological hallmarks in patients with Alzheimer's disease (AD). It can occur before significant Aβ deposition and appears to \"spread\" into anatomically connected brain regions. To determine whether this early-stage pathology is sufficient to cause disease progression and cognitive decline in experimental models, we overexpressed mutant human tau (hTauP301L) predominantly in layer II/III neurons of the mouse EC. Cognitive functions remained normal in mice at 4, 8, 12 and 16 months of age, despite early and extensive tau accumulation in the EC. Perforant path (PP) axon terminals within the dentate gyrus (DG) contained abnormal conformations of tau even in young EC-hTau mice, and phosphorylated tau increased with age in both the EC and PP. In old mice, ultrastructural alterations in presynaptic terminals were observed at PP-to-granule cell synapses. Phosphorylated tau was more abundant in presynaptic than postsynaptic elements. Human and pathological tau was also detected within hippocampal neurons of this mouse model. Thus, hTauP301L accumulation predominantly in the EC and related presynaptic pathology in hippocampal circuits was not sufficient to cause robust cognitive deficits within the age range analyzed here.

The authors show that astrocytes produce high levels of the adenosine receptor A2A in Alzheimer brains. Reducing the levels of astrocytic A2A boosted memory in young and aging mice and mouse models of Alzheimer disease, whereas activating a related molecular pathway impaired memory. Thus, astrocytes regulate memory and abnormal receptor activity in these cells may contribute to memory disorders. Astrocytes express a variety of G protein–coupled receptors and might influence cognitive functions, such as learning and memory. However, the roles of astrocytic G s -coupled receptors in cognitive function are not known. We found that humans with Alzheimer's disease (AD) had increased levels of the G s -coupled adenosine receptor A 2A in astrocytes. Conditional genetic removal of these receptors enhanced long-term memory in young and aging mice and increased the levels of Arc (also known as Arg3.1 ), an immediate-early gene that is required for long-term memory. Chemogenetic activation of astrocytic G s -coupled signaling reduced long-term memory in mice without affecting learning. Like humans with AD, aging mice expressing human amyloid precursor protein (hAPP) showed increased levels of astrocytic A 2A receptors. Conditional genetic removal of these receptors enhanced memory in aging hAPP mice. Together, these findings establish a regulatory role for astrocytic G s -coupled receptors in memory and suggest that AD-linked increases in astrocytic A 2A receptor levels contribute to memory loss.

Alzheimer’s Disease (AD) is a neurodegenerative disorder that is still not fully understood. Sex modifies AD vulnerability, but the reasons for this are largely unknown. We utilize two independent electronic medical record (EMR) systems across 44,288 patients to perform deep clinical phenotyping and network analysis to gain insight into clinical characteristics and sex-specific clinical associations in AD. Embeddings and network representation of patient diagnoses demonstrate greater comorbidity interactions in AD in comparison to matched controls. Enrichment analysis identifies multiple known and new diagnostic, medication, and lab result associations across the whole cohort and in a sex-stratified analysis. With this data-driven method of phenotyping, we can represent AD complexity and generate hypotheses of clinical factors that can be followed-up for further diagnostic and predictive analyses, mechanistic understanding, or drug repurposing and therapeutic approaches. Sex modifies Alzheimer’s Disease vulnerability, but the reasons for this are largely unknown. Here, the authors utilize two independent electronic medical record systems to perform deep clinical phenotyping and network analysis to gain insight into clinical characteristics and sex-specific clinical associations.

Platelet factors regulate wound healing and can signal from the blood to the brain 1,2 . However, whether platelet factors modulate cognition, a highly valued and central manifestation of brain function, is unknown. Here we show that systemic platelet factor 4 (PF4) permeates the brain and enhances cognition. We found that, in mice, peripheral administration of klotho, a longevity and cognition-enhancing protein 3–7 , increased the levels of multiple platelet factors in plasma, including PF4. A pharmacologic intervention that inhibits platelet activation blocked klotho-mediated cognitive enhancement, indicating that klotho may require platelets to enhance cognition. To directly test the effects of platelet factors on the brain, we treated mice with vehicle or systemic PF4. In young mice, PF4 enhanced synaptic plasticity and cognition. In old mice, PF4 decreased cognitive deficits and restored aging-induced increases of select factors associated with cognitive performance in the hippocampus. The effects of klotho on cognition were still present in mice lacking PF4, suggesting this platelet factor is sufficient to enhance cognition but not necessary for the effects of klotho—and that other unidentified factors probably contribute. Augmenting platelet factors, possible messengers of klotho, may enhance cognition in the young brain and decrease cognitive deficits in the aging brain.

