@article {pmid42522369,
year = {2026},
author = {Hackshaw, KV},
title = {Central sensitization syndromes as a neuropsychiatric risk state for dementia: Clinical and epidemiologic perspectives.},
journal = {CNS spectrums},
volume = {31},
number = {1},
pages = {e29},
doi = {10.1017/S1092852926101114},
pmid = {42522369},
issn = {2165-6509},
support = {R61/R33 NS117211/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *Dementia/epidemiology ; *Central Nervous System Sensitization/physiology ; Sleep Wake Disorders/epidemiology ; Risk Factors ; },
abstract = {Dementia prevention increasingly targets modifiable midlife risk states contributing to neurodegenerative vulnerability. While vascular and metabolic factors are established, a substantial proportion of risk remains unexplained. Central sensitization syndromes (CSS)-chronic conditions characterized by neural amplification-are highly prevalent, co-occur with depression and sleep disturbance, and involve neuroimmune and network-level mechanisms implicated in early Alzheimer's disease. To synthesize epidemiologic evidence linking CSS with incident dementia and evaluate competing causal explanations, including shared vulnerability, reverse causation, and medication-related confounding. A structured narrative review was conducted of longitudinal cohort and meta-analytic studies assessing incident dementia across CSS-related conditions. Multiple CSS-including migraine, fibromyalgia, irritable bowel syndrome, restless legs syndrome, and PTSD disorder-are associated with modest-to-moderate increases in dementia risk. Multisite chronic pain demonstrates dose-response relationships with hippocampal atrophy and incident dementia. However, many conditions lack dedicated longitudinal studies. Interpretation is limited by residual confounding, reverse causation, healthcare utilization bias, and medication effects. CSS are associated with increased dementia risk but causality remains unproven. Central sensitization may represent a clinically identifiable vulnerability state integrating pain, affective burden, and sleep disruption. This highlights a potentially high-risk population that may not be fully captured by traditional dementia risk models. Biomarker-integrated longitudinal studies and advanced causal modeling are needed to clarify mechanisms.},
}

Humans
*Dementia/epidemiology
*Central Nervous System Sensitization/physiology
Sleep Wake Disorders/epidemiology
Risk Factors

@article {pmid42579211,
year = {2026},
author = {Wang, F and Wang, X and Chen, Y and Li, Q and Wang, S and Cai, M and Zhao, J},
title = {Integrative transcriptomic and genetic analysis implicates fatty acid metabolic reprogramming in perivascular macrophages in Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42579211},
issn = {1573-7365},
support = {232102521029//International cooperation projects of Henan Province/ ; 182300410389//Natural Science Foundation of Henan Province/ ; },
mesh = {*Alzheimer Disease/metabolism/genetics ; *Fatty Acids/metabolism/genetics ; *Macrophages/metabolism ; Animals ; Humans ; *Transcriptome/genetics ; Mice ; Metabolic Reprogramming ; Gene Expression Profiling ; Lipid Metabolism/genetics ; Mice, Transgenic ; },
abstract = {Dysregulated lipid metabolism and neuroinflammation are increasingly recognized as interacting contributors to Alzheimer's disease (AD), but the cell-type-specific genetic links between fatty acid metabolism and AD remain incompletely defined. This study aimed to identify fatty acid metabolism-related genes associated with AD risk and to characterize their relevance to perivascular macrophage (PVM) states. Single-cell RNA-sequencing data from GSE160936 and bulk transcriptomic data from GSE270454 were integrated to evaluate cell-type-specific fatty acid metabolism activity in AD and control samples.The primary data sources, fatty acid metabolism gene set, AUCell scoring strategy, CellChat workflow, GSEA resources, and MR software settings were specified to improve reproducibility. PVMs were further analyzed for differential expression, ligand-receptor communication, pathway enrichment, transcription factor regulation, and pseudotime-associated transcriptional changes. Cis-eQTL-based two-sample Mendelian randomization was performed using eQTLGen exposure data and AD GWAS summary statistics, followed by sensitivity analyses, reverse MR, and Bayesian colocalization.The analyses were interpreted across three distinct evidence levels: cell-type-resolved transcriptional association, systemic genetic expression prioritization, and tissue-level protein expression. Nominal MR findings were interpreted alongside multiple-testing considerations and colocalization support.Candidate protein expression was examined in hippocampal tissue from APP/PS1 and wild-type mice by Western blotting. Single-cell analysis identified eight major cell populations and showed increased fatty acid metabolism activity in PVMs from AD samples. Mendelian randomization prioritized ten fatty acid metabolism-related genes associated with AD risk, among which ACSL1, EPM2AIP1, MALT1, and RASGRP3 showed strong colocalization support (PP.H4 > 0.9). Pathway analyses linked these genes to lipid metabolic regulation, inflammatory signaling, phagocytosis, and mitochondrial/peroxisomal fatty acid metabolism. Co-expression analysis suggested associations between MALT1 and fatty acid oxidation-related genes, including ACADM and ACOX1. Western blotting in whole hippocampal lysates from APP/PS1 mice provided exploratory tissue-level protein evidence, showing increased ACSL1 and MALT1 and decreased RASGRP3 expression; these findings should not be interpreted as confirmatory PVM-specific validation. This integrative analysis prioritizes ACSL1, EPM2AIP1, MALT1, and RASGRP3 as candidate genes connecting fatty acid metabolic dysregulation with AD-associated neuroinflammatory processes. Because the genetic instruments were blood-derived and the protein assays used whole hippocampal lysates, the findings should be interpreted as candidate-gene prioritization and hypothesis generation rather than proof of direct PVM-specific causality.Accordingly, the study supports a prioritized candidate framework for future functional testing, not validated therapeutic targets or direct causal proof.},
}

*Alzheimer Disease/metabolism/genetics
*Fatty Acids/metabolism/genetics
*Macrophages/metabolism
Animals
Humans
*Transcriptome/genetics
Mice
Metabolic Reprogramming
Gene Expression Profiling
Lipid Metabolism/genetics
Mice, Transgenic

@article {pmid42579351,
year = {2026},
author = {Liu, S and Han, D and Bai, T and Chen, H and Li, JP},
title = {Interpreting Divergent Short-Chain Fatty Acid Effects in Alzheimer's Disease: A Seven-Axis Framework.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0777},
pmid = {42579351},
issn = {2152-5250},
abstract = {Studies of short-chain fatty acids (SCFAs) in Alzheimer's disease (AD) report protective, neutral, and adverse findings, but the same class label often conceals non-equivalent exposures and endpoints. We propose an AD-specific interpretive framework that organizes this heterogeneity as a causal sequence: source or intervention → SCFA species, dose, and route → absorption and metabolic filtering → target-compartment exposure → host and disease state → responding cell type → endpoint. Seven interdependent axes-SCFA species, dose, route, compartment, exposure context, disease stage, and responding cell type-identify the coordinates needed to compare studies. This organization separates administered dose from achieved exposure, direct entry into the central nervous system from blood-brain barrier or peripheral gut-brain signaling, and stage-related disease biology from evidence of stage-specific treatment efficacy. It also requires symmetric interpretation of null findings according to exposure verification, target engagement, power, cellular resolution, and endpoint specificity. The framework integrates rather than replaces established microbiome, pharmacological, and neuroimmune principles and has not been validated as a predictor of effect direction. Its explanatory value can be tested by prespecified meta-regression, variance partitioning, interaction analysis, matched-exposure replication, and causal mediation. Persistent opposite effects under matched coordinates would indicate missing dimensions or failure of the framework. This Perspective therefore supports mechanism-linked, biomarker-informed research rather than nonspecific SCFA supplementation in unselected patients.},
}

@article {pmid42579359,
year = {2026},
author = {Marcinkowska, AB and Grzywińska, M and Winklewski, PJ},
title = {Glymphatic System Function and Cognition: Converging Evidence from DTI-ALPS Imaging - A Narrative Review.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0511},
pmid = {42579359},
issn = {2152-5250},
abstract = {The glymphatic system, a brain-wide perivascular network mediating cerebrospinal fluid-interstitial fluid exchange, has emerged as a candidate determinant of cognitive health through its role in clearing metabolic waste, neurotoxic proteins, and neuroactive metabolites. The diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index provides a non-invasive means to assess glymphatic activity in vivo, yet no synthesis has consolidated what this marker captures, how reliably it predicts cognitive outcomes, and what pathways may account for observed associations. This narrative review, informed by selected principles from the PRISMA 2020 framework but not constituting a formal systematic review, synthesizes evidence linking DTI-ALPS to domain-specific cognitive performance in healthy aging and neurological disease, encompassing the Alzheimer's disease continuum, cerebral small vessel disease, Parkinson's disease, multiple sclerosis, stroke, and HIV-associated neurocognitive disorder. Lower DTI-ALPS values were consistently associated with worse cognitive performance. The strongest associations were observed for memory and global cognition, followed by executive functions and processing speed; evidence for language and visuospatial abilities was less consistent. Longitudinal data indicate that DTI-ALPS decline may precede detectable amyloid pathology, positioning this index as a candidate early prognostic marker. Three mechanistic pathways are discussed: disruption of sleep-dependent waste clearance; compromise of gray matter integrity through neurotoxic metabolite accumulation; and facilitation of amyloid-β and tau pathology via impaired perivascular protein clearance. Limitations include the indirect nature of DTI-ALPS as a clearance measure, predominance of cross-sectional designs, small samples, and absence of sex-stratified analyses despite known hormonal modulation of glymphatic function. Longitudinal studies, randomized trials of glymphatic-targeting interventions, and acquisition protocol standardization represent priority directions for future research.},
}

@article {pmid42579377,
year = {2026},
author = {Liu, B},
title = {Temporal dissociation of semantic degradation and interference in Alzheimer's disease: Evidence from Chinese character processing.},
journal = {Journal of neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jnp.70071},
pmid = {42579377},
issn = {1748-6653},
abstract = {Chinese characters serve as the psychological entry point for lexical recognition in reading. Over 80% of these characters are phonetic compounds containing a semantic radical. Understanding how individuals with Alzheimer's disease (AD) process these structurally distinct characters is crucial for revealing the underlying nature of their cognitive decline. This study examined 180 older adults (60 Healthy Controls, 60 Mild AD, 60 Moderate AD) in a semantic categorization task across four radical-character relationships: fully related (FR), fully unrelated (FU), radical-only related (RR) and radical-only, related (RO-R). To disentangle semantic degradation from executive control demands, this study employed signal detection theory (SDT) and mixed-effects modelling. Results demonstrated significant group-by-condition interactions for accuracy, reaction time and perceptual sensitivity (d'). AD patients exhibited globally reduced d' and prolonged reaction times. Crucially, an error pattern analysis revealed that Mild AD patients produced significantly more false alarms in the RR condition, a deficit strongly correlated with their Stroop Interference scores (r = .58), reflecting a pronounced susceptibility to semantic interference, exacerbated by atypical executive inhibitory control. Furthermore, a temporal dissociation emerged: while explicit semantic sensitivity (d') collapsed early in the disease, Mild AD patients partially preserved the automatic reaction time advantage for isolated radicals (RO-R), yet suffered an exacerbated reaction time interference effect when resolving radical-related semantic interference (RR > FU). These findings suggest that explicit semantic boundaries and executive conflict resolution abilities degrade early in AD, whereas automatic semantic spreading activation is briefly preserved but highly susceptible to multifaceted semantic interference.},
}

@article {pmid42579441,
year = {2026},
author = {Sun, F and Liu, Y and Zhou, Q and Hu, Q and Wang, W and Xiao, Y and Su, J and Liu, G and Sun, M and Chen, L and Li, H and Yang, Y and Wang, JZ},
title = {A Small-Molecule DEPTAC Rescues Cognitive Deficits by Targeted Dephosphorylation of Pathological Tau.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e77088},
pmid = {42579441},
issn = {2198-3844},
support = {82571635//National Natural Science Foundation of China/ ; 82230041//National Natural Science Foundation of China/ ; 82371436//National Natural Science Foundation of China/ ; YCJJ20252412//Fundamental Research Funds for the Central Universities/ ; 241111310400//Key R&D Program of Henan Province/ ; },
abstract = {Accumulation of hyperphosphorylated Tau (p-Tau) is a central driver of neurodegeneration in Alzheimer's disease (AD). Addressing the limitations of current therapeutics, we developed TP2, a small-molecule DEPhosphorylation-TArgeting Chimera (DEPTAC). TP2 is engineered to physically tether endogenous PP2A to Tau, facilitating targeted dephosphorylation. Mechanistically, TP2 induces ternary complex formation and potently reduces p-Tau in neurons. Systemic administration of TP2 in distinct tauopathy mouse models (P301L and AAV-hTau-N368) significantly lowered brain p-Tau levels, oligomers, and neurofibrillary tangles without altering global PP2A activity. Crucially, by rebalancing the phosphorylation of Tau, TP2 restored Tau's physiological function, as evidenced by the preservation of neuronal morphology, synaptic integrity, and microtubule stability. TP2 also ameliorated the dysregulated neuroimmune microenvironment. Consequently, TP2 treatment robustly reversed cognitive deficits in multiple behavioral paradigms. These findings establish TP2 as a promising therapeutic candidate that targets upstream pathological phosphorylation to halt neurodegeneration and restore cognitive function.},
}

@article {pmid42579930,
year = {2026},
author = {Go, M and Reich, LA and Harris, DA and Daiello, LA and Berry, SD and D'Amico, AM and Zullo, AR and Hayes, KN},
title = {Drug-Drug Interactions in Nursing Home Residents With vs Without Dementia.},
journal = {Journal of the American Medical Directors Association},
volume = {27},
number = {10},
pages = {106417},
doi = {10.1016/j.jamda.2026.106417},
pmid = {42579930},
issn = {1538-9375},
abstract = {OBJECTIVES: To examine whether nursing home (NH) residents with Alzheimer's disease and related dementias (ADRD) are more likely than those without ADRD to be exposed to potential drug-drug interactions (DDIs) and to experience longer durations of exposure to DDIs.

DESIGN: Retrospective observational study.

SETTING AND PARTICIPANTS: Long-stay US NH residents.

METHODS: We leveraged Medicare Fee-for-Service enrollment and claims data linked to Minimum Data Set 3.0 clinical assessments from 2018 to 2020 and identified NH residents aged ≥66 years with observable part D prescription drug data. We identified exposure to 98 potential DDIs during the duration of their NH stay. We described the number of DDIs with a clinically meaningful difference in prevalence and/or duration between groups, defined as a ≥1% difference in prevalence and ≥7 days' duration, respectively. We used a log-binomial model to estimate the association between ADRD and exposure to any DDI as an adjusted prevalence ratio with 95% CIs and predicted the marginal prevalence of exposure to any DDI for those with vs without ADRD, standardized to population covariate distributions.

RESULT: We identified 485,251 eligible NH residents (average age, 84.6 [SD, 8.1] years; 67.1% female; 70.1% with ADRD; 56.6% with a potential DDI). A diagnosis of ADRD was associated with a higher prevalence of DDI exposure (prevalence ratio, 1.09 [95% CI, 1.08, 1.09]; marginal predicted prevalence for those with vs without ADRD: 58.0% vs 53.3%). Twelve DDIs had different prevalences between groups, and 34 DDIs had different differences in duration. For example, 29.6% of residents with vs 21.2% without ADRD were exposed to ≥3 central nervous system-active drugs.

CONCLUSIONS AND IMPLICATIONS: NH residents with ADRD had a higher prevalence and duration of potential DDIs. Future research should evaluate whether the interactions we identified have causal effects on adverse outcomes such as falls.},
}

@article {pmid42579954,
year = {2026},
author = {Fernandes, F and Dey, A and Ma, A and Churchill, NW and Fischer, CE and Graham, SJ and Munoz, DG and Schweizer, TA},
title = {Choroid plexus volume in pathology-confirmed Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100648},
doi = {10.1016/j.tjpad.2026.100648},
pmid = {42579954},
issn = {2426-0266},
abstract = {INTRODUCTION: The choroid plexus (CP) increases in volume across the Alzheimer's disease (AD) continuum, suggesting its potential as a clearance-related biomarker. However, few studies have examined ante-mortem CP volume in relation to post-mortem AD pathology, the gold standard for diagnosis.

METHODS: Participants who had structural magnetic resonance imaging and post-mortem pathology, with an interval of ≤ 5 years between imaging and death, were examined. Normalized CP volume (NCPV) was semi-automatically segmented from the lateral ventricles and analyzed using Bayesian linear regression to estimate associations with cognitive impairment (CI), AD pathology, and relevant clinical/demographic data.

RESULTS: Intermediate and high levels of AD pathology and CI were associated with larger NCPV, whereas female sex was associated with lower NCPV. Subgroup analyses showed larger NCPV in individuals with greater CI despite comparable levels of AD pathology.

DISCUSSION: These findings link CP enlargement to neuropathologically confirmed AD burden and CI, supporting further investigation of CP structure and function in AD.},
}

@article {pmid42579974,
year = {2026},
author = {Cui, J and Ye, W and Wen, J and Zhu, Q},
title = {Dual-contrastive modality recovery for incomplete multi-modal brain disease diagnosis.},
journal = {Medical image analysis},
volume = {114},
number = {},
pages = {104259},
doi = {10.1016/j.media.2026.104259},
pmid = {42579974},
issn = {1361-8423},
abstract = {Multi-modal learning is extensively applied to diagnose brain diseases such as epilepsy and Alzheimer's disease. However, incomplete multi-modal data, where some imaging modalities are unavailable or difficult to collect, limits the application of conventional methods. Additionally, existing approaches primarily focus on reconstructing missing imaging data but rarely enforce cross-modal semantic alignment. To address these challenges, we propose BrainCLIP, a CLIP inspired two-stage framework designed for incomplete multi-modal learning, with a focus on diagnosing representative brain diseases, i.e., epilepsy and Alzheimer's disease. The key novelty of our framework lies in its joint design of dual contrastive modality recovery and multi-modal representation learning in a two-stage pipeline. Specifically, we introduce a multi-modal contrastive learning stage that aligns text, fMRI, and DTI representations in a shared embedding space using complete samples. The recovered features are then refined through a dual contrastive recovery strategy with modality level and sample level contrastive objectives, thereby ensuring that the recovered features are semantically consistent and discriminative. For multi-modal representation learning, the recovered and available modalities are fused with fixed textual embeddings to learn task aware representations for disease classification. Extensive experiments demonstrate the effectiveness of our method in diagnosing epilepsy and Alzheimer's disease.},
}

@article {pmid42580032,
year = {2026},
author = {Zhu, Y and Walker, AIB and Bekena, S and Singh, RK and Strain, JF and Phuah, CL and Millar, PR and Canfield, P and Hill, CV and Hudson, DL and Williams, MM and Mohamed, EA and Williams, JP and Harrison, K and Laurido-Soto, OJ and Lee, JM and Ances, BM and Trani, JF and Babulal, GM},
title = {Structural and social determinants of health shape the impact of neurodegeneration and cerebrovascular pathology on cognitive functioning in black adults.},
journal = {Social science & medicine (1982)},
volume = {406},
number = {},
pages = {119636},
doi = {10.1016/j.socscimed.2026.119636},
pmid = {42580032},
issn = {1873-5347},
abstract = {INTRODUCTION: Black adults in the United States experience a disproportionately higher risk of dementia due to cumulative exposure to structural and social determinants of health (S/SDOH). Although structural neuroimaging provides markers of atrophy and cerebrovascular injury, less is known about how these biomarkers interact with S/SDOH to influence cognitive performance within minoritized populations. This study examined independent and interactive associations between a multidimensional S/SDOH Composite Index (S/SDOH-CI) and structural imaging-derived biomarkers among Black adults in an urban setting.

METHODS: We analyzed data from a community-based sample of Black adults aged ≥45 who completed brain MRI, the Preclinical Alzheimer Cognitive Composite (PACC), the Montreal Cognitive Assessment (MoCA), and a comprehensive assessment of structural and social determinants of health (S/SDOH). Structural biomarkers included total brain volume, hippocampal volume, global and regional white matter hyperintensities (WMH), and brain-age gap (BAG). Linear regression models examined independent and interactive associations between the S/SDOH-CI and MRI biomarkers with cognitive performance, adjusting for demographic characteristics and Charleston comorbidity index.

