UNLABELLED: Gait reflects cognitive function and may serve as a window into cognitive health. This study investigates the relationship between gait speed (GS) and the onset of cognitive impairments. A systematic review and meta-analysis of cohort and longitudinal studies from PubMed, Scopus, and Web of Science (up to July 2024) was conducted. Hazard ratios (HR) were analyzed using R software. Forty studies were included. Slow GS showed an HR of 1.47 (1.19-1.82) for dementia risk. A GS decrement of ≥0.05 m/s resulted in an HR of 2.01 (1.34-3.01). A faster baseline GS was not significantly associated with a reduced risk of dementia (HR 0.97, 0.94-1.01). Subjective GS decrement displayed an HR of 1.74 (1.61-1.87). Declining GS and slower gait performance are significant factors for cognitive impairment. GS may serve as an early indicator for neurocognitive disorders. Regular GS assessments should be embedded into screening programs for older adults to help mitigate cognitive decline. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s40200-026-02073-5.

Alzheimer's disease (AD) is a complex neurodegenerative condition marked by amyloid-β accumulation, tau pathology, and neuroinflammation, while current single-target therapies largely provide symptomatic relief without effectively halting disease progression. Therefore, the rational design and synthesis of novel small molecules capable of simultaneously modulating multiple AD-related targets represent a promising therapeutic strategy. Based on this rationale, novel pyrazoline derivatives were synthesized and their therapeutic potential was evaluated using an integrative computational framework. AD-related genes were retrieved from GeneCards, CTD, and DisGeNET databases, and hub genes were identified through topological and centrality analyses, followed by functional enrichment analyses to explore their biological relevance. Molecular docking was used to evaluate the binding affinities of the synthesized compounds toward the identified hub targets, while 3D-QSAR modeling was used to predict their inhibitory potential. A total of 63 common genes were identified across the three databases, with APOE, BACE1, and CSF1R emerging as key hub genes. Enrichment analysis revealed their involvement in PI3K-Akt, mTOR, NF-κB, TNF, AMPK, and FoxO signaling pathways associated with amyloid processing, tau pathology, and neuroinflammation. Among the evaluated compounds, compound 2a exhibited the strongest binding affinities toward the hub targets along with favorable drug-likeness, pharmacokinetics, toxicity, and promising IC values (226-336 nM). The 3D-QSAR models showed high predictive reliability (R = 0.93-0.96; Q = 0.94-0.95). These findings highlight APOE, BACE1, and CSF1R as key therapeutic targets and identify compound 2a as a promising multi-target lead candidate for additional experimental validation in AD.

INTRODUCTION: Venous blood collection through phlebotomy is critical for biomarker development and genetics research on Alzheimer's disease (AD) and related dementias. In this research setting, phlebotomy is often performed by clinical research coordinators (CRCs) rather than professional nurses or phlebotomists. Even though phlebotomy in older adults with cognitive impairment can be empirically challenging, data on the factors associated with phlebotomy failure in this special population are lacking. We addressed this question in the Massachusetts Alzheimer's Disease Research Center (MADRC) Longitudinal Cohort. METHODS: We applied mixed-effects logistic regression with phlebotomy failure as the dependent variable; age at visit, sex, education, body mass index (BMI), under-represented minority (URM) status, and Clinical Dementia Rating (CDR) scale global score as fixed effects; and participant ID as a random effect to account for multiple visits per participant. RESULTS: Full data were available for a total of 1365 visits from 659 individual participants (average 2.1 visits/participant, range 1-7). Greater BMI (odds ratio [95% confidence interval]: 1.10 [1.05-1.16], < 0.001) and CDR global score (1.51 [1.13-2.03], = 0.005), but not age, sex, or education, were independently associated with higher odds of phlebotomy failure. URM participants had twice the odds of a phlebotomy failure compared to non-Hispanic Whites, although this trend did not reach statistical significance due to insufficient power (2.07 [0.97-4.41], = 0.059). DISCUSSION: Greater BMI and CDR as well as URM status are independently associated with higher odds of phlebotomy failure. Potential strategies to maximize participation of these subpopulations in biomarker and genetics research are discussed.

Vascular dementia (VaD), the second most common form of dementia, lacks approved disease-modifying therapies. White matter injury and demyelination are major pathological features, and oligodendrocyte-lineage damage directly limits myelin repair. M2-associated microglial responses regulate inflammation, clear cellular and myelin debris, and support oligodendrocyte differentiation and maturation. Single-cell studies, however, have exposed the limitations of the classical M1/M2 dichotomy in brain disease. In this review, M2a-, M2b-, and M2c-like states are interpreted based on experimentally specified inducing conditions and concordant molecular or functional evidence. We examine how these programs relate to oligodendrocyte injury, myelin loss, and white matter repair in VaD. with particular attention to their potentially stage-dependent contributions. Integrating these findings may inform the timing and functional focus of future interventions aimed at preserving oligodendrocyte function and promoting white matter repair in VaD.

