OBJECTIVES: This study explored how elderly care physicians (ECPs) perceive their role in preventing crisis admissions among home-dwelling people with dementia, how they view their position within community-based dementia care, and which barriers hinder them in assuming this role. METHODS: A qualitative study was conducted using semi-structured interviews with ECPs. Participants reflected on anonymized dementia cases involving crisis situations to identify opportunities for prevention. Interviews were analyzed through inductive thematic analysis, supported by iterative coding, researcher triangulation, and application of Strauss and Corbin's coding paradigm. RESULTS: Timely ECP involvement emerged as central to preventing or delaying crisis admissions. Participants described how ECPs can recognize crisis-prone situations early and initiate multidisciplinary interventions. Timely consultation depended on collaboration with GPs, local expertise, stepped-care role distribution and regional coordination. Limited capacity, organizational constraints and communication barriers impeded early involvement. CONCLUSION: ECPs perceive their role in preventing crisis admissions as meaningful, but their timely involvement depends on well-functioning proactive care networks. Such networks must identify emerging risks early, ensure that concerns reach the appropriate professionals, and align interventions with the individual's valuesand circumstances. Strengthening coordination, clarifying escalation pathways, improving communication structures, and expanding workforce capacity are essential to enable early mobilization of ECP expertise.

Autophagy preserves neuronal integrity by clearing damaged proteins and other subcellular components, yet it declines with age and exacerbates in Alzheimer's disease (AD). Although autophagy reduces tauopathy, whether it can proactively restrict early tau pathology via post-translational modifications (PTMs) has remained unclear. In a recent paper, we have identified a mitophagy-based metabolic signaling mechanism linking the autophagy-initiating kinase Unc-51-like autophagy activating kinase 1 (ULK1) to the inhibition of pathogenic tau acetylation via the ULK1-NAD/SIRT1 axis. Analyses of human biofluidic to postmortem and transcriptomic data reveal an age-associated decline of ULK1; this situation gets worse in AD with the extent of ULK1 reduction positively correlates with Tau-based Braak stage progression, consistent with a bidirectional vicious cycle in which pathological tau disrupts mitochondrial homeostasis and impairs autophagy. Restoring ULK1-dependent mitophagy breaks this cycle in the upstream: in the hTau.P301S mice, ULK1 overexpression reduces ac‑tauK174 leading to reduced tau pathology and improved cognition. Mechanistically, ULK1 activates PINK1- and FUNDC1- as well as AMBRA1-dependent mitophagy to eliminate damaged mitochondria, restore bioenergetics, and elevate intracellular NAD, which activates the deacetylase SIRT1 to directly deacetylate tau at Lys174. Pharmacological ULK1 activation with a small molecule Rac‑BL‑918 phenocopies these protective effects in a mitophagy- and SIRT1-dependent manner. Collectively, our recent findings position mitophagy as a metabolic signaling hub that couples mitochondrial turnover to NAD/SIRT1 activity to shape neuronal tau PTMs, supporting ULK1-mitophagy activation as an upstream strategy to limit tauopathy before overt aggregation.

BACKGROUND: White matter hyperinxtensity (WMH) and normal-appearing white matter (NAWM) are critical markers for tracking disease progression in cerebral small vessel disease (CSVD), indicative of a spectrum of white matter injury. The core pathological alteration underlying such injury is the disruption of myelin integrity and loss of axons. We hypothesized that the myelin content in WMH and NAWM may exert distinct effects on brain networks and cognition in CSVD. METHODS: A total of 129 diagnosed CSVD patients were retrospectively enrolled. Myelin content was assessed with sub-voxel precision using iterAtive magnetic suscePtibility sources sepARaTion Quantitative Susceptibility Mapping (APART-QSM). Structural network redundancy was derived from diffusion tensor imaging (DTI). WMH and NAWM masks were generated. Associations between WMH/NAWM myelin content, structural network redundancy, and cognitive performance were examined using partial correlation and mediation analyses. RESULTS: Myelin content was significantly higher in NAWM than in WMH. Decreased structural network redundancy was significantly linked to myelin loss in NAWM but not in WMH. Moreover, redundancy indirectly linked NAWM myelin to cognition, whereas no such indirect pathway was observed for WMH myelin. No direct or total effect of myelin content on cognition was observed. CONCLUSIONS: These findings highlight the critical role of NAWM-related myelin integrity in preserving cognition through its association with structural network redundancy in CSVD.

