A cDNA sensor based on gold nanoparticles (Au) supported on nickel metal-organic framework nanosheets (MOF-NS) modified fluorine-tin oxide (FTO) glass electrode for the ultrasensitive and selective detection of miRNA-128 biomarker associated with the progression of Alzheimer's disease (AD) has been reported. The MOF-NS and Au nanoparticles were electrodeposited onto FTO electrode using chronoamperometry to immobilize 5'-biotinylated DNA (btn-cDNA) complementary to miRNA-128 by streptavidin-biotin interaction, generating the modified electrode (btn-cDNA/SV/Au/MOF-NS/FTO). The fabricated electrode was characterized using various surface characterization techniques, including FESEM, XPS, FTIR, and electrochemical methods. The fabricated electrode was then utilized for the selective detection of miRNA-128 using electrochemical impedance spectroscopy. The results indicated a linear response range of 1.0 × 10 fM-1.0 × 10 nM with limit of detection of 0.017 fM, and sensitivity of 180.11 Ω fMcm. Moreover, the cDNA sensor showed satisfactory performance with real serum samples from AD patients and healthy individuals, as validated by real time-PCR technique with area under curve of 0.93 and a sensitivity of 90%, respectively, demonstrating the potential of present cDNA sensing approach in the biomedical field.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which immune dysregulation has emerged as an important component of disease pathogenesis; however, the contribution of circulating proteins and their cellular context remains incompletely understood. Here, we performed an integrative multi-omics analysis combining Mendelian randomization (MR), bulk transcriptomics, single-cell RNA sequencing, and peripheral blood validation to systematically identify plasma proteins associated with AD. Proteome-wide MR analysis identified multiple circulating proteins associated with AD risk. Integration with transcriptomic data identified AIF1 (allograft inflammatory factor 1) as a shared candidate supported by both genetic prioritization and differential expression analysis. Although bulk transcriptomic data showed reduced AIF1 expression in AD, single-cell analysis revealed distinct cell type-specific expression patterns, with predominant enrichment in monocytes and other innate immune populations. PBMC-based qPCR further confirmed an overall reduction in AIF1 expression in AD. Further analyses suggested that AIF1-associated immune alterations were linked to changes in inflammatory signaling pathways, including STAT, IRF, and NF-κB-related activity, as well as differences in intercellular communication involving MIF, GALECTIN, ANNEXIN, and CypA-related signaling. Peripheral immune cell composition analysis indicated differences between AD and control samples, characterized by relative changes in innate immune cell proportions. Collectively, these findings identify AIF1 as an immune-associated factor linked to genetic and transcriptional alterations in AD and suggest its association with monocyte-related immune states and altered immune signaling patterns. This study provides a multi-layered framework for investigating peripheral immune involvement in AD and highlights potential directions for understanding immune-related alterations and biomarker discovery.

OBJECTIVES: To quantify the magnitude and trends the national and subnational burden of Alzheimer's disease and other dementias (ADOD) in Mexico from 1990 to 2023, analyzing patterns by sex and age and exploring their association with the Socio-Demographic Index (SDI) and the Healthcare Access and Quality Index (HAQI). METHOD: A secondary ecological study was conducted using updated estimates from the Global Burden of Disease and Risk Factors Study (GBD) 2023. Prevalence, incidence, mortality, and disability-adjusted life years (DALYs) were examined. Temporal trends were assessed using joinpoint regression. Pearson correlation and linear regression were used to evaluate associations between DALYs rates and SDI and HAQI. RESULTS: Between 1990 and 2023, ADOD prevalence and incidence increased, despite significant declines in age-standardized prevalence and incidence rates. Females consistently experienced higher mortality and disability, with age-standardized DALYs rates 1.28 times those of males. The ADOD burden increased sharply with age, peaking among those aged 85 years and older, with premature mortality accounting for 63.0% of total DALYs. A significant increase in DALYs rates occurred during 2020-2023 after previous periods of gradual decline. DALYs rates were negatively correlated with both SDI and HAQI. CONCLUSION: ADOD disproportionately affect women, while higher modeled burden was observed in several states with lower socioeconomic development and weaker health system performance. The post-2020 increase represents an epidemiological signal warranting further investigation into excess mortality among people with dementia, healthcare disruption, social isolation, and changes in long-term care during the COVID-19 period. Strengthening early diagnosis, long-term care, and management of modifiable risk factors is essential to reduce the future burden and persistent regional and sex-based inequalities in ageing populations.

