Qing-Guo Ren

Background: Frailty and pain frequently coexist in later life, yet how frailty transitions and prior frailty history relate to subsequent pain, and whether depressive symptoms contribute to this association, remain unclear. Methods: We analyzed 44,288 initially pain-free adults aged ≥50 years across five prospective ageing cohorts (HRS, CHARLS, SHARE, ELSA, and MHAS). Frailty was defined as a frailty index (FI) ≥0.25. Associations were estimated using multivariable Cox and logistic regression and generalized estimating equations, with random-effects pooling of cohort-specific estimates. Additional analyses examined temporally ordered mediation by depressive symptoms and mutually adjusted associations of six frailty domains. Incremental discrimination for 2-year incident pain was evaluated using leave-one-cohort-out internal–external cross-validation. Findings: Baseline frailty was associated with incident pain (pooled hazard ratio [HR]: 1.78, 95% confidence interval [CI]: 1.62–1.95). Each 0.1 increase in FI was associated with recurrent pain (pooled odds ratio [OR]: 1.48, 95% CI: 1.42–1.55), persistent pain (OR: 1.47, 95% CI: 1.42–1.52), and high cumulative pain burden (OR: 1.57, 95% CI: 1.50–1.64). Transition into frailty was associated with higher risk than remaining non-frail (HR: 1.43, 95% CI: 1.19–1.71). Recovery was associated with lower risk than persistent frailty (HR: 0.80, 95% CI: 0.69–0.93), but higher risk than consistently non-frail status (HR: 1.63, 95% CI: 1.44–1.83). Depressive symptoms accounted for an estimated 12.95% of the baseline association. Mobility limitations and chronic disease burden showed the strongest domain associations; adding FI improved discrimination across held-out cohorts (ΔAUC: 0.019–0.059). Interpretation: Frailty was associated with both pain onset and an adverse longitudinal course. Frailty history may help characterize subsequent pain risk, while the FI provides complementary prognostic information beyond conventional predictors and depressive symptoms.

Alzheimer’s disease (AD) is characterized by extracellular Aβ deposition and tau hyperphosphorylation, leading to synaptic dysfunction and cogni

Background: Systemic infections are associated with the development of AD, especially in individuals carrying the APOE4 genotype. However, the detailed mechanism through which APOE4 affects microglia inflammatory response remains unclear.Methods: We obtained human snRNA‐seq data from the Synapse AD Knowledge Portal and assessed the DEGs between APOE3 and APOE4 isoforms in microglia. To verify the interaction between ApoE and infectious products, we used ApoE to stimulate in vitro and in vivo models in the presence or absence of LPS (or ATP). The NLRP3 gene knockout experiment was performed to demonstrate whether the APOE‐NLRP3 axis was indispensable for microglia to regulate inflammation and mitochondrial autophagy. Results were evaluated by biochemical analyses and fluorescence imaging.Results: Compared with APOE3, up‐regulated genes in APOE4 gene carriers were involved in pro‐inflammatory responses. ApoE4‐stimulation significantly increased the levels of NLRP3 inflammasomes and ROS in microglia. Moreover, compared with ApoE4 alone, the co‐incubation of ApoE4 with LPS (or ATP) markedly promoted pyroptosis. Both NF‐κB activation and mitochondrial autophagy dysfunction were contributed by the increased level of NLRP3 inflammasomes induced by ApoE4. Furthermore, the pathological impairment induced by ApoE4 could be reversed by NLRP3 KO.Conclusions: Our study highlights the importance of NLRP3 inflammasomes in linking ApoE4 with microglia innate immune function. These findings not only provide a molecular basis for APOE4‐mediated neuroinflammatory but also reveal the potential reason for the increased risk of AD in APOE4 gene carriers after contracting infectious diseases.

Alzheimer's disease (AD) is a neurodegenerative disorder condition linked to various systemic comorbidities. Numerous studies have shown bidirectional crosstalk between the heart and the brain, but the specifics of how these interactions occur in AD are poorly understood. This narrative review summarizes the clinical evidence for a firm link between AD and cardiovascular health and discusses the bidirectional roles of AD and the cardiovascular system. AD pathogenic proteins, AD risk genes, neurohormones, the autonomic nervous system, and neurotransmitters may affect cardiovascular health, and cardiac-derived proteins, neurohormones, vascular function, inflammation, and other potential specific molecules or neural pathways may also influence AD pathology and cognitive function. Additionally, we propose potential AD intervention strategies based on the heart-brain axis to provide novel insights into AD prevention and treatment.