OBJECTIVE: Alzheimer's disease (AD) care has been reshaped by the integration of fluid biomarkers. This review addressed the question "What are the ethical considerations of fluid biomarker use in eligibility assessments for treatment in AD and mild cognitive impairment?" METHODS: A rapid review following established guidelines was performed. Relevant data were identified and organised within the four pillars of biomedical ethics. Results were reported in line with the PRISMA checklist. RESULTS: Searches identified 10,611 records; 34 were included following screening. Narrative synthesis suggests there are a greater number of ethical risks over benefits within the current clinical context. However, interpretation is subjective and empirical data is lacking. CONCLUSIONS: Multiple ethical concerns surround the use of fluid biomarkers in AD treatment decisions, and there is limited empirical evidence to substantiate claims about benefits and harms. Uncertainty in biomarker performance, particularly in underrepresented groups, raises risks to non-maleficence, autonomy, and justice and complicates clinical decision making.

BACKGROUND: Alzheimer's disease (AD) is increasingly conceptualised as a biological and clinical continuum that includes Subjective cognitive decline (SCD), mild cognitive impairment (MCI), and overt dementia. We conducted a systematic review and meta-analysis to assess the prevalence of APOE ε4 allele in individuals with SCD. METHODS/AIMS: Main databases were searched to identify studies published up to 15 April 2026, plus citation checking. Eligible studies included participants with SCD defined according to standardized criteria, with available APOE genotype data. Application of SCD-plus criteria was also recorded. RESULTS: Of 474 screened records, 49 studies were included in the quantitative synthesis. The pooled prevalence of APOE ε4 allele carriers was 28.3% (95% CI 25.1-31.8%) in SCD, 41.0% (95% CI 35.3-46.8%) in MCI, and 22.0% (95% CI 18.6-25.9%) in cognitively normal (CN) individuals. Multivariate analysis showed that the odds of being an APOE ε4 allele carrier were significantly higher in SCD compared to HC (OR = 1.28, 95% CI 1.12-1.46, p <0.001) and higher in MCI compared to SCD (OR = 1.48, 95% CI 1.23-1.76, p <0.0001). Meta-regression analyses indicated that age and education contributed to heterogeneity in SCD cohorts, while sex distribution did not. Sensitivity analyses restricted to SCD-plus studies confirmed the robustness of these findings. CONCLUSION: The prevalence of APOE ε4 allele in SCD falls between that observed in CN and MCI populations, supporting its role as an intermediate stage in the AD continuum. However, substantial heterogeneity persists, highlighting the need for more accurate stratification approaches integrating genetic and clinical markers.

BACKGROUND: The prognostic significance of pharyngeal residue during routine swallowing assessment remains unclear in older adults at regional hospitals. METHODS: We conducted a single-center retrospective cohort study of 107 consecutive patients (median age 87 years) undergoing swallowing assessment at a regional hospital in Japan (January 2021-December 2024; follow-up until June 2025). The primary outcome was all-cause mortality, and the secondary outcome was aspiration events. Time-to-event analyses used Kaplan-Meier methods, multivariable Cox proportional hazards models, and Fine-Gray subdistribution hazard models to account for the competing risk of death. RESULTS: During a median follow-up of 72 days (IQR 36-156), 72 deaths and 63 aspiration events occurred. Pharyngeal residue was independently associated with aspiration events (HR 3.26; 95% CI 1.70-6.26;  < 0.001) and all-cause mortality (HR 2.65; 95% CI 1.38-5.10;  = 0.003). These findings were consistent in sensitivity analyses excluding antipsychotic use and in Fine-Gray competing risks analysis (SHR 2.76; 95% CI 1.51-5.04;  = 0.001). Dementia was also independently associated with mortality (HR 1.83; 95% CI 1.02-3.29;  = 0.044). CONCLUSIONS: Pharyngeal residue was independently associated with all-cause mortality and aspiration events, supporting its utility as a simple prognostic marker for risk stratification in older adults with suspected dysphagia.

Evidence comparing directly pharmacological and non-pharmacological treatments for Alzheimer's disease (AD) is scarce. The ABC symptoms-activities of daily living (ADLs) (A), behavioral and psychological symptoms (BPSs) (B), cognitive function (C), and quality of life (QoL)-are critical for diagnosing and assessing treatment effects in AD. This study aims to evaluate five interventions for AD: pharmacological therapy (PT), photobiomodulation (PBM), cognitive therapy (CT), exercise therapy (ET), and repetitive transcranial magnetic stimulation (rTMS) using a Bayesian network meta-analysis approach. Among 6,450 records screened, 91 randomized controlled trials (RCTs) involving 12,242 participants met the inclusion criteria. PBM and rTMS showed significant benefits for cognitive function in AD patients. PT and CT showed notable effectiveness in enhancing activities of daily living. For QoL, CT and ET were identified as more favorable outcomes. Collectively, each intervention exerts unique merits targeting ABC symptoms and QoL, implying combined pharmacological and non-pharmacological regimens could optimize therapeutic gains for AD management.