RESULTS: Total brain volume and BAG were associated with MoCA. Significant interactions were observed between S/SDOH-CI and BAG for cognitive outcomes. Across S/SDOH factors, discrimination, and coping moderated associations between WMH and PACC, while education moderated associations between brain volume and MoCA.

DISCUSSION: These findings underscore that biological vulnerability cannot be fully understood without accounting for structural and social disparities. Differential sensitivity of MRI biomarkers highlights the need for neuroimaging research tailored to diverse populations and supports integrating S/SDOH to inform precision-equity approaches to dementia prevention.},
}

@article {pmid42580292,
year = {2026},
author = {Luca, A and Piccoli, T and Di Marco, S and Nicoletti, A and Lo Coco, D and Rolandi, E and Sensi, SL and Russo, M and Ferri, R and Sucapane, P and Bruni, AC and Perani, D and Guarnieri, B and , },
title = {Sleep quality and caregiver burden in Alzheimer's disease: focus on sex differences.},
journal = {Sleep medicine},
volume = {148},
number = {},
pages = {109185},
doi = {10.1016/j.sleep.2026.109185},
pmid = {42580292},
issn = {1878-5506},
abstract = {INTRODUCTION: The relationship between sleep characteristics in caregivers and care recipients with Alzheimer's disease (AD) and caregiver burden, especially regarding sex-related differences, still needs to be clarified. The aims of the present study were to examine associations between caregiver and patient sleep characteristics and caregiver burden, including sex-differences and menopausal status among female caregivers.

METHODS: The SexDemCare study is a multicenter Italian study conducted within the SINdem Study Group "Sex and Gender Differences in Dementia." Caregivers and their non-institutionalized care recipients with clinically diagnosed AD across different stages of disease severity were enrolled. The Caregiver Burden Inventory was administered. Sleep characteristics of both caregivers and care-recipients were assessed using the Pittsburgh Sleep Quality Index.

RESULTS: 238 caregivers (65.9% women; mean age 59.6 ± 12.4 years) and 238 care-recipients (153 women; mean age 77.5 ± 7.9 years) were enrolled. Caregiver burden was associated with snoring, daytime hypersomnolence, longer sleep latency, and use of sleep medication. In sex-stratified analysis, caregiver burden was associated with several sleep characteristics only among female caregivers.

DISCUSSION: Female caregivers may be especially vulnerable to the negative consequences of poor sleep on caregiving burden.},
}

@article {pmid42580332,
year = {2026},
author = {Dries, DR and Yu, G},
title = {Breathing new life into the rational design of Alzheimer's therapeutics.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2026.07.046},
pmid = {42580332},
issn = {1097-4172},
}

@article {pmid42580389,
year = {2026},
author = {Bu, J and Nie, X and Luo, H and Wang, J and Jiang, D and Xu, N and Zhuang, P and Zhang, Y and Yin, Q},
title = {Neuron-Derived Neuroinflammation in Neurodegenerative Diseases: Mechanisms and Intervention Prospects.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108383},
doi = {10.1016/j.phrs.2026.108383},
pmid = {42580389},
issn = {1096-1186},
abstract = {Neurodegenerative diseases represent a major global public health challenge, imposing substantial societal and economic burdens. Their complex pathogenesis and limited therapeutic options underscore an urgent need for new paradigms. Emerging evidence indicates that dysregulation of the brain's immune microenvironment is a critical driver of disease progression. Conventional wisdom posits that peripheral immune cells and central glial cells serve as the primary initiators of neuroimmune responses, whereas neurons are regarded merely as passive recipients of inflammatory damage. Emerging evidence suggests that upon receiving pathological signals in the central nervous system, neurons may become more vulnerable and participate in the onset of neuroimmune processes, positioning them as potential targets for early intervention in neurodegenerative diseases. This article systematically reviews the contribution of neuron-derived immune-inflammatory responses in neurodegenerative diseases and potential intervention strategies. We first outline the capacity of neurons to regulate neuroimmune responses and detail the underlying molecular mechanisms. Then we compare the specific mechanisms by which neurons with different susceptibility drive and amplify neuroinflammation in various neurodegenerative diseases such as alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, vascular cognitive impairment, and transformed these mechanisms into intervention strategies targeting neurons,. This article aims to break through the traditional concept of passive neuronal damage, systematically integrate intervention strategies that shift from targeting peripheral immune and glial cells to regulating neuron-derived immunity, thereby providing a new theoretical framework for overcoming current clinical limitations and identifying effective therapeutic targets for the prevention and treatment of neurodegenerative diseases.},
}

@article {pmid42580438,
year = {2026},
author = {Silva, AC},
title = {Current Clinical Evidence on Nose-to-Brain Drug Delivery.},
journal = {Drug discovery today},
volume = {},
number = {},
pages = {104765},
doi = {10.1016/j.drudis.2026.104765},
pmid = {42580438},
issn = {1878-5832},
abstract = {Intranasal delivery is increasingly recognised as a promising strategy for direct drug transport to the brain via the nose-to-brain pathway, bypassing the blood-brain barrier and improving therapeutic efficacy. This approach has shown potential in the treatment of neurological disorders, including Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, and acute psychiatric conditions, as well as in emergencies such as anxiety attacks and migraine episodes. Recent clinical studies investigating intranasal formulations of rivastigmine, insulin, and olanzapine, among other drugs, have provided encouraging evidence supporting the clinical translation of this delivery strategy. In addition, FDA-approved intranasal products indicated for central nervous system disorders, including diazepam and midazolam for seizure management, and triptans for migraine, demonstrate the growing clinical relevance of intranasal drug delivery. Both preclinical and clinical studies have reported encouraging outcomes, particularly when intranasal delivery is combined with nanoformulations and specialised delivery devices designed to enhance olfactory deposition. Intranasal administration is non-invasive, painless, and may improve patient adherence while enhancing brain bioavailability. Nevertheless, further well-designed clinical studies are required to establish the long-term safety, efficacy, and clinical applicability of this delivery strategy.},
}

@article {pmid42580461,
year = {2026},
author = {Murray, HC and Dieriks, BV and Dodd, S and Usdin, T and Hamlin, D and Highet, B and Sit, Z and Kim, M and Faull, R and Turner, C and Scadeng, M and Curtis, MA and Koretsky, A},
title = {High-field MRI correlates with immunohistochemical analysis of the normal and Alzheimer's disease anterior olfactory nucleus.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122166},
doi = {10.1016/j.neuroimage.2026.122166},
pmid = {42580461},
issn = {1095-9572},
abstract = {The human anterior olfactory nucleus (AON) is one of the earliest brain regions affected by tau and beta amyloid pathology in Alzheimer's disease, potentially serving as a conduit for the spread of aggregated proteins to downstream cortical regions. However, the architecture of the human AON remains poorly understood. Here, we applied a multimodal imaging framework combining ultra-high-field magnetic resonance (MR) microscopy, thin-section immunofluorescence, and whole-mount tissue clearing with confocal and light-sheet microscopy to characterise the three-dimensional architecture of the AON and its involvement in Alzheimer's disease (AD). In neurologically normal cases, we identified tear-shaped AON clusters using MR microscopy that aligned with cytoarchitectural boundaries defined by PGP9.5, CNPase, and UEA lectin immunolabelling in serial sections, confirming the validity of AON segmentation in intact bulbs. In AD cases, MR microscopy, immunofluorescence, and light-sheet imaging revealed concentrated tau and beta-amyloid pathology within the AON clusters. Despite this pathology burden, neither total olfactory bulb volume nor AON volume differed significantly between neurologically normal and AD groups, and pathology load did not correlate with either volumetric measure. These findings refine our understanding of the human olfactory bulb and AON structure and demonstrate that high-resolution MR microscopy is a reliable tool for investigating substructural changes in the olfactory system.},
}

@article {pmid42580472,
year = {2026},
author = {Chen, J and Chen, J and Chen, Y and Xia, J and Fang, H and Zhang, P and Ge, RS and Wang, Y},
title = {Chain-length-selective inhibition of human and rat steroid 5α-reductase type 1 by alkyltrimethylammonium chloride disinfectants: kinetic, surface plasmon resonance, computational, and network toxicology analyses with implications for neurosteroidogenesis.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {112273},
doi = {10.1016/j.cbi.2026.112273},
pmid = {42580472},
issn = {1872-7786},
abstract = {Alkyltrimethylammonium chlorides (ATMAs) are a major subclass of cationic quaternary ammonium compound (QAC) surfactants whose human exposure has risen sharply since 2020, but their effect on the brain neurosteroidogenic enzyme steroid 5α-reductase type 1 (SRD5A1) is unknown. Eight ATMAs from C1 to C22 were tested on human and rat SRD5A1 microsomes using HPLC-MS/MS, complemented by surface plasmon resonance (SPR), molecular docking, three-dimensional quantitative structure-activity relationship (3D-QSAR) modelling, and a network toxicology workflow. Screening at 100 μM identified ATMA-C14 and ATMA-C16 as the only active inhibitors against either species. The C14 and C16 compounds inhibited human SRD5A1 with IC50 of 50.94 μM and 46.98 μM respectively (Ki 55.51 and 52.95 μM); against rat SRD5A1, ATMA-C16 retained equal potency (IC50 46.75 μM) but ATMA-C14 lost approximately half its activity (IC50 108.62 μM), revealing a species shift around the C14 homologue. An equimolar C14/C16 mixture was synergistic against the human enzyme but antagonistic against the rat enzyme, mirroring the species difference in single-agent potency. Both compounds behaved as mixed/non-competitive inhibitors with respect to testosterone, and cofactor-titration kinetics together with SPR competition data placed the binding site at the NADPH pocket. SPR returned KD of 52.8 and 59.3 μM with rapid dissociation, consistent with reversible non-covalent binding. In intact SF126 cells the order was reversed, ATMA-C14 suppressing DHT production more than ATMA-C16, in keeping with differential membrane permeability. Docking located both ligands in the NADPH pocket (ΔG -5.78 to -6.65 kcal/mol), and a 3D-QSAR pharmacophore emphasised one hydrogen-bond acceptor and four hydrophobic features. Network toxicology pointed, in silico, to Alzheimer's disease as the most enriched disease intersection. ATMA-C14 and ATMA-C16 thus emerge as moderate, reversible SRD5A1 inhibitors with chain-length and species-dependent potency, raising potential endocrine-disruption concerns that warrant exposure-relevant assessment.},
}

@article {pmid42580481,
year = {2026},
author = {Chen, P and Guo, L and Guo, X and Hong, W and Meng, W},
title = {A new method for the production of recombinant human Aβ(1-42) peptide.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106238},
doi = {10.1016/j.neuint.2026.106238},
pmid = {42580481},
issn = {1872-9754},
abstract = {BACKGROUND: The amyloid-β protein (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD). Chemically synthesized Aβ(1-42) is the most widely employed resource for AD mechanistic research and drug screening. However, solid-phase synthesis introduces truncated and modified byproducts, causing batch-to-batch heterogeneity and compromised experimental reproducibility.

METHODS: Herein, we established an optimized recombinant expression system utilizing a thermal green protein (TGP) fusion tag combined with TEV protease site-specific cleavage to produce tag-free, authentic human Aβ(1-42) in Escherichia coli. We systematically performed side-by-side biophysical characterization, including secondary structural transition and amyloid aggregation kinetics, to compare purified recombinant Aβ(1-42) (RecAβ) and conventional synthetic Aβ(1-42) (SynAβ). Human iPSC-derived neurons (iNs) and primary murine microglia were further applied to evaluate and compare their neurotoxicity and microglial regulatory functions.

RESULTS: The optimized TGP-TEV platform enabled robust production of high-purity RecAβ(1-42), yielding 6-7 mg intact peptide per liter of bacterial culture. Biophysical assays demonstrated that RecAβ shares highly conserved secondary structural features with SynAβ but exhibits significantly enhanced aggregation propensity. Functional assays revealed that RecAβ- and SynAβ-derived ADDLs exert equivalent neurotoxicity in human iNs. While both fibril preparations display comparable microglial binding recognition and lysosomal clearance kinetics with subtle temporal differences, RecAβ fibrils induce more severe microglial phagolysosomal dysfunction than SynAβ fibrils.

CONCLUSION: This work establishes a robust, reproducible recombinant strategy for generating authentic human Aβ(1-42). RecAβ recapitulates core AD-relevant bioactivities of commercial SynAβ while possessing stronger aggregation potency and enhanced capacity to disrupt microglial homeostatic function. This standardized recombinant Aβ preparation provides a useful tool for the investigation of Aβ biology and screening of AD therapeutic candidates.},
}

@article {pmid42580558,
year = {2026},
author = {Armoundas, AA and Piperi, C},
title = {Epigenetic Drift and LINE-1 Activation in Aging Brain: Implications for Neurodegenerative Disease.},
journal = {Mechanisms of ageing and development},
volume = {},
number = {},
pages = {112235},
doi = {10.1016/j.mad.2026.112235},
pmid = {42580558},
issn = {1872-6216},
abstract = {Brain aging and age-associated neurological diseases, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), and Amyotrophic Lateral Sclerosis (ALS), are largely attributed to epigenetic drift which is characterized by the gradual accumulation of alterations in neural cell methylation patterns over time. These methylation changes are particularly evident in transposable element (TE)-derived sequences such as Long interspersed element-1 (LINE-1) which comprises approximately 17% of the human genome. During aging, LINE-1 elements gradually lose their methylation, as well as the regulatory safeguard mechanisms that usually keep them inactive. This repression loss can lead to LINE-1 reactivation, contributing to harmful effects including genomic instability, neuroinflammation, and more. Together these findings indicate that impaired epigenetic maintenance, especially in repetitive genome regions, plays a key role in biological aging of neurons and glial cells. In this narrative review, we discuss the methylation dynamics and regulatory mechanisms of LINE-1 retrotransposons, their activation processes during aging, and contribution to age-associated neurological diseases. We also highlight the potential of targeting LINE-1 methylation to restore methylation homeostasis, epigenetic stability and delay brain aging.},
}

@article {pmid42580680,
year = {2026},
author = {Gupta, P and Pozzilli, V and De Giovanni, A and Sapio, E and Motolese, F and Capone, F and Pozzilli, P},
title = {GLP-1 receptor agonists, metabolic syndrome, and Alzheimer's disease: Lessons and opportunities from the EVOKE trials.},
journal = {Journal of neuroendocrinology},
volume = {38},
number = {8},
pages = {e70246},
doi = {10.1111/jne.70246},
pmid = {42580680},
issn = {1365-2826},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Metabolic Syndrome/drug therapy/metabolism/complications ; Semaglutide ; Animals ; *Hypoglycemic Agents/therapeutic use/pharmacology ; Glucagon-Like Peptides/therapeutic use ; },
abstract = {Metabolic syndrome and Alzheimer's disease (AD) are increasingly recognised as interconnected, sharing vascular, metabolic and inflammatory pathways that accelerate brain ageing and cognitive decline. This review critically examines the evidence that glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for diabetes and obesity, may influence AD related pathways or reduce AD risk in metabolically vulnerable populations. Metabolic syndrome and AD related cognitive impairment share biological mechanisms including vascular damage, insulin resistance and chronic inflammation, suggesting that therapies targeting metabolic dysfunction could influence neurological outcomes. GLP-1RAs are notable for combining systemic benefits, like weight loss, improved glycaemic control, and reduced cardiovascular risk, with possible but incompletely established central nervous system effects. Experimental studies suggest that some GLP-1RAs may reduce amyloid and tau pathology, support mitochondrial function, and limit neuroinflammation, although recent preclinical studies and limited brain penetrance argue against a direct neuroprotective effect. Observational data suggest lower dementia rates among users compared with other antidiabetic treatments. However, the recent EVOKE and EVOKE + trials showed that oral semaglutide did not slow clinical progression in early symptomatic AD, despite positive biomarker effects. This highlights the challenge of translating biological plausibility into meaningful clinical benefit and refocuses attention on disease stage, target population, and mechanism. Beyond summarising evidence, this review advocates a more cautious and mechanism specific framework: preserving cognitive health may require addressing systemic metabolic dysfunction rather than targeting the brain alone. GLP-1 RAs have failed to show an effect in symptomatic AD, but their effects on metabolism might still be beneficial at earlier stages, such as the preclinical phase of AD. Future studies should determine whether earlier intervention in metabolically enriched groups can alter AD related cognitive, vascular, and biomarker trajectories.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Glucagon-Like Peptide-1 Receptor Agonists
*Metabolic Syndrome/drug therapy/metabolism/complications
Semaglutide
Animals
*Hypoglycemic Agents/therapeutic use/pharmacology
Glucagon-Like Peptides/therapeutic use

@article {pmid42580784,
year = {2026},
author = {Souza, HJBC and Souza, KM and Dos Santos, MB and Silva, MAP and Grassi, TF and Destro, MV and Braz, MG},
title = {Evaluation of genetic instability in patients with amyotrophic lateral sclerosis.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {913},
number = {},
pages = {503953},
doi = {10.1016/j.mrgentox.2026.503953},
pmid = {42580784},
issn = {1879-3592},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Female ; Male ; Case-Control Studies ; Middle Aged ; *Genomic Instability ; Mouth Mucosa/pathology ; Micronucleus Tests ; Aged ; Chromosomal Instability ; Micronuclei, Chromosome-Defective ; },
abstract = {Genetic instability has been reported in several neurodegenerative diseases, such as Alzheimer's and Parkinson's, but only a few studies have addressed sclerosis. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Micronuclei (MNi) and nuclear buds (NBUDs) are established markers of chromosomal instability, yet no data are available regarding a possible link between genetic instability and ALS. The novelty of this case-control study lies in the assessment of genetic instability in oral exfoliated cells from ALS patients (n = 20) and matched controls (n = 20), contributing to the identification of potential novel markers related to the molecular pathogenesis of this severe disorder. Groups were matched for age, sex, and lifestyle (p > 0.05). No significant differences were observed in MNi or NBUD frequencies between groups (p > 0.05). These findings suggest no association between ALS and MN/NBUD frequencies in oral cells.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/pathology
Female
Male
Case-Control Studies
Middle Aged
*Genomic Instability
Mouth Mucosa/pathology
Micronucleus Tests
Aged
Chromosomal Instability
Micronuclei, Chromosome-Defective

@article {pmid42581113,
year = {2026},
author = {Jomova, K and Alomar, SY and Valko, R and Nepovimova, E and Kuca, K and Valko, M},
title = {Oxidative stress and inflammation in neurodegenerative disorders.},
journal = {Archives of toxicology},
volume = {},
number = {},
pages = {},
pmid = {42581113},
issn = {1432-0738},
abstract = {The brain's consumption of approximately 20% of the body's oxygen contributes to oxidative stress, a significant pathological factor in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. This oxidative stress, linked to low levels of antioxidant enzymes, drives neuronal death by facilitating membrane peroxidation of fatty acids, proteins, and DNA. Alzheimer's disease is characterized by amyloid-beta (Aβ) plaque accumulation and hyperphosphorylated tau aggregates, both of which interact with mitochondria to generate reactive oxygen species (ROS). Aβ peptides bind metals such as iron and copper, catalyzing the formation of damaging hydroxyl radicals. Peripheral markers of oxidative damage, such as elevated malondialdehyde and protein carbonyls, are correlated with these processes in affected patients. In Parkinson's disease, the loss of dopaminergic neurons in the substantia nigra is associated with pathological iron accumulation and mitochondrial complex I dysfunction, which are worsened by misfolded α-synuclein and mutations in antioxidant genes such as PINK1 and Parkin. The autooxidation of dopamine also drives oxidative stress through the generation of hydrogen peroxide and reactive quinones. Huntington's disease involves the degeneration of medium spiny neurons in the striatum due to a polyglutamine repeat expansion in the huntingtin gene, which disrupts mitochondrial function and downregulates antioxidants, leading to excitotoxicity and ROS spikes. Amyotrophic lateral sclerosis primarily affects motor neurons due to the mutations in SOD1, which result in the production of aggregates that impair mitochondria and generate reactive nitrogen species (RNS), such as peroxynitrite. Mitigating oxidative stress in neurodegenerative disorders presents a considerable translational challenge. While low-molecular-weight antioxidant therapies for neurodegenerative disorders have shown promising results in preclinical and animal studies because they mitigate oxidative stress, their clinical efficacy is hampered by low bioavailability and difficulty in penetrating the blood‒brain barrier. To overcome these limitations, current medical research is focused on alternative delivery systems. Innovations such as nanoparticle-based drug delivery are being actively studied to help transport low-molecular-weight antioxidants across the blood‒brain barrier more safely and effectively. Several promising epidemiological trials linked high dietary intake of vitamins C and E to a reduced risk of Parkinson's disease, and plant-derived antioxidants such as polyphenols were explored for their ability to combat neuroinflammation and reduce cognitive decline. Refined oxidative stress-suppressing strategies involve the (ii) application of mitochondrial-targeted agents to preserve ATP production; (ii) boosting the Nrf2 pathway may trigger a cascade of detoxifying enzymes; (iii) supplementation with polyphenols such as quercetin, resveratrol, and curcumin can suppress oxidative stress and dampen microglial activation (neuroinflammation); (iv) and the use of substances affecting the bidirectional network linking oxidative stress and autophagy can clear ROS-generating components. Despite some promising epidemiological data, translating oral or systemic antioxidant therapy into effective clinical treatments for humans requires further effort. A survey of current knowledge of oxidative stress and antioxidant therapy in neurodegenerative diseases is the main subject of this review.},
}