BACKGROUND: Informed consent is a fundamental ethical requirement in medical practice and an expression of respect for patient autonomy. However, when adult patients lack decision-making capacity and no legal representative is available, Polish law requires substitute consent from a guardianship court. Empirical data on this mechanism in routine clinical practice remain limited. METHODS: We conducted a retrospective review of court petitions submitted by a tertiary academic medical center in eastern Poland seeking judicial authorization for medical procedures involving adult patients between June 2019 and June 2024. In total, 240 case files were analysed, including data on patient characteristics, causes of incapacity, requested procedures, court decisions, and time to judicial decision. RESULTS: The median patient age was 73 years (interquartile range 62-83), and 76.7% of patients were aged 61 years or older. The most common cause of incapacity was impaired verbal-logical communication (65.0%), followed by unconsciousness (20.8%) and dementia (7.5%). The most frequently requested procedures were blood transfusions or administration of blood products (n = 201), placement of a percutaneous endoscopic gastrostomy tube (n = 149), and tracheostomy (n = 27). Court authorization was granted in 97.1% of cases, with a median decision time of 5 days. CONCLUSIONS: Judicial substitute consent in Poland primarily concerns older patients with acute neurological impairment or advanced multimorbidity. Although approval rates are high and median processing times are relatively short, even brief delays may have clinically and ethically significant consequences in time-sensitive situations. These findings highlight the need to balance legal safeguards, patient autonomy, and timely access to care.

BACKGROUND: Mild Cognitive Impairment (MCI) is a heterogeneous clinical condition characterized by a wide spectrum of cognitive and behavioural manifestations. Despite numerous studies, the link between neuropsychological performance and pathophysiological signatures of the disease-including Aβ and tau accumulation along with altered excitation/inhibition (E/I) balance and brain rhythms-remains elusive. METHODS: Here Aβ/tau biomarkers were used to distinguish positive (MCI- prodromal Alzheimer's disease) and negative (MCI) subjects in a cohort of 30 MCI patients (18 MCI and 12 MCI). Virtual brain models based on high-field magnetic resonance imaging data were then developed to determine the inter-node coupling and E/I profile in resting-state networks, while node spectral information was obtained from source analysis of high-density electroencephalography (HD-EEG). Finally, virtual brains and HD-EEG parameters, creating brain digital twins of individual subjects, were correlated with cognitive performance. RESULTS: While virtual brain simulations did not reveal E/I differences between MCI and MCI, a positive correlation emerged between synaptic parameters of the limbic network and verbal episodic memory for both groups. EEG power spectral density revealed a lower high-frequency/low-frequency ratio in MCI largely due to a reduced alpha band in the default mode, limbic, attention, frontoparietal, visual and somatomotor networks. A strong correlation emerged between multimodal parameters and memory functions, supporting that brain digital twin simulations can effectively explain the variability of neuropsychological performance in MCI patients beyond the sensitivity of individual techniques alone. In particular, the combination of HD-EEG and virtual brain parameters explained more than 90% of variance for episodic memory patients' scores, confirming the compound origin of memory performance involving network specific E/I levels and electroencephalographic activity acting in concert. CONCLUSIONS: This multimodal and multiparametric analysis combining virtual brain modelling with HD-EEG and molecular data enhances the stratification of MCI patients and could be used to develop digital biomarkers of progression to dementia, opening new perspectives for personalized prognosis and treatment.

Glucocorticoid receptor (GR) is a member of the nuclear hormone receptor family, which acts as a transcription factor when bound by glucocorticoid (GC) ligands. GR is expressed in nearly all tissue types and regulates essential processes such as inflammation, immune regulation and metabolism. Given its ubiquitous role, GR has frequently been associated with a wide range of illnesses, particularly in the fields of allergy, pulmonary, dermatology, rheumatology, or ophthalmology. It was reported that GCs either contribute to their development or serve as part of their treatment, making them the most prescribed drugs worldwide. GR activity and signaling is finely regulated by a network of post-translational modifications (PTMs). Indeed, PTMs can alter GR behavior and function by modifying its localization, stability, interaction with other proteins and transcriptional activity. Aside from the well-characterized phosphorylation events, additional PTMs are implicated in GR activity and their dysregulation has been described in various diseases. This review provides an integrated overview of current knowledge on GR PTMs, highlighting both mechanistic insights and their relevance in disease. We will present how aberrant PTMs contribute to extremely prevalent diseases, such as cancer, chronic inflammatory diseases, Alzheimer's disease and other neurological diseases. Special attention will be given to the specific readers of these PTMs and to the enzymes catalyzing these modifications, as they represent promising therapeutic targets.