BACKGROUND: Excessive daytime sleepiness may reflect increased vulnerability to postoperative neurocognitive disorders given its association with neurodegenerative disease, cognitive decline, and dementia. However, the role of excessive daytime sleepiness in postoperative neurocognitive disorders is unknown. Here, we investigated whether preoperative moderate-severe excessive daytime sleepiness is associated with postoperative neurocognitive disorder severity. METHODS: This prospective observational cohort study included older non-cardiac surgery patients who completed preoperative Epworth sleepiness scale questionnaires, home sleep apnea testing, and pre- and postoperative delirium assessments and cognitive testing. Cognitive scores were combined with reflective factor analysis into a global cognitive index. Moderate-severe excessive daytime sleepiness was defined as an Epworth Sleepiness Scale score greater than 12. Postoperative neurocognitive disorder severity was assessed by the global cognitive index change from before to 6-weeks and 1-year after surgery. RESULTS: Of the 96 subjects who completed testing, 11 subjects exhibited moderate-severe excessive sleepiness. In a multivariable analysis adjusting for prespecified confounders and precision variables (age, sex, respiratory event index, baseline cognitive performance and surgery duration), moderate-severe EDS was significantly associated with 6-week postoperative change in global cognition (mean difference -0.24; 95% CI -0.48, -0.004; p = 0.046), but was not associated with peak postoperative delirium severity scores (OR 3.66; 95% CI, 0.96, 13.91; p = 0.057). CONCLUSIONS: Preoperative moderate-severe EDS is associated with decreased 6-week postoperative global cognitive performance after adjustment for relevant confounders and precision variables. These results suggest that pre-existing moderate-severe excessive daytime sleepiness is a risk factor for increased postoperative neurocognitive disorder severity. TRIAL REGISTRATION: clinicaltrials.gov: NCT03273335.

BACKGROUND: Effective care of people with cognitive impairment and their families depends, among other things, on the cooperation of the professionals involved in their care. An effective dementia care management support model for people with dementia and their families for the outpatient sector has been further developed for ambulatory and hospital settings. The intersec-CM randomized controlled trial (RCT) implemented this intersectoral care management (iCM) model into routine care in three hospitals in Bielefeld and Greifswald (Germany). Care managers (CMs) trained in advance for the study used a computer-based information management system (IMS) to assess patients' health and care needs and to develop individualized care plans. The iCM aimed to improve hospital-to-primary-care transitions and ensure cross-sectoral care. This was accompanied by a process evaluation to complement the data collected in the RCT. The aim was to understand how the complex intervention works in the selected real-world setting. This paper presents the results of this process evaluation. METHODS: For the process evaluation, a mixed-method design was chosen and applied. The evaluation was based on the guidelines of the British Medical Research Council for the implementation and process evaluation of complex interventions (MRC framework). A method triangulation was conducted consisting of several successive phases (t1: qualitative, t2: quantitative, t3: qualitative). RESULTS: The sample (t1: individual interviews n = 30, t2: survey n = 177, t3: individual interviews n = 33) consisted of patients and their relatives, clinical physicians, social workers, carers, general practitioners, care managers (CMs), and project management. The process evaluation showed that intersectoral iCM could be implemented in the hospitals. The CMs were partially successful in assessing needs, developing individual treatment plans, and coordinating and monitoring the needs of people with cognitive impairment and their families. They found it difficult to work with the different actors in the healthcare system because of the rigid daily routines and lack of time in the clinics. Overall, the results show that (1) people with cognitive impairment and their families can benefit from the intervention and (2) iCM can help with the flow of information between health professionals. CONCLUSIONS: The present process evaluation underlines the necessity and meaningfulness of process evaluations to understand the functionality and procedural feasibility of an RCT. Through the study, significant insights into the "black box" of the implementation of the iCM intervention could be gained. TRIAL REGISTRATION: ClinicalTrials.gov NCT03359408. The trial was registered on December 2, 2017.