@article {pmid42581131,
year = {2026},
author = {Rahim, A and Zubair, SM and Ahamed, M and Das, S and Patel, R and Debnath, B and Porel, P},
title = {cGAS-STING as a Neuroimmune Traffic Molecule: Unraveling Pathogenic Mechanisms and Therapeutic Potential in Neurological Disorders.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42581131},
issn = {1557-1904},
mesh = {Humans ; cGAS-STING Signaling Pathway ; Animals ; *Nucleotidyltransferases/metabolism/immunology ; *Membrane Proteins/metabolism/immunology ; *Nervous System Diseases/immunology/metabolism/drug therapy ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; STING Protein ; Signal Transduction ; },
abstract = {The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is an essential cytosolic DNA-sensing system that plays an important role in the regulation of innate immune and inflammatory responses in the central nervous system (CNS). It was first discovered as a promising antiviral defense cascade and has since been shown to execute broader functions in neuroinflammation and neurodegeneration. The pathway can become hyperactive with the release of endogenous DNA from damaged nuclei, mitochondria, or genomic instability, leading to chronic production of type I interferon (TI-IFN), various pro-inflammatory cytokines, and eventually contributing to chronic neuroinflammatory diseases. Recent studies have found that dysregulated cGAS-STING signaling is associated with several neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), stroke, and age-related neurodegeneration. In the CNS, chronic activation of this pathway leads to activation of microglia, oxidative stress, breakdown of the blood-brain barrier (BBB), impaired function of the synapses, and neuronal death. Mitochondrial dysfunction and cytosolic release of mitochondrial DNA (mtDNA) further promote inflammatory signaling, thus perpetuating neurodegeneration. This review highlights the molecular and pathological mechanisms of cGAS-STING signaling in a broader aspect of neurological disorders and appraises the novel therapeutics already under development to inhibit this pathway to regulate neuroinflammation and enhance neurological outcomes.},
}

Humans
cGAS-STING Signaling Pathway
Animals
*Nucleotidyltransferases/metabolism/immunology
*Membrane Proteins/metabolism/immunology
*Nervous System Diseases/immunology/metabolism/drug therapy
Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
STING Protein
Signal Transduction

@article {pmid42581224,
year = {2026},
author = {Stefano, GB and Esch, T},
title = {Microbiome-Inflammation-Mitochondria Coupling in Neurodegeneration and Depression: An Integrative Opinion.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42581224},
issn = {1559-1182},
mesh = {Humans ; *Mitochondria/metabolism/pathology ; Animals ; *Inflammation/pathology/microbiology/metabolism ; *Depression/microbiology/metabolism/pathology ; *Neurodegenerative Diseases/microbiology/pathology/metabolism ; *Microbiota ; *Gastrointestinal Microbiome/physiology ; *Nerve Degeneration/pathology ; },
abstract = {There is increasing evidence that gut microbiome dysbiosis, systemic inflammation, and mitochondrial dysfunction interact in ways that influence psychiatric and neurodegenerative disease vulnerability. Recent findings indicate that microbial signaling, inflammatory activation, and mitochondrial stress responses form dynamic bidirectional networks that may influence neurotransmission, neuroplasticity, metabolism, and behavior. This integrative opinion article distinguishes major depressive disorder (MDD), Parkinson's disease (PD), and Alzheimer's disease (AD) as mechanistically distinct disorders while proposing that they may share overlapping upstream modulatory pathways involving inflammation, microbial dysregulation, and mitochondrial dysfunction. Importantly, the microbiome-inflammation-mitochondria axis is presented as a disease-modifying and vulnerability-associated framework rather than a singular unifying etiology. Current limitations including reverse causation, microbiome heterogeneity, and differences in treatment responsiveness are also discussed.},
}

Humans
*Mitochondria/metabolism/pathology
Animals
*Inflammation/pathology/microbiology/metabolism
*Depression/microbiology/metabolism/pathology
*Neurodegenerative Diseases/microbiology/pathology/metabolism
*Microbiota
*Gastrointestinal Microbiome/physiology
*Nerve Degeneration/pathology

@article {pmid42581253,
year = {2026},
author = {Berisha, DE and Benca, RM and Mander, BA},
title = {Sleep apnea in REM sleep as an amplifier of vascular contributions to Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71735},
doi = {10.1002/alz.71735},
pmid = {42581253},
issn = {1552-5279},
support = {K01AG068353/AG/NIA NIH HHS/United States ; R21AG079552/AG/NIA NIH HHS/United States ; R01AG096669/AG/NIA NIH HHS/United States ; F31AG084308/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/etiology/complications ; *Sleep, REM/physiology ; *Sleep Apnea Syndromes/complications/physiopathology ; *Cerebrovascular Disorders/complications/physiopathology ; Hypoxia/physiopathology ; },
abstract = {Obstructive sleep apnea (OSA), a common though underdiagnosed disorder in older adults, represents a potential upstream vascular stressor linked to increased Alzheimer's disease (AD) risk. In this Perspective article, we propose a stage-informed framework in which rapid eye movement (REM) sleep-related respiratory events amplify vascular contributions to AD. This framework is unified across four linked lines of evidence suggesting that (1) REM sleep physiology magnifies the hypoxic and hemodynamic burden of OSA, (2) the cardiometabolic consequences of sleep apnea are heightened in REM sleep, (3) REM-related hypoxemia is associated with markers of cerebrovascular pathology, and (4) vascular effects associated with REM-related hypoxemia are associated with medial temporal lobe vulnerability and memory dysfunction: core features of AD. Although direct evidence linking REM-specific OSA to AD biomarkers is lacking, we highlight REM sleep as a potentially critical window through which sleep-disordered breathing may amplify vascular contributions to AD.},
}

Humans
*Alzheimer Disease/physiopathology/etiology/complications
*Sleep, REM/physiology
*Sleep Apnea Syndromes/complications/physiopathology
*Cerebrovascular Disorders/complications/physiopathology
Hypoxia/physiopathology

@article {pmid42581297,
year = {2026},
author = {Iruela-Arispe, ML and Hinman, JD and Yang, AC and Dabertrand, F and Lee, JM and Howell, GR and , },
title = {A collaborative framework for uncovering molecular and cellular drivers of VCID: Foundations for future interventions in dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71701},
doi = {10.1002/alz.71701},
pmid = {42581297},
issn = {1552-5279},
support = {NS139949//Northwestern CWOW/ ; NS139972//UCLA VIBRANT CWOW/ ; NS139975//The Gladstone/UCSF/UCI/Rush CWOW/ ; NS140137//The Colorado Neurovascular Energetics CWOW/ ; NS139970//The WashU UNWIND CWOW/ ; NS139948//JAX/Emory/Columbia/Rush MINT-VCID CWOW/ ; },
mesh = {Humans ; Animals ; *Dementia ; *Dementia, Vascular ; *Cognitive Dysfunction ; },
abstract = {Vascular-related factors are now considered major contributors to most forms of dementia, including Alzheimer's disease. However, the degree to which vascular deficits contribute to risk, onset, and progression of cognitive impairment and dementia has only recently been appreciated. Our understanding of the mechanisms by which vascular deficits drive cognitive decline in dementia is still limited. Further, the testing of therapeutic approaches to prevent vascular deficits to treat dementia are few. These factors motivated the establishment of the Vascular Contributions to Cognitive Impairment and Dementia (VCID) Center Without Walls (CWOW) network, comprising institutes across the United States. We describe the current gaps and opportunities, and how, in collaboration with other relevant groups, the VCID CWOW network is aiming to tackle the major unmet need of developing improved therapeutic approaches targeting vascular deficits to treat dementia.},
}

Humans
Animals
*Dementia
*Dementia, Vascular
*Cognitive Dysfunction

@article {pmid42581300,
year = {2026},
author = {Shen, X and Wang, S and Song, W},
title = {Alzheimer's disease: erasing the peptidyl-arginine deiminase 2 (PAD2) stamp to restore microglial defense.},
journal = {Signal transduction and targeted therapy},
volume = {11},
number = {1},
pages = {},
pmid = {42581300},
issn = {2059-3635},
support = {82230043//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
}

@article {pmid42581306,
year = {2026},
author = {Fyfe, I},
title = {Circular RNAs outperform established Alzheimer disease biomarkers.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42581306},
issn = {1759-4766},
}

@article {pmid42581323,
year = {2026},
author = {Lee, D and Vicari, JM and Porras, C and Spencer, C and Pjanic, M and Wang, X and Kinrot, S and Weiler, P and Kosoy, R and Bendl, J and N M, P and Psychogyiou, K and Malakates, P and Hennigan, E and Monteiro Fortes, J and Zheng, S and Therrien, K and Mathur, D and Kleopoulos, SP and Shao, Z and Argyriou, S and Alvia, M and Casey, C and Hong, A and Beaumont, KG and Sebra, R and Kellner, CP and Bennett, DA and Yuan, GC and Voloudakis, G and Theis, FJ and Haroutunian, V and Hoffman, GE and Fullard, JF and Roussos, P},
title = {Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer's disease.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {42581323},
issn = {1546-1718},
support = {R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG10161, P30AG72975, R01AG15819, R01AG17917, U01AG46152, U01AG61356//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG065582, R01AG067025, R01AG082185//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Myeloid cells, including microglia and perivascular macrophages, are central to Alzheimer's disease (AD) neurobiology, yet their role remains incompletely understood. We profiled 832,505 human myeloid cells from the prefrontal cortex of 1,607 donors spanning the lifespan and showing varying degrees of AD neuropathology. We delineated six subclasses comprising 13 transcriptionally distinct subtypes and identified adaptive changes associated with aging and AD progression. Here we show that a disease-associated microglial subtype, characterized by elevated GPNMB expression and enriched for polygenic AD risk, expands with AD pathology and shows increased phagocytic activity. We identify MITF as an upstream regulator required to maintain this microglial state. Cell-cell interaction analyses prioritize APOE-SORL1 and APOE-TREM2 signaling pairs associated with disease progression. Using human and mouse models, we demonstrate that the neuroprotective effects of this microglial subtype depend on TREM2. These findings provide mechanistic insights into myeloid cell function in aging and AD, aiding therapeutic discovery.},
}

@article {pmid42581442,
year = {2026},
author = {Chen, C and Cheng, J and Yang, M and Li, JP and Tao, SS and Wang, P and Pan, HF},
title = {Immunosuppressant Use Mediates Neuroprotection Against Alzheimer's Disease in Rheumatoid Arthritis-A Two-Step Mendelian Randomization and NHANES Study.},
journal = {International journal of rheumatic diseases},
volume = {29},
number = {8},
pages = {e70823},
doi = {10.1111/1756-185x.70823},
pmid = {42581442},
issn = {1756-185X},
support = {82404354//National Natural Science Foundation of China/ ; 82273710//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/prevention & control/genetics/diagnosis/psychology/epidemiology ; *Arthritis, Rheumatoid/drug therapy/genetics/diagnosis/epidemiology/psychology ; Female ; Mendelian Randomization Analysis ; Male ; *Immunosuppressive Agents/therapeutic use ; Aged ; *Cognition/drug effects ; Risk Factors ; Nutrition Surveys ; Middle Aged ; United States/epidemiology ; *Neuroprotection/drug effects ; Protective Factors ; Risk Assessment ; Genetic Predisposition to Disease ; *Neuroprotective Agents/therapeutic use ; Genome-Wide Association Study ; Phenotype ; },
abstract = {OBJECTIVES: To investigate whether immunosuppressant (IS) use contributes to the inverse association between rheumatoid arthritis (RA) and Alzheimer's disease (AD).

METHODS: We analyzed NHANES 2011-2014 data, including 217 RA patients aged ≥ 60 years on prescription medications. Cognitive function was assessed using the Digit Symbol Substitution Test (DSST), CERAD, Animal Fluency Test (AFT), and a global cognition z-score (Z-score). Associations between IS use and cognition were evaluated using multivariable linear regression. Additionally, two-sample Mendelian randomization (TSMR) and multivariable MR (MVMR) analyses were performed with GWAS datasets for RA, AD, and IS to examine potential causal effects.

RESULTS: We observed that patients with RA using IS performed better in z.DDST (β: 0.335, p = 0.036) and Z-score (β: 0.214, p = 0.032) after adjusting for covariates, with sex-specific differences in cognitive domains. TSMR indicated that genetically predicted RA was associated with lower AD risk (OR: 0.936, p = 4.531E-04), and this effect was largely mediated by IS use. MVMR further validated the independent neuroprotective effect of IS on AD (OR = 0.884, p = 0.003) after adjusting for glucocorticoid and NSAID use, while these other medications showed no significant association with AD risk.

CONCLUSIONS: These results suggest that the reduced risk of AD observed in RA patients may be partly related to IS use, highlighting a potential role of IS in improving cognitive function and modulating AD risk.},
}

Humans
*Alzheimer Disease/prevention & control/genetics/diagnosis/psychology/epidemiology
*Arthritis, Rheumatoid/drug therapy/genetics/diagnosis/epidemiology/psychology
Female
Mendelian Randomization Analysis
Male
*Immunosuppressive Agents/therapeutic use
Aged
*Cognition/drug effects
Risk Factors
Nutrition Surveys
Middle Aged
United States/epidemiology
*Neuroprotection/drug effects
Protective Factors
Risk Assessment
Genetic Predisposition to Disease
*Neuroprotective Agents/therapeutic use
Genome-Wide Association Study
Phenotype

@article {pmid42581647,
year = {2026},
author = {Zhang, SY and Ren, HJ and Liu, HY and Xu, SY and Peng, YJ},
title = {Emerging Trends and Hot Spots in Tauopathy Research (2003-2025): A Bibliometric Analysis.},
journal = {Brain and behavior},
volume = {16},
number = {8},
pages = {e71645},
doi = {10.1002/brb3.71645},
pmid = {42581647},
issn = {2162-3279},
mesh = {*Bibliometrics ; *Tauopathies ; Humans ; *Biomedical Research/trends ; },
abstract = {PURPOSE: This study aimed to systematically analyze the developmental trajectory, research landscape, and thematic evolution of tauopathy research from 2003 to 2025 using bibliometric methods.

METHODS: A total of 6752 publications retrieved from the Web of Science Core Collection (WoSCC) were analyzed using the R package bibliometrix and VOSviewer to construct bibliometric networks, including co-authorship, co-citation, and keyword co-occurrence analyses. Scimago Graphica was used to visualize international collaboration patterns.

RESULTS: The annual number of publications on tauopathy increased markedly during the period 2003-2025, reflecting sustained global research interest. The United States was the leading contributor in both publication output and citation impact, while the University of Pennsylvania emerged as a key institution. Among individual researchers, the most productive authors and influential scholars were identified through publication output and citation-based metrics. Citation analysis highlighted the enduring impact of highly cited studies, particularly those establishing key biomarker frameworks for Alzheimer's disease research.Keyword-based analysis further revealed a shift from traditional mechanistic studies toward more integrative research themes, such as tau-amyloid-β interactions, neurodegeneration, and glial involvement, alongside continued interest in tau-targeted therapeutic strategies.

CONCLUSION: This bibliometric analysis provides a quantitative and structured overview of the global tauopathy research landscape. Beyond confirming established patterns, it captures the dynamic evolution of research priorities and identifies emerging directions, offering a data-driven basis for future investigations.},
}

*Bibliometrics
*Tauopathies
Humans
*Biomedical Research/trends

@article {pmid42581666,
year = {2026},
author = {Williams, A and Reddy, ABS and Velayudhan, L},
title = {A Systematic Review of Effects of Cholinesterase Inhibitors and Memantine on Cognitive Domains in Alzheimer's Disease.},
journal = {Journal of geriatric psychiatry and neurology},
volume = {},
number = {},
pages = {8919887261470005},
doi = {10.1177/08919887261470005},
pmid = {42581666},
issn = {1552-5708},
abstract = {BackgroundAlzheimer's Disease (AD) is characterised by progressive cognitive decline. Cholinesterase inhibitors (ChEI) (donepezil, rivastigmine and galantamine) and memantine have been the mainstay treatment and have showed their effectiveness on total cognitive scores, but their effects on individual cognitive domains remain unclear. This systematic review examined their impact on individual cognitive domains.MethodPubMed, Cochrane, MEDLINE, Web of Science and PsycINFO were searched (1st January 1999 - 31st March 2025) for studies evaluating the effects of ChEI and memantine on cognitive domains using standardised cognitive scales in individuals with AD. The review followed PRISMA guidelines. Risk of bias was assessed using the Cochrane ROB1 tool and a narrative synthesis was used to report the main findings.ResultsSixteen studies were included. Rivastigmine demonstrated dose-dependent benefits across memory, language, and praxis domains, with higher-doses generally producing less cognitive decline and greater improvements than lower-dose patches or capsules. Donepezil yielded benefits in language, praxis, and visuospatial abilities. Galantamine showed significant improvements in memory, praxis, visuospatial function, and language, and was superior to donepezil in language in one comparative study. Memantine demonstrated benefits across memory, language, praxis, attention, and visuospatial domains, both as monotherapy and as an adjunct to donepezil, with adjunct therapy producing sustained improvements in language and praxis. Overall, higher treatment doses were consistently associated with greater preservation of cognitive function across domains.DiscussionChEIs and memantine provide domain-specific cognitive benefits beyond global cognitive improvement. Future studies should examine whether treatment tailored to domain-specific deficits improves patient outcome.PROSPEROCRD42024493998.},
}

@article {pmid42581716,
year = {2026},
author = {Dabour, Z},
title = {The NeuroCommunity Ageing Framework: A Nursing Model for Brain-Health Assessment Towards Diagnostic Justice in Minority Older Adults.},
journal = {Journal of advanced nursing},
volume = {},
number = {},
pages = {},
doi = {10.1111/jan.70723},
pmid = {42581716},
issn = {1365-2648},
abstract = {AIM(S): To propose the NeuroCommunity Ageing Framework as a nursing-centred theoretical model for integrated brain-health assessment towards diagnostic justice in minority ageing populations.

DESIGN: Discursive theoretical paper presenting a conceptual framework derived from cross-disciplinary synthesis.

METHODS: A structured theoretical synthesis integrated literature on gerontological nursing, dementia epidemiology, multidomain prevention, clinical pharmacology, family caregiving, culturally responsive care, service access and systemic factors relevant to blood-based Alzheimer's disease biomarkers.

RESULTS: The framework integrates metabolic-vascular, cognitive-clinical, pharmacological, family-caregiving, cultural-linguistic and systemic-service determinants of brain health. It positions nurses to recognise cognitive vulnerability earlier, conduct culturally informed medication review, support caregivers, address language and stigma barriers and navigate service access. Hepatic calibration is presented strictly as a hypothesis-generating research construct for future biomarker validation in multimorbid older adults, not as a clinical interpretation rule.

CONCLUSION: The framework offers a nursing-oriented model for culturally valid dementia assessment, medication safety, caregiver support and equitable service navigation.

The framework may support nurses in embedding brain-health case-finding within primary care, chronic disease and community settings.