BACKGROUND: Vascular cognitive impairment (VCI) is a devastating clinical endpoint of microvascular senescence. However, the mechanisms by which age-related focal vascular insults cause systemic brain network failure and molecular vulnerability remain unknown. To decode the multi-scale neurobiology of VCI, we conducted a systematic review and meta-analysis of whole-brain voxel-based morphometry studies comparing patients with VCI and healthy controls. METHODS: We used coordinate-based network mapping on a normative functional connectome to identify convergent structural atrophy networks. To decode multi-scale biological substrates, we checked the resulting macroscopic topography against the Allen Human Brain Atlas and 28 positron emission tomography-derived neurotransmitter maps. RESULTS: 18 studies contributed to the analysis, including 682 VCI patients and 643 healthy controls. VCI-related atrophy, despite appearing disparate, functionally converges onto a robust macroscopic architecture that is anchored predominantly in the somatomotor and salience networks. Transcriptomic profiling further showed that this network colocalizes significantly with Layer 6 corticothalamic and subcortical projection neurons. These neuron populations feature exceptionally long axonal projections, a property that heightens their metabolic susceptibility to chronic hypoperfusion. At the neurochemical level, this structural degradation exhibited profound spatial coherence with the macroscopic distribution of dopamine transporter (DAT) and 5-hydroxytryptamine transporter (5‑HTT). CONCLUSION: These findings suggest that VCI may represent a quintessential "disconnection syndrome" associated with the vulnerability of long-range projection pathways to vascular aging, providing a novel multi-scale neurobiological template to identify network-level targets for intervention.

Depression is a recognized risk factor and potential prodromal feature of Alzheimer's disease (AD). While associations between depressive symptoms and AD pathology have been observed using cerebrospinal fluid (CSF) and PET imaging, it remains unclear whether these relationships can be captured by accessible plasma biomarkers, particularly the highly specific phosphorylated tau-217 (p-Tau217). We analyzed 615 participants from Alzheimer's disease Neuroimaging Initiative (ADNI) cohort, of whom 374 had minimal depressive symptoms (MDS). Plasma biomarkers included phosphorylated tau-217 (p-Tau217), amyloid-β 42/40 ratio (Aβ42/Aβ40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Linear regression models and mediation analyses were employed to examine associations between MDS, plasma biomarkers (p-Tau217, Aβ42/Aβ40, NfL, and GFAP), and cognitive impairment, with adjustments for age, sex, and APOE ε4 carrier status. Participants with MDS demonstrated significantly elevated plasma p-Tau217 levels (mean difference = 0.105, 95% CI [0.046, 0.163]; P < 0.001) and reduced Aβ42/Aβ40 (mean difference = -0.024, 95% CI [-0.041, -0.006]; P = 0.007) compared with those without MDS. These associations were primarily observed in non-demented individuals and influenced by age, sex, and APOE ε4 status. In mediation analyses, plasma p-Tau217 accounted for 41.57%-42.18% of the association between MDS and cognitive impairment, while Aβ42/Aβ40 mediated 7.13%-8.45% of this relationship. Plasma biomarkers of p-Tau217 and Aβ42/Aβ40 were associated with early depressive symptoms and mediate their associations with cognitive impairment. These findings identify plasma p-Tau217 as a key mediator linking MDS to cognitive impairment, extending evidence from CSF to accessible blood-based biomarkers. This highlights the value of monitoring plasma p-Tau217 and Aβ42/Aβ40 to unravel the pathological basis of depressive symptoms in early AD.

In memory disorders such as Alzheimer's disease, recent autobiographical memories are disproportionately vulnerable to loss, yet most traditional reminiscence therapies focus on remote past events. We present a case study examining whether a digital reminiscence intervention designed to support memory for recent experiences can improve episodic recall and psychosocial outcomes in neurodegenerative memory impairment. G.F., a 79-year-old man with early-stage dementia, completed an 11-week personalized intervention using HippoCamera, a neuroscience-based smartphone application that helps users generate and review multimodal memory cues from everyday events. Events that G.F. reviewed using HippoCamera were recalled with greater episodic detail than events that were recorded but not reviewed. Post-intervention, G.F. reported improvements in quality of life, life satisfaction, self-concept, and perceived episodic and spatial memory abilities, along with reduced depressive symptoms. Qualitative feedback revealed that the intervention helped G.F. regain confidence, re-engage socially, and feel more optimistic about the future. These findings suggest that digital interventions targeting memory for recent experiences - a domain often overlooked in traditional reminiscence therapy - may provide benefits to cognition and quality of life in the early stages of dementia. This work highlights the promise of HippoCamera as an accessible, neuroscience-informed tool to support memory and well-being in those experiencing memory loss.