( +)-Borneol (Bor) has been shown to enhance drug penetration across the blood-brain barrier (BBB); yet its mechanisms of action and adjuvant effects on Alzheimer's disease (AD) drugs remain insufficiently investigated. This study systematically explored the adjuvant effects of Bor and its underlying mechanisms by employing AB wild-type zebrafish and APP transgenic zebrafish models. Results demonstrated that Bor at concentrations of 0.05 mM or lower exhibited no toxicity toward AB wild-type zebrafish, whereas 0.01 and 0.05 mM Bor significantly increased the expression of green fluorescent protein (GFP) in the zebrafish brain. Genetic analyses revealed that Bor downregulated genes encoding tight junction proteins and P-glycoprotein (P-gp). Drug treatment experiments showed that Bor enhanced the efficacy of AD therapeutic agents, including Zhenbaopill (ZBP, a traditional medicinal preparation) and the synthetic drug 8e. Specifically, Bor ameliorated AD-related behavioral impairments, inhibited cerebral apoptosis, restored the expression of AD-associated genes, normalized the activities of acetylcholine (ACh)-related enzymes, and downregulated both the mRNA and protein levels of Claudin 5. In summary, Bor enhances BBB permeability by regulating the expression of genes encoding BBB-related proteins, thereby increasing the brain concentration and bioavailability of AD drugs with anticholinesterase activity. An appropriate dose of Bor may thus contribute to enhancing the therapeutic efficacy of AD drugs.

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder with progressive cognitive decline and neuronal loss. This study investigated the neuroprotective effects of AMBMP Hydrochloride, a Wnt/β-catenin agonist, in a streptozotocin (STZ)-induced mice model of AD, elucidating the interplay between dysregulated Wnt/β-catenin signaling and Toll-Like Receptor 4 (TLR4)-mediated inflammation, with Palmitic acid used as a TLR4 pathway modulator. Mice received bilateral intracerebroventricular (i.c.v.) injections of STZ (3 mg/kg) on Day 1 and Day 3, followed by administration of Donepezil (3 mg/kg)/ AMBMP Hydrochloride (5 mg/kg and 10 mg/kg)/Palmitic acid (TLR4 agonist, 20 mg/kg) via the intraperitoneal (i.p.) route from Day 4 to Day 22. STZ-treated mice exhibited significant cognitive dysfunction, characterized by impaired performance in the Morris Water Maze (MWM) task along with increase in acetylcholinesterase (AChE) activity, oxidative stress (thiobarbituric acid reactive substances; TBARS), neuroinflammation [tumor necrosis factor alpha (TNF-α)/Interleukin-6 (IL-6)/Interleukin-1 beta (IL-1β) and nuclear factor kappa B (NF-κB)] and decreased reduced glutathione (GSH) levels. However, AMBMP Hydrochloride significantly improved behavioral and biochemical alterations possibly through modulation of Wnt/β-catenin signaling and attenuation of TLR4-mediated inflammation. Interestingly, Palmitic acid co-treatment was found to counteract these protective effects, further pointing to a role of TLR4 in the pharmacological effect of AMBMP Hydrochloride. In summary, we confirmed that AMBMP Hydrochloride exhibits potent neuroprotective effects associated with modulating Wnt/β-catenin/TLR4 signaling, offering a promising therapeutic approach against Alzheimer-Type Dementia. Future studies should delve deeper into the molecular mechanisms and translational promise of AMBMP hydrochloride, paving the way for its development as a potential candidate for AD management.

Several dietary patterns have been associated with better health outcomes. However, the extent to which adherence to different so-called healthy diets overlaps, whether these dietary patterns are equally beneficial, and whether they are associated with similar DNA methylation profiles, remains unclear. Therefore, we investigate the overlap in adherence to ten diet quality scores, and examine the associations of these scores with both biological aging markers and DNA methylation profiles. We use data from the Rhineland Study, a large population-based cohort, and validated our findings using corresponding data from the EPIC-Potsdam cohort. Here, we show minimal overlap of participants classified in the highest quartile (top 25%) of adherence across different diet quality scores. Adherence to a healthy dietary pattern is associated with reduced epigenetic aging, although associations differed in magnitude across diet quality scores. Different dietary patterns are associated with distinct methylation profiles, which however largely converged onto the same biological pathways. Our findings suggest that general adherence to a healthy dietary pattern could promote health through similar epigenetic mechanisms, despite variations in dietary composition.