IMPACT: The paper addresses delayed dementia recognition among minority older adults and proposes a practical nursing framework advancing diagnostic justice.

REPORTING METHOD: No specific reporting guideline directly applies to this discursive theoretical paper; it was prepared according to principles of transparent narrative synthesis.

This study did not include patient or public involvement in its design, conduct or reporting.},
}

@article {pmid42582058,
year = {2026},
author = {Yang, J and Wan, D and Ren, L and Lv, Y and Zhao, H},
title = {Revisiting TREM2: from multi-omics signaling networks to clinical translation.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1782384},
pmid = {42582058},
issn = {1664-3224},
mesh = {Humans ; *Receptors, Immunologic/genetics/metabolism/immunology/chemistry ; *Membrane Glycoproteins/genetics/metabolism/immunology/chemistry ; *Signal Transduction ; Animals ; Multiomics ; Neoplasms/immunology/metabolism ; Translational Research, Biomedical ; Alzheimer Disease ; },
abstract = {TREM2 is a cell surface receptor that plays a crucial role in regulating immune responses, particularly in myeloid cells such as macrophages, dendritic cells, and microglia. Initially studied for its involvement in neuroinflammation and neurodegenerative diseases, while recent evidence has highlighted its broader implications in cancer and various other diseases. Recent studies show that TREM2 plays an immunoprotective role prompted by central nervous system-enriched sphingolipids during GBM progression. TREM2 overexpression represses GBM and synergizes with anti-PD-1 therapy, suggesting a potential therapeutic avenue in cancer immunotherapy. This review provides a comprehensive overview of TREM2 biology, focusing on its molecular structure, signaling pathways, and functional roles in different disease contexts. In Alzheimer's disease, TREM2 mutations are associated with altered immune responses and impaired amyloid-beta clearance, suggesting a potential therapeutic target. In cancer, TREM2 contributes to immune evasion, tumor progression, and metastasis, with emerging strategies aiming to target TREM2 to enhance anti-tumor immunity. Additionally, TREM2 is implicated in a range of other conditions, including autoimmune diseases, multiple sclerosis, and Parkinson's disease, where it may regulate inflammatory responses and tissue damage. Despite promising findings, several challenges remain in understanding TREM2's complex role across diverse diseases. Future research directions include unraveling its precise mechanisms, validating its therapeutic potential, and exploring clinical interventions targeting TREM2. This review provides a comprehensive overview of TREM2 biology, synthesizing insights from recent single-cell transcriptomics and metabolic profiling. We focus on its molecular structure, complex signaling networks, and context-dependent functional roles across diverse disease landscapes.},
}

Humans
*Receptors, Immunologic/genetics/metabolism/immunology/chemistry
*Membrane Glycoproteins/genetics/metabolism/immunology/chemistry
*Signal Transduction
Animals
Multiomics
Neoplasms/immunology/metabolism
Translational Research, Biomedical
Alzheimer Disease

@article {pmid42582107,
year = {2026},
author = {Zou, DZ and Li, J and Long, QS and Zhang, RQ and Zhu, BL and Tan, JZ},
title = {CD22 regulates Aβ clearance in microglia through INPP5D signaling.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1886995},
pmid = {42582107},
issn = {1662-5102},
abstract = {INTRODUCTION: Impaired microglial clearance of amyloid-β (Aβ) is a central driver of Alzheimer's disease (AD), yet the mechanisms governing intracellular Aβ degradation remain poorly defined.

METHODS: We investigated the role of CD22 in microglial Aβ processing using primary microglia, transcriptomic profiling, and hippocampal samples from AD patients and transgenic mice.

RESULTS: We identified CD22 as an Aβ-inducible signaling regulator that restrains microglial Aβ processing. CD22 expression was elevated in the hippocampus of AD patients and transgenic mice and was rapidly induced by Aβ in microglia. Functionally, CD22 knockdown enhanced intracellular Aβ degradation without affecting initial uptake. Transcriptomic profiling identified the AD risk gene INPP5D as a key downstream effector of CD22. Loss of CD22 suppressed INPP5D expression and promoted AKT activation, while INPP5D overexpression partially rescued the enhanced Aβ clearance phenotype. These findings define a CD22-INPP5D signaling axis that acts as a molecular brake on microglial Aβ processing. Aβ itself induces CD22 expression, revealing a feed-forward inhibitory loop in which amyloid accumulation limits its own clearance.

DISCUSSION: Collectively, these findings identify a regulatory mechanism controlling intracellular Aβ degradation and suggest the CD22-INPP5D axis as a potential therapeutic target for AD.},
}

@article {pmid42582162,
year = {2026},
author = {Zhang, Z and Zhang, P and Li, Y and Chu, J and Su, C and Hu, Z and Xiong, H and Xu, G},
title = {Associations of childhood-to-adulthood body size trajectories with dementia risk and brain structural imaging markers: a study from UK Biobank.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1764658},
pmid = {42582162},
issn = {2296-861X},
abstract = {BACKGROUND: Childhood and adulthood adiposity may influence dementia risk and brain structure; however, their life-course interplay and potential sex-specific effects remain incompletely understood.

METHODS: We analyzed 488,397 UK Biobank participants with self-reported comparative body size at age 10 (categorized as thinner, average, or plumper relative to peers) and measured adulthood BMI, followed prospectively for incident dementia. Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs). A subsample (n = 45,759) underwent brain MRI.

RESULTS: Compared with average childhood body size, a plumper body size at age 10 was associated with a higher risk of all-cause dementia (HR 1.12, 95% CI 1.04-1.20), particularly among men (HR 1.15, 95% CI 1.04-1.28), whereas a thinner body size was not significantly associated with dementia risk. In adulthood, overweight was associated with lower risks of all-cause dementia (HR 0.86, 95% CI 0.81-0.92) and Alzheimer's disease (HR 0.83, 95% CI 0.76-0.91), while obesity was associated with a higher risk of vascular dementia (HR 1.38, 95% CI 1.19-1.59) but not all-cause dementia. For body size trajectories, transitioning from thinner childhood body size to overweight in adulthood was associated with lower risks of all-cause dementia (HR 0.82, 95% CI 0.75-0.90) and Alzheimer's disease (HR 0.77, 95% CI 0.67-0.88), whereas transitioning to obesity was associated with a higher risk of vascular dementia (HR 1.54, 95% CI 1.24-1.92). In addition, higher adiposity, particularly obesity, was associated with lower gray matter and total brain volumes and greater white matter hyperintensity burden.

CONCLUSION: Life-course adiposity patterns are associated with dementia risk and brain structural changes, with differences by subtype and sex. Childhood adiposity and weight gain may be linked to adverse outcomes, whereas moderate adiposity in adulthood was associated with lower dementia risk.},
}

@article {pmid42582182,
year = {2026},
author = {Bhargava, Y and Tripathi, S and Baths, V and Deshpande, BM},
title = {Navigation performance in virtual reality-based cognitive assessment games as a candidate digital cognitive marker of hippocampal vulnerability: a scoping review.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70434},
pmid = {42582182},
issn = {2352-8729},
abstract = {Virtual reality-based cognitive assessment games (VR-CAGs) are an emerging digital paradigm in dementia and Alzheimer's disease research. Although multiple studies report correlations between VR-CAG performance and standard neuropsychological assessments, clinical adoption remains limited, indicating that behavioral evidence alone is insufficient and that consolidated neuroimaging evidence is required. Existing neuroimaging studies link VR-CAG performance to regional brain activation, volumetric change, and brainwave dynamics, but this evidence remains scattered. We conducted a scoping review of 29 neuroimaging studies on VR-CAGs. Three functional neural systems were associated with VR-CAG performance: the spatial map system, the response system, and the executive control system. Two VR-CAG archetypes - hippocampal-based and adaptive navigation - were identified. A reporting and evaluation checklist is proposed to standardize VR-CAG research. Review findings indicate that VR-CAGs based on allocentric and egocentric tasks may be sensitive to hippocampal health, potentially acting as candidate digital markers of dementia-relevant functional cognitive decline.},
}

@article {pmid42582266,
year = {2026},
author = {Yang, X and Li, Y and Bibic, A and Wang, J and Wan, M and Duan, W and Lu, H and Wei, Z},
title = {Differential presence of cerebral microbleeds in an amyloid mouse model compared with a CADASIL mouse model.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70308},
pmid = {42582266},
issn = {2352-8737},
abstract = {INTRODUCTION: Cerebral microbleeds are commonly observed on susceptibility-based magnetic resonance imaging (MRI) in Alzheimer's disease (AD) and are often interpreted as markers of small-vessel disease. However, how microbleed occurrence differs between amyloid-associated vascular pathology and non-amyloid vascular conditions remains incompletely understood. In this study, we performed a comparative analysis between an amyloidosis mouse model and a non-amyloid arteriopathy cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) model to assess whether microbleed occurrence differs across these distinct vascular contexts.

METHODS: Multimodal in vivo MRI at 11.7T, including gradient echo (GRE), spin echo, and diffusion-weighted imaging, was performed in 5xFAD mice and a CADASIL mouse model across 9 to 20 months of age. Ex vivo high-resolution GRE imaging and Prussian blue staining were used to validate microbleeds. Quantitative analyses focused on microbleed counts, parenchymal and cerebrospinal fluid volumes, and regional apparent diffusion coefficient (ADC). In addition, blood-brain barrier (BBB) integrity was assessed in the CADASIL mice.

RESULTS: Both in vivo and ex vivo GRE MRI consistently revealed hippocampal microbleeds in 5xFAD mice, whereas no microbleeds were detected in CADASIL mice at any examined age. Microbleeds in 5xFAD mice occurred in the absence of brain atrophy or ventricular enlargement. ADC elevation was observed selectively in the midbrain of 5xFAD mice but not in other regions or in the CADASIL cohort. BBB permeability remained normal in CADASIL mice, indicating preserved vascular barrier integrity despite vascular smooth muscle cell loss.

DISCUSSION: Cerebral microbleeds emerged selectively in the amyloid model and were absent in a non-amyloid arteriopathy driven by vascular smooth muscle cell degeneration, suggesting that microbleed occurrence may depend on the underlying pathology. These findings show consistency with the possibility that cerebral microbleeds may reflect disease-associated vascular conditions, refining their interpretation as translational MRI biomarkers in AD.},
}

@article {pmid42582267,
year = {2026},
author = {Winzell, F and Arvidsson, I and Overgaard, NC and Heyden, A and Åström, K and Karlsson, L and Vogel, JW and Hansson, O and Mattsson-Carlgren, N and , },
title = {Benchmarking privacy and utility in synthetic tabular cohorts for Alzheimer's disease research.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70430},
pmid = {42582267},
issn = {2352-8729},
abstract = {INTRODUCTION: The scarcity of large, clinically relevant cohorts is becoming a bottleneck in Alzheimer's disease (AD) research, as their sensitive nature makes open data sharing difficult. Privacy-preserving synthetic datasets generated with machine learning may help address this challenge.

METHODS: We compared five frameworks for generating synthetic tabular data from the Alzheimer's Disease Neuroimaging Initiative and Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease cohorts, with a set of empirical privacy and utility metrics. Two of the methods, DataSynthesizer and TableDiffusion, provide ε -differential privacy guarantees.

RESULTS: Methods with differential privacy achieved high privacy ratings but low levels of utility. Deep learning methods like Tabular Prior-data Fitted Network (TabPFN) and Conditional Generative Adversarial Network (CTGAN) also showed high privacy with limited utility. In contrast, non-private DataSynthesizer and Synthpop offered higher utility at a cost of lower privacy.

DISCUSSION: The evaluated methods demonstrated a clear trade-off between privacy and utility. High privacy was generally associated with insufficient utility, highlighting the need for further research into synthetic data generation for AD.},
}

@article {pmid42582435,
year = {2026},
author = {Wu, M and Zeng, X and Cai, Y and Chen, H and Li, Q and Yang, H},
title = {Parvalbumin interneurons in Alzheimer's disease: Physiological insights and pathophysiological mechanisms.},
journal = {Journal of cell communication and signaling},
volume = {20},
number = {3},
pages = {e70105},
pmid = {42582435},
issn = {1873-9601},
abstract = {Fast-spiking parvalbumin-positive (PV[+]) interneurons, a specialized class of inhibitory neurons, possess unique morphological and functional properties that govern spatiotemporal precision in local microcircuits, large-scale network synchronization, and memory-related computations. Since their initial identification in the late 19th century, technological innovations in cellular neuroscience have progressively elucidated the multifaceted roles of these neurons. In this review, we first delineate the embryonic origins and developmental trajectory of PV[+] interneurons, emphasizing their unique properties for high-frequency firing with remarkable temporal precision. These specialized features enable PV[+] interneurons to orchestrate network oscillations and critically modulate memory encoding, consolidation, and retrieval, despite their substantial metabolic demands. We subsequently integrate multiple lines of evidence implicating region- and subtype-specific PV[+] interneuron impairment as a pivotal pathological hallmark in Alzheimer's disease (AD). Furthermore, we dissect molecular and cellular mechanisms driving PV[+] interneuron dysfunction in AD, including numerical alterations, morphological remodeling, and electrophysiological disruptions. Critically, we propose that the pathological transformation of PV[+] interneuron physiology emerges as a key driver in AD progression, bridging cellular dysfunction to system-level cognitive failure.},
}

@article {pmid42582438,
year = {2026},
author = {Tan, M and Lan, X and Anayiti, X and Chen, P and Liu, Y and Lin, B and Wang, P},
title = {The role of glymphatic-related structural and functional imaging biomarkers in the pathological progression of Alzheimer's disease: a multimodal imaging-based study.},
journal = {Quantitative imaging in medicine and surgery},
volume = {16},
number = {8},
pages = {609},
pmid = {42582438},
issn = {2223-4292},
abstract = {BACKGROUND: The comparative utility of choroid plexus volume (CPV) and the diffusion tensor imaging-based perivascular space (DTI-ALPS) index as glymphatic biomarkers across the Alzheimer's disease (AD) continuum is unclear. This study aimed to perform a head-to-head comparison of their relationships with AD pathology, cognition, and diagnostic performance.

METHODS: This study analyzed data from 848 AD Neuroimaging Initiative (ADNI) participants [426 cognitively normal (CN), 309 with mild cognitive impairment (MCI), and 113 with AD dementia]. Group differences in CPV and the ALPS index were assessed using generalized linear models (GLM), and their associations with AD biomarkers and cognition were examined via partial correlation. Diagnostic performance using logistic regression, and longitudinal predictive value was assessed with linear mixed models.

RESULTS: Compared with the CN and MCI groups, patients with AD exhibited significantly increased CPV and reduced ALPS indices (all P<0.001). Amyloid-β-positive (Aβ[+]) participants also showed significantly higher CPV and lower ALPS indices than Aβ-negative (Aβ[-]) individuals (all P<0.001). Elevated CPV was associated with lower cerebrospinal fluid (CSF) Aβ42 (r=-0.15, P<0.001), poorer Mini-Mental State Examination (MMSE; r=-0.12, P<0.001), Montreal Cognitive Assessment (MoCA; r=-0.17, P<0.001), and reduced hippocampal volume (r=-0.21, P<0.001). Conversely, higher ALPS indices were associated with increased CSF Aβ42 (r=0.12, P<0.001), better MMSE (r=0.13, P<0.001), and preserved hippocampal volume (r=0.15, P<0.001). CPV achieved superior diagnostic performance for differentiating AD from MCI [area under the curve (AUC) =0.774] and CN (AUC =0.912). Moreover, integrating CPV, ALPS, and hippocampal volume further improved classification performance across diagnostic and Aβ stratification tasks. Longitudinal analyses demonstrated that higher baseline CPV was associated with better baseline cognitive performance and slower decline in executive, language, and memory functions, whereas lower baseline ALPS indices predicted accelerated memory decline over time.

CONCLUSIONS: Our findings identify CPV and the ALPS index as a pair of promising, complementary neuroimaging biomarkers for AD. Their synergistic integration into diagnostic models improves the precision of early detection and intervention strategies.},
}

@article {pmid42582463,
year = {2026},
author = {Trudel, L and Therriault, J and Macedo, AC and Rahmouni, N and Soucy, JP and Gauthier, S and Vitali, P and Guiot, MC and Hazrati, LN and Rosa-Neto, P},
title = {Posterior cortical atrophy and logopenic variant primary progressive aphasia are more specific for Alzheimer's disease pathology than probable Alzheimer's disease.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag304},
pmid = {42582463},
issn = {2632-1297},
abstract = {Accurately diagnosing Alzheimer's disease is challenging, as 15-30% of individuals diagnosed clinically lack evidence of Alzheimer's disease neuropathological changes (ADNC) at autopsy. While the typical amnestic presentation of Alzheimer's disease may have limited specificity due to coexisting age-related pathologies, atypical presentations such as logopenic variant primary progressive aphasia (lvPPA) or posterior cortical atrophy (PCA) are often associated with ADNC. This study evaluated how well clinical diagnoses of amnestic and atypical Alzheimer's disease predict ADNC and how co-pathologies contribute to clinical-pathological discordance. To evaluate how clinical diagnosis predicts ADNC, we calculated positive predictive values (PPVs) and negative predictive values (NPVs) for clinical diagnoses of PCA, lvPPA, amnestic Alzheimer's disease or non-Alzheimer's disease dementia for ADNC, using four neuropathological thresholds defined by combinations of the Consortium to Establish a Registry for Alzheimer's disease (CERAD) neuritic plaque frequency (moderate or frequent) and Braak stage (III-VI or V-VI). Analyses were replicated in vivo using amyloid- and tau-PET positivity (A+T+) as a surrogate for Alzheimer's disease pathology. We also quantified the frequency of co-pathologies and assessed their contribution to false-positive Alzheimer's disease diagnoses. This study included 6363 autopsy-confirmed cases from the National Alzheimer's Coordinating Center (NACC) database (mean age: 80.0 ± 11.4 years; 46.0% female) and 76 participants from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (mean age: 67.9 ± 9.94 years; 55.3% female). The PPV of probable Alzheimer's disease dementia ranged from 58 to 80%, while PCA and lvPPA showed higher PPVs (81-96% and 80-92%, respectively) for ADNC. The NPV of probable Alzheimer's disease dementia ranged from 66 to 83%, compared with 38-58% for PCA and lvPPA. In TRIAD, individuals with PCA or lvPPA had 100% PPV for Alzheimer's disease biomarker abnormality, whereas amnestic Alzheimer's disease dementia showed a PPV of 78.1%. Among Alzheimer's disease dementia cases, 20.2% were ADNC-negative, with a higher frequency of false-positive diagnoses in late-onset compared with early-onset cases (23.8% versus 6.9%). Among ADNC-negative Alzheimer's disease dementia cases, vascular pathology was the most common pathology (early-onset: 93%; late-onset: 98%). In the late-onset group, limbic-predominant age-related TDP-43 encephalopathy occurred in 31% of the cases, followed by Lewy body pathology (28.8%) and primary age-related tauopathy (24.3%). Visuospatial and language variants of clinical Alzheimer's disease offer excellent predictive value for underlying Alzheimer's disease pathology, both in vivo and at autopsy, outperforming the amnestic presentation classically associated with Alzheimer's disease. Clinical-pathological discordance in amnestic Alzheimer's disease dementia is frequently associated with coexisting age-related and vascular pathologies, highlighting the complexity of interpreting clinical Alzheimer's disease diagnoses in the absence of ADNC.},
}

@article {pmid42582587,
year = {2026},
author = {Eid, TM and Lashley, T and Warner, TT and Khan, A and Jantrachotechatchawan, C and Francis, PT and Hardy, J and Bandopadhyay, R},
title = {Altered synaptic and astrocytic proteins in Lewy body disorders associated with GBA mutations.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag246},
pmid = {42582587},
issn = {2632-1297},
abstract = {Mutations in the glucocerebrosidase (GBA) gene, originally implicated in Gaucher's disease, are now recognized as a major risk factor for developing Parkinson's disease (PD). While up to 70% of PD patients eventually progress to dementia, GBA mutations further increase the risk of Lewy body dementias (LBD), an umbrella term encompassing both dementia with Lewy bodies and Parkinson's disease dementia. Collectively, these disorders are classified as synucleinopathies. To date, there is no clear understanding of the mechanistic relationships between GBA mutations and synucleinopathies, although, synaptic protein changes have been shown to correlate with cognitive change in LBD as well as in Alzheimer's disease (AD). The aim of this study was to examine synaptic dysfunction in α-synucleinopathies with GBA mutations. The research cohort consisted of 10 controls, 7 PD/LBD-GBA N370S, and 20 PD/LBD-wild type (WT) where seven synaptic markers including four pre-synaptic [synaptosomal-associated protein 25; (SNAP25), synaptophysin; (SYP), ras-related protein; (Rab3A), and vesicle associated membrane proteins 2; (VAMP2)], two post-synaptic [post-synaptic density protein 95; (PSD95), and neurogranin; (NRGN)], and one astrocytic [vesicle associated membrane proteins 3; (VAMP3)] protein were investigated in four cortical regions (prefrontal, temporal, anterior cingulate and parietal) using immunoblot technique. Four markers (NRGN, SNAP25, VAMP2, and VAMP3) were found to be significantly and regionally altered between the three groups. The expression of pre-synaptic (SNAP25), post-synaptic (NRGN), and the astrocytic protein (VAMP3) is different between PD/LBD with GBA mutation and PD/LBD-WT suggesting the potential role of GBA gene due to mutations which could alter the levels of some synaptic markers. Our study is the first to validate several synaptic markers in human post-mortem-associated GBA N370S mutation.},
}

@article {pmid42582950,
year = {2026},
author = {Budak, M and Heffernan, KS and Ishaq, M and Paruzel, V and Abdalla, D and Moallemian, S and Fausto, BA and Elahi, FM and Gluck, MA},
title = {ABCA7-80 moderates vascular stiffness-p-tau217 association in older African Americans.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70297},
pmid = {42582950},
issn = {2352-8737},
abstract = {INTRODUCTION: Compromised vascular health is increasingly linked to Alzheimer's disease (AD) risk. Estimated pulse wave velocity (ePWV), derived from age and blood pressure, and provides a practical, non-invasive index of vascular stiffness and overall vascular health. Older African Americans experience a disproportionate burden of vascular disease and AD. Genetic risk factors such as APOE ε4 and ABCA7-80 (rs115550680) further increase AD susceptibility. However, whether these genetic risks influence vascular stiffness and how that may interact with AD pathology remains unknown, especially in African Americans.