Alzheimer's therapy remains limited by poor drug targeting and multifactorial pathology. The therapeutic potential of SGLT-2 inhibitors like empagliflozin (EGZ) is constrained by poor brain bioavailability. Current study investigates the potential of EGZ-nanostructured lipid carrier (ENLC) for brain delivery via nasal route. The ENLC were prepared using hot melt emulsification technique followed by probe sonication and optimized using Box-Behnken design. ENLC were incorporated into poloxamer 407-chitosan in situ gel (ENPCG) to improve nasal retention, controlled release, and direct brain transport via olfactory and trigeminal uptake. ENPCG demonstrated a sustained drug release of 56.36 ± 3.37 % and enhanced nasal permeation. Nasal kinetics revealed high C (48.2 ± 1.42 µg/cm) relative to plain EGZ-suspension (15.9 ± 0.7 µg/cm) in goat nasal mucosa. ENPCG significantly improved cognitive memory in sporadic AD model, as confirmed by behavioural, biochemical, and histopathological assessments in Wistar rats. Pharmacokinetic study in Sprague Dawley rats revealed a 4.5-fold increase in AUC of intranasal ENPCG (30.56 ± 0.45 μg/mL*h) relative to intravenous ENLC (6.73 ± 0.15 μg/mL*h). ENPCG showed 95.31 ± 3.89 % drug targeting potential. Furthermore, a strong point-to-point ex vivo-in vivo correlation (R = 0.9952) was observed, suggesting a non-invasive potential of ENPCG for translating AD interventions.

Mutations in the MAPT gene encoding tau protein can be causative for frontotemporal lobar degeneration, FTLD-tau. Preclinical mouse models expressing these disease-causing MAPT alleles have successfully modeled biochemical and neuropathological phenomena similar to those seen in human FTLD-tau. One such model, rTg4510, features P301L human tau primarily expressed in the forebrain under the control of a Tet-off system, using the CaMKII promoter to drive transgene expression. While this model allows temporal manipulation of the transgenic tau, many experiments do not require such manipulation, and the bigenic tet-off system adds to the costs of simple transgenics, introduces additional genetic variation, and increases animal usage. Here, we have generated and characterized mice that constitutively overexpress P301L human tau under the CaMKII promoter. The initial founder and offspring were produced in the FVB/N background where we identified a line of constitutive "cTau" mice that stably expresses the 0N4R isoform of P301L human tau at levels comparable to the rTg4510 mouse. The cTau line features a relatively small deletion at the transgene insertion site and demonstrates no overt motor phenotype. There was, however, unexpectedly high early lethality on the FVB background that was mitigated after just one crossing to C57BL/6 mice. In both backgrounds, Tau expression resulted in an age-dependent accumulation of tau and gliosis that occur prominently in the forebrain and hippocampus. In transgenic F1 B6/FVB mice, spatial memory deficits were detected by 6 months of age. Overall, this new cTau model recapitulates disease-associated pathology and memory deficits, with limited disruption of the murine genome and a lack of longevity-restricting motor phenotypes. The cTau mouse is a robust, new alternative to existing mouse models of tauopathy.

Alzheimer's disease (AD) is a severe neurodegenerative disorder. With current therapies failing to halt clinical progression, identifying novel disease-modifying therapeutics is of paramount urgency. Although ferroptosis has emerged as a crucial driver of AD pathogenesis, effective pharmacological strategies targeting this pathway remain limited. Bioinformatic analysis revealed close associations among ferroptosis, oxidative stress, the Keap1-Nrf2 pathway, and AD. Compound 4-95, a selective Keap1-Nrf2 protein-protein interaction (PPI) inhibitor, significantly alleviated Erastin and RSL-3-induced ferroptosis in SH-SY5Y and HT-22 cells. In Aβ-treated cell models, 4-95 dose-dependently decreased Aβ and p-Tau expression, while increasing the anti-ferroptotic proteins GPX4 and SLC7A11. Keap1 and GPX4 knockdown verified that 4-95 inhibits ferroptosis via the Keap1-Nrf2-GPX4 axis. In vivo, 4-95 markedly improved cognitive and spatial memory deficits in Aβ-induced AD mice, promoted Nrf2 nuclear translocation, upregulated the downstream antioxidant targets HO-1 and NQO1, and attenuated neuronal injury. Collectively, the study reveals a new mechanism of a Keap1-Nrf2 PPI inhibitor that mitigates AD pathogenesis by directly inhibiting ferroptosis. This novel mechanism underscores a new class of disease-modifying candidates for AD treatment, representing a new therapeutic strategy for this devastating disorder.