Alzheimer’s disease (AD) is a pervasive neurodegenerative disorder that disproportionately affects women. Since neural anatomy and disease pathophysiology differ by sex, investigating sex-specific mechanisms in AD pathophysiology can inform new therapeutic approaches for both sexes. Previous bulk human brain RNA sequencing studies have revealed sex differences in dysregulated molecular pathways related to energy production, neuronal function, and immune response; however, the sex differences in disease mechanisms are yet to be examined comprehensively on a single-cell level. We leveraged nearly 74,000 cells from human prefrontal and entorhinal cortex samples from the first two publicly available single-cell RNA sequencing AD datasets to perform a case versus control sex-stratified differential gene expression analysis and pathway network enrichment in a cell type-specific manner for each brain region. Our examination at the single-cell level revealed sex differences in AD prominently in glial cells of the prefrontal cortex. In the entorhinal cortex, we observed the same genes and networks to be perturbed in opposing directions between sexes in AD relative to healthy state. Our findings contribute to growing evidence of sex differences in AD-related transcriptomic changes, which can fuel the development of therapies that may prove more effective at reversing AD pathophysiology.

Amyloid-β oligomers may cause cognitive deficits in Alzheimer’s disease by impairing neuronal NMDA-type glutamate receptors, whose function is regulated by the receptor tyrosine kinase EphB2. Here we show that amyloid-β oligomers bind to the fibronectin repeats domain of EphB2 and trigger EphB2 degradation in the proteasome. To determine the pathogenic importance of EphB2 depletions in Alzheimer’s disease and related models, we used lentiviral constructs to reduce or increase neuronal expression of EphB2 in memory centres of the mouse brain. In nontransgenic mice, knockdown of EphB2 mediated by short hairpin RNA reduced NMDA receptor currents and impaired long-term potentiation in the dentate gyrus, which are important for memory formation. Increasing EphB2 expression in the dentate gyrus of human amyloid precursor protein transgenic mice reversed deficits in NMDA receptor-dependent long-term potentiation and memory impairments. Thus, depletion of EphB2 is critical in amyloid-β-induced neuronal dysfunction. Increasing EphB2 levels or function could be beneficial in Alzheimer’s disease. EphB2: a factor in memory loss Association studies have previously implicated the EphB2 receptor in Alzheimer's disease. As a member of a large family of tyrosine kinase receptors that regulate diverse biological functions, its role in the condition remained unknown. Cissé et al . now show that amyloid-β oligomers interact with EphB2 and trigger its degradation. EphB2 regulates NMDA-type glutamate receptors, and its depletion in normal mice reduces NMDAR currents and impairs long-term potentiation, both of which are important for memory formation. Increasing EphB2 levels in a mouse model of Alzheimer's disease improves memory, suggesting that increasing EphB2 levels or function could be of therapeutic value in Alzheimer's disease. It is shown that amyloid-β oligomers interact with the receptor tyrosine kinase EphB2 and trigger its degradation. EphB2 regulates NMDA-type glutamate receptors and its depletion in normal mice reduces NMDA receptor currents and impairs long-term potentiation, both of which are important for memory formation. Increasing EphB2 levels in a mouse model of Alzheimer's disease improves memory.

Cognitive dysfunction in aging is a major biomedical challenge. Whether treatment with klotho, a longevity factor, could enhance cognition in human-relevant models such as in nonhuman primates is unknown and represents a major knowledge gap in the path to therapeutics. We validated the rhesus form of the klotho protein in mice showing it increased synaptic plasticity and cognition. We then found that a single administration of low-dose, but not high-dose, klotho enhanced memory in aged nonhuman primates. Systemic low-dose klotho treatment may prove therapeutic in aging humans.