BACKGROUND: In Huntington's disease (HD), clinical heterogeneity in age at onset and disease progression poses demands on precision medicine approaches. Biofluid biomarkers are needed to monitor disease progression, but may also provide insights into pathogenic mechanisms and support the development of disease-modifying therapies (DMTs). OBJECTIVE: To identify dysregulated cerebrospinal fluid (CSF) proteins in HTT gene expansion carriers (HDGECs), and to evaluate their relationship with disease progression. METHOD: CSF was collected from a discovery and a validation cohort, both comprising HDGECs and neurologically unaffected controls (HCs). A total of 734 proteins were quantified using a high-sensitive Proximity Extension Assay (PEA) (Olink Neuro Explore panel 1 and 2). Protein association with disease progression was evaluated using the composite Unified HD Rating Scale (cUHDRS). Disease stage was classified according to the HD Integrated Staging System (HD-ISS). RESULTS: In total, samples included HDGECs (n=61), HCs (n=54), and longitudinal HDGEC samples (n=21). Sixteen proteins were nominally dysregulated in HDGECs vs. HCs. Most pronounced was a twofold decrease of TNFRSF8 (sCD30) in HDGECs, and longitudinally declining levels were found. TNFRSF8 correlated significantly with cUHDRS, after adjustment for age, sex, and CAG. Levels of TNFRSF8 were similarly reduced in the validation cohort, and correlated with Total Functional Capacity (TFC). CONCLUSION: TNFRSF8 recently emerged as a biomarker of neuroimmune dysfunction in HD. The results indicate and confirm that it is highly dysregulated in HDGECs and also tracks clinical disease progression. This pathway may be a promising potential target for DMTs.

High calorie-high fat diet (HFD) has been implicated as a pathological modifier of brain diseases including neurodegenerative dementias, but the detailed molecular mechanisms remain largely unknown. Here we report that HFD suppresses PPARγ-mediated transcriptional expression of PQBP1, a RNA splicing factor implicated in human intellectual disability and Alzheimer's disease. RNAseq-based comprehensive analyses of alternative RNA splicing (AS) in HFD-fed mice for 1 or 6 weeks and in PQBP1-cKO mice reveal their common changes, which weigh on synapse-related genes. Betweenness-based extraction of core molecules from the common changes reveals CASK, Cacnb1 and Cyfip2 as key molecules of the network. Both CASK and Cacnb1 regulate STXBP1, a causative gene for infantile epilepsy syndrome and an essential factor for synapse vesicle release, via their direct interaction. In addition, our analysis suggests that Syt1 plays a role specifically in HFD for 1 week. HFD-induced AS isoforms of CASK, Cacnb1, Cyfip2 and Syt1 impair pre-synapse vesicle release in primary neurons. AAV-PQBP1, AAV-CASK, AAV-Cacnb1, AAV-Cyfip2 or AAV-Syt1 rescues synapse and/or cognitive dysfunctions in HFD mice, genetically supporting the pathological PQBP1-presynapse axis in HFD. Moreover, immunohistochemistry experiments suggest that the pathological axis plays roles not only in excitatory neurons, but also in inhibitory neurons of the brain. Collectively, our results unravel a novel molecular mechanism for brain dysfunction when mice are exposed to a HFD.

BACKGROUND: This study characterised overall transdiagnostic associations between psychological and behavioural symptoms and carer burden, and examined syndrome-specific contributions across clinically probable FTLD and AD groups. METHODS: A total of 432 individuals with clinically probable FTLD and AD were included. The primary analytic cohort comprised 358 participants with complete carer burden data, including 230 and 128 individuals in the FTLD and AD diagnostic groups, respectively. Behavioural and psychological symptoms were assessed using the Cambridge Behavioural Inventory-Revised (CBI-R). Carer burden was measured with the Zarit Burden Interview (ZBI). Longitudinal CBI-R and ZBI data were analysed in 172 participants with available ZBI data at both baseline and follow-up (mean interval ≈ 1 year). RESULTS: Behavioural rigidity (standardised β = 0.15, 95% CI [0.03, 0.28], p = 0.015) and apathy (standardised β = 0.14, 95% CI [0.02, 0.26], p = 0.020) showed the strongest associations with carer burden overall. Behavioural rigidity was salient in the FTLD group (standardised β = 0.18, 95% CI [0.02, 0.33], p = 0.024), whereas apathy (standardised β = 0.26, 95% CI [0.04, 0.47], p = 0.021) and abnormal behaviour (standardised β = 0.26, 95% CI [0.05, 0.48], p = 0.018) were salient in the AD group. Longitudinal increases in mood-related symptoms (standardised β = 0.24, 95% CI [0.001, 0.48], p = 0.048) predicted greater carer burden at follow-up. CONCLUSIONS: Our findings highlight the relevance of symptom-focussed strategies for managing carer burden across dementia syndromes. Group-specific analyses suggest prioritising behavioural rigidity in FTLD syndromes and apathy and abnormal behaviour in AD subtypes, while timely management of changes in mood symptoms may help alleviate carer burden over time.