INTRODUCTION: Plasma proteomics detect multi-pathway biological changes preceding dementia onset. The Dementia SomaSignal Test (dSST) is a validated 25-protein score predicting 5- and 20-year all-cause dementia risk. Preclinical and clinical data suggest glucagon-like peptide-1 receptor agonists may have neuroprotective effects. METHODS: In a post hoc analysis of the Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial, adults ≥ 65 years with overweight/obesity and cardiovascular disease without diabetes ( = 2970) were randomized to semaglutide 2.4 mg or placebo. Non-fasted serum samples at baseline and week 104 were analyzed using the dSST. RESULTS: Semaglutide reduced increases in predicted dementia risk versus placebo: 2.5-fold less increase in 5-year risk (26.0% lower predicted event rate; odds ratio [OR] 0.74, 95% confidence interval [CI] 0.65-0.85) and 1.67-fold less increase in 20-year risk (8.8% lower; OR 0.91, 95% CI 0.88-0.94). It also reduced odds of higher dementia risk classification by 36% (β -0.44;  < 0.001). DISCUSSION: Semaglutide slowed progression of a validated proteomics-based dementia risk signature.

BACKGROUND: Persons living with dementia (PLWDs) and their care partners (CPs) often face decisions about future supportive care transitions. METHODS: We conducted in-depth interviews with a purposive sample of healthcare professionals (HCPs) experienced in supporting PLWDs and CPs with transitions in care. Interviews were audio recorded, transcribed, and coded using a hybrid deductive-inductive approach. We used thematic analysis to identify key themes regarding factors influencing supportive care decisions and planning and decision-making facilitators used by HCPs. RESULTS: Qualitative analysis of 18 interviews revealed four themes: (1) difficulty thinking about the future; (2) increasing CP burden with disease progression; (3) uncertainty about costs and resources; and (4) the impact of cultural values. HCP strategies to support decision-making included building trust; timely education; and facilitating access to resources. HCP input suggested the importance of an accessible decision tool, sensitive to sociocultural values, and administered by trusted experts. CONCLUSION: We identified themes to inform development of a decision tool to support PLWDs and CPs supportive care transitions. HCPs highlighted the importance of early access to decision-making tools to facilitate dementia care planning and education.

Inhibition of indoleamine 2,3-dioxygenase (IDO) is a promising therapeutic strategy for cognitive impairment in Alzheimer's disease (AD). The pro-cognitive effect is often attributed to restoring glycolysis by preventing tryptophan (Trp) conversion to kynurenine (Kyn). However, this overlooks the metabolic fate of Trp when IDO is blocked. Since IDO and tryptophan 2,3-dioxygenase (TDO) compete for the same substrate, inhibiting IDO may shunt Trp toward TDO, potentially increasing Kyn and its downstream catabolites. This commentary explores the hypothesis that the upregulation of anthranilic acid (AA), a Kyn catabolite, contributes to the cognitive benefits of IDO inhibition. Recent evidence shows elevated AA in animal models of AD and individuals with mild cognitive impairment and preclinical AD, where it may serve as an early biomarker. Notably, these elevations and the pro-cognitive effects of AA-modulating compounds like sodium benzoate exhibit sex-specificity, being more prominent in females. The mechanism may involve AA's dual action on G-protein coupled receptors: antagonism of GPR17 promotes myelination, while agonism of GPR109A may protect myelin from degradation. Preserving myelin integrity is critical, as demyelination is an early event in AD pathogenesis. We propose that AA upregulation is not merely a biomarker but part of a compensatory defense mechanism. Therefore, the pro-cognitive effect of IDO inhibition may be partly mediated by the subsequent shunting of Trp toward TDO and production of the myelin-preserving metabolite, AA. This reframes the therapeutic goal from reducing neurotoxic kynurenines to leveraging the protective potential of the entire pathway.

BACKGROUND: Semantic fluency is commonly assessed in the diagnostic work-up of individuals with suspected cognitive impairment due to neurodegenerative disease. Semantic fluency has a predictive value for survival in clinical AD and in healthy elderly individuals, but it is unknown if this also applies to biomarker-confirmed AD and non-AD memory clinic patients. Potential associations with and added value of imaging biomarkers of amyloid pathology and neurodegeneration have yet to be explored. METHODS: From our clinical registry, we included patients who were assessed at a memory clinic with the neuropsychological assessment battery of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-NAB) and whose vital status could be retrieved in 07/2024. We tested the association of semantic fluency performance at first assessment and over time (and, for comparison, further CERAD-NAB subtest scores) with mortality risk using age-adjusted single-predictor Cox proportional hazard models. Amyloid status (positive vs negative on clinical PET reads) and global cognitive impairment (MMSE) were included as covariates. In addition, we explored associations between semantic fluency performance and both regional cortical glucose metabolism (FDG PET) and global amyloid load (centiloids; PiB PET). Finally, the predictive value of global amyloid load and glucose metabolism in comparison to and in combination with semantic fluency performance was assessed. RESULTS: 583 patients were included (age 68.9 ± 8.7, 45% female). 280 patients (48%) had died and 303 (52%) were alive after a median of 8.0 years [95% C.I. 7.7-8.4]. Better semantic fluency (age-, sex- and education adjusted Z score, based on normative data) was significantly associated with lower mortality risk (HR = 0.71 [0.63 - 0.80], Bonferroni-corrected p < 0.001). Its predictive value was higher than that of all other CERAD-NAB subscores (e.g., memory, visuospatial abilities). Semantic fluency remained a significant predictor when amyloid status and global cognitive impairment were accounted for (HR = 0.75 [0.61 - 0.91], p = 0.0035). In patients with more than one assessment (N = 163), longitudinal change of semantic fluency (derived from a linear mixed effects model) was also a significant predictor (HR = 0.66 [0.53-0.83], p < 0.001). In 218/583 patients who had received amyloid and FDG PET, worse semantic fluency was associated with decreased FDG uptake of left inferior and middle temporal, dorsolateral frontal, and posterior parietal cortical regions (Bonferroni-corrected p < 0.05), but not with amyloid load. FDG uptake of the left IFG (pars opercularis) was itself a predictor of survival (HR = 0.68 [0.55 - 0.84], Bonferroni-corrected p < 0.05), but to a lesser degree than semantic fluency (and MMSE, naming and figure drawing). Predictive accuracy of semantic fluency was further improved by including FDG uptake of the right anterior cingulate (Bonferroni-corrected p = 0.078). Global amyloid load was not associated with survival. CONCLUSIONS: Survival of memory clinic patients can be predicted by semantic fluency, independently from amyloid status and global cognitive impairment. Anterior cortical glucose metabolism is itself a significant predictor of survival and slightly improves prediction by semantic fluency.