METHODS: A total of 143 older African Americans (mean age = 71.10 ± 6.83 years; 109 women) were included. We examined the effects of both ABCA7-80 and APOE ε4 genotypes on ePWV and plasma phosphorylated tau 217 (p-tau217). All regression models controlled for sex, education, pulse pressure, waist-to-hip ratio, global cognitive status, hypertension status, and APOE genotype (APOE genotype only used for ABCA7-80 regression models).

RESULTS: ABCA7-80 risk allele carriers exhibited higher ePWV (F (1,130) = 8.16, p = 0.005, η[2] p = 0.064) and higher p-tau217 levels (F (1,130) = 30.11, p < 0.001, η[2] p  = 0.201). APOE ε4 allele carriers also showed higher p-tau217 levels (F (1,131) = 12.96, p < 0.001, η[2] p = 0.092). ABCA7-80 significantly moderated the relationship between ePWV and p-tau217 (F(1,130) = 6.58, p < 0.001), such that higher ePWV was associated with higher p-tau217 among ABCA7-80 risk carriers (β = 0.52, t (130) = 2.69, p = 0.008).

DISCUSSION: ABCA7-80 risk, but not APOE ε4, heightens susceptibility to the tau-related effects of compromised vascular health among older African Americans. These findings identify a genetically vulnerable subgroup in which vascular stiffness may disproportionately accelerate AD-related tau pathology and highlight vascular health as a modifiable target for reducing AD risk in African Americans.},
}

@article {pmid42583026,
year = {2026},
author = {Erdal, M and Arı, A and Emekli, AS and Yılmaz, NÇ and Kürtüncü, M},
title = {Clinical Use of Interleukin-6 Blockade in Neuroimmunological Disorders.},
journal = {Noro psikiyatri arsivi},
volume = {63},
number = {},
pages = {482-494},
pmid = {42583026},
issn = {1300-0667},
abstract = {Interleukin-6 (IL-6) is a multifunctional cytokine that plays a critical role in immune regulation, host defense, and tissue repair. Within the central nervous system (CNS), IL-6 contributes to both neuroprotection and neuroinflammation, depending on the signaling pathway involved; classic signaling, trans-signaling, or trans-presentation. Dysregulation of IL-6, particularly through sustained overexpression, disrupts the blood-brain barrier (BBB) integrity, promotes glial activation, and amplifies chronic inflammation, thereby contributing to the pathophysiology of numerous neurological disorders. This review aims to evaluate the role of IL-6 in neuroinflammatory processes and its clinical implications across a spectrum of neurological diseases. It focuses on the therapeutic potential and safety profile of IL-6 inhibitors, particularly tocilizumab and satralizumab. Key conditions discussed include neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein-associated disease (MOGAD), autoimmune encephalitis (AE), neuro-Behçet's disease (NBD), myasthenia gravis (MG), epilepsy, multiple sclerosis (MS), and Alzheimer's disease (AD). Clinical trials have demonstrated the efficacy of IL-6 receptor blockade in reducing relapse rates in NMOSD, leading to regulatory approvals. Promising off-label results have also been reported in treatment-resistant cases of MOGAD, epilepsy, and autoimmune conditions. However, IL-6 inhibition carries risks such as serious infections and paradoxical inflammatory reactions. Targeting the IL-6 pathway represents a significant advancement in neuroimmunology, offering new therapeutic opportunities for otherwise refractory conditions. Future research should focus on large-scale randomized controlled trials and the development of IL-6 inhibitors capable of crossing the BBB to enhance CNS-specific efficacy. Cost-related accessibility also remains a major challenge for broader clinical application.},
}

@article {pmid42583149,
year = {2026},
author = {Binte Iqbal, H and Janjua, A and Mahato, RK},
title = {AI-driven neuroimaging for Alzheimer's disease: Addressing genetic and ethnic bias in diagnostic modeling.},
journal = {Journal of public health research},
volume = {15},
number = {3},
pages = {22799036261474536},
pmid = {42583149},
issn = {2279-9028},
}

@article {pmid42583477,
year = {2026},
author = {Jiakponnah, NN and Biose, IJ and Fischer, T and Cherry, K and Cronin, J and Jazwinski, SM and Kim, S},
title = {Alzheimer's Disease DNA Methylation Index (AD-DMI) and its Association with Late-Life Cognitive Function.},
journal = {NPJ dementia},
volume = {2},
number = {},
pages = {},
pmid = {42583477},
issn = {3005-1940},
abstract = {Alzheimer's disease (AD) is driven by genetic and epigenetic factors. A knowledge gap remains in applying DNA methylation (DNAm) to capture AD-specific signatures. We developed the AD DNA Methylation Index (AD-DMI), a brain-derived risk index constructed from 100 CpG sites identified by elastic-net logistic regression of methylation data from postmortem dorsolateral prefrontal cortex tissue. AD-DMI was evaluated in 722 older adults, including individuals with normal cognition (NC), mild cognitive impairment (MCI), and AD. AD-relevant associations were tested using generalized linear models, logistic regression, and path analyses, with applicable covariate adjustments. Higher AD-DMI scores were associated with lower global cognitive function, greater global AD neuropathologic burden, and increased odds of subjective memory complaints. AD-DMI predicted clinical diagnosis across the continuum, independent of cognition and pathology. Compared to the Cortical clock, AD-DMI showed stronger and more specific associations with both cognitive and pathological outcomes. Genes mapped to AD-DMI CpGs overlapped with eight genetic loci identified in AD genome-wide association studies, including RELN, LRP1B, and PDE9A. AD-DMI was significantly associated with increased methylation at CpGs in APOE, HOXA3, and ANK1. AD-DMI provides a biologically grounded framework for linking disease-relevant methylation changes with cognitive and pathological outcomes in AD.},
}

@article {pmid42583594,
year = {2026},
author = {Grady, ST and Andrews, RM and Peters, JL and Adar, SD and Levy, JI and Beck, T and Dhana, K and Desai, P and Haupt, BJ and Kaufman, JD and Szpiro, AA and Wilson, RS and Rajan, KB and Weuve, J},
title = {Residential aircraft and road noise exposure, cognition, and Alzheimer's dementia in a US cohort of older adults.},
journal = {Environmental epidemiology (Philadelphia, Pa.)},
volume = {10},
number = {4},
pages = {e518},
pmid = {42583594},
issn = {2474-7882},
abstract = {BACKGROUND: There is limited evidence of the associations between transportation noise and dementia risk. We examined associations of road and aircraft noise with cognitive function, cognitive decline, and Alzheimer's dementia (AD) in a cohort of older adults.

METHODS: We set our study in the Chicago Health and Aging Project, a longitudinal cohort of community-dwelling older adults from four Chicago, Illinois, neighborhoods, followed from 1993 to 2012. Every 3 years, participants underwent in-home cognitive assessments (episodic memory, perceptual speed, global cognition). A stratified random sample underwent clinical evaluation for AD diagnosis. We estimated 5-year time-weighted day-night average sound levels before baseline for road and, in analyses, we considered exploratory because of a limited exposure range, aircraft noise. We fit covariate-adjusted linear mixed models to estimate associations with cognitive performance and decline, and a multiple logistic regression model weighted by the sampling design to estimate incident AD odds ratios.

RESULTS: Of the 10,681 participants, an interquartile range increment in road noise (8.5 dBA) corresponded to a 0.06-SD unit lower baseline global cognitive score (95% confidence interval: -0.08, -0.03); there were no differences in cognitive decline. In exploratory analyses limited by power, higher aircraft noise was associated with a higher baseline score yet a faster rate of cognitive decline. Among 2147 participants evaluated for dementia (460 cases), road noise was not noticeably associated with greater AD risk, as there was substantial uncertainty (odds ratio per interquartile range = 1.17 [95% confidence interval: 0.86, 1.59]).

CONCLUSION: We observed mixed associations of transportation noise with cognitive functioning and dementia across noise sources. These findings underscore the need to better characterize noise sources relevant to the cognitive health of older adults.},
}

@article {pmid42583767,
year = {2026},
author = {Brewer, EH and Williams, CA and Cary, GA and Betarbet, R and Pranoto, IKA and Zoeller, EL and Fu, H and Levey, AI and Wiley, JC and Carter, GW and Young, JE and , },
title = {Inhibition of Moesin and CD44 in stem cell-derived neurons affects the pathological genetic signature associated with Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71734},
doi = {10.1002/alz.71734},
pmid = {42583767},
issn = {1552-5279},
support = {U54AG065187/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/pathology ; *Neurons/metabolism/pathology ; *Hyaluronan Receptors/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Phosphorylation ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Gene Knockdown Techniques ; Microfilament Proteins ; },
abstract = {INTRODUCTION: Post mortem proteomic analysis of Alzheimer's disease (AD) brain tissue has identified novel target genes and proteins for potential therapeutic development. Moesin (MSN) and CD44 were identified as candidate targets. Using human induced pluripotent stem cells (hiPSCs)-derived neurons, we assayed how reducing gene expression of MSN and CD44 affected amyloid beta secretion, tau phosphorylation, and transcriptional state.

METHODS: Knockdown of MSN and CD44 in hiPSC-derived neurons was performed using short hairpin RNA (shRNA). Amyloid precursor protein processing and intracellular tau phosphorylation was measured using chemiluminescent ELISA assays. Global gene expression was analyzed by bulk RNA sequencing (RNA-seq).

RESULTS: Knockdown of CD44 and MSN increased secretion of amyloid beta and soluble APP beta and differentially altered tau generation and phosphorylation. RNA-seq revealed diverse effects of CD44 and MSN knockdown and the reversal of some expression shifts found in late-onset AD.

DISCUSSION: These findings connect reduced CD44 and MSN expression to AD-related signatures in neurons and inform their role in the disease.},
}

Humans
*Alzheimer Disease/genetics/metabolism/pathology
*Neurons/metabolism/pathology
*Hyaluronan Receptors/genetics/metabolism
*Induced Pluripotent Stem Cells/metabolism
Phosphorylation
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
Amyloid beta-Protein Precursor/metabolism
Gene Knockdown Techniques
Microfilament Proteins

@article {pmid42583778,
year = {2026},
author = {Lisgaras, CP and Jacobs, T and Figueredo, L and Pirraglia, E and Radtke, CH and Keller, JN and Karvelas, N and Bernal, J and Ruiz, J and Zetterberg, H and Glodzik, L and de Leon, MJ and McIntire, LB and Boutajangout, A and Wisniewski, T and Ramos-Cejudo, J and Alcolea, D and Giménez, S and Fortea, J and Akassoglou, K and Elahi, FM and Osorio, RS},
title = {CSF fibrinogen predicts longitudinal Tau accumulation in cognitively unimpaired older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71720},
doi = {10.1002/alz.71720},
pmid = {42583778},
issn = {1552-5279},
support = {R01AG012101/AG/NIA NIH HHS/United States ; R01AG022374/AG/NIA NIH HHS/United States ; R01AG056031/AG/NIA NIH HHS/United States ; R01AG013616/AG/NIA NIH HHS/United States ; R01AG056531/AG/NIA NIH HHS/United States ; R01AG056682/AG/NIA NIH HHS/United States ; R01AG068248/AG/NIA NIH HHS/United States ; R01AG070821/AG/NIA NIH HHS/United States ; R01AG080609/AG/NIA NIH HHS/United States ; R01AG056850/AG/NIA NIH HHS/United States ; RF1AG080769/AG/NIA NIH HHS/United States ; P30AG066512/AG/NIA NIH HHS/United States ; R21AG086880/AG/NIA NIH HHS/United States ; R21AG056974/AG/NIA NIH HHS/United States ; R01AG061566/AG/NIA NIH HHS/United States ; R01AG081394/AG/NIA NIH HHS/United States ; R61AG066543/AG/NIA NIH HHS/United States ; R35NS143067/AG/NIA NIH HHS/United States ; R01AG092953/AG/NIA NIH HHS/United States ; R01AG079282/AG/NIA NIH HHS/United States ; //Cure Alzheimer's Fund/ ; //Citizens United for Research in Epilepsy/ ; A2025013S//Brightfocus Foundation Award/ ; 26-144745//Alzheimer's Association Zenith Award/ ; H2020-SC1-BHC-2018-2020//Horizon 2020-Research and Innovation Framework Programme from the European Union/ ; PI22/00611//Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España)/ ; PI25/00422//Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España)/ ; INT23/00048//Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España)/ ; INT21/00073//Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España)/ ; PI20/01473//Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España)/ ; PI23/01786//Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España)/ ; PI20/00836//Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España)/ ; GBHI_ALZ-23-971107//Global Brain Health Institute/ ; 1801Cycle2020//Jérôme Lejeune Foundation/ ; 2023-00356//Swedish Research Council/ ; 2022-01018//Swedish Research Council/ ; 2019-02397//Swedish Research Council/ ; 201809-2016862//Alzheimer Drug Discovery Foundation (ADDF)/ ; ADSF-21-831376-C//Alzheimer's Disease Strategic Fund and the Alzheimer's Association/ ; ADSF-21-831381-C//Alzheimer's Disease Strategic Fund and the Alzheimer's Association/ ; ADSF-21-831377-C//Alzheimer's Disease Strategic Fund and the Alzheimer's Association/ ; ADSF-24-1284328-C//Alzheimer's Disease Strategic Fund and the Alzheimer's Association/ ; NEuroBioStand,22HLT07//European Partnership on Metrology/ ; //Bluefield Project/ ; //Olav Thon Foundation/ ; //Erling-Persson Family Foundation/ ; FO2022-0270//Familjen Rönströms Stiftelse, Familjen Beiglers Stiftelse, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; UKDRI-1003//UK Dementia Research Institute at UCL/ ; IK2CX002180/VA/VA/United States ; 2019A012SUP//Larry L. Hillblom Foundation/ ; //New Vision Research/ ; //Rainwater Charitable Foundation/ ; //Chan Zuckerberg Initiative/ ; //Rockefeller Philanthropies/ ; },
mesh = {Humans ; *tau Proteins/cerebrospinal fluid ; *Fibrinogen/cerebrospinal fluid ; Aged ; Female ; Male ; Biomarkers/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Longitudinal Studies ; Alzheimer Disease/cerebrospinal fluid ; Blood-Brain Barrier ; Disease Progression ; Peptide Fragments/cerebrospinal fluid ; Chitinase-3-Like Protein 1/cerebrospinal fluid ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Blood-brain barrier (BBB) dysfunction is an early feature of Alzheimer's disease (AD). Fibrinogen represents a sensitive marker of BBB leakage, but whether it modifies longitudinal tau progression in cognitively unimpaired (CU) individuals remains unknown.

METHODS: CU older adults underwent clinical evaluation and cerebrospinal fluid (CSF) assessment of fibrinogen, Aβ42, total tau (tTau), phosphorylated tau 181 (pTau181), and YKL-40. Linear regression tested baseline associations. Linear mixed-effects models tested whether baseline fibrinogen predicted longitudinal pTau181 change.

RESULTS: Among 169 CU participants with baseline fibrinogen, 87 had longitudinal pTau181 measurements (mean follow-up 2.5-years). Higher fibrinogen was associated with elevated YKL-40 (β = 0.28, 95% confidence interval [CI] [0.11, 0.45]) but not Aβ42, tTau, or pTau181 at baseline. Baseline fibrinogen modified longitudinal pTau181 trajectories (interaction β = 0.11, 95% CI [0.04, 0.19]), with only participants above the median showing significant pTau181 increases (β = 0.13, 95% CI [0.08, 0.18]).

DISCUSSION: CSF fibrinogen associates cross-sectionally with glial inflammation and predicts accelerated tau accumulation in preclinical AD.},
}

Humans
*tau Proteins/cerebrospinal fluid
*Fibrinogen/cerebrospinal fluid
Aged
Female
Male
Biomarkers/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
Longitudinal Studies
Alzheimer Disease/cerebrospinal fluid
Blood-Brain Barrier
Disease Progression
Peptide Fragments/cerebrospinal fluid
Chitinase-3-Like Protein 1/cerebrospinal fluid
Aged, 80 and over

@article {pmid42583783,
year = {2026},
author = {Zufiria-Gerbolés, B and Vereb, D and Mijalkov, M and Passaretti, M and Volpe, G and Xu, Z and Hinault, T and Garcia-Ptacek, S and Pereira, JB and , },
title = {Vulnerability of locus coeruleus connections to aging and Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71737},
doi = {10.1002/alz.71737},
pmid = {42583783},
issn = {1552-5279},
support = {2022-01108//Swedish Research Council/ ; //Alzheimer Foundation/ ; 2022-014//Brain Foundation/ ; //European Union - NextGenerationEU and the Romanian Government, under National Recovery and Resilience Plan for Romania/ ; //Romanian Ministry of Research, Innovation and Digitalization, within Component 9,Investment I8/ ; //Strategic Research Area Neuroscience (StratNeuro)/ ; //KIConsolidator grant/ ; //KID-funding/ ; //Center for Medical Innovation (CIMED)/ ; //KonungGustaf V:s och Drottning Victorias Stiftelse/ ; //Foundation for Geriatric Diseases at Karolinska Institutet/ ; //Gamla Tjänarinnor/ ; //Stohnes Foundation/ ; //Lars Hiertas Memorial Foundation/ ; //Innovative ways to fight Alzheimer´s disease - Leif Lundblad Family and others/ ; //National Academic Infrastructure for Super-computing in Sweden/ ; 2022-06725//Swedish ResearchCouncil/ ; //Karolinska Institutet/ ; },
mesh = {Humans ; *Locus Coeruleus/pathology/diagnostic imaging ; *Alzheimer Disease/pathology/diagnostic imaging/genetics ; *Aging/pathology ; Female ; Aged ; Male ; Neural Pathways/pathology ; Magnetic Resonance Imaging ; tau Proteins/metabolism ; Aged, 80 and over ; White Matter/pathology ; Middle Aged ; Adult ; },
abstract = {INTRODUCTION: The locus coeruleus (LC) is important in coordinating communication between brain regions through its widespread connections. However, the organization of its connections, and its changes with aging and Alzheimer's disease (AD), remains unclear.