BACKGROUND: Artificial intelligence (AI)-based voice and speech analysis is emerging as a promising, noninvasive biomarker for Alzheimer's disease (AD) and mild cognitive impairment (MCI). This study aimed to systematically review AI voice and speech models for detecting AD and MCI, and to evaluate their translational potential. METHODS: Following PRISMA guidelines, two investigators searched PubMed, Scopus, and the Cochrane Library for studies reporting diagnostic and prognostic outcomes of AI voice and speech models in AD and MCI. Data were extracted from studies applying machine learning (ML) or deep learning (DL) to human speech with quantitatively reported, clinically interpretable outcomes. Methodological quality and risk of bias were formally appraised using the PROBAST and CLAIM tools. RESULTS: Sixty-three studies were included. Of the 18,540 participants, there were 8,044 patients (mean age: 73.1 years), 9,736 controls (mean age: 67 years), and 760 with unspecified dementia diagnoses. There were 9,571 females and 8,341 males (628 unspecified). Most reported high diagnostic performance for distinguishing AD from healthy controls using prosody (n = 41), temporal (n = 38), spectral (n = 35), and linguistic (n = 21) measures, frequently achieving areas under the curve greater than 0.80. In contrast, MCI was less reliably distinguished from normal aging. AI-based speech analysis thus represents a promising and scalable digital biomarker, but the current evidence base remains heavily constrained by small, single-center datasets and a widespread lack of external validation. CONCLUSION: AI-driven speech analysis holds significant potential for the early detection of cognitive decline. However, its clinical translation is currently limited by methodological bias. Future validation efforts must shift toward large-scale, multicenter, longitudinal studies with standardized speech assessments.

BACKGROUND: Type 2 diabetes (T2DM) and cognitive impairment are common long-term chronic conditions affecting older people in hospital. Cognitive impairment can complicate glucose monitoring and lead to diabetes-related emergencies in T2DM. Traditionally, point of care test measurements of capillary blood glucose are conducted in-hospital for T2DM while continuous glucose monitoring (CGM) is not widely used. AIM: To understand the feasibility, acceptability and tolerability of using CGM in older inpatients with T2DM and cognitive impairment. METHODS: 32 older people (mean age=78.7±6.7 years) with comorbid T2DM and cognitive impairment (Abbreviated Mini-Mental Test ≤8/10 and Mini-Addenbrooke's Cognitive Examination ≤22/30) were recruited within a tertiary care hospital in the UK. All participants were naive to CGM and were asked to wear blinded Dexcom G7 sensors for up to 10 days. Participants were asked about feasibility, acceptability and tolerability questions at the point of sensor removal. RESULTS: 29 participants (96%) reported no pain during CGM fitting. All participants (100%) agreed that they did not notice wearing the sensor, and it did not affect their day-to-day hospital activities. All participants (100%) found it 'very easy' or 'easy' to have the sensor fitted and wearing it for 10 days, with 27 participants (90%) finding CGM convenient. 17 participants (57%) reported favourable perceptions of the subcutaneous sensor sensation. CONCLUSION: CGM use in older inpatients with T2DM and cognitive impairment is highly feasible and acceptable for patients. Future studies and trials are now needed to evaluate the clinical use of CGM for glucose monitoring in hospitalised or community-dwelling older individuals with T2DM and cognitive impairment.

OBJECTIVE: Home-based primary care has been suggested to reduce emergency department visits among vulnerable older adults but how it should be organised to achieve this effect is unclear. This study aimed to increase the understanding of how older adults receiving home-based primary care and their family caregivers' experience care during the period prior to an emergency department visit and to identify components of home-based primary care delivery that could help reduce such visits. DESIGN: Qualitative study using semi-structured interviews with older adults receiving home-based primary care who had recently visited the emergency department, along with their family caregivers. Interviews were analysed using inductive thematic analysis. SETTING: Interviews were conducted in the homes of informants receiving home-based primary care in Region Stockholm, Sweden, 2022-2023. PARTICIPANTS: Fourteen adults aged ≥65 years receiving home-based primary care who had visited an emergency department within the past 3 months were interviewed; seven interviews also included a family member. RESULTS: An overarching theme, , describes how patient trust-in home-based primary care in general and in specific individual healthcare professionals-seems important in reducing emergency department visits, especially when patients experience symptoms of uncertain urgency or gradual onset. Four subthemes describe how primary care may build trust: through (1) access to care, (2) medical competence, (3) respect and relationship and (4) coordination and teamwork. CONCLUSION: Trust in both home-based primary care in general and in individual healthcare professionals is crucial in reducing emergency department visits among older adults receiving home-based primary care. Trust may be strengthened by accessible and competent care, familiarity with both general practitioners and the responsible nurse and working as a collaborative team.