Patients with Alzheimer's disease (AD) frequently experience inflammatory insults; however, the mechanisms by which microglia respond to these challenges remain unclear. Although AD microglia have been proposed to be primed for exaggerated inflammatory responses, single-cell evidence remains limited. To investigate microglial responses to inflammation in AD, we challenged AD mouse models with intraperitoneal lipopolysaccharide (LPS) and used single-cell RNA sequencing to characterize microglial states, along with in vivo immunostaining and in vitro models to define their features and underlying mechanisms. We found that, in response to an inflammatory challenge, microglia adopted a low-inflammatory state accompanied by elevated expression of mitochondrial respiratory chain genes. This state was associated with the phagocytosis of dystrophic neurites and was recapitulated in vitro using an efferocytosis-based model, with apolipoprotein E implicated in its underlying mechanism. In summary, we identified a distinct microglial state that provides new insights into the dynamic role of microglia in AD.

Histopathologic staging models of neuronal α-synuclein pathology (n-asyn) in Lewy body disease (LBD) seldom evaluate brain regions with direct synaptic connectivity to model the role of microglial processes. We address this gap by testing the hypothesis that, within the well-defined synaptic connectivity of the intrahippocampal circuit, n-asyn is associated with activated microglial phenotypes. We selected a cohort of autopsy-confirmed LBD patients and minimal age-related copathologies (n = 62) and a control cohort of cognitively healthy patients with isolated hippocampal tau accumulation (i.e., primary age-related tauopathy, PART; n = 12), to control for neurodegenerative pathology without amyloid plaques. We immunostained consecutive hippocampal sections for n-asyn and established markers of activated microglial phenotypes, Iba1, HLA-DR, and CD68. With validated digital histology methods, we measured percent area occupied (%AO) of each marker in 6 hippocampal subfields to compare and correlate microglial morphologic and proteomic activation phenotypes between cohorts and used linear mixed effects models to compare the %AO between subfields while covariying for demographics. We also constructed groups of n-asyn restricted to the cornu ammonis (CA) 2-3 subfields (Focal Subtype) or widespread n-asyn within additional subfields (Widespread Subtype) to model hypothesized n-asyn spread within the intrahippocampal circuit. LBD patients exhibited increased HLA-DR and CD68%AO in most hippocampal subfields compared with PART. In LBD patients, all microglial markers were the highest in the CA2. CA2 n-asyn correlated with HLA-DR and CD68 but not Iba1%AO. Patients classified as Widespread Subtype had worse cognitive impairment and increased CA2 HLA-DR and CD68%AO. CA2 HLA-DR and CD68%AO correlated with distal n-asyn in retrograde, but not anterograde connected subfields. Our data show that activated microglial phenotypes in the CA2 of LBD patients are associated with worse clinical outcomes and retrograde n-asyn transmission. These data suggest that measures of microglial states can refine LBD histopathological progression models.