METHODS: We mapped whole-brain white matter connections from the LC in two independent cohorts: one spanning the adult lifespan and another covering the AD continuum.

RESULTS: We identified a novel dorsal-ventral organization of LC connectivity that showed changes common to aging and AD or specific to AD, was linked to gene expression patterns, and was associated with cognitive performance and tau pathology in the entorhinal cortex. We also developed an imaging marker, LC gap, capturing LC connectivity deviations associated with slower tau accumulation in cognitively normal individuals at high risk for AD.

DISCUSSION: These findings provide new insights into LC connectivity in aging and AD, highlighting its potential role as a resilience marker against AD neurodegeneration.},
}

Humans
*Locus Coeruleus/pathology/diagnostic imaging
*Alzheimer Disease/pathology/diagnostic imaging/genetics
*Aging/pathology
Female
Aged
Male
Neural Pathways/pathology
Magnetic Resonance Imaging
tau Proteins/metabolism
Aged, 80 and over
White Matter/pathology
Middle Aged
Adult

@article {pmid42583837,
year = {2026},
author = {Zhu, N and Xu, H and Garcia-Ptacek, S and Mitra, S and Eriksdotter, M},
title = {Oral anticoagulants, cognition, and clinical outcomes in atrial fibrillation and Alzheimer's disease: a Swedish nationwide study.},
journal = {European heart journal},
volume = {},
number = {},
pages = {},
doi = {10.1093/eurheartj/ehag584},
pmid = {42583837},
issn = {1522-9645},
support = {FoUI-1002840//Center for Innovative Medicine/ ; AF-1032116//Swedish Alzheimer's Foundation/ ; M24-0221//Åke Wiberg Foundation/ ; 2022-01428//Swedish Research Council/ ; 2022-01425//Swedish Research Council/ ; 2024-03599//Swedish Research Council/ ; M-2024-2526//Petrus and Augusta Hedlund Foundation/ ; 2024-1370//Magnus Bergvall Foundation/ ; //Swedish Kidney Foundation/ ; //Karolinska Institutet internal funds/ ; //Karolinska Institutet/ ; //Emil and Wera Cornell Foundation/ ; //Swedish Dementia Foundation/ ; //Stockholm County Council and Karolinska Institutet/ ; //New Innovative Roads Call/ ; //Leif Lundblad/ ; //Loo and Hans Osterman Foundation/ ; //Gun and Bertil Stohne Foundation/ ; //Swedish Dementia Foundation/ ; //Tore Nilson Foundation/ ; //Gamla Tjänarinnor Foundation/ ; //Lindhés Advokatbyrå Foundation/ ; //Mats Paulsson Foundation/ ; FO2024-0339//Swedish Brain Foundation/ ; 2021-02680//PREDEM/ ; },
abstract = {BACKGROUND AND AIMS: Use of non-vitamin K oral anticoagulants (NOACs) is associated with reduced dementia risk in patients with atrial fibrillation (AF), but their impact on cognitive function and clinical outcomes in AF patients with Alzheimer's disease (AD) remains unclear.

METHODS: Based on the Swedish Registry for Cognitive/Dementia Disorders, individuals with incident AD during May 2007-December 2020 and pre-existing AF were identified. Anticoagulant use at baseline was categorized as non-use, warfarin, or NOACs. Inverse probability of treatment weighting was employed to balance covariates. Mixed-effects models were used to assess the association between anticoagulant use and cognitive decline measured by the Mini-Mental State Examination (MMSE). Cox proportional hazards models were used to examine risks of all-cause mortality, ischaemic stroke/systemic embolism, major bleeding, and fracture.

RESULTS: Among 7308 eligible individuals (3341 non-users, 2277 warfarin users, and 1690 NOAC users), NOAC users exhibited significantly slower cognitive decline compared to non-users (difference in MMSE scores β = 0.23 points/year, 95% confidence interval [CI] 0.11-0.36) and warfarin users (β = 0.21 points/year, 95% CI 0.10-0.33). Compared to non-use of anticoagulants, NOAC use was associated with significantly lower rates of mortality (hazard ratio [HR] 0.81; 95% CI 0.72-0.91), ischaemic stroke/systemic embolism (HR 0.66; 95% CI 0.53-0.82), and fracture (HR 0.79; 95% CI 0.64-0.97), without an increased rate of major bleeding (HR 1.05; 95% CI 0.84-1.32); in contrast, warfarin use was associated with significantly lower rates of mortality (HR 0.88; 95% CI 0.80-0.97) and ischaemic stroke/systemic embolism (HR 0.85; 95% CI 0.72-1.00), but a higher rate of major bleeding (HR 1.31; 95% CI 1.09-1.56). Compared to warfarin, NOAC use was associated with lower rates of ischaemic stroke/systemic embolism (HR 0.78; 95% CI 0.62-0.98) and major bleeding (HR 0.80; 95% CI 0.64-1.01), and non-significant reductions in mortality and fracture.

CONCLUSIONS: In patients with AF and AD, NOAC use was associated with modestly slower cognitive decline and more favourable effectiveness and safety profiles, compared to warfarin or no anticoagulation.},
}

@article {pmid42583902,
year = {2026},
author = {Laishram, D and Du, G and Kanekar, S and Nagaraja, N},
title = {White Matter and Perivascular Imaging Changes in Alzheimer's Disease and Cerebral Amyloid Angiopathy.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70506},
pmid = {42583902},
issn = {2328-9503},
abstract = {OBJECTIVE: Peak-width of skeletonized mean diffusivity (PSMD) and diffusion tensor imaging-analysis along the perivascular space (DTI-ALPS), reflecting white matter integrity and glymphatic function, are altered in Alzheimer's disease (AD). We evaluated whether these biomarkers differ between AD participants with and without concomitant cerebral amyloid angiopathy (CAA).

METHODS: The study included 50 AD participants with mild cognitive impairment/mild dementia, and intermediate to high AD neuropathologic change at autopsy. AD was categorized as AD with CAA and AD without CAA based on CAA neuropathology. We evaluated global and regional (frontal, parietal, temporal and occipital) PSMD; left, right and mean DTI-ALPS indices and their association with clinical measures [Clinical dementia rating sum-of-boxes (CDR-SB) from CDR Dementia Staging Instrument, mini mental state examination (MMSE), cognitive composites: memory, processing speed, executive function, and language].

RESULTS: AD participants with CAA (n = 17) had higher global [4.02 ± 1.44 (mean ± SD × 10[-4] mm[2]/s) vs. 3.12 ± 0.91, β = -0.80, 95% CI (-1.42, -0.18), p = 0.012] and occipital PSMD [4.02 ± 1.10 vs. 3.00 ± 1.08, β = -0.88, 95% CI (-1.51, -0.26), p = 0.026] than those without CAA. No PSMD metric was associated with any clinical measure. However, imaging-by-group interactions showed global PSMD associated with language [β = -0.89, 95% CI (-1.53, -0.26), p = 0.027] and parietal PSMD with language [β = -1.05, 95% CI (-1.74, -0.36), p = 0.014] and memory [β = -0.83, 95% CI (-1.38, -0.28), p = 0.015]. DTI-ALPS indices did not differ by group. Higher mean and right DTI-ALPS indices were associated with preserved language function [mean: β = 9.33, 95% CI (2.05, 16.62), p = 0.036; right: β = 7.75, 95% CI (1.54, 13.95), p = 0.043] without imaging-by-group interactions.

INTERPRETATION: Global and occipital PSMD may help identify AD participants with concomitant CAA.},
}

@article {pmid42583949,
year = {2026},
author = {Takahashi, M and Matsuoka, K and Yamamuro, K and Toritsuka, M and Makinodan, M},
title = {Facial Emotion Recognition Deficits in Alzheimer's Disease Are Associated With Bilateral Uncinate Fasciculus Abnormalities and Frontotemporal-Limbic Microstructural Disorganisation.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70206},
pmid = {42583949},
issn = {1479-8301},
mesh = {Humans ; *Alzheimer Disease/psychology/diagnostic imaging/pathology/physiopathology ; Female ; Male ; Aged ; Cross-Sectional Studies ; Diffusion Tensor Imaging/methods ; *Emotions/physiology ; *Uncinate Fasciculus/pathology/diagnostic imaging ; *Facial Expression ; *Temporal Lobe/pathology/diagnostic imaging ; Neuropsychological Tests ; Aged, 80 and over ; *Facial Recognition/physiology ; *Limbic System/pathology/diagnostic imaging ; Gray Matter/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; *Frontal Lobe/pathology ; White Matter/pathology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is associated with memory impairment and social cognitive dysfunction, including facial emotion recognition (FER) deficits. Our previous diffusion tensor imaging (DTI) study linked poor recognition of negative facial emotions in patients with AD to increased mean diffusivity (MD) in the left uncinate fasciculus (UF). Whether FER deficits in AD reflect microstructural alterations in related grey matter regions remains unclear.

METHODS: In this cross-sectional study, 74 patients with AD and 28 cognitively normal (CN) subjects underwent behavioural assessments using the Facial Emotion Selection Test (FEST). A subset of 67 AD patients and 23 CN patients underwent magnetic resonance imaging. DTI was used to assess the fractional anisotropy (FA) and MD of the bilateral UF, and neurite orientation dispersion and density imaging (NODDI) was used to evaluate the neurite density index (NDI) and orientation dispersion index (ODI) of the insula, amygdala and temporal lobe.

RESULTS: Patients with AD showed significantly lower FEST total, negative emotion, positive emotion and neutral expression scores. DTI revealed significantly lower FA and higher MD in the bilateral UF. In the AD group, higher bilateral UF MD was significantly associated with lower total FEST and negative emotional scores. NODDI analyses demonstrated significantly lower ODI in the insula, amygdala and temporal lobe in the AD group, whereas no significant between-group differences were observed in the NDI. In the uncorrected analyses, ODI showed trend-level positive associations with FEST performance; however, these associations did not remain significant after false discovery rate correction. Bilateral UF MD was negatively correlated with ODI in the insula and temporal lobes.

CONCLUSIONS: FER is broadly impaired in AD and is associated with bilateral UF abnormalities and reduced ODI in the frontotemporal-limbic regions. These findings suggest that social cognitive dysfunction in AD involves broader frontotemporal-limbic network disruption than isolated white matter abnormalities.},
}

Humans
*Alzheimer Disease/psychology/diagnostic imaging/pathology/physiopathology
Female
Male
Aged
Cross-Sectional Studies
Diffusion Tensor Imaging/methods
*Emotions/physiology
*Uncinate Fasciculus/pathology/diagnostic imaging
*Facial Expression
*Temporal Lobe/pathology/diagnostic imaging
Neuropsychological Tests
Aged, 80 and over
*Facial Recognition/physiology
*Limbic System/pathology/diagnostic imaging
Gray Matter/pathology/diagnostic imaging
Magnetic Resonance Imaging
*Frontal Lobe/pathology
White Matter/pathology

@article {pmid42584422,
year = {2026},
author = {Chen, M and Zhang, Q and Wu, Z and Lei, Z and Ling, Y},
title = {Integrated UHPLC-Q-Orbitrap HRMS and Network Pharmacology Approach for Exploring Potential Active Ingredients and Pharmacological Mechanisms of Epimedii Folium Against Alzheimer's Disease.},
journal = {Biomedical chromatography : BMC},
volume = {40},
number = {9},
pages = {e70594},
pmid = {42584422},
issn = {1099-0801},
support = {82560886//National Science Foundation of China/ ; 20252BAC240556//Jiangxi Provincial Natural Science Foundation/ ; GJJ2401823//Science and the Educational Department of Jiangxi Province of China/ ; },
mesh = {Chromatography, High Pressure Liquid/methods ; Molecular Docking Simulation ; *Alzheimer Disease/drug therapy ; *Network Pharmacology/methods ; *Drugs, Chinese Herbal/chemistry/pharmacology/analysis ; Humans ; Flavonoids/chemistry/analysis/pharmacology ; *Epimedium/chemistry ; },
abstract = {Epimedii Folium has been widely used to treat Alzheimer's disease (AD) in China. However, the potential active components of Epimedii Folium and its mechanism against AD are still not clear. In this study, an ultra-high performance liquid chromatography coupled to quadrupole Orbitrap high-resolution mass spectrometry (UHPLC-Q-OrbitrapHRMS) method was applied to screen the ingredients of Epimedii Folium. Network pharmacology was utilized to explore the potential active components and pharmacological mechanisms of Epimedii Folium against AD. The binding affinity and conformation of key active ingredients and core targets were performed by molecular docking. Consequently, 72 chemical constituents were identified in Epimedii Folium, including four phenolic acids, two quinones, three 9,10-dihydrophenanthrenes, and 63 flavonoids. Network pharmacology analysis revealed that quercetin, apigenin, kaempferol, and luteolin exhibit favorable pharmacological activities. Molecular docking demonstrated that apigenin-TNF, kaempferol-TNF, kaempferol-TP53, and quercetin-TP53 represent compound-target pairs with strong binding affinities. These findings help elucidate the material basis and underlying mechanisms of Epimedii Folium against AD and offer valuable evidence supporting the further development and clinical application of Epimedii Folium.},
}

Chromatography, High Pressure Liquid/methods
Molecular Docking Simulation
*Alzheimer Disease/drug therapy
*Network Pharmacology/methods
*Drugs, Chinese Herbal/chemistry/pharmacology/analysis
Humans
Flavonoids/chemistry/analysis/pharmacology
*Epimedium/chemistry

@article {pmid42584479,
year = {2026},
author = {Huang, CW and Chang, HI and Chang, TY and Lin, KJ and Hsu, SW and Lee, CC and Huang, SH and Chang, CC},
title = {Selective white matter tract vulnerability associated with tau burden in progressive supranuclear palsy and Alzheimer's disease.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42584479},
issn = {1619-7089},
support = {NSTC113-2321-B-182A-005//National Science and Technology Council/ ; NSTC114-2321-B-182A-004 and 115-2321-B-182A-001//National Science and Technology Council/ ; },
abstract = {PURPOSE: Progressive supranuclear palsy (PSP) and Alzheimer's disease (AD) exhibit different tau distributions. We compared tract-specific associations between florzolotau(18F) retention, white matter (WM) microstructure, and clinical impairment.

METHODS: Forty-nine patients with PSP, 40 with AD, and 30 cognitively unimpaired controls underwent florzolotau(18F) PET. Tractography evaluated projection and association fibers, including the dentatorubrothalamic tract (DRTT) and superior longitudinal fasciculus (SLF). Regional SUVRs were calculated using WM-PERSI normalization. Associations among uptake, diffusion measures, brain volume, and clinical outcomes were evaluated using covariate-adjusted correlations with Bonferroni correction, partial canonical correlation, and exploratory path analyses.

RESULTS: PSP was characterized by predominantly subcortical and brainstem florzolotau(18F) retention and more extensive WM abnormalities, including DRTT involvement. AD showed predominantly cortical retention and microstructural abnormalities of SLF branches. In PSP, regional subcortical uptake was associated with DRTT microstructure, while DRTT mean diffusivity and frontal volume contributed most strongly to the canonical variate associated with motor impairment (canonical correlation = 0.82, p = 0.001). In AD, cortical uptake was associated with SLF microstructure, while cortical volume and SLF mean diffusivity contributed to the canonical variate associated with executive function (canonical correlation = 0.83, p = 0.001). Exploratory path models were consistent with indirect associations involving white matter microstructure and cortical volume.

CONCLUSION: PSP and AD showed distinct patterns of tract vulnerability associated with regional florzolotau(18F) retention and clinical impairment. These cross-sectional findings support further longitudinal investigation of disease-specific network degeneration.},
}

@article {pmid42584743,
year = {2026},
author = {Wani, OH and Dhaka, P and Pinky, and Choudhary, SS and Wani, AA and Iqbal, A and Parvez, S and Dar, TA},
title = {Majoon-e-Boolis as a neurotherapeutic agent: cognitive and neuronal restoration in alzheimer's disease model.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42584743},
issn = {1573-7365},
support = {3-67/2022-CCRUM/Tech//Central Council for Research in Unani Medicine/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; Rats ; Oxidative Stress/drug effects ; Male ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology/therapeutic use ; Amyloid beta-Peptides ; *Cognition/drug effects ; *Neurons/drug effects/metabolism ; Antioxidants/pharmacology/therapeutic use ; Peptide Fragments ; Rats, Wistar ; },
abstract = {Majoon-e-Boolis (MB), a traditional Unani formulation, has been used for neurological conditions; however, its molecular mechanism remains largely unexplored. The current study was designed to explore the novel mechanistic insights between antioxidant activity, anti-inflammatory effects, dopaminergic support and anti-aggregation properties of the formulation for modulating the pathogenesis of Alzheimer's Disease (AD). Behavioral deficits were studied via Novel Object Recognition, Elevated Plus Maze and Open Field Test. In addition, the study looked at the immunohistochemistry of superoxide dismutase 2, tumor necrosis factor-alpha, tyrosine hydroxylase and α-synuclein (α-Syn) against Aβ1-42-induced AD model. Additionally, histopathological alterations were also performed against the AD model. The observed findings demonstrated that MB treatment in Aβ1-42-induced AD in rat models significantly improved their cognitive impairments and alleviated anti-anxiety behaviour with enhanced locomotor activity. Moreover, MB induced significant reduction in oxidative stress and neuroinflammation with enhanced dopaminergic neuronal activity. GC-MS analysis of MB revealed the presence of bioactive phytochemicals such as thiophene, guanidinopropionic acid, 5-hydroxymethylfurfural etc. The findings underscore the potential of MB as a promising therapeutic agent in mitigating the multifaceted pathology of Aβ1-42-induced AD in a rat model by exerting its neuroprotective effects, cognition restoration and overall maintenance of neuronal architecture through a combination of antioxidant, anti-inflammatory and anti-aggregation mechanisms, making it a multifaceted therapeutic candidate for AD.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/chemically induced
Rats
Oxidative Stress/drug effects
Male
Disease Models, Animal
*Neuroprotective Agents/pharmacology/therapeutic use
Amyloid beta-Peptides
*Cognition/drug effects
*Neurons/drug effects/metabolism
Antioxidants/pharmacology/therapeutic use
Peptide Fragments
Rats, Wistar

@article {pmid42584831,
year = {2026},
author = {Perez, A and Hammer, HL and Andersson, V and Saarinen, T and Alfonsín, S and Giuffrè, GM and Caraglia, N and Martellacci, N and Ramírez-Toraño, F and Tveitstøl, T and Kinnunen, A and Liljeström, M and Hotta, J and Koivisto, AM and Quaranta, D and Quijano-Rubio, C and Kollmorgen, G and Zetterberg, H and Christensen, E and Renvall, H and Marra, C and Maestú, F and Rossini, PM and Hatlestad-Hall, C and Haraldsen, IH},
title = {Cognitive components derived from traditional neuropsychological tests and their associations with plasma p-tau217 and p-tau181 in mild cognitive impairment: a multisite analysis.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42584831},
issn = {2509-2723},
support = {964220//Horizon 2020/ ; 2024019//Helse Sør-Øst RHF/ ; },
abstract = {BACKGROUND: Currently, no single biomarker can reliably identify preclinical Alzheimer's disease (AD), particularly at or before the mild cognitive impairment (MCI) stage. Given the heterogeneity of MCI, integrative approaches are needed to improve early risk stratification.

OBJECTIVES: (i) To derive robust latent cognitive components from a multicenter, clinically defined MCI cohort using principal component analysis (PCA); (ii) to investigate the associations between these components and plasma p-tau217 and p-tau181 levels.

METHODS: Data from 742 MCI participants in the AI-Mind cohort were analyzed. Cognitive domains were derived using PCA with varimax rotation and tested for associations with plasma p-tau biomarkers using site-specific linear regressions, adjusted for age, sex, and education.

RESULTS: A reproducible four-component cognitive structure emerged (memory, executive/processing speed, verbal fluency, visuospatial ability), with memory as the most p-tau-sensitive domain. The p-tau217 measure showed stronger associations with memory than p-tau181, though effects varied by site.