Chronic microglial activation and the resulting neuroinflammatory cascade drive Alzheimer's disease (AD) progression. Systemic lipopolysaccharide (LPS) triggers robust microglial responses and is linked to neurodegenerative disorders, yet the full spectrum of neuroinflammatory and neuronal changes associated with chronic peripheral endotoxemia remains incompletely characterized. We hypothesized that sustained peripheral endotoxemia establishes a neuroinflammatory environment characterized by microglial activation, mitochondrial dysfunction, and neuronal apoptosis, accompanied by amyloid precursor protein (APP) accumulation. We analyzed public transcriptomic datasets for inflammatory signatures associated with LPS exposure in BV2 microglia (GSE18740) and mouse brain tissue (GSE3253). HT22 neurons were exposed to conditioned medium from LPS-stimulated BV2 cells, and apoptotic markers were measured. Adult rats received repeated systemic LPS injections over six months to model chronic endotoxemia; brain sections were then analyzed by immunohistochemistry for CD68 (microglial activation), cleaved caspase-3 (apoptosis), and App. Inflammatory-related pathways were consistently upregulated across datasets. Conditioned medium from activated microglia increased neuronal apoptosis. Both LPS-treated microglial cells and HT22 neurons cultured with BV2-conditioned medium exhibited increased reactive oxygen species production and reduced mitochondrial membrane potential. The endotoxemia model exhibited cortico-hippocampal microgliosis, elevated cleaved caspase-3, and App accumulation. These results support the hypothesis that peripheral endotoxemia probably propagates microglial hyperactivation, which subsequently promotes neuronal apoptosis and App accumulation. Whether modulation of the inflammation-related pathways identified here can attenuate this microglia-mediated neurodegeneration warrants dedicated investigation.

Influenza vaccination may confer benefits that extend well beyond seasonal protection against respiratory infection: reduced cardiovascular morbidity and mortality, lower dementia incidence, fewer cardio-renal complications, improved survival in the very old, and emerging signals in oncology and diabetes. Although vulnerable to confounding and evidence in adults aged ≥75-80 years and in frail populations remains scarce, their magnitude, cross-organ consistency and apparent dose-response suggest that protection is not explained solely by prevention of infection, but points to a shared upstream mechanism: modulation of chronic inflammation. Recent single-cell multiomic studies provide a plausible substrate: inactivated influenza vaccine induces persistent epigenetic remodelling in monocytes and myeloid dendritic cells, lasting up to six months,and, consistent with a regulatory recalibration of innate reactivity, termed trained tolerance. This myeloid axis is also central to inflammaging, whose clinical expression in older people is frailty. We review multiomic, preclinical and epidemiological evidence supporting a framework in which influenza vaccination may exert effects beyond pathogen-specific protection. Murine models provide causal evidence that vaccination can modify vascular, neurodegenerative and tumour pathology through systemic immune mechanisms. We position these findings alongside heterologous effects of other vaccines and examine their relevance to chronic inflammation. Although innate immune reprogramming involves pathways shared with inflammaging, a direct effect on chronic low-grade inflammation remains unproven. Key uncertainties including healthy-vaccinee bias, the absence of frailty stratification and the age discordance between mechanistic and clinical evidence are discussed.