BACKGROUND: Vascular depression (VaD) is a subtype of late-life depression (LLD) associated with cerebrovascular disease, cognitive impairment, and poor response to standard antidepressants. Despite its clinical relevance and association with increased risk of dementia, no specific treatment guidelines currently exist. OBJECTIVES: To systematically review randomised controlled trials (RCTs) on the clinical efficacy of pharmacological and non-pharmacological interventions for VaD in older adults. METHODS: A systematic search of MEDLINE, EMBASE, Web of Science and ClinicalTrials.gov registry identified 7994 records, of which 8 RCTs met inclusion criteria. Studies included participants with late-life VaD. Interventions comprised pharmacological treatments (augmentation with tandospirone and nimodipine) and neuromodulation techniques (rTMS and tDCS). Outcomes included treatment response and remission, change in depressive symptoms, and other clinical outcomes. RESULTS: Augmentation with tandospirone was associated with faster early symptom improvement in three of four trials. Nimodipine improved remission at 2 months and reduced recurrence in one of two trials. Neuromodulation interventions showed promising antidepressant effects and cognitive benefits (based on two trials). Treatments were generally well tolerated. However, study heterogeneity, small sample sizes, and short follow-up durations limited comparability and precluded meta-analysis. The overall certainty of evidence was low to very low. CONCLUSIONS: Evidence on treatment for VaD remains limited, highlighting the need for large, well-designed RCTs and integrated approaches combining vascular risk management with targeted therapies.

Hyperhomocysteinemia (HHcy) is a recognized risk factor for cognitive impairment, including Alzheimer's disease, but the mechanisms linking homocysteine (Hcy) accumulation to cerebral dysfunction remain unclear. Brain microvascular endothelial cells (BMECs) are an important cellular component of the blood-brain barrier (BBB) and play a key role in maintaining central nervous system homeostasis. However, how Hcy affects BMECs remains incompletely understood. In this study, we used the human brain microvascular endothelial cell line hCMEC/D3 to determine the half-maximal inhibitory concentration (IC) of Hcy by CCK-8 assay, and then performed transcriptomic analysis to identify Hcy-regulated genes associated with endothelial cell injury. Hcy reduced hCMEC/D3 cell viability in a dose-dependent manner, with an IC of approximately 12.25 mM; therefore, 10 mM Hcy was selected for subsequent experiments. Transcriptomic sequencing revealed significant upregulation of the transferrin receptor (Tfrc) gene, which we confirmed by quantitative real-time PCR and Western blot analysis. Functionally, TFRC overexpression mimicked the Hcy-induced reduction in cell viability, whereas TFRC knockdown partially rescued cells from Hcy-induced cytotoxicity. TFRC overexpression reduced hCMEC/D3 cell viability, whereas TFRC knockdown partially alleviated Hcy-induced cytotoxicity. These results suggest that TFRC is involved in Hcy-induced injury of brain microvascular endothelial cells. Taken together, our in vitro findings provide a possible clue for future in vivo studies on HHcy-associated BBB dysfunction.

Principal Illness Navigation (PIN) represents an important Medicare policy advance, but coverage has not translated reliably into access. PIN addresses a real need: patients with cancer and other serious chronic illnesses often struggle with fragmented communication, scheduling complexity, insurance confusion, caregiver burden, and uncertainty about next steps. Medicare recognizes PIN under Healthcare Common Procedure Coding System (HCPCS) Level II codes G0023 and G0024, with payment established through the Medicare Physician Fee Schedule. Yet the main barriers to PIN implementation are administrative and operational rather than clinical. The billing practitioner must perform an initiating visit and remains responsible for supervision, documentation, and billing, even when auxiliary personnel furnishing navigation are external to the practice. Many private practices and oncology groups lack the infrastructure or patient volume to employ dedicated navigators. Specialized outside navigation organizations may offer a scalable alternative, but contracting, enrollment, and billing remain difficult; reassignment adds further friction when an eligible organization seeks to submit claims and receive Medicare Part B payment. This commentary argues that PIN's implementation challenges reflect not only physician education gaps but also a broader trust problem in the administrative pathway. Historical warnings from the U.S. Department of Health and Human Services Office of Inspector General help explain physician caution. Experience from other Centers for Medicare & Medicaid Services programs, including the Medicare Diabetes Prevention Program and the Guiding an Improved Dementia Experience (GUIDE) Model, shows that CMS can modify delivery rules and formally evaluate implementation when operational barriers emerge. To make PIN function as a real benefit rather than a paper benefit, CMS should provide plain-language guidance, clarify risk boundaries, simplify enrollment and payment pathways, and measure activation, onboarding time, and successful service delivery.

Mitochondrial dysfunction is a cardinal, causative, and convergent hallmark in both Alzheimer's disease (AD) and Parkinson's disease (PD). However, therapeutics that target the process of mitophagy, the selective removal of damaged mitochondria, are relatively undeveloped. Prior work has largely centered around post-translational modifications of the PINK1-Parkin signaling pathway while ignoring the key need for sustained protein synthesis of Parkin. In this review, we explore an innovative transcriptional circuit involving the gut microbiome, AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and mitophagy: gut-derived metabolites, such as Urolithin A (UA), activate AMPK and SIRT1, both of which converge to deacetylate and phosphorylate peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The transcription of the mitophagy protein, Parkin, is then driven by activation of PGC-1α. This UA/AMPK/SIRT1/PGC-1α/Parkin/mitophagy pathway is disrupted in multiple layers in AD and PD; this includes impaired gut function, lowering the level of UA produced in the body, proteinopathy leading to reduced PGC-1α activity, and decreased transcription of Parkin. Therapeutic targets of these various nodes include UA, PGC-1α activator ZLN005, and SIRT1 activators, such as resveratrol or nicotinamide riboside. By shifting the paradigm from post-translational activation to transcriptional restoration of Parkin, this gut-brain metabolic axis offers a unifying, testable, and therapeutically tractable framework for mitigating mitophagy failure in AD and PD.