BACKGROUND: Lipids represent a significant component of the human brain, exerting crucial functions in both physiological and pathological conditions. Mapping brain lipids distribution is an emerging area of research, with mass spectrometry imaging allowing the detection of lipid species and their localization within tissue sections. However, comprehensive spatial mapping of lipids in the human brain remains to be achieved. This systematic review addresses this gap by critically synthesizing the available literature in the field. METHODS: A bibliographic search on PubMed, Scopus and Web of Science for original articles employing mass spectrometry imaging to analyze lipids and their distribution in the human brain was performed. The included articles were grouped according to the clinical characteristics of the studied populations, including healthy subjects and selected neurological and psychiatric disorders. Studies on human brain tissue from tumoral specimens, animals, or in vitro models such as organoids were excluded to maintain focus on translational findings directly applicable to human neurological and psychiatric diseases. RESULTS: Following the inclusion criteria, 34 articles were selected. Alzheimer's disease, schizophrenia and multiple sclerosis were the most frequently investigated conditions, alongside studies in healthy subjects describing lipid distribution under physiological conditions. We observed considerable heterogeneity across studies in terms of research questions and methodological approaches. Nevertheless, our critical synthesis allowed us to identify both consistencies and discrepancies in experimental strategies and in the lipid signatures reported. CONCLUSIONS: Studying lipids by mass spectrometry imaging enables the identification of spatially defined profiles in distinct brain areas, providing valuable insights into both human neurobiology and brain disorders' pathophysiology. In this context, spatial information is crucial for linking lipid alterations to specific structures or lesions, thereby supporting translational applications. Finally, we identified key methodological issues that must be addressed to advance this emerging field.

BACKGROUND: Previous research links frailty to cognitive decline, but the relationship between frailty and motoric cognitive risk syndrome (MCR), a dementia precursor, is underexplored. METHODS: This study used CHARLS data with 3388 participants aged ≥45. Data from 2011 to 2012, 2013, and 2015 were analyzed to examine the relationship between frailty index (FI), total FI, and changes in FI (△FI) with MCR risk. Nine machine learning models were built using baseline FI to predict MCR risk, and changes in frailty status over time were assessed for their impact on MCR risk. RESULTS: By follow-up end, 127 participants (3.74%) developed MCR. Higher baseline FI, total FI, and △FI were associated with increased MCR risk. Restricted cubic splines (RCS) showed a linear relationship between FI and MCR risk (p > 0.05). Trend regression analysis confirmed a significant upward trend in MCR risk (P < 0.05), with odds ratios of 1.434 (1.195, 1.721), 1.766 (1.450, 2.151), and 1.278 (1.081, 1.511) for different FI categories. Logistic regression and GBDT models had AUC > 0.6, indicating baseline FI showed modest predictive performance associated with MCR. Participants transitioning from robust to frail/pre-frail showed higher MCR prevalence, while those regaining robustness from frailty showed lower MCR prevalence. Remaining pre-frail or improving to robust status also associated with reduced MCR occurrence compared to progressing from pre-frailty to frailty. CONCLUSION: This study highlights the crucial associations of frailty with MCR. Early detection and intervention in frailty might be promising targets for mitigating MCR development and potentially linked to dementia prevention.

BACKGROUND: Alzheimer's disease (AD) poses a growing global health challenge, highlighting the urgent need for reliable and minimally invasive diagnostic tools. This study aimed to develop and comprehensively validate an automated chemiluminescence immunoassay (CLIA) for the simultaneous quantification of six core plasma AD biomarkers: Aβ1-40, Aβ1-42, p-Tau181, p-Tau217, GFAP and NfL. METHODS: A fully automated CLIA platform (Shine i2910, Vazyme, China) was utilized for biomarker detection. A total of 87 plasma samples from hospitalized patients with confirmed diagnosis at Beijing Tiantan Hospital were stratified into three cohorts: AD, Other Dementia (OD), and Mild Cognitive Impairment (MCI). The analytical performance of the assay, including precision, accuracy, linearity, and detection limits, was validated in accordance with Clinical and Laboratory Standards Institute (CLSI) guidelines (EP15-A3, EP09-A3, EP06-A2, EP17-A2). RESULTS: This CLIA panel achieved robust analytical metrics, with within-run coefficient of variation (CV) < 3%, between-run CV < 5%, relative bias < ±10%, and linear correlation coefficient (R) > 0.99 for all six biomarkers, along with sub-picogram level detection sensitivity. Clinical sample analysis revealed that AD patients had significantly higher plasma concentrations of p-Tau181 and p-Tau217, along with a significantly reduced Aβ1-42/Aβ1-40, compared with OD and MCI patients (p < 0.05). GFAP and NfL concentrations were significantly elevated in both AD and OD patients relative to the MCI patients (p < 0.05), with no significant difference between AD and OD patients. Receiver operating characteristic (ROC) curve analysis demonstrated an area under the curve (AUC) > 0.7 for all biomarkers, supporting auxiliary differential diagnosis of AD and demonstrating the assay's clinical discriminatory ability. CONCLUSION: The developed fully automated CLIA platform enables rapid, high-performance quantification of six core plasma AD biomarkers with satisfactory analytical performance. As a single-center exploratory study without matched healthy controls, this study only provides analytical validation and preliminary clinical discriminatory evidence. It offers a cost-effective, minimally invasive alternative for auxiliary AD screening under clinical research conditions, while large multi-center cohorts are required to verify its real-world large-scale screening value.