Resilience has become an integral component of theory and research in brain aging. Recent frameworks have provided guidelines for identifying and investigating resilience in the context of diversity (e.g., sex and risk exposure differences). We leverage a multi-factorial longitudinal approach to operationalize and predict pathways of resilience, stability and vulnerability as a function of differential within-person trajectory patterns of hippocampal volume and cognitive change. Participants included cognitively unimpaired (at baseline) older adults (n = 415; M age = 74.9; 59.9% Female) from the Alzheimer's Disease Neuroimaging Initiative with longitudinal imaging and cognition data, plus multimodal risk indicators. We used latent class growth analyses to identify hippocampal and cognitive trajectory classes. Machine learning applications identified risk indicators associated separately by pathway in the entire sample and disaggregated by sex. Based on differential combined class membership, we identified three subgroups: resilience (declining hippocampal/stable cognitive trajectories), stable (stable hippocampal/stable cognitive trajectories), vulnerable (stable hippocampal/declining cognitive trajectories). Leading risk indicators of resilience (e.g., lower plasma Aβ1-42) and vulnerability (e.g., lower education) originated from the biological and demographic domains. Leading risk indicators of stability originated from the biological and genetic domains (e.g., higher CSF Aβ1-42, lower polygenic hazard score). Sex-disaggregated results highlighted indicators unique to the females, such as higher body mass index (stability) and lower geriatric depression score (stability, vulnerability). Pathway patterns of resilience, stability and vulnerability were characterized objectively in initially cognitively unimpaired older adults based on specified hippocampal and cognitive trajectory combinations. Risk factors from a broad range of modalities should be considered in future research.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and is characterized by progressive cognitive decline, cholinergic dysfunction, oxidative stress, and neuroinflammation. Despite extensive research, effective disease-modifying therapies remain unavailable. 6-Hydroxyflavanone (6-OH-F), a naturally occurring flavonoid with antioxidant and anti-inflammatory properties, has not been investigated in AD. This study evaluated the neuroprotective potential of 6-OH-F against amyloid-β (Aβ)-induced AD pathology. Network pharmacology was employed to identify potential targets and pathways associated with 6-OH-F in AD. Neuro-2a cells were pretreated with 6-OH-F (12.5-50 μM) before Aβ exposure, followed by assessment of cell viability, reactive oxygen species (ROS), acetylcholinesterase (AChE), NLRP3, TNF-α, and IL-1β levels. AD was induced in mice by intracerebroventricular administration of pre-aggregated Aβ. Animals received 6-OH-F (15, 30, or 60 mg/kg, p.o.) for four weeks. Behavioral, biochemical, molecular, imaging, and histopathological analyses were subsequently performed. Network pharmacology revealed significant overlap between 6-OH-F targets and AD-associated genes, with enrichment of pathways related to neuronal function and inflammation. In vitro, 6-OH-F attenuated Aβ-induced cytotoxicity and reduced ROS, AChE, NLRP3, TNF-α, and IL-1β levels. In vivo, 6-OH-F improved cognitive performance, alleviated oxidative stress and cholinergic dysfunction, and suppressed the expression of TLR4, pNF-κB, NLRP3, ASC, caspase-1, GSDMD, pro-inflammatory cytokines, IBA1, and GFAP. Furthermore, it reduced neuronal degeneration, blood-brain barrier disruption, and cerebral hemodynamic abnormalities. 6-OH-F ameliorates Aβ-induced cognitive impairment by attenuating oxidative stress, neuroinflammation, and pyroptotic signaling, potentially through modulation of the TLR4/NF-κB/NLRP3 pathway, highlighting its therapeutic potential in Alzheimer's disease.

Growing evidence demonstrates that olfactory dysfunction and disease-related pathology in the olfactory areas occur early in Alzheimer's disease (AD), which is the most common neurodegenerative disorder. Oxidative stress is strongly linked to AD-associated changes in the brain, yet very little is known about redox homeostasis in the peripheral olfactory tissues, and its link to olfactory dysfunction associated with early AD. The olfactory mucosa (OM), located at the rooftop of the nasal cavity is the primary organ for olfaction through odorant detection and transmission of these signals to the brain via the olfactory nerves. This study collected patient-derived biopsies of the OM from cognitively healthy donors, individuals with mild cognitive impairment (MCI) and AD. Shotgun proteomics of the biopsies provided new insights into the molecular mechanisms associated with early AD and olfactory dysfunction, which was assessed by odor identification testing. Furthermore, microRNA sequencing and quantitative analyses of electron carriers, cofactors and glutathione from the biopsy-derived primary cells of the OM were used to link these findings to cellular redox status. The results revealed mitochondrial changes and alterations to cellular defense against oxidative stress, specifically the potentially dampened NRF2 pathway, in MCI and AD OM, which were linked to impairments in odor identification. Understanding the early cellular and molecular changes occurring in the olfactory system and olfaction could aid in the early identification of individuals at risk of developing AD and pathophysiological changes of the OM in AD.