Central nervous system (CNS) disorders are fundamentally linked to metabolic dysregulation within immune and glial cells. This review provides a systematic synthesis of immunometabolic reprogramming-encompassing glucose, lipid, and amino acid metabolism, and oxidative phosphorylation-in CNS-resident microglia, immunomodulatory astrocytes, and peripherally infiltrating immune cells (T cells, B cells, and neutrophils) across Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ischemic stroke. Critically, rather than presenting all reported metabolic alterations as equivalently established, we introduce an evidence-transparency framework that systematically distinguishes the nature of supporting data-ranging from direct metabolic flux measurements (Seahorse, isotope tracing, lipidomics) and molecular correlates, to genetic/pharmacological perturbations, human tissue validation, and model-specific observations-enabling readers to independently assess the strength of each major conclusion. We further delineate aging as an active analytical dimension, demonstrating how age-related changes in mitochondrial quality control, lipid handling, redox buffering, and glial-immune crosstalk establish a permissive baseline that modifies disease-specific reprogramming trajectories. By integrating analyses of intercellular crosstalk, neuroinflammation, blood-brain barrier integrity, and oxidative stress, we illustrate both convergent and divergent metabolic mechanisms across diseases. Finally, we critically assess therapeutic strategies targeting immunometabolism, emphasizing shared translational obstacles including target selectivity, blood-brain barrier penetration, stage-dependent efficacy, and the inherent challenge of pathway pleiotropy. This review provides a conceptually grounded framework for interpreting immunometabolic evidence, navigating the gap between correlative findings and causal mechanisms, and guiding future hypothesis-driven therapeutic design for CNS disorders.

Microglia are central regulators of the cellular phase of Alzheimer's disease (AD). Under chronic exposure to amyloid-β, pathological tau, and aging-associated bioenergetic decline, these cells undergo immunometabolic remodeling that may initially be adaptive. As stress persists, this remodeling can become maladaptive, marked by disordered glycolysis, disturbed lipid handling, mitochondrial dysfunction, and compensatory failure. In this review, we organize these changes as a stage-dependent trajectory from adaptive remodeling to functional decompensation. We introduce the "metabolic paradox" as an operational descriptor: a concurrent, same-cell mismatch between increased substrate uptake or inflammatory activation and declining bioenergetic efficiency and homeostatic function. Along this trajectory we examine neurovascular energy bottlenecks, substrate redistribution, triggering receptor expressed on myeloid cells 2 (TREM2)/apolipoprotein E (APOE)-dependent lipid homeostasis, mitochondrial and proteostatic collapse, and their links to persistent neuroinflammation, defective phagocytosis, aberrant synaptic pruning, and senescence-like dysfunction. We synthesize prior primary findings and stratify each major claim by evidentiary strength, avoiding the overinterpretation of model-specific results as patient-level mechanisms. Finally, we frame immunoprevention as mechanism-based, early-stage metabolic intervention to preserve homeostatic microglial function, a strategy whose clinical benefit remains a hypothesis requiring prospective testing.

BACKGROUND: Glymphatic dysfunction is thought to underlie neurodegenerative dementia; however, its interplay with dopaminergic degeneration and concurrent amyloid-β (Aβ) pathology in Parkinson's disease (PD) remains unresolved. This study aimed to evaluate MRI-based glymphatic metrics (the diffusion tensor image analysis along the perivascular space [DTI-ALPS] index and choroid plexus volume [CPV]) and their associations with dopaminergic degeneration, Aβ burden, and cognitive impairment (CI) in PD. METHODS: 79 PD patients (48 with CI (PD-CI), and 31 cognitive normal (PD-N)) and 28 age-, gender-matched normal controls (NC) were included. Dopaminergic degeneration was measured by dopamine transporter (DAT) availability using 11C-CFT-PET in PD. Additionally, 46 out of 79 PD patients conducted 18F-Florbetapir-PET for quantifying global Aβ burden (Centiloid values) and regional Aβ burden (voxel-wise regression analysis). RESULTS: PD-CI showed a significantly reduced DTI-ALPS index (1.31 ± 0.12 vs. 1.40 ± 0.12, p = 0.014; and 1.41 ± 0.12, p = 0.004) and enlarged CPV (1.43 ± 0.31 vs. 1.07 ± 0.18; and 1.14 ± 0.24; p < 0.001 respectively) compared to NC and PD-N. Both the DTI-ALPS index and CPV were significantly correlated with age and caudate DAT availability (CAU_DAT), but not correlated with DAT availability in anterior / posterior putamen, Centiloid values or regional Aβ burden. Further mediation analyses indicated that CAU_DAT mediated the associations between glymphatic metrics and CI after adjustment for covariates, as assessed by the DTI-ALPS index (p = 0.026) and CPV (p = 0.042). CONCLUSIONS: The caudate dopaminergic degeneration corelates with MRI-based glymphatic metrics and cognitive deterioration in PD.