BACKGROUND & OBJECTIVES: Dementia represents a growing global health crisis, yet disease-modifying therapies remain limited. Impaired brain energy metabolism, neuroinflammation, and synaptic dysfunction are some shared pathological features across dementia subtypes that may be amenable to metabolic intervention. Creatine supplementation, through its role in the phosphocreatine/ATP buffering system and proposed neuroprotective properties, has attracted growing scientific and public interest as a candidate intervention for dementia. This scoping review maps the existing evidence on creatine supplementation and dementia-related cognitive outcomes, with attention to intervention characteristics including dose, duration, formulation, route of administration as well as the characteristics of preclinical models. METHODS: Following the Joanna Briggs Institute (JBI) methodology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines, a systematic search of PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) was conducted. No date restrictions were applied to the search; eligibility was limited to English-language reports. Studies were eligible if they evaluated creatine supplementation in older adults or preclinical animal models with dementia and reported at least one cognitive outcome. RESULTS: From 8,317 records identified and screened, six studies reported across seven publications, met eligibility criteria comprising one in vitro study, four in vivo animal model studies, and one human pilot trial resulting in two publications. No relevant randomized controlled trials (RCTs) were identified in the search. Evidence was heterogeneous across study design, population, and intervention characteristics. Preclinical studies demonstrated predominantly neuroprotective effects through bioenergetic support and neuroinflammatory modulation, though one rodent study reported worsening spatial memory. A single human pilot trial (n=20) found that high-dose supplementation (20g/day for 8 weeks) increased brain total creatine by 11% and was associated with improved fluid cognition. Sex-specific effects were identified in one rodent study, with female animals demonstrating cognitive benefit and males showing a trend toward harm. This was paralleled by sex-divergent bioenergetic responses in the human trial. CONCLUSION: Current evidence for creatine supplementation in dementia is limited, heterogeneous, and predominantly preclinical. While not supporting a causal inference, preliminary human data does suggest biological plausibility and feasibility, supporting the need for adequately powered, sex-stratified randomized controlled trials in adults with dementia. While preclinical data support a mechanistic rationale for its use, this review identifies critical gaps including the absence of any controlled clinical trials, limited understanding of optimal dosing for brain penetrance, and the need to prospectively examine sex as a biological moderator of treatment response.

Alzheimer's disease (AD) is a neurodegenerative disorder with intricate pathogenic factors. Multi-target drug design offers a promising approach to address AD's complex pathogenesis. α-Mangostin (α-M), a natural product with multifunctional anti-AD potential, is limited by poor aqueous solubility and bioavailability. This work employed regioselective Williamson O-alkylation to semi-synthesize three novel α-M alkylamine derivatives (1-3), enabling tunable mono- and disubstitution. In silico predictions demonstrated that disubstituted compounds 2 and 3 exhibited markedly improved blood-brain barrier permeability and oral bioavailability. While experimental results showed that monosubstitution optimally balanced intrinsic antioxidant activity with target binding. Compound 1 displayed potent AChE inhibition (IC = 0.11 μM) with high selectivity (SI = 59.27), effectively inhibited both self-induced and AChE-induced Aβ aggregation (53.8% and 57.3%, respectively), and exhibited excellent antioxidant capacity (·OH IC = 0.19 μM). Meanwhile, disubstitution achieved superior BuChE inhibition by occupying both sides of the expanded active site pocket. Furthermore, 1 significantly reduced ROS levels by ~48% in C. elegans. These results highlight the potential of tunable α-M derivatives as promising anti-AD candidates.