CONCLUSION: The findings indicate that a robust four-factor cognitive structure can be identified in clinically defined MCI cohorts without prior biological selection. The association between latent memory factors and plasma p-tau217, observed primarily in cohorts with higher biomarker burden or clearer amnestic profiles, highlights the potential for blood-based biomarkers to refine risk assessment in routine clinical practice.},
}

@article {pmid42584956,
year = {2026},
author = {Zhao, M and Zhou, N and Liu, R and Li, X and Li, J and Xue, F and Hou, Q},
title = {Biochemically Constrained Multi-Omics Integration Reveals Protein-Metabolite Dependencies Across Diseases.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e77067},
doi = {10.1002/advs.77067},
pmid = {42584956},
issn = {2198-3844},
support = {82473733//National Natural Science Foundation of China/ ; ZR2024ZD18//Shandong Provincial Natural Science Foundation/ ; },
abstract = {Integrating proteomic and metabolomic data is essential for understanding complex diseases, yet current approaches that rely primarily on statistical associations often overlook the structured biochemical relationships between molecular entities and suffer from discriminative instability in small clinical cohorts. Here, we present ProMetNet, a biochemically constrained framework that incorporates pathway-derived connectivity from the Reactome database into neural network architecture. By encoding protein-metabolite relationships based on reaction topology, ProMetNet models structured cross-omics dependencies rather than relying solely on statistical correlations, reducing spurious associations while preserving global molecular context and improving robustness in data-limited settings. Across four heterogeneous disease cohorts, including Alzheimer's disease, type 2 diabetes, COVID-19, and glioblastoma, ProMetNet consistently outperforms evaluated multi-omics integration methods, including MOGONET, P-NET, PEARL, and MOINER, maintaining high discriminative performance under substantial data downsampling. In addition to classification accuracy, the framework prioritizes biologically plausible protein-metabolite dependencies that are not captured by conventional differential or correlation-based analyses. Importantly, pathway-level signals identified by ProMetNet demonstrate consistent discriminative performance in independent large-scale population data from the UK Biobank (N = 47,507), supporting their robustness and generalizability. Together, these results establish ProMetNet as a biologically grounded and interpretable framework for multi-omics integration, enabling robust identification of structured molecular dependencies across diseases.},
}

@article {pmid42585241,
year = {2026},
author = {Majumder, R and Datta, P and Moolayadukkam, S and Puri, IK},
title = {Repurposing Alzheimer's and ovarian cancer drugs as sonosensitizers for glioblastoma via a positive-unlabeled learning and 3D bioprinting-based new approach methodology (NAM).},
journal = {PloS one},
volume = {21},
number = {8},
pages = {e0354981},
doi = {10.1371/journal.pone.0354981},
pmid = {42585241},
issn = {1932-6203},
mesh = {Humans ; *Glioblastoma/drug therapy/pathology/therapy ; Female ; *Drug Repositioning/methods ; *Bioprinting/methods ; *Ovarian Neoplasms/drug therapy/pathology ; Cell Line, Tumor ; *Antineoplastic Agents/pharmacology/therapeutic use ; *Brain Neoplasms/drug therapy/pathology ; *Alzheimer Disease/drug therapy ; Tumor Microenvironment/drug effects ; Ultrasonic Therapy/methods ; Spheroids, Cellular/drug effects ; },
abstract = {Glioblastoma (GBM) remains a lethal primary brain tumor, in part because therapeutic efficacy is limited by the blood-brain barrier (BBB) and the complex tumor microenvironment (TME). Sonodynamic therapy (SDT), i.e., use of ultrasound to activate chemical sensitizers and generate cytotoxic stress, offers a non-invasive strategy for treating deep-seated intracranial disease, but progress is constrained by the scarcity of validated sonosensitizers and the inefficiency of conventional in vitro screening methods. Here, we introduce a New Approach Methodology (NAM) that couples a neural network-based positive-unlabeled (PU) learning framework with a high-throughput, magnetic field-guided 3D bioprinting platform to accelerate identification and experimental validation of SDT-sensitizing agents. Using curated drug and small-molecule data and RDKit-derived molecular descriptors, the PU classifier identifies candidate ultrasound-responsive compounds without requiring reliable negative labels. We then validate the AI-based predictions in physiologically relevant U-87 MG glioblastoma spheroids that reproduce key TME features, including spatial heterogeneity and a hypoxic core. The NAM identifies two FDA-approved drugs, carboplatin (advanced ovarian cancer) and memantine hydrochloride (Alzheimer's disease), as effective ultrasound-responsive agents. In 3D spheroids, combining low-intensity pulsed ultrasound with either drug significantly reduces viability compared with drug-only controls, and both combinations outperform temozolomide (TMZ), the current standard chemotherapeutic. Time-resolved responses reveal distinct kinetics: memantine produces strong early cytotoxicity (24 h) enhanced by ultrasound, whereas carboplatin shows delayed but pronounced cytotoxicity (72 h), also improved by ultrasound. Together, these results establish an integrated computational-experimental NAM that enables rapid repurposing of approved drugs as SDT sensitizers and provides a scalable framework for advancing GBM therapeutic discovery while reducing reliance on animal studies.},
}

Humans
*Glioblastoma/drug therapy/pathology/therapy
Female
*Drug Repositioning/methods
*Bioprinting/methods
*Ovarian Neoplasms/drug therapy/pathology
Cell Line, Tumor
*Antineoplastic Agents/pharmacology/therapeutic use
*Brain Neoplasms/drug therapy/pathology
*Alzheimer Disease/drug therapy
Tumor Microenvironment/drug effects
Ultrasonic Therapy/methods
Spheroids, Cellular/drug effects

@article {pmid42585279,
year = {2026},
author = {Barnes, DE and Benjamin, C and Boscardin, WJ},
title = {Development and validation of machine learning models to predict risk of undiagnosed dementia using healthcare claims and electronic health record data.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474534},
doi = {10.1177/13872877261474534},
pmid = {42585279},
issn = {1875-8908},
abstract = {BackgroundApproximately half of people living with Alzheimer's disease and related dementias are undiagnosed.ObjectiveTo develop and validate algorithms that predict risk of undiagnosed dementia using electronic health record (EHR) and/or healthcare claims data.MethodsStudy participants were adult patients aged 65 years or older without evidence of dementia (diagnosis/medication) at baseline in two U.S. data sources: 1) Medicare claims (2010 to 2021); 2) EHR and claims from a primary care network (2016 to 2023). We applied coefficients from an existing, validated EHR-based algorithm to predictors defined using Medicare claims and used machine learning to develop new EHR- and claims-based predictive models. We assessed model discrimination using c-statistics.ResultsStudy participants included 8,374,400 Medicare beneficiaries (mean [SD] age, 76 [7] years; 57% female) and 29,983 primary care patients (age: 75 [6] years; 56% female). Model discrimination was good when applying EHR-based coefficients to Medicare claims-based predictors (c-statistic [95% confidence interval]: 0.770 [0.767, 0.773]) and was improved by refitting the model (0.795 [0.792, 0.798]) with a small added benefit from incorporating new claims-based predictors (0.801 [0.799; 0.804]). Similarly, when both EHR and claims data were available, discrimination was improved by refitting the model with a small additional benefit from including new predictors, regardless of the data source (EHR, claims, or either).ConclusionsA validated EHR-based algorithm predicted risk of undiagnosed dementia in Medicare claims with good discrimination. Model accuracy was improved by refitting and, to a lesser extent, by including novel predictors.},
}

@article {pmid42585283,
year = {2026},
author = {Barker, CCH and Koza, LA and Almuhanna, L and Trujillo, KR and Linseman, DA},
title = {Lack of effect of repetitive mild traumatic brain injury early in life on the neuropathological and behavioral hallmarks of Alzheimer's disease in 3xTg-AD mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476274},
doi = {10.1177/13872877261476274},
pmid = {42585283},
issn = {1875-8908},
abstract = {Repetitive traumatic brain injuries (rTBIs) are predicted to increase risk for neurodegenerative disorders including Alzheimer's disease (AD). Objective: By using a combination of behavioral tests and histopathology, we investigated whether brain trauma worsens cognitive dysfunction and brain pathology in 3xTg-AD mice subjected early in life to repetitive mild TBI (rmTBI). Methods: At 3 months old, mice in the rmTBI group were given 5 mTBIs, each separated by 48 h. Mice were aged to 10 months old and assessed for cognitive function using the Barnes maze and Novel Object Recognition behavioral tests. Hippocampal sections were stained for amyloid-β and phosphorylated-tau proteins that constitute pathological hallmarks of AD. Immunostaining for GFAP and Iba1 was also employed to assess glial reactivity in the hippocampus. Results: Results from the behavioral tests indicate that there are no significant differences in the severity of cognitive dysfunction between any of the 3xTg-AD mouse groups (naïve, SHAM, or rmTBI). As expected, wild-type mice perform better across all behavioral tests than any of the 3xTg-AD mice. Furthermore, we do not find any significant difference in the amount of amyloid-β aggregation, tau phosphorylation, or gliosis between rmTBI and control (naïve or SHAM) 3xTg-AD mouse groups. Conclusions: Collectively, our data show that rmTBIs early in life do not accelerate progression or enhance the magnitude of disease in mice that are genetically predisposed to developing AD. These findings suggest that the young brain is quite resilient to trauma and that an enhanced risk of neurodegeneration is not an inescapable conclusion of a history of rmTBI.},
}

@article {pmid42585284,
year = {2026},
author = {Aksoy Gündoğdu, A and Samancı, B and Alaylıoğlu, M and Şahin, E and Ulukan, Ç and Gürvit, İH and Dursun, E and Hanağası, HA and Gezen-Ak, D and Bilgiç, B},
title = {Prognostic significance of cerebrospinal fluid tau biomarkers in amyloid-negative A-T + N + neurodegeneration: A retrospective cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476236},
doi = {10.1177/13872877261476236},
pmid = {42585284},
issn = {1875-8908},
abstract = {BackgroundAmyloid-negative tau-related neurodegeneration represents a non-Alzheimer biomarker-defined profile; however, its clinical heterogeneity and prognostic relevance remain unclear within Alzheimer's disease-related frameworks.ObjectiveTo characterize the clinical spectrum and identify predictors of mortality in patients with this profile.MethodsIn this retrospective cohort study, 1280 patients evaluated at a tertiary neurology center were screened, and 130 with an amyloid-negative cerebrospinal fluid (CSF) pattern [amyloid-β (Aβ)42 normal, phosphorylated tau (pTau), and total tau (tTau) elevated] were included. Survival was assessed using Kaplan-Meier analysis, and predictors of mortality were evaluated using Cox models.ResultsThe cohort (mean age 68.8 ± 10.1 years; 45.4% female) showed heterogeneous diagnoses, mainly mild cognitive impairment and frontotemporal dementia (each 30%). Survival differed across diagnostic groups (log-rank p = 0.037), with more favorable outcomes in mild cognitive impairment. Male sex was more frequent among non-survivors (88.9% versus 45.6%, p < 0.001). Higher CSF tTau levels were associated with mortality in the joint Cox model (HR 1.003, 95% CI 1.001-1.006, p = 0.006) and faster clinical progression (r = 0.22, p = 0.011). When modeled separately, neither tTau nor pTau was independently associated with mortality; however, both became significant in opposite directions when included jointly.ConclusionsThe amyloid-negative A-T + N + profile represents a clinically heterogeneous subgroup with prognostic relevance. CSF tTau was associated with mortality and faster clinical progression, but the joint-model findings involving tTau and pTau should be interpreted cautiously as hypothesis-generating. Further studies are needed to clarify the prognostic value of tau-related biomarkers in this population.},
}

@article {pmid42585285,
year = {2026},
author = {Lu, YT and Guo, ZM and Liu, MY and Ji, CH and Luo, YT and Zhou, SY and Ma, T and Zhu, XC and , },
title = {Correlation analysis between complement proteins and Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261475358},
doi = {10.1177/13872877261475358},
pmid = {42585285},
issn = {1875-8908},
abstract = {BackgroundThe prominent pathological features of Alzheimer's disease (AD) are amyloid-β (Aβ) plaques and tau pathology. The complement cascade is closely related to AD-associated pathological processes; however, the precise mechanisms underlying its contributions remain incompletely elucidated.ObjectiveWe aim to investigate the changes in complement protein expression during AD progression.MethodsThis study enrolled 285 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Participants were classified into biomarker-defined groups based on predefined cutoff values for Aβ42 and phosphorylated tau (P-tau). We compared cerebrospinal fluid (CSF) levels of complement proteins (C1q, C2, C3, C4a, C5, C6, C8b, and factor B) across these subgroups. Furthermore, we explored their associations with core AD biomarkers (Aβ42, P-tau, and T-tau) and clinical characteristics. Additionally, we investigated age-related changes in complement gene expression within the cerebral cortex of 3xTg mice using single-nucleus RNA sequencing.ResultsComplement protein levels in the CSF of A + subjects were significantly lower than those in A- subjects, and complement protein levels were positively correlated with Aβ pathology. Complement protein levels were influenced by factors such as age, gender, body mass index, APOE genotype, and hypertension. Compared with control mice, the complement gene C1qa in microglia was upregulated throughout the entire pathological cycle in 3xTg AD mice.ConclusionsComplement proteins undergo significant changes during the pathogenesis of AD, and alterations in their levels may reflect early pathological changes in AD and warrant further investigation. Notably, our findings suggest that microglia may contribute to complement-mediated pathological processes associated with AD.},
}

@article {pmid42574987,
year = {2026},
author = {Liu, Z and Li, P and Cecarini, V and Eleuteri, AM and Nan, B and Piao, C},
title = {Ginsenoside Rg2 attenuates Alzheimer-like phenotypes in 3xTg-AD mice: Associations with gut microbiota and brain metabolomic profiles.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {160},
number = {},
pages = {158678},
doi = {10.1016/j.phymed.2026.158678},
pmid = {42574987},
issn = {1618-095X},
abstract = {BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is the most common form of dementia. The microbiota-gut-brain axis represents a critical pathway bridging peripheral metabolic signals and central AD pathology. This study aimed to evaluate the effects of ginsenoside Rg2 on AD-like phenotypes in 3xTg-AD mice and to examine its associations with gut microbiota and brain metabolomic profiles.

STUDY DESIGN AND METHODS: A 3xTg-AD mouse model was used to assess the effects of Rg2 intervention in vivo. Behavioral performance was assessed using open field and water maze tests, Aβ and inflammatory factors were detected by ELISA, gut microbial changes were analyzed by 16S rRNA sequencing, and brain metabolic alterations were investigated using untargeted metabolomics.

RESULTS: The results showed that Rg2 improved behavioral performance in mice, reduced Aβ deposition in the brain, and decreased serum and brain tissue inflammatory factors. Rg2 treatment was associated with alterations in gut microbial community characteristics. Metabolomics indicated that Rg2 was associated with alterations in the brain metabolic profile, with differential metabolites mainly involved in energy and lipid metabolism as well as inflammation-related pathways. The correlation network further revealed a close relationship between microbiota, SCFAs and brain metabolites, inflammation and behavioral indicators.

CONCLUSION: Rg2 attenuated AD-related pathology and functional impairment in 3xTg-AD mice. These protective effects were accompanied by changes in gut microbiota composition, brain metabolic profiles, and the inflammatory microenvironment. This study provides multi-omics evidence supporting the potential of Rg2 as a natural product for AD intervention and highlights its associations with gut microbiota and brain metabolism.},
}

@article {pmid42575163,
year = {2026},
author = {Thurber, KR and Lee, M and Tycko, R},
title = {Brain-seeded 42-residue amyloid-β fibrils that resemble fibrils directly extracted from Alzheimer's disease brain tissue.},
journal = {Journal of molecular biology},
volume = {},
number = {},
pages = {169983},
doi = {10.1016/j.jmb.2026.169983},
pmid = {42575163},
issn = {1089-8638},
abstract = {Fibrils formed by the 42-residue amyloid-β peptide (Aβ42) are known to be polymorphic, with molecular conformations and supramolecular structures that depend on conditions of nucleation, growth, seeding, or other factors. Structural studies of Aβ42 fibrils that develop in human brain tissue have been based on two different approaches, either direct extraction and partial purification of fibrils from brain tissue for characterization by cryogenic electron microscopy (cryo-EM) or growth of fibrils in vitro from seeds in amyloid-containing brain tissue extracts for characterization by solid state nuclear magnetic resonance (ssNMR) or cryo-EM. To date, studies of brain-extracted and brain-seeded Aβ42 fibrils have produced qualitatively different sets of structures. Here we report structures of two new brain-seeded Aβ42 fibril polymorphs, derived from cortical tissue of an Alzheimer's disease (AD) patient, that share certain structural features with previously characterized polymorphs extracted from AD brain tissue. These structures contribute to our understanding of the relationships between brain-seeded and brain-extracted fibril structures and expand our understanding of the full range of polymorphism in amyloid-β fibrils.},
}

@article {pmid42575313,
year = {2026},
author = {Fang, J and Wang, X},
title = {Opposing kinase signaling may underlie the inverse relationship between cancer and Alzheimer's disease.},
journal = {Journal of proteomics},
volume = {},
number = {},
pages = {105723},
doi = {10.1016/j.jprot.2026.105723},
pmid = {42575313},
issn = {1876-7737},
abstract = {Cancer and Alzheimer's disease (AD) are leading causes of mortality and exhibit an inverse relationship, where AD patients have reduced cancer risk and vice versa. However, the molecular basis of this relationship remains poorly understood. We reanalyzed published proteomic and phosphoproteomic datasets to investigate this relationship. Differentially abundant proteins were identified in lung adenocarcinoma and glioblastoma samples relative to controls and compared with proteins altered in AD brains, revealing 37 proteins with opposing abundance patterns. Protein-protein interaction and pathway analyses revealed enrichment in kinase signaling and phosphorylation pathways. Phosphoproteomic analysis identified 52 differentially phosphorylated sites with opposing patterns, while kinase-substrate enrichment analysis identified 44 kinases with opposing inferred activity profiles. Integration of kinase activity and phosphosite data identified 29 kinase-phosphosite pairs, including 4 prioritized pairs with opposing patterns relevant to both diseases. Across seven independent cancer cohorts, 17 of 20 statistically significant phosphosite-cohort comparisons (85%) were concordant with the discovery findings, supporting reproducibility of the prioritized phosphosites. Together, these findings highlight opposing kinase signaling as a prominent feature of the inverse relationship and suggest potential biomarkers and therapeutic targets. This study provides a novel systems-level framework for investigating inverse relationships, supported by an R Shiny application for data exploration (https://advscancer.shinyapps.io/advscancer/). SIGNIFICANCE: This study presents an integrated proteomic and phosphoproteomic framework for investigating the inverse relationship between cancer and Alzheimer's disease (AD). By integrating differential protein abundance, phosphosite phosphorylation, inferred kinase activity, and curated kinase-substrate relationships, we identified opposing signaling patterns and prioritized four kinase-phosphosite pairs. Independent evaluation across seven CPTAC cancer cohorts supported the reproducibility of the prioritized phosphosite patterns. These findings provide insight into molecular processes potentially associated with the inverse relationship between cancer and AD, identify candidate biomarkers and therapeutic targets, and demonstrate the value of systems-level, data-driven approaches for investigating shared and opposing disease processes.},
}

@article {pmid42575342,
year = {2026},
author = {Lobyntseva, A and Guz, LS and Galushkin, A and Gozes, I},
title = {Dramatic sex differences leading to different brain disease presentation: The requirement for sex-specific medications with ADNP/davunetide as a case study.},
journal = {Frontiers in neuroendocrinology},
volume = {},
number = {},
pages = {101274},
doi = {10.1016/j.yfrne.2026.101274},
pmid = {42575342},
issn = {1095-6808},
abstract = {Focusing on the brain-essential gene revealed in our laboratory, activity-dependent neuroprotective protein (ADNP) and its neuroprotective site, the investigational drug davunetide (NAP), we discuss ADNP regulating steroid hormone biosynthesis and sex chromosome genes coupled with sex-dependent shuttling between the nuclei and cytoplasm. Further coupled with sex-dependent transcriptional control, ADNP/davunetide cytoplasmic microtubule/Tau targeting is translated into differential sex regulation of key cellular processes including neurogenesis, synaptic function, and axonal transport, then decoded into sexual dichotomy in multicellular processes directing sex-dependent behavioral outcomes. ADNP regulation of these sex-specific processes serves as a target for davunetide intervention, toward sex-directed precision medicine, revealing sexually dichotomized neuroprotection against tauopathy risk and progression spanning from coronary artery bypass grafting (CABG) to prodromal Alzheimer's disease, progressive supranuclear palsy (PSP), and schizophrenia, as well as the pediatric ADNP syndrome. Sex-specific intranasal bioavailability of davunetide, regulated by the estrous cycle, provides a mechanistic foundation for these differential outcomes.},
}

@article {pmid42575373,
year = {2026},
author = {Ding, G and Liu, Y and Zhao, Y and Chen, X and He, Y and Li, Y and Chen, N and Cui, J},
title = {Metabolic Vulnerability Indices and Alzheimer's Disease Risk: A Prospective Analysis of the UK Biobank Cohort.},
journal = {The Journal of nutrition},
volume = {},
number = {},
pages = {101777},
doi = {10.1016/j.tjnut.2026.101777},
pmid = {42575373},
issn = {1541-6100},
abstract = {BACKGROUND: Metabolic dysfunction is implicated in Alzheimer's disease (AD) pathogenesis. Branched-chain amino acids (BCAAs) have been prospectively linked to dementia risk, yet prospective associations of composite metabolic vulnerability indices with incident AD remain untested.