AIMS AND OBJECTIVES: To explore the experiences of receiving and living with a diagnosis of prodromal Alzheimer's disease. BACKGROUND: Alzheimer's disease is a progressive dementia disorder, with pathology potentially developing years before clinical symptoms. Evidence concerning patients' perspectives on living with a prodromal Alzheimer's disease diagnosis remains scarce. DESIGN AND METHODS: A qualitative, descriptive design was employed. Semi-structured interviews were conducted with 16 participants diagnosed with prodromal Alzheimer's disease in memory clinics in Denmark, Norway and Iceland. The data were analysed using thematic analysis. FINDINGS: Four main themes emerged: 1) what led to the assessment, 2) receiving the diagnosis of prodromal Alzheimer's disease, 3) everyday life after the diagnosis and 4) planning for the future. The participants experienced diverse trajectories to diagnosis, with some being alerted by others to symptoms and some recognising the symptoms themselves. The diagnostic process was often perceived as intimidating, and person-centred care was valued. After the diagnosis, the participants focused on managing daily life, experienced changes in relationships and harboured mixed emotions about the future. CONCLUSION: Receiving a prodromal Alzheimer's disease diagnosis impacts patients' perceptions of their abilities, relationships and future. There is a need for interventions targeting both patients and their families to maintain a close bond between them and support hope. Clear communication about the distinction between prodromal Alzheimer's disease and Alzheimer's dementia is crucial. PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution.

INTRODUCTION: In Australia, nearly 400,000 people live in residential aged care, of those, 40% experience a hospital admission annually. High-quality care transitions are crucial for ensuring safe and effective continuity of care. Ineffective information sharing increases risks of harm for already vulnerable consumers, contributing to adverse health outcomes, creating care delays and causing distress to individuals moving between care settings. AIM: This study aimed to co-design, pilot and evaluate the implementation of a comprehensive discharge documentation and medication package aligned with the electronic medical record to support quality care transitions between hospital and residential aged care. METHODS: Mixed-methods, participatory action approach, incorporating workshops, surveys, and interviews. Ten RNs from four residential aged care sites participated, and ten hospital-to-residential aged care transitions were evaluated. RESULTS: 80% (n = 8) stated the discharge package met the standard for providing comprehensive care, and 100% (n = 10) identified improved medication safety. Three themes were identified from the interviews: 1) Enhancing system improvements supports more effective care transitions; 2) Effective cross-sector information sharing depends on well-defined and replicable processes; 3) Historical standards drive lower expectations. CONCLUSION: This participatory action research co-designed an effective discharge package for hospital-to-residential aged care. Developed by a nurse-led multidisciplinary team, this work established a strategy that supports patient safety, quality information sharing, and is aligned with hospital and residential aged care standards. Based on the difficulties of effective communication, the use of the documentation package demonstrates an effective tool to support information sharing processes between hospital and residential aged care.

BACKGROUND: The global population is ageing at an unprecedented rate, creating substantial pressures on healthcare systems to deliver personalised, proactive, and cost-effective care for older adults. Digital twin (DT) technology, where dynamic virtual replicas of physical entities are continuously updated through real-time data, has emerged as a transformative tool in precision medicine. Despite its growing application across clinical specialties, its specific utility within geriatrics and gerontology remains underexplored in the academic literature. AIM: This narrative review aims to synthesise existing evidence on the applications of digital twin technology in geriatric and gerontological care, examine associated challenges and identify future research priorities. METHOD: A narrative review methodology was employed, with a systematic search of PubMed, Scopus, Web of Science, and IEEE Xplore databases covering publications from January 2014 to December 2025. Studies were selected based on relevance to digital twins, ageing populations, or geriatric clinical domains, with data synthesised thematically. RESULTS: Digital twins demonstrate significant potential benefit across multiple geriatric domains, with use in cardiovascular monitoring, fall prevention, dementia management, polypharmacy optimisation, and chronic disease self-management. Key enablers include advances in Internet of Things (IoT), artificial intelligence, and electronic health records. Persistent challenges include data privacy concerns, interoperability deficits, computational costs, and ethical questions surrounding autonomy and consent in cognitively impaired populations. CONCLUSION: Digital twin technology holds considerable promise for revolutionising geriatric and gerontological care, by enabling hyper-personalised clinical decision-making, predictive risk management, and remote patient monitoring. Translating this potential into practice requires focused investment in regulatory frameworks, equitable access infrastructure, and interdisciplinary collaboration. Future research should prioritise standardisation, caregiver integration, and longitudinal validation studies within older adult populations.