Microtubule associated protein tau (tau) contributes to the pathogenesis of AD and some forms of Frontotemporal Lobar Dementia wherein dendritic simplification is strongly related to cognitive dysfunction. Loss of function mutations in PTEN-induced kinase 1 (PINK1) cause recessive early-onset Parkinson's disease with dementia, and reduced wild-type PINK1 expression is observed in Alzheimer's disease (AD). We previously found that PINK1 interacts with valosin-containing protein (VCP) and promotes phosphorylation of the VCP co-factor NSFL1C (p47). This study was designed to test the hypothesis that PINK1 rescues tau-induced dendritic simplification through the VCP-p47 pathway, and to define neuroprotective mechanisms downstream of p47 phosphorylation. Mouse primary cortical neurons were transfected with 2N4R-Tau and plasmids encoding components of the PINK1-VCP-p47 signaling pathway and the impact on Tau-mediated dendritic injury was assessed. Immunoprecipitation-mass spectrometry, immunoblotting, RNAi and Sholl analysis were performed to define downstream mechanisms of neuroprotection. Tau-induced dendritic shortening and simplification was fully rescued by co-expression of PINK1, VCP, p47 or the p47-S176D phosphomimic (p47D), but not by the non-phosphorylatable p47-S176A (p47A) variant. Pathway analysis showed enhanced interactions of p47D with proteins in the Rho-GTPase pathway. Immunoprecipitation confirmed that STIP1 interacts with p47D to a significantly higher degree than p47A. Overexpression of STIP1 rescued tau-mediated dendritic simplification. Moreover, STIP1 siRNA impaired the neuroprotective effects of both PINK1 and p47D, indicating an essential role in the PINK1-p47D neuroprotection pathway. The current study highlights a novel PINK1-(phospho)p47-STIP1 signaling axis that promotes dendritic complexity and protects against tau-induced neurodegeneration in cortical neurons.

BACKGROUND: Reduced [F]Fluorodeoxyglucose ([F]FDG)-PET uptake is a core imaging feature of Alzheimer's disease (AD). While tau load correlates with this metabolic signature, it remains unclear whether the spatial extent of tauopathy (SEOT) more accurately explains brain glucose hypometabolic patterns. Here, we compared SEOT versus tau load to determine their ability to predict brain hypometabolic signatures in AD. METHODS: We performed a cross-sectional study of amyloid-β positive participants from ADNI (n = 150) and an atypical AD subset from the McGill University Research Centre for Studies in Ageing (MCSA; n = 44). Participants underwent [F]AV1451 or [F]MK6240 tau-PET and [F]FDG-PET. Tau load was indexed with regional SUVR, and SEOT with the proportion of abnormal voxels. Linear regressions related temporal and whole-cortex tau-PET load or SEOT to [F]FDG-PET. We also compared the accuracy of tau-PET metrics for identifying AD-like hypometabolism. Spearman correlations assessed SEOT/tau load-FDG associations at regional and network levels. Partial Least Squares (PLS) regression investigated whether distributed tau load and SEOT predicted [F]FDG-PET signatures. Structural equation modelling and hierarchical linear models assessed associations between tau metrics and cognition dependent and independent of [F]FDG-PET. FINDINGS: Whole-cortex SEOT best predicted decreased signal in the [F]FDG-PET AD-meta-ROI. SEOT also performed better in classifying AD-related brain hypometabolism. Across regions and networks, SEOT performed similarly or better than tau load in predicting metabolic dysfunction. Voxelwise analyses suggested complementary predictive value of SEOT and tau load, each capturing slightly distinct spatial associations with [F]FDG-PET. PLS demonstrated partially non-redundant contributions from tau load and SEOT. Cortical SEOT showed the strongest predictive value for cognition. INTERPRETATION: SEOT provides complementary, independent, and often stronger predictive value than tau load for brain metabolism, particularly for network-level dysfunction. SEOT may improve diagnostic characterisation and prediction of cognitive impairment beyond [F]FDG-PET. FUNDING: TRIAD is supported by the Weston Brain Institute, Canadian Institutes of Health Research, Canadian Consortium of Neurodegeneration and Aging, Brain Canada Foundation, the Fonds de Recherche du Québec - Santé, and the Colin J Adair Charitable Foundation. ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and the Canadian Institutes of Health Research.

Dancing can be an alternative to traditional intervention programs for caregivers. This study aims to examine the effects of the Brazilian Circle Dance Program (CircleCare) on the physical and mental health of family caregivers of older adults with Alzheimer's disease (AD). Twenty-five caregivers over the age of 50 were randomized into an Intervention Group (IG, n = 13, CircleCare, 60 min, 2x/week for 12 weeks) and a Control Group (CG, n = 12, without intervention). Physical health was assessed using measures of functional mobility, walking speed, and lower limb strength. Mental health was assessed using measures of cognition, caregiver burden, perceived stress, depressive symptoms, and quality of life. Frailty was assessed using the frailty phenotype. The Statistical analysis was performed using two-way repeated-measures ANOVA (significance level 5%). Only the IG shows improvements in functional mobility (p < 0.001), burden (p = 0.001), stress level (p = 0.045) and contribution to a transition from pre-frail to non-frail. However, CircleCare was not sufficient to induce applied responses concerning walking speed, lower limb strength, cognition and quality of life. CircleCare can be considered as an intervention option for caregivers of older people with AD, especially middle-aged and older women, as it was effective in improving functional mobility, burden, stress level and contributed to the transition from pre-frailty to non-frailty. TRIAL REGISTRATION: ClinicalTrials.gov Number NCT03081533. Registered 2 March 2017, https://clinicaltrials.gov/study/NCT03081533.