ETHNOPHARMACOLOGICAL RELEVANCE: Alpiniae Oxyphyllae Fructus, first documented in Bencao Shiyi, is a classical traditional Chinese herb traditionally used to warm the kidney, invigorate the spleen, consolidate essence and relieve chronic diarrhea. Guided by the TCM theory that kidney essence nourishes brain marrow, modern studies have confirmed its notable neuroprotective and anti-neuroinflammatory activities. BACKGROUND: Neuroinflammation is a key pathological hallmark of Alzheimer's disease (AD), and spleen tyrosine kinase (SYK) serves as a critical signaling regulator. Our previous work confirmed that Alpiniae Oxyphyllae Fructus extract (AE) exerts notable neuroprotection; nevertheless, its blood-brain barrier-permeable components and detailed mechanisms remain poorly clarified. OBJECTIVE: The purpose of this study is to identify the main active components in AE and clarify its mechanism of improving AD pathology by regulating the SYK signaling pathway. METHODS: A preliminary dose-finding study with two AE doses (180 mg/kg, 360 mg/kg) was performed via open field test and inflammatory indexes to select the optimal dose for subsequent experiments. Behavioral assays assessed AE-related neurobehavioral improvements. LC-QTOF-MS/MS identified brain-permeable components, while network pharmacology combined with GEO database analysis screened potential targets and underlying mechanisms. Molecular docking was applied to filter SYK-binding candidates, further validated by molecular dynamics simulation and Cellular thermal shift assay (CETSA). In vivo, a piceatannol-induced SYK inhibition model was established to verify whether the candidate component alleviated LPS-triggered behavioral deficits in mice in a SYK-dependent manner. In vitro, BV2 microglia were used to detect microglial polarization, Aβ phagocytosis and migration through qRT-PCR, glucose/ATP/lactate measurement, wound healing assay and immunofluorescence staining. RESULTS: Chrysin was identified as the primary brain-permeable constituents targeting SYK. In AD mice, it significantly ameliorated cognitive deficits and reduced Aβ accumulation. Mechanistically, Chrysin modulated the SYK/BTK/PLCγ2 and NF-κB axes to trigger a microglial M1-to-M2 phenotypic shift. This phenotypic transition is accompanied by metabolic reprogramming-shifting from glycolysis to oxidative phosphorylation, thereby notably enhancing microglial migration capacity and Aβ phagocytosis. These neuroprotective effects were confirmed to be SYK-dependent. CONCLUSION: Chrysin is the primary brain-permeable constituent of AE. that targets SYK to restore microglial metabolic homeostasis, offering a promising therapeutic strategy for AD.

BACKGROUND: Social and structural determinants of health (SSDH) are key drivers of disparities in cognitive aging and dementia risk, yet their collection in aging and dementia research remains inconsistent. We examined SSDH data collection practices across Canadian longitudinal cohorts of aging and dementia, aiming to identify which SSDH are collected and how they are operationalized. METHODS: We conducted an environmental scan using three sources: (1) literature databases (Cochrane, Embase, Medline, PubMed, and Web of Science), 2) grey literature (e.g., Alzheimer Society of Canada's website), and 3) key informants. We included Canadian longitudinal cohorts of community-dwelling older adults that assessed at least one cognitive or dementia-related outcome, including seven key cohorts previously identified by our group. For each study, we extracted information from data collection instruments on whether specific SSDH were assessed, and which tools were used. RESULTS: From 1043 non-duplicated articles identified through database searches, fourteen unique cohorts met inclusion criteria, eleven of which provided data collection instruments. Five additional cohorts were identified from other sources, and together with 7 pre-identified key cohorts, yielded 23 included cohorts. Disability-related measures and ethnicity- and culture-related constructs were among the most comprehensively assessed domains, whereas literacy, environmental context, and economic conditions were among the least frequently assessed. CONCLUSION: SSDH that shape dementia risk and brain resilience, many modifiable at the community and policy levels, remain unevenly collected in Canadian aging and dementia cohorts. Strengthening and harmonizing SSDH measurement is a critical step toward equitable dementia prevention and reducing health disparities.