BACKGROUND: Predicting cognitive decline as a continuum, from healthy age-related decline to mild cognitive impairment and dementia, enables more precise individual-level predictions. However, the practical value of such models for early intervention and prevention depends on their ability to generalize to independent cohorts, a property that is often not evaluated. OBJECTIVES: This study investigated whether adding structural magnetic resonance imaging (MRI) to non-brain data improved machine learning predictions of continuous cognitive decline and analyzed the models' generalizability. DESIGN: Multi-target random forest regression models predicted annual decline in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) and Mini-Mental State Examination (MMSE) using non-brain data, structural MRI data, or their combination from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 1237) and Open Access Series of Imaging Studies (OASIS-3; N = 662) datasets. Cross-site generalizability was evaluated. SETTING: Data from ADNI and OASIS-3 were used for this study. PARTICIPANTS: A total of 1899 participants who had demographic, clinical, and brain imaging data from a baseline session and clinical data from at least 2 follow-up sessions were included. MEASUREMENTS: Baseline non-brain (demographics, clinical and neuropsychological scores, information on APOE genotype, cognitive diagnosis, health, and number of sessions before baseline) and/or structural MRI data were used to predict the yearly rate of change in CDR-SOB and MMSE scores. RESULTS: Including structural MRI data improved prediction of CDR-SOB and MMSE change, reaching respective R values of .41 and .33 in ADNI and .42 and .33 in OASIS-3. Model performance for across-dataset predictions was reduced (R between .18 and .35), unexplained by distributional shifts of target variables. Models using only top predictive features performed similarly to full models when tested externally (R between .18 and .34), suggesting predictor redundancy. CONCLUSIONS: Incorporating structural MRI data enhances within-dataset prediction of continuous cognitive decline, allowing for more precise individual-level prediction and advancing towards precision medicine. Even though external validation remains limited, quantifying the generalizability gap is a crucial step towards the responsible use of ML models in clinical intervention and prevention.

BACKGROUND: Recent studies suggest a decreased risk of dementia in patients treated with glucagon-like peptide-1 receptor agonist (GLP-1 RA). In this study, we compare the risk of dementia associated with GLP-1 RA versus long-acting insulin in adults aged over 50 years with type 2 diabetes (T2DM) using real-world administrative data from a large Taiwan cohort DESIGN: A population-based retrospective cohort study SETTING: We analyzed 10,783 propensity score-matched pairs of adults with T2DM who initiated either GLP-1 RA or long-acting insulin from Taiwan's National Health Insurance Research Database (2011-2021). MEASUREMENTS: Primary outcome was new-onset dementia; secondary outcomes included dementia requiring treatment and specific dementia subtypes (Alzheimer's disease, vascular dementia, and unspecified dementia). Hazard ratios (HRs) were estimated using Cox models. RESULTS: Analysis of matched pairs identified 375 cases of newly diagnosed dementia. The incidence rate was 4.86 per 1,000 person-years in GLP-1 RA users versus 7.56 in insulin users. GLP-1 RA use was associated with significantly lower risk of overall dementia (HR 0.64, 95% CI 0.46-0.89, P=0.0072) and unspecified dementia (HR 0.41, 95% CI 0.24-0.68, P=0.0006), but not for Alzheimer's disease (HR 1.48, 95% CI 0.61-3.63, P=0.3867) or vascular dementia (HR 1.66, 95% CI 0.21-13.03, P=0.6324). Among GLP-1 RAs, both liraglutide (HR 0.40, 95% CI 0.20-0.80, P=0.0091) and dulaglutide (HR 0.42, 95% CI 0.19-0.92, P=0.0311) showed significant protective effects against unspecified dementia. CONCLUSIONS: GLP-1 RA use was associated with lower dementia risk versus long-acting insulin in T2DM patients, especially with liraglutide and dulaglutide. As observational, causality requires confirmation from randomized controlled trials.