Lifelong antiretroviral therapy extends the lifespan of individuals with human immunodeficiency virus (HIV). However, HIV-associated neurocognitive disorders (HAND) remain with age-linked comorbidities. Despite viral suppression, the co-development of Alzheimer's disease (AD) remains a concern. Both HAND and AD share key mechanisms, including chronic neuroinflammation, glial dysfunction, and progressive neurodegeneration. Microglial activation is a key contributor that generates persistent proinflammatory neurotoxins, promoting amyloid-β aggregation, disrupting clearance, and accelerating neurodegeneration. Persistent viral reservoirs and low-level viral protein expression disrupt glial homeostasis, enhancing oxidative stress, tau hyperphosphorylation, and synaptic damage in the brain. This review highlights the intersections between both disorders and discusses emerging rodent models to investigate convergent pathways with the goal of improving therapeutic strategies to preserve cognitive health.

Sporadic Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disorder characterized by numerous pathological processes occurring both in the brain and in the periphery, including chronic local or systemic inflammation, cerebrovascular impairment, oxidative stress, mitochondrial dysfunction, amyloidosis, synaptic and neuronal network dysfunction, metabolic syndrome, and disrupted cell signaling pathways. Although these mechanisms have been extensively studied, the contribution of the peripheral immune system to the etiology and progression of AD remains poorly understood. Emerging evidence suggests that pathological events in the brain, such as amyloid and phosphorylated tau accumulation, neurodegeneration, and neuroinflammation, may trigger systemic immune responses that alter the distribution and function of peripheral immune cells. However, available findings remain inconsistent. In the present study, we examined age-dependent alterations in peripheral blood immune cell populations in Tg-SwDI mice, a transgenic model of AD. We documented for the first time that transgenic mice exhibited increased proportions of neutrophils and an elevated neutrophil-to-lymphocyte ratio (NLR), along with reduced percentages of T lymphocytes compared with wild-type controls. Furthermore, significant differences in T-cell subpopulations were observed between Tg-SwDI and wild-type animals. Our findings are partially consistent with reported clinical observations in patients with AD. Because no single transgenic mouse model fully recapitulates the complex pathology of AD, and many therapeutic approaches successful in preclinical models have failed in clinical trials, a detailed characterization of disease-related alterations in each model is essential for selecting the most appropriate model to investigate specific mechanisms or therapeutic approaches.

BACKGROUND: Cognitive dysfunction is increasingly recognized as an extra-nasal manifestation of chronic rhinosinusitis (CRS). This scoping review characterizes the primary evidence on cognition in adult CRS, covering measures, treatment response, and incident dementia. METHODS: We searched EMBASE, PubMed/MEDLINE, Web of Science, the Cochrane Library, CINAHL, and Global Index Medicus through May 2026 using a MeSH and free-text strategy. Inclusion criteria include primary studies of adult CRS with a formal clinical diagnosis (AAO-HNS, EPOS or ICD-coded) reporting at least one validated cognitive measure or recognized cognitive impairment. Two reviewers screened independently. Animal studies, reviews, conference abstracts, and non-CRS populations were excluded. PRISMA-ScR reporting was performed; heterogeneity precluded meta-analysis. RESULTS: Twenty-four primary studies met inclusion criteria. Adults with CRS perform worse than controls on subjective (Cognitive Failures Questionnaire [CFQ], Neuro-QoL) and objective (Montreal Cognitive Assessment [MoCA], Automated Neuropsychological Assessment Metrics [ANAM], eye movement assessment, P300) cognitive instruments. Deficits correlate with disease-specific QoL severity (SNOT-22, Rhinosinusitis Disability Index [RSDI]). Cognitive measures improve after medical therapy or endoscopic sinus surgery. Two resting-state fMRI analyses identified altered orbitofrontal-precuneus connectivity scaling with sinonasal inflammation. Dementia results are mixed: a UK Biobank analysis (7176 CRS cases among 364,945 participants) reported increased Alzheimer disease risk (HR 1.33), while two Korean cohorts and a 2025 meta-analysis found no association. CONCLUSION: Adults with CRS show measurable cognitive dysfunction that may improve with treatment, with a plausible neuroinflammatory pathophysiology. Whether this translates to incident dementia is contested. Outcome heterogeneity limits synthesis; therefore, development of a CRS-specific cognitive measurement set is recommended.