The role of the locus coeruleus in aging and neurodegenerative diseases has recently attracted attention. There is growing evidence of changes in the locus coeruleus-norepinephrine system in aging and neurodegenerative diseases, including increased tau accumulation, an inverted U-shaped pattern in the neuromelanin signal, and altered functional connectivity. This review summarizes the research applications and advancements in the study of cognitive aging and dysfunction of the locus coeruleus-norepinephrine system in neurodegenerative diseases. Recent evidence has suggested pathologic protein accumulation, locus coeruleus degeneration, reduced neuromelanin signal, and altered functional connectivity in neurodegenerative diseases in both human and animal models. Notably, the specific regions affected and the severity of these changes can vary subtly among different neurodegenerative disorders. Additionally, recent studies have shown a link between alterations in the locus coeruleus-norepinephrine system and both Alzheimer's and Parkinson's diseases. The possible mechanisms include promoting pathological protein accumulation, pro-inflammatory responses, synaptic plasticity dysfunction, oxidative stress, and blood- brain barrier dysfunction. Advanced experimental technologies have recently been applied to investigate the role of the locus coeruleus-norepinephrine system in aging, Alzheimer's disease, and Parkinson's disease. These advanced technologies, including optogenetic or chemogenetic methods and omics analysis help uncover the effects of specific locus coeruleus activation patterns and the locus coeruleus-related circuit mechanisms underlying its vulnerability during aging and neurodegenerative diseases. Thus, therapies targeting the locus coeruleus-norepinephrine system, including drugs and vagus nerve stimulation, have the potential for clinical application. Many studies have demonstrated the effects of adrenoreceptor-targeted drugs on cognitive function and Parkinson's disease, although some showed no effects. Limited data are available for norepinephrine-targeted drugs, which have demonstrated less-than-ideal results. Recent studies have demonstrated that vagus nerve stimulation can improve cognitive function in Alzheimer's disease and reduce the symptoms of Parkinson's disease, including gait function, suggesting that vagus nerve stimulation could be a new supplementary treatment for neurodegenerative diseases. Overall, the evidence reviewed suggests that the locus coeruleus-norepinephrine system is disrupted during aging and neurodegenerative diseases, and that this disruption can aggravate disease progression. Thus, the locus coeruleus-norepinephrine system is a potential therapeutic target in slowing disease progression. Future studies should focus on the locus coeruleus-norepinephrine system and use advanced experimental and neuroimaging technologies to reveal early pathological alterations and the underlying mechanisms of its vulnerability during aging and neurodegenerative diseases, along with exploring potential therapeutic approaches.

Communication between astrocytes and microglia establishes a basis for maintaining cellular homeostasis, metabolic processes, and injury response in the central nervous system. Activation of astrocytes and microglia is a major initial phase of the response of the organism to pathogenic conditions that facilitate immune response causing neuroinflammation. The neuroprotective effects of neuroinflammation manifest in various contexts, including trauma, aging, and neurodegeneration. However, chronic glial reactivity can become a source of progressive central nervous system damage and suppress neuroprotective functions, ultimately exacerbating neurodegenerative diseases. In this scenario, signal transduction by glial cells, combined with mitochondrial dysfunction, leads to the establishment of a self-sustaining cycle of inflammation and metabolic stress. Modulating glial reactivity, correcting mitochondrial impairments, and targeting immune signaling pathways may offer a potential therapeutic strategy. Such interventions could involve suppressing excessive mitochondrial fission and targeting key molecular pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells, mammalian target of rapamycin, and immune receptors such as triggering receptor expressed on myeloid cells 2. The primary goal of such approach would not be complete suppression of neuroinflammation but rather the restoration of balance between pro-and anti-inflammatory programs, promoting the transition of glial cells toward neuroprotective phenotypes that slow neurodegenerative progression.

The diagnostic efficacy of tau positron emission tomography (PET) relative to amyloid PET in memory clinic settings remains underexplored. In this study, 1008 consecutive Han Chinese individuals with cognitive impairments were recruited between March 2020 and July 2025. They underwent comprehensive clinical assessment, amyloid PET, and tau PET. Diagnostic reclassification, accuracy, and changes in diagnostic confidence were evaluated across cognitive stages and etiologic categories. For Alzheimer's disease (AD) diagnosis, tau PET demonstrated high sensitivity (97.8%) and specificity (95.4%), showing substantial agreement with amyloid PET. Moreover, tau PET provided additional information beyond that offered by amyloid PET alone. In patients clinically diagnosed with non-AD disorders, tau PET led to a significantly higher rate of diagnostic change compared with amyloid PET (p = 0.018). After a diagnosis based on amyloid PET results, the subsequent addition of tau PET information still resulted in a diagnostic change in 10.0% of patients, highlighting its incremental value. Furthermore, tau PET significantly improved diagnostic confidence (from 68.6% to 84.2%), and the confidence gained from tau PET was significantly greater than that from amyloid PET alone within non-AD diseases. Our findings suggest tau PET offers diagnostic performance for AD comparable to that of amyloid PET, while providing additional value in detecting non-AD tauopathies and clarifying complex cases. These observations support the potential for tau PET to complement existing diagnostic workflows in memory clinic settings.