The inhibitory microglial receptor LILRB4 (ILT3) suppresses amyloid-β (Aβ) clearance in Alzheimer's disease (AD) through ApoE-dependent signaling. Here, we report an independent artificial intelligence-guided approach for discovering small-molecule inhibitors of the LILRB4-ApoE interaction. Ultralarge-scale screening of approximately 500 million compounds identified chemically distinct molecules that bind LILRB4 with nanomolar affinity and inhibit ApoE engagement, as validated using orthogonal biophysical and biochemical assays. Structural modeling and mutational analysis defined an interdomain pocket and key residues associated with ligand recognition. In human induced pluripotent stem cell-derived microglia, compound 4 reduced SHP1/2 phosphorylation, attenuated NF-κB activation and IL-1β secretion, and restored Aβ uptake without compromising cell viability. The compound exhibited oral bioavailability and brain penetration. In male and female 5xFAD mice, once-daily oral administration improved Y-maze performance and reduced regional Aβ42 levels, inflammatory cytokines, and CD86-positive microglia. These findings establish retrieval-based artificial intelligence as a complementary route to LILRB4 ligand discovery and identify compound 4 as a pharmacologically differentiated candidate for further optimization.

BACKGROUND: The MIND diet supports healthy cognitive aging. Yet, a challenge remains to identify individuals who do not adhere to the MIND and could be at risk for accelerated cognitive decline. A multi-metabolite biomarker panel could facilitate population screening. OBJECTIVES: To determine and validate a blood metabolomics signature of MIND adherence in a large cohort of older adults, and to estimate its association with subsequent cognitive decline. DESIGN, SETTING AND PARTICIPANTS: Participants were older adults (≥65 years) from the population-based three-City (3C) cohort, free of dementia at study baseline and followed for up to 12 years for cognition, who were included in two case-control samples on cognitive decline nested within two centers (Bordeaux and Dijon cities, n = 838). EXPOSURES: 155 diet-related serum metabolites measured with a multianalyte metabolomics platform. MAIN OUTCOMES AND MEASUREMENTS: The primary outcome was adherence to the MIND diet, assessed in a subsample of 344 participants from Bordeaux center (which underwent the dietary surveys, 24 h recall and food-frequency questionnaire). A metabolomics signature of MIND diet adherence was characterized with penalized regression and a metabolomics score ("metaboscore") reflecting the overall MIND biological fingerprint was calculated. The secondary outcome was cognitive decline status (coded as binary: accelerated, vs. null or minimal decline) over follow-up, assessed using repeated cognitive measures in the two case-control samples. The metaboscore was reconstructed and linked to the odds of cognitive decline. RESULTS: Eight metabolites were identified: three were associated with higher MIND adherence (3-hydroxyhippuric acid, 5-hydroxyindole-3-acetic acid, betaine - phenolic acids and amino acid related to plant foods) and five with lower MIND adherence (1-methylhistidine from red meat; cyclo(L-leucyl-L-prolyl) from coffee; tartaric acid from wine; myristoyl-carnitine and dehydroepiandrosterone sulfate, endogenous). The French-MIND metaboscore was linked to lower odds of cognitive decline, although replication was not statistically significant after multivariable adjustment. CONCLUSION: A novel metabolomic signature of the MIND diet was characterized, which may help screen older adults at risk of poor brain nutrition and could support personalized dietary prevention strategies.

BACKGROUND: While global frameworks highlight modifiable risk factors for cognitive decline, evidence on how these risks affect diverse populations remains limited. This study determines the prevalence of probable and possible dementia, identifies primary predictors, and investigates risk variations across racial and ethnic groups in a nationally representative sample. METHODS: Using a sample of 7,574 older adults from the 2023 National Health and Aging Trends Study (NHATS), cognitive status was classified as probable, possible, or no dementia. Survey-weighted multinomial logistic regression models with interaction terms examined conditional effects of age, health conditions, and sensory corrections across demographics. RESULTS: Advanced age, low education, stroke, falls, and depression/anxiety were associated with higher Odds of possible and probable dementia (Prb-D), while female, vision and hearing aid use lowered Prb-D odds. Hispanic adults aged 85 and older faced a 60.2% predicted probability of Prb-D, compared to 35.1% for Non-Hispanic (NH) White adults. Low education disproportionately increased Prb-D prevalence, especially among Hispanics. Among hearing aid users, NH White and NH Black adults showed lower of Prb-D probability than non-users, whereas Hispanic users showed a higher probability. Chewing or swallowing problems severely escalated Prb-D probability for Hispanic adults (42.2%) compared to NH Whites (19.3%), and depression doubled the overall risk of Prb-D. CONCLUSION: The burden of cognitive decline is deeply unequal, proving standardized interventions insufficient for minority older adults. Addressing these disparities necessitates culturally responsive care pathways and the elimination of structural barriers, particularly inadequate insurance coverage for audiology and dental services.