Axonal dysfunction is a critical event in neurodegenerative diseases, which can precede neuronal loss. For instance, in multiple sclerosis, chronic demyelination leads to axonal transection and downstream neurological deficits, yet in other neurodegenerative conditions, the causal relationship between axonal pathology and disease progression remains elusive. While defects in axonal transport, cytoskeletal integrity, and organelle trafficking are observed in Alzheimer's disease and the frontotemporal dementia-amyotrophic lateral sclerosis spectrum, a question remains: Are axonal defects merely downstream consequences of somatic neurodegeneration, or do they actively drive pathogenesis? Emerging evidence suggests that early axonal dysfunction may accelerate disease progression through disrupted connectivity, retrograde degeneration, and neuroinflammation. Here, we highlight current evidence on axonal pathophysiology across Alzheimer's disease and frontotemporal dementia-amyotrophic lateral sclerosis. We first outline the makeup of the mature axonal compartment, as well as the processes related to axonal maintenance, which include myelination, glial support, and microtubule-dependent transport mechanisms. We further compare axonal perturbations in Alzheimer's disease and frontotemporal dementia-amyotrophic lateral sclerosis, exploring commonalities as potential convergent mechanisms. Therapeutic strategies to stabilize axons by maintaining microtubule dynamics, restoring energetics, or modulating glial support could therefore theoretically offer neuroprotection if performed selectively on vulnerable neuronal subsets and early in the disease course. Ultimately, by reframing axonal pathology as a primary driver rather than an epiphenomenon, this review underscores the importance of targeting axonal health in neurodegenerative diseases.

Postoperative delirium (POD) and Alzheimer's disease (AD) are increasingly recognized as related neurocognitive conditions, but the aging-associated cell states that may connect them remain poorly defined. Here, we integrated two brain transcriptomic discovery datasets analyzed at single-cell/single-nucleus resolution, including a POD-related cohort (GSE291019) and an AD cohort (GSE129308), together with two independent peripheral-blood bulk transcriptomic datasets (GSE163943 and GSE63060), to identify aging-associated cellular programs and prioritize convergent molecular candidates. Across 184,168 high-quality cells, inhibitory neurons showed the most consistent aging-associated perturbation across the POD- and AD-related datasets. Re-clustering further identified three inhibitory-neuron subtypes, Inh_Neurons2, Inh_Neurons3, and Inh_Neurons5, with relatively high aging-related gene activity and preferential localization to later pseudotime states. Cross-platform integration of aging-associated inhibitory-neuron genes with a shared bulk DEG set identified four convergent candidates: RGL2, AKT1, SYK, and TNFSF13B. Among them, RGL2 emerged as the leading candidate, with the strongest downstream support concentrated in AD-related analyses. In two-sample Mendelian randomization, genetically predicted higher RGL2 expression was associated with increased AD risk, whereas the estimate for the delirium genome-wide association study proxy used for POD-related analyses was not significant. Pathway analyses further linked higher RGL2 expression to complement/coagulation and innate immune-inflammatory programs in AD-related analyses. These findings suggest a model in which POD and AD may partially intersect through aging-vulnerable inhibitory-neuron states and identify RGL2 as a prioritized candidate for downstream mechanistic investigation.

PURPOSE: We examined whether cognitive function statistically accounted for associations between stroke and quality of life (QOL). METHODS: A cross-sectional survey included adults aged ≥ 60 years in Segamat, Malaysia. Cognition was assessed using the Identification and Intervention for Dementia in Elderly Africans instrument, and QOL was assessed using the WHOQOL-BREF. Stroke survivors were matched 1:3 with non-stroke participants by propensity scores based on age, sex, and education. Stroke status was the exposure, cognition the proposed statistical mediator, and four QOL domains, overall QOL, and overall health the outcomes. Models were adjusted for sociodemographic and vascular factors, accounted for matching and multiple testing, and p < 0.05 was considered statistically significant. RESULTS: Among 596 participants, 149 reported stroke; the mean age was 70.36 years (SD 6.81); 41.6% female; 58.4% male. An indirect association between stroke and physical QOL via cognition was observed (β = -0.67, 95% CI - 1.30 to - 0.18; BH-adjusted p = 0.018). A residual correlation of ρ = 0.16 between cognition and physical-QOL models would attenuate this association to the null. The indirect association did not differ by sex (index β = -0.49, 95% bootstrap CI - 1.48 to 0.18; p = 0.164). Item-level physical-QOL analysis identified an indirect association with greater pain interference through lower cognition (β = -0.051, 95% CI - 0.113 to - 0.009; BH-adjusted p = 0.028). CONCLUSION: Reduced cognition partly accounted for associations of stroke with reduced physical QOL and greater pain interference. Findings were sensitive to modest unmeasured confounding but require confirmation from longitudinal studies.