INTRODUCTION: This study evaluated the psychometric properties of the Farsi version of the Saint Louis University Mental Status (SLUMS) examination, marking the first such investigation. METHODS: The sample comprised 200 participants: 75 with normal cognition, 74 with mild cognitive impairment (MCI), and 51 with dementia. Concurrent validity was assessed using the MMSE and NUCOG; divergent validity employed the GDS-15. RESULTS: Exploratory factor analysis showed a unidimensional structure. Internal consistency (Cronbach's α = .719) and test-retest reliability (ICC = .717) were satisfactory. SLUMS correlated highly with MMSE (r = .787) and NUCOG (r = .861), but moderately with GDS-15 (r = -.376). It effectively discriminated dementia from MCI but showed limited ability to differentiate normal cognition from MCI. CONCLUSION: The Persian SLUMS is a suitable screening tool for detecting dementia, though caution is advised when distinguishing MCI from normal cognition.

Hearing impairment has emerged as a consistently associated and potentially modifiable risk factor for cognitive decline and dementia, including Alzheimer's disease (AD). Epidemiological studies demonstrate an increased dementia risk among individuals with hearing loss, with evidence of dose-response relationships across levels of auditory decline. Despite the robustness of this association, the mechanisms linking auditory dysfunction to cognitive deterioration remain multifactorial and incompletely understood. Current evidence points to several interacting pathways, including sensory deprivation and cortical reorganization, increased cognitive load during effortful listening, psychosocial consequences such as social isolation and depression, and potentially overlapping neurobiological processes. Emerging research further suggests that central auditory processing deficits may represent early functional markers of cortical vulnerability associated with neurodegeneration. Clinically, these insights emphasize the importance of routine hearing assessment in older adults and highlight observational evidence indicating that hearing rehabilitation, particularly hearing aid use, may be associated with more favorable cognitive outcomes, although causal effects have yet to be established. By integrating biological, cognitive, and psychosocial perspectives while explicitly addressing persistent uncertainties, this critical narrative review provides a balanced framework for interpreting the relationship between hearing impairment and AD and discusses its implications for prevention and clinical practice. Overall, hearing loss should be regarded as a robustly associated and potentially modifiable marker of dementia risk rather than a confirmed causal determinant. From a neurological standpoint, central auditory dysfunction may therefore reflect underlying brain vulnerability in aging rather than act as a direct causal driver of Alzheimer's disease.

Neurofibrillary tangles, composed of aggregated Tau proteins, are a pathological hallmark of Alzheimer's disease (AD). Within these tangles, the amyloid core is primarily formed by the microtubule-binding (MTB) repeats. Although site-specific acetylation has been implicated in the regulation of Tau aggregation, the atomic-level mechanisms by which individual acetylation events modulate the structure and interactions of amyloid-forming motifs remain incompletely understood. In particular, whether dual acetylation events may act cooperatively during early Tau assembly is still unclear. In this study, we used microsecond-scale all-atom molecular dynamics simulations to systematically examine the dimerization dynamics of the four Tau MTB repeat homodimers (R1-R4). Our simulations suggest that the relatively higher aggregation propensity of R3 and R4 may be associated with amyloidogenic, β-sheet-prone core sequences, in which the key lysine residues K311 and K353 are located. Further analysis indicates that acetylation at these sites attenuates early Tau dimerization: K353 acetylation appears to moderately destabilize the R4 dimer through steric effects and the disruption of intrachain salt bridges, resulting in a more disordered conformational ensemble. K311 acetylation shows a more pronounced inhibitory effect on R3 dimerization by neutralizing the positive charge of K311 and weakening key interchain salt bridges and π-cation interactions associated with the PHF6 motif. Notably, dual acetylation of K311 and K353 in the R3-R4 dimer produces a stronger-than-additive reduction in β-sheet formation. This potential synergistic effect arises from the combined disruption of the hydrophobic core and distal electrostatic interaction networks. In summary, our results provide a molecular-level explanation for how acetylation at K311 and K353 cooperatively modulates Tau dimerization and early amyloid nucleation, offering mechanistic insight into the role of lysine acetylation in Tau aggregation.