BackgroundNon-pharmacological interventions are increasingly used as complementary strategies for Alzheimer's disease (AD), yet their comparative effects on cognitive outcomes remain insufficiently defined.ObjectiveTo compare and rank the cognitive effects of different non-pharmacological interventions in patients with mild-to-moderate AD.MethodsRandomized controlled trials of non-pharmacological interventions for mild-to-moderate AD were searched in MEDLINE, PubMed, Embase, Web of Science, and the Cochrane Library from inception to May 2026. Eligible studies reported cognitive outcomes, including the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), or Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Risk of bias was assessed using the Cochrane tool, and certainty of evidence was evaluated with GRADEpro. Bayesian network meta-analysis was conducted in R using gemtc. The surface under the cumulative ranking curve was used to estimate intervention rankings.ResultsFifty randomized controlled trials involving 2856 participants and 11 categories of interventions were included. Among participants with available baseline age data, the weighted mean age was approximately 75 years; among those with available sex information, 1410 participants were female (54.0%). Dual-task training ranked first for MMSE (SUCRA = 88.84%) and MoCA (SUCRA = 90.67%). Transcranial direct current stimulation (tDCS) also showed favorable rankings for MMSE (SUCRA = 85.69%) and MoCA (SUCRA = 75.63%). For ADAS-Cog, repetitive transcranial magnetic stimulation (rTMS) ranked highest (SUCRA = 85.22%) and was the only intervention showing significant improvement compared with usual care.ConclusionsDual-task training and tDCS showed relatively consistent advantages on global cognitive screening outcomes in mild-to-moderate AD. rTMS showed the clearest benefit for ADAS-Cog, but this finding requires cautious interpretation.

BackgroundThe choroid plexus (CP) is involved in cerebrospinal fluid production, immune surveillance, and brain fluid homeostasis. CP enlargement has been linked to neuroinflammation, glymphatic dysfunction, and white matter lesion (WML) burden, but the mechanisms underlying these associations remain uncertainObjectiveTo investigate the relationships among CP volume, glymphatic function estimated using diffusion tensor imaging along the perivascular space (DTI-ALPS), WML burden, and global cognitive performance in individuals with suspected neurodegenerative conditions, and to assess whether DTI-ALPS mediates the association between CP enlargement and white matter damage.MethodsWe retrospectively analyzed 104 participants, including 63 individuals with neurodegenerative conditions and 41 without neurodegeneration, who underwent multimodal MRI with 3D-T1-weighted, 3D-FLAIR, and diffusion-weighted sequences. CP volume was segmented using ASCHOPLEX and normalized to total intracranial volume. DTI-ALPS indices were derived from diffusion imaging, WML burden was quantified by automated segmentation, and global cognition was assessed using the Mini-Mental State Examination. Associations were tested using linear and quantile regression models. Mediation analysis evaluated indirect effects through DTI-ALPS.ResultsGreater CP volume was associated with lower DTI-ALPS values and higher WML burden. DTI-ALPS partially mediated the relationship between CP volume and WML burden, although the magnitude of mediation was modest. No significant mediation effect was observed for global cognitive performance. DTI-ALPS also showed strong associations with white matter integrity metrics, suggesting possible sensitivity to non-glymphatic microstructural changes.ConclusionsCP enlargement is associated with reduced DTI-ALPS and greater WML burden, but the contribution of glymphatic impairment remains uncertain. Alternative mechanisms, including neuroinflammation, blood-brain barrier dysfunction, and white matter microstructural damage, may contribute to these findings.

PURPOSE: To investigate whether urinary tract infection (UTI) diagnoses assigned in the emergency department (ED) were true UTI infections, characterize hospitalized UTI patients, and analyze the 12-month mortality and institutionalization rates. METHODS: A retrospective study among older adults (75+) who were admitted to the ED in 2017 and diagnosed UTI by the ED physician. Patients were categorized into four groups based on the level of UTI diagnosis and the follow-up treatment location: discharged cystitis, hospitalized cystitis, discharged pyelonephritis, and hospitalized pyelonephritis. Group differences were analyzed using Chi-squared, Fisher´s exact, or Mann-Whitney U tests. Logistic regression adjused for confounders was used to compare symptoms. Kaplan-Meier and Cox regression analyses were applied to asses mortality and institutionalization during the 12-month follow-up. RESULTS: Of 658 ED-diagnosed UTIs, only 354 (54%) had significant bacterial growth in urine cultures. Nevertheless, antibiotics were prescribed in 98% of cases. Institutionalization was significantly higher among hospitalized (31%) than among discharged (11%) cystitis patients (log-rank test, p < 0.001); age, Carlson Comorbidity Index and frailty adjusted HR=2.72, 95% CI 1.62-4.55, p < 0.001). Interestingly, hospitalized cystitis patients had higher institutionalization rates (31%) than hospitalized pyelonephritis patients (15%) (log-rank test, p = 0.003; age and gender adjusted HR=0.52, 95% CI 0.31-0.87, p = 0.014). CONCLUSIONS: In ED UTIs are frequently overdiagnosed in older adults, often masking more complex underlying conditions. Because a hospitalization for cystitis serves as a major red flag for institutionalization within a year, these patients require an urgent comprehensive geriatric assessment rather than just a standard infection diagnosis.