INTRODUCTION: Cognitive impairment is common in older adults with cancer but often remains undetected due to time constraints and limited specialized resources in routine oncology care. We evaluated whether a 2-min cognitive screener predicts all-cause mortality in this population and explored whether functional dependence mediates this association. MATERIAL AND METHODS: We conducted a longitudinal study of consecutive patients aged ≥60 years with cancer who were referred for geriatric oncology assessment at a tertiary outpatient cancer center in Brazil. Cognitive status was assessed using the 10-point Cognitive Screener (10-CS), a brief clinical tool that evaluates orientation, memory, and verbal fluency. Cognitive impairment was defined as 10-CS scores ≤5. We used Cox proportional hazards models to examine the association between 10-CS scores and 3-year all-cause mortality, as well as sociodemographic factors, comorbidities, cancer type, metastasis, and sensory deficits. Harrell's C-index was calculated to assess whether adding 10-CS improved mortality discrimination. Mediation analysis incorporated activities of daily living (ADLs) dependence. RESULTS: Among 508 patients (mean age = 78.0 ± 7.1 years; female = 42.5%), 224 (44.1%) had cognitive impairment. Of these, 87 (38.8%) had no previous cognitive impairment documented in their medical records. Three-year mortality was higher among patients with impairment (63.6% vs 37.4%, p < 0.001). After adjustment, cognitive impairment remained strongly associated with mortality (HR = 1.87; 95% CI: 1.38-2.54). Adding 10-CS to the model with sociodemographic, comorbidities, and cancer variables improved mortality discrimination (Harrell's C-index 0.72 vs. 0.68; p = 0.01). The 10-CS stratified mortality across subgroups defined by the absence (40.0% vs. 62.9%; p < 0.001) or presence (25.1% vs. 63.6%; p < 0.001) of previous chart-documented cognitive impairment or dementia. Cognitive impairment was associated with dependence in ADL (adjusted prevalence ratio = 4.01; 95% CI = 2.57-6.25). Disability mediated part of the effect on 3-year all-cause mortality, but 62% remained unexplained, indicating that most of the association was independent of functional decline. DISCUSSION: Cognitive impairment evaluated with the 10-CS predicted 3-year all-cause mortality in older adults with cancer. This brief clinical tool provided valuable prognostic information beyond standard oncology measures and may assist clinicians in identifying high-risk patients whose cognitive impairment might otherwise go unrecognized.

The pathological progression of Alzheimer's disease (AD) involves multiple interconnected pathways, including β-amyloid (Aβ) deposition, oxidative stress, and microglial dysfunction, which together form a self-reinforcing vicious cycle. This complexity poses a major challenge to conventional single-target therapeutic strategies. To address this limitation, we developed a biomimetic nanoplatform integrating active brain targeting, multiple therapeutic bioactivities, and immunomodulatory function. The core of this platform was an iron-porphyrin-based covalent organic framework (COF) that possesses enzyme-mimetic antioxidant activity, metal-ion-chelating capability, and Aβ-modulating properties. The COF core was cloaked with a BV2 microglial membrane (BM) to enhance biocompatibility and further functionalized with Angiopep-2 peptide to enable efficient blood brain barrier (BBB) penetration. In vitro studies demonstrated that the platform effectively scavenged various reactive oxygen species, achieved a copper-ion chelation rate of 41.78%, inhibited Aβ aggregation, and depolymerized pre-formed fibrils. At the cellular level, the nanoplatform not only protected neurons from β-amyloid-induced toxicity but also improved the redox status and mitochondrial function of microglia. Furthermore, it promoted the polarization of microglia from the pro-inflammatory M1 phenotype toward the neuroprotective M2 phenotype, which was correlated with enhanced β-amyloid phagocytic capacity. In APP/PS1 (APPswe/PSEN1dE9) transgenic mice, treatment with this nanoplatform markedly reduced cerebral Aβ plaque deposition, attenuated neuroinflammation and oxidative stress, and improved BBB integrity, ultimately leading to the remarkable recovery of spatial learning, memory, and spontaneous exploration abilities in mice. In summary, this integrated nano-strategy, which combines delivery, clearance, and modulation, represents an effective multi-target approach for intervening in the complex pathological network of AD.

BackgroundThe apolipoprotein E () ε4 allele is the strongest known genetic risk factor for late-onset Alzheimer's disease (AD), but its prevalence and impact vary substantially across populations. No previous study has characterized allele distribution among Syrian patients with AD.ObjectiveThis investigation aimed to assess the association between genotypes and AD risk in a Syrian cohort.MethodsIn this case-control study, genomic DNA was extracted from 52 clinically diagnosed AD patients and 38 cognitively healthy controls. The genotype was determined by direct sequencing of the rs429358 and rs7412 polymorphisms defining the ε2, ε3, and ε4 alleles. Genotypic and allelic frequencies were compared using Fisher's exact test, and Hardy-Weinberg equilibrium was assessed in the controls.ResultsThe ε3/ε3 genotype was predominant in both groups (73.1% of cases, 94.7% of controls). The ε3/ε4 genotype appeared in 23.1% of AD patients but was absent among controls (Corrected OR = 12.37, 95% CI = 0.65-233.7, p < 0.01). The overall ε4 allele frequency in patients (0.117) was significantly higher than in controls (0.000) (Corrected OR = 10.76, 95% CI = 0.59-195.7, p < 0.01). The ε2/2, ε4/4, and ε2/4 genotypes were not detected in any participants.ConclusionsThis study is the first to investigate the prevalence of the ε4 allele in Syrian patients with Alzheimer's disease. These results underscore the importance of investigating genetic architectures when assessing AD risk and call for larger, multi-center studies across the Middle East to elucidate the interplay between variants and metabolic determinants of cognitive decline.