Alzheimer's disease (AD) involves early disruptions in brain connectivity, yet how AD risk markers relate to resting-state dynamic functional connectivity (rs-dFC) remains unclear. We examined associations of AD pathology, genetic risk, and blood-based biomarkers (BBMs) of neurodegeneration with local and distant rs-dFC in cognitively normal older adults and explored links with cognitive performance. Baseline data from 86 cognitively normal older adults in the AGUEDA trial (NCT05186090) were analyzed. Participants underwent amyloid-beta (Aβ)-PET, APOE4 genotyping, and plasma BBM quantification (Aβ42/40, BD-tau, GFAP, NfL, p-tau181, and p-tau217). rs-fMRI was used to compute voxel-wise local and distant rs-dFC using a stepwise connectivity framework. Models tested associations between AD markers and rs-dFC adjusting for age, sex, and education; secondary models examined extracted cluster values and six cognitive domains. Aβ-positive individuals and APOE4 carriers showed lower local connectivity in frontal regions. APOE4 carriers also exhibited higher distant connectivity in the superior motor area, inferior frontal gyrus, and anterior insula. Among BBMs, only NfL was associated with both lower local (insula and cingulate) and higher distant (precuneus, putamen, thalamus, supramarginal, and superior motor area) connectivity. Secondary analyses suggested additional cluster-cognition associations. Across AD risk markers, higher risk (Aβ-positivity, APOE4 carriage, and higher NfL) converged on a consistent rs-dFC signature characterized by reduced local and increased distant connectivity. This local-to-distant shift may serve as a candidate functional marker of early AD-related network vulnerability in cognitively normal aging and could support risk monitoring and stratification pending longitudinal validation.

Age acceleration, or the difference between biological and chronological age, is a research area of growing interest, particularly in the field of age-related and neurodegenerative disorders, including Alzheimer's disease (AD). First-generation epigenetic clocks that predict chronological age utilising DNA methylation data were the first to derive estimates of age acceleration, which have been associated with several age-related conditions. More recently, second-generation epigenetic clocks that are predictors of specific traits such as age-related health, disease or morbidity and mortality phenotypes have been developed. These are considered better predictors of health-related traits and show stronger associations with lifespan and mortality than most first-generation clocks. This study aimed to extend on our previous findings of associations of first-generation clocks with hippocampal volume, by investigating the relationship between ten second-generation clocks and brain volumetrics, brain Aβ burden and cognition in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts. Significant associations were found between age acceleration, as estimated by the Principal Components PhenoAge (PCPhenoAge) epigenetic clock, and hippocampal volume in the AIBL study, with replication in the ADNI dataset. Several other significant cross-sectional findings were observed between hippocampal volume and GrimAge, PCGrimAge, PCHorvathS2013, PCHorvathS2018 and PCHannumG2013 and between a DNA methylation-derived estimate of telomere length and change in brain Aβ burden. However, these results were not validated in the ADNI cohort. This investigation of second-generation epigenetic clocks further adds to the body of existing literature on the application of epigenetic clocks in relation to the ageing process and in the development of AD-related traits.

BACKGROUND: Comprehensive geriatric assessment and resilience evaluation are central to modern geriatric care. While geriatricians strongly advocate healthy ageing and prevention, little is known about their own resilience profiles. METHODS: During an international meeting of the European Academy for Medicine of Ageing (EAMA) held in July 2025 in Zeist, the Netherlands, and the 21st EuGMS Congress in Reykjavik, Iceland, we conducted a cross-sectional survey paired with standardized physical and cognitive performance tests. A composite resilience score was derived from standardized handgrip strength (sex-specific), chair stand performance, reaction time, and optimism and was associated with several person- and work-related characteristics in regression models. RESULTS: Ninety-four geriatricians (mean age 45.4 years; 66% women) participated. In age- and sex-adjusted analyses, resilience was lower among geriatricians working in Western and Southern Europe compared with Northern Europe. Poorer electronic health record availability and unbalanced work-life conditions were independently associated with lower resilience. CONCLUSIONS: Even among physicians highly aware of healthy ageing principles, resilience varies meaningfully across regions and working conditions. Organizational and contextual factors appear to matter more than individual lifestyle characteristics, highlighting the need to address physician well-being as part of sustainable geriatric care systems.