BACKGROUND: Executive functions are entangled with language production, particularly during word retrieval. Verbal fluency and action naming tasks are widely used to assess both executive control and lexical access in brain disorders. AIM: To provide updated Italian norms for a set of brief language-executive tests, including Phonemic Verbal Fluency (PVF), Semantic Verbal Fluency (SVF), Alternate Verbal Fluency (AVF), Verb Verbal Fluency (VVF) and a short form of the Action Verb-Naming Test (AVNT-SF). METHODS: A sample of 317 Italian healthy adults (195 females; age range = 40-89 years; education range = 5-23) underwent the abovementioned set of tests. For the PVF and SVF, we considered three scores: the number of words produced in 1', in the first 30", and in the last 30". Regression-based norms were derived via the Equivalent Score method. The association between these measures was examined with correlations. RESULTS: Age and education significantly predicted performance across all measures, while sex only affected the SVF. Fluency measures were highly and positively related to each other (strong correlations), whereas correlations between the AVNT-SF and fluency tasks were weaker - albeit significant. CONCLUSION: The study provides updated Italian norms for a set of tests assessing lexical access and executive functioning to be employed in clinical practice and research.

INTRODUCTION: Explore association between a weighted social determinants of health (SDOH) score and incident dementia in adults with and without type 2 diabetes (T2D). METHODS: Among 10,071 UK Biobank adults with T2D and 11,780 euglycemic individuals, SDOH indicators were weighted using elastic net and categorized as favorable, medium, or unfavorable. Sex- and T2D-stratified associations with incident dementia were estimated using multivariable Cox models and validated in All of Us. RESULTS: Over 14 years of follow-up in UKB, 247 T2D and 149 euglycemic participants developed dementia. In T2D, higher SDOH score was significantly associated with increased risk of all-cause dementia. Comparing unfavorable vs. favorable SDOH, hazard ratios (HRs) were 2.4 (95% CI: 1.7-3.6) overall, 1.7 (1.1-2.6) in men, and 5.4 (2.0-13.9) in women (interaction p 0.009). In euglycemic, corresponding HRs were 2.4 (1.4-3.8) overall, 2.4 (1.3-4.3) in men, 2.9 (0.9-8.9) in women. Stratified by SDOH category, T2D (vs. euglycemia) was significantly associated with higher dementia risk in the unfavorable/medium SDOH group: 2.9 (1.8-4.6) in all,1.7 (0.8-3.6) in men, and 3.1 (1.1-8.7) in women. CONCLUSIONS: Adverse SDOH was associated with higher dementia risk, with stronger T2D-related risk among medium/unfavorable SDOH groups, especially in women with T2D.

PURPOSE: Matrix metalloproteinases (MMPs) regulate extracellular matrix remodeling and are implicated in neurodegeneration and brain ageing. Tissue inhibitor of metalloproteinase-2 (TIMP2) has been associated with hippocampal plasticity and cognitive function. We investigated whether cerebrospinal fluid (CSF) TIMP2 levels and genetic variants are associated with clinical features in Parkinson's disease (PD) and its continuum with dementia with Lewy bodies (DLB), with a particular focus on ageing-related processes. METHODS: CSF TIMP2 levels were analyzed in 480 patients with PD, 67 patients with DLB and 16 control participants. PD patients were stratified by GBA1 mutation status. Cross-sectional analyses included clinical scales and established CSF biomarkers (β-amyloid 1-42, h-TAU, p-TAU, neurofilament light chain (NfL) and α-synuclein). Longitudinal analyses assessed cognitive impairment and motor progression using TIMP2 tertiles and selected single nucleotide polymorphisms (SNPs) within the TIMP2 gene. RESULTS: CSF TIMP2 levels were positively associated with age and correlated with markers of neurodegeneration. Higher levels were observed in male PD patients compared to females and in female DLB GBA1 patients compared to controls. TIMP2 levels were not significantly associated with incidence or time to cognitive impairment. Higher TIMP2 levels were linked to increased postural instability in PD GBA1 patients. Exploratory genetic analyses suggested that specific SNPs (rs1384364, rs8068674) were associated with more favorable cognitive outcomes or delayed motor progression. CONCLUSIONS: CSF TIMP2 levels primarily reflect ageing-related processes associated with neurodegeneration rather than disease-specific effects. Genetic variation in TIMP2 may contribute to clinical heterogeneity. These findings support a role of extracellular matrix-related ageing mechanisms in PD and related disorders.