OBJECTIVE: To examine associations of the Metabolic Vulnerability Index (MVX), Inflammatory Vulnerability Index (IVX), and Metabolic Malnutrition Index (MMX) with incident AD in the UK Biobank.

METHODS: Among 367,715 dementia-free UK Biobank participants (mean age 56.93 years, 54.3% female; 2006-2010 baseline), incident AD was ascertained through hospital and death registry linkage. Fully adjusted Cox models (Model 3) constituted the pre-specified primary analysis; three Bonferroni-corrected tests (α = 0.0167) addressed multiple comparisons. Restricted cubic splines characterized association shape; interaction analyses examined potential effect modification by sex, age group, diabetes status, BMI, inflammatory status, and polygenic risk.

RESULTS: Over 13.7 years, 2,615 participants developed AD. Per 1-SD increase, MMX (HR = 1.16, 95% CI: 1.12-1.21, p = 4.93×10[-13]) and MVX (HR = 1.12, 95% CI: 1.07-1.17, p = 3.72×10[-6]) were each associated with higher AD risk, both meeting the Bonferroni-corrected threshold; IVX showed no association (p = 0.108). Associations were approximately linear and monotonically increasing. Sex-specific associations were observed for MMX (stronger in males, p-interaction = 0.004) and MVX (stronger in females, p-interaction = 0.003). Sensitivity analyses confirmed robustness.

CONCLUSION: MMX and MVX are independently associated with incident AD, supporting the clinical relevance of metabolic health monitoring in neurodegeneration risk stratification.},
}

@article {pmid42575375,
year = {2026},
author = {Ali, S and Ayaz, A and Zaman, W},
title = {Establishing causality for protein lactylation in Alzheimer's disease: site validation, evidence standards, and experimental priorities.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118343},
doi = {10.1016/j.bcp.2026.118343},
pmid = {42575375},
issn = {1873-2968},
abstract = {Protein lysine lactylation has emerged as a candidate interface between metabolic stress and Alzheimer's disease (AD), but the strength of individual claims varies. This focused review evaluates whether reported histone and non-histone lactylation events meet analytical and experimental requirements for causal interpretation. Direct AD evidence is more robust for plaque-associated microglial histone H4 lysine 12 lactylation (H4K12la)-pyruvate kinase M2 (PKM2) feedback in an amyloid model. Histone H3 lysine 18 lactylation (H3K18la)-nuclear factor-κB (NF-κB) signaling is supported principally in senescent microglia and ageing or AD-related models. Human tau K331 lactylation demonstrates disease-associated occurrence but not quantitative occupancy, temporal precedence or residue-specific necessity. Amyloid precursor protein (APP) K612 lactylation provides a potentially protective mechanism supported by site-resolved identification, cellular perturbation and in vivo rescue. Histone H3 lysine 9 lactylation (H3K9la) and additional substrates remain hypothesis-generating. We distinguish putative enzymatic L-lactylation from methylglyoxal-derived D-lactoylation and define minimum standards for antibody specificity, stereochemistry, site localization, occupancy, protein abundance, cell composition, post-mortem quality, isotope tracing, genetic substitution and rescue. A four-tier framework separates extrapolated evidence, human occurrence or relevant in vivo association, site-specific AD-model mechanisms supported by intervention and rescue, and quantified, cell-resolved, residue-causal evidence independently replicated in human-relevant systems. Six experimental stages are proposed for advancing a candidate site from detection to human relevance. Current evidence supports protein lactylation as a context-dependent disease-modifying layer rather than a single upstream driver. Therapeutic development should prioritize validated sites and biomarker-defined cell states rather than indiscriminate suppression of lactate metabolism or global lactylation.},
}

@article {pmid42575412,
year = {2026},
author = {Liu, Y and Peng, L and Li, M and Yan, W and Xiang, Q},
title = {Let-7d-5p improves mouse cognitive function by targeting bach1 in Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115957},
doi = {10.1016/j.expneurol.2026.115957},
pmid = {42575412},
issn = {1090-2430},
abstract = {BACKGROUND: MicroRNAs (miRNAs) have emerged as critical modulators in Alzheimer's disease (AD) pathogenesis. The lethal-7 (let-7) family functions as key regulators of cell apoptosis, differentiation, and immune response. Herein, we explore the functions and underlying mechanisms of let-7d-5p in AD progression.

METHODS: Eight-month-old male APP/PS1 transgenic mice and wild-type C57BL/6 J mice were assigned to the model and control groups, respectively. Model mice received intrahippocampal injections of either a negative control adenovirus (Ad-NC) or a let-7d-5p overexpression adenovirus (Ad-let-7d-5p). The Morris water maze test was conducted to assess cognitive function. Hippocampal histopathological changes were evaluated using hematoxylin and eosin staining. Aβ deposition was detected via immunohistochemical staining. SH-SY5Y cells were transfected with let-7d-5p mimics prior to treatment with 10 μM Aβ1-42. Cell viability and apoptosis were examined using MTT assays and flow cytometry. The expression levels of let-7d-5p and bach1 were measured using RT-qPCR. Western blotting was conducted to evaluate bach1, Bcl-2, and cleaved caspase-3 protein levels. The binding relationship between let-7d-5p and bach1 was verified using luciferase reporter assays.

RESULTS: In vitro, Aβ1-42 treatment induced the downregulation of let-7d-5p and decrease of cell viability. However, overexpression of let-7d-5p significantly increased let-7d-5p level, enhanced cell viability and inhibited cell apoptosis of Aβ1-42-treated SH-SY5Y cells. Moreover, overexpression of let-7d-5p upregulated Bcl-2 protein levels and downregulated cleaved caspase-3 protein levels in Aβ1-42-treated SH-SY5Y cells. Furthermore, let-7d-5p overexpression ameliorated oxidative stress injury in Aβ1-42-treated SH-SY5Y cells. Importantly, bach1 upregulation counteracted the inhibitory effects of let-7d-5p overexpression on Aβ1-42-induced cellular injury. In vivo, let-7d-5p overexpression mitigated cognitive deficits of AD mice, as indicated by reduced escape latency and increased platform crossings. Additionally, let-7d-5p overexpression attenuated hippocampal histopathological changes and Aβ deposition in APP/PS1 mice. At the molecular level, let-7d-5p targeted bach1 3'UTR and repressed its mRNA and protein expression in vitro and in vivo. Rescue assays further validated that bach1 overexpression restored the protective effect of let-7d-5p on cognitive deficits and pathological injuries.

CONCLUSION: Let-7d-5p alleviates cognitive deficits in AD by inhibiting Aβ deposition and neuronal apoptosis through targeting bach1.},
}

@article {pmid42575452,
year = {2026},
author = {Dai, X and Ye, Z and Zhang, X and Huang, Y and Wang, C and Liu, Y and Gao, B and Zhang, J and Chen, X},
title = {SIK2-P300 axis Orchestrates the metabolic reprogramming and Immunological functions in microglia of Alzheimer's disease mice via a dual modulation of lactylation and Acetylation: An epigenetic Perspective.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106953},
doi = {10.1016/j.bbi.2026.106953},
pmid = {42575452},
issn = {1090-2139},
abstract = {Metabolic dysfunction in microglia is increasingly recognized as a core driver of Alzheimer's disease (AD) pathogenesis, and yet the underlying mechanisms remain elusive. Here, we identified salt-inducible kinase 2 (SIK2) as a critical metabolic checkpoint that was downregulated in microglia across the AD mouse models (5 × FAD, APP/PS1, and SAMP8). We found that a loss of SIK2 in microglia induced a pro‑inflammatory phenotype, thus impairing amyloid β-protein (Aβ) phagocytosis and rewiring glucose and lipid metabolism toward enhanced glycolysis and lipid accumulation. Mechanistically, SIK2 directly interacted with the histone acetyltransferase P300; SIK2 deficiency increased the activity of P300, elevating H3K9 acetylation and H4K8/12 lactylation at promoters of metabolic genes. The microglia‑specific SIK2 overexpression in the 5 × FAD mice mitigated cognitive deficits, Aβ pathology, neuroinflammation, and aberrant histone modifications. A pharmacological inhibition of P300 regained these protective effects. Our findings highlight the SIK2-P300 epigenetic axis as a key regulator of the metabolic homeostasis in microglia and a potential therapeutic target for AD treatments.},
}

@article {pmid42575718,
year = {2026},
author = {Dzib, E and Hernández-Ayala, LF and Silva-Aguirre, S and Galano, A},
title = {Rational Design of Multifunctional Tacrine Derivatives as Candidates for the Treatment of Alzheimer and Parkinson Diseases.},
journal = {ChemMedChem},
volume = {21},
number = {15},
pages = {e70429},
doi = {10.1002/cmdc.70429},
pmid = {42575718},
issn = {1860-7187},
support = {CBF2023-2024-1141//SECIHTI/ ; },
mesh = {*Tacrine/chemistry/pharmacology/chemical synthesis/therapeutic use/analogs & derivatives ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Design ; Humans ; Monoamine Oxidase/metabolism/chemistry ; Acetylcholinesterase/metabolism/chemistry ; *Parkinson Disease/drug therapy/metabolism ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis/therapeutic use ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism ; Structure-Activity Relationship ; *Monoamine Oxidase Inhibitors/chemistry/pharmacology/chemical synthesis ; Catechol O-Methyltransferase/metabolism ; Molecular Structure ; Molecular Docking Simulation ; Catechol O-Methyltransferase Inhibitors/chemistry/pharmacology/chemical synthesis ; },
abstract = {Alzheimer disease (AD) and Parkinson disease (PD) are multifactorial neurodegenerative disorders for which there is currently no therapy that prevents or slows their progress. Some drugs used to treat AD are inhibitors of acetylcholinesterase (AChE) and antagonists of N-methyl-D-aspartate receptor (NMDAr), while inhibitors of catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAO-B) are used for PD. Tacrine was the first FDA (Food and Drug Administration) approved drug against AD. Although later withdrawn due to hepatotoxicity, it remains a pivotal scaffold for drug development. Herein, 1295 tacrine derivatives, meant to enhance therapeutic efficacy and safety of the parent compound, were designed through the CADMA-Chem protocol. The chemical space was screened using selection scores based on ADME properties, toxicity, and synthetic accessibility. Two derivatives with the best drug-like behavior were chosen for further investigation. Acid-base constants and reactivity descriptors were estimated for them. Our findings show that these derivatives are promising inhibitors of AChE, COMT, NMDAr, and MAO-B. Therefore, according to in silico predictions they are expected to be beneficial for AD and PD. One of the compounds investigated here is the first reported tacrine-derived compound with potential as COMT inhibitor.},
}

*Tacrine/chemistry/pharmacology/chemical synthesis/therapeutic use/analogs & derivatives
*Alzheimer Disease/drug therapy/metabolism
*Drug Design
Humans
Monoamine Oxidase/metabolism/chemistry
Acetylcholinesterase/metabolism/chemistry
*Parkinson Disease/drug therapy/metabolism
*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis/therapeutic use
Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism
Structure-Activity Relationship
*Monoamine Oxidase Inhibitors/chemistry/pharmacology/chemical synthesis
Catechol O-Methyltransferase/metabolism
Molecular Structure
Molecular Docking Simulation
Catechol O-Methyltransferase Inhibitors/chemistry/pharmacology/chemical synthesis

@article {pmid42575772,
year = {2026},
author = {Russo, AG and Hawkshaw, MJ and Sataloff, RT},
title = {Voice Disorders as Early Biomarkers of Cognitive Decline.},
journal = {Journal of voice : official journal of the Voice Foundation},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jvoice.2026.07.037},
pmid = {42575772},
issn = {1873-4588},
abstract = {BACKGROUND: Dementia affects greater than 57 million people worldwide. With an aging population and limited disease-curing treatments available, early identification of biomarkers is crucial. The 2020 Lancet Commission identified hearing loss as the largest modifiable risk factor for dementia globally, and a randomized controlled trial found that hearing intervention reduced 3-year cognitive change in older adults who were at increased risk for cognitive decline. Similarly, studies have found that abnormalities in acoustic measures of voice are correlated with cognitive status and can potentially predict decline. The association between hearing loss and cognitive decline might have both social and neurological mechanisms. Dysphonia might pose similar problems. Socially, voice disorders may reduce engagement in social and cognitively stimulating activities. Neurologically, one example is in Parkinson's disease in which the vagus nerve is one of the earliest sites of Lewy body pathology in Braak staging, and dysphonia and dysarthria can precede motor symptoms by years. Voice changes have been associated with different neurological conditions such as amyotrophic lateral sclerosis, multiple system atrophy, and Alzheimer's disease. Despite this, no prior large-scale study has examined whether diagnosed voice disorders are associated independently with incident cognitive decline. Our study is the first to examine this potential association, using the TriNetX US Collaborative Health Network platform to compare patients with diagnosed voice disorders and matched controls, with a hearing loss cohort as a standard of comparison given that it is the largest established modifiable risk factor for dementia, as dysphonia is also a modifiable condition.

RESULTS: This study included 833,417 total patients in the voice disorders and control cohorts. Voice disorders were associated with a significantly elevated risk of incident cognitive decline compared to controls (HR=1.291, 95% CI 1.155-1.443, P<0.0001). Hearing loss alone was associated with a slightly lower risk of cognitive decline (HR=1.267, 95% CI 1.203-1.334, P<0.0001). Voice disorders without concurrent hearing loss were associated with an elevated risk of incident cognitive decline compared to hearing loss alone (HR=1.261, 95% CI 1.121-1.419, P=0.0001), while voice disorders with hearing loss were associated with the highest risk among all cohorts (HR=2.038 vs controls; HR=1.545 vs hearing loss). Both voice disorder subgroups did not differ when compared with each other (HR=1.088, P=0.376).

CONCLUSION: The results from our study indicate that voice disorders are associated with an elevated risk of incident cognitive decline and may represent a stronger early biomarker than hearing loss alone. These findings highlight otolaryngology and family medicine/internal medicine encounters as potential entry points for cognitive assessment, and early voice treatment needs to be investigated for possible beneficial cognitive effect.},
}

@article {pmid42575819,
year = {2026},
author = {Despa, F and Lashley, T},
title = {Amyloidogenic amylin signaling links diabetes to dementia pathogenesis.},
journal = {Trends in pharmacological sciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tips.2026.07.009},
pmid = {42575819},
issn = {1873-3735},
abstract = {Recent studies identify amyloidogenic human amylin, secreted by the pancreas, as a potential link between type-2 diabetes and Alzheimer's disease. Evidence suggests that pathogenic amylin signaling impairs cerebral bioenergetics, promoting tau hyperphosphorylation and neurodegeneration. Selective targeting of circulating amyloidogenic amylin and its pathogenic signaling may enable biomarker development and disease-modifying therapies.},
}

@article {pmid42575873,
year = {2026},
author = {Frank, LE and Flack, N and Faulk, C and Block, AJ and Bartz, JC and Larsen, PA},
title = {Epigenetic changes associated with the progression of prion disease in Syrian hamsters (Mesocricetus auratus).},
journal = {Prion},
volume = {20},
number = {1},
pages = {52-65},
doi = {10.1080/19336896.2026.2710965},
pmid = {42575873},
issn = {1933-690X},
mesh = {Animals ; *Epigenesis, Genetic ; DNA Methylation/genetics ; *Prion Diseases/genetics/pathology ; Mesocricetus ; Cricetinae ; Disease Progression ; Brain/metabolism/pathology ; },
abstract = {Prion diseases are fatal neurodegenerative disorders characterized by abnormally folded prion proteins inducing misfolding of normal prion proteins, leading to neurotoxic fibrils and plaques. Epigenetic mechanisms, particularly DNA methylation, are increasingly implicated in prion-like diseases (e.g. Alzheimer's disease), but their role in prion pathogenesis remains unclear. To investigate, we used nanopore sequencing and RNAseq to measure genome-wide methylation and gene expression in the brains of Syrian hamsters (Mesocricetus auratus) experimentally infected with a hamster-adapted murine synthetic prion strain (n = 9) and age-matched mock-infected controls (n = 9) at 80, 120, and 160 days post-infection (dpi). We identified 1,586, 1,692, and 2,429 differentially methylated regions (DMRs) at 80, 120, and 160 dpi, respectively. Early- and mid-stage prion disease (80 and 120 dpi) skewed towards hypermethylation, whereas late-stage prion disease (160 dpi) skewed towards hypomethylation. Gene ontology (GO) of DMR-associated genes at 160 dpi included neuron regulation and signalling, neurodevelopment, and cellular stress pathways. We identified 178 differentially expressed genes (DEGs) at 80 dpi, 90 at 120 dpi, and 616 at 160 dpi. The majority of DEGs were downregulated at 80 dpi, and at 120 and 160 dpi, most were upregulated. Overlap in DEGs across timepoints was limited, and GO terms were related to upregulation of disease/injury response and cell death pathways in later timepoints. Overall, we found a stage-specific transcriptional shift from immune suppression to widespread immune and inflammation activation. These findings provide time-resolved data on methylation and transcriptional changes associated with impaired neuronal structure, function, and communication during disease.},
}

Animals
*Epigenesis, Genetic
DNA Methylation/genetics
*Prion Diseases/genetics/pathology
Mesocricetus
Cricetinae
Disease Progression
Brain/metabolism/pathology

@article {pmid42575875,
year = {2026},
author = {Satake, Y and Kanemoto, H and Taomoto, D and Takeda, K and Katakami, S and Kobayashi, M and Matsunaga, K and Isohashi, K and Suehiro, T and Yoshiyama, K and Ikeda, M},
title = {Progression to Dementia in Very Late-Onset Schizophrenia-Like Psychosis Stratified by Alzheimer's Disease and Lewy Body Disease Biomarkers: A Retrospective Cohort Study.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70205},
doi = {10.1111/psyg.70205},
pmid = {42575875},
issn = {1479-8301},
support = {TK21K15730//Japan Society for the Promotion of Science/ ; Overseas Study grant//SENSHIN Medical Research Foundation/ ; },
mesh = {Humans ; Disease Progression ; *Lewy Body Disease/diagnosis/psychology ; Retrospective Studies ; Female ; Biomarkers/blood ; Male ; *Alzheimer Disease/diagnosis/psychology ; *Schizophrenia/diagnosis ; Aged ; *Psychotic Disorders/diagnosis ; Age of Onset ; Aged, 80 and over ; *Dementia/diagnosis ; Japan ; },
abstract = {BACKGROUND: Very late-onset schizophrenia-like psychosis (VLOSLP) is clinically heterogeneous, and its relationship with dementia-related neurodegenerative disease remains unresolved. We examined whether Alzheimer's disease (AD) and Lewy body disease (LBD) biomarker status were associated with dementia progression in VLOSLP.

METHODS: We retrospectively identified patients who visited the University of Osaka Hospital between January 2018 and December 2023 and met criteria for VLOSLP. Twenty-two participants with AD and/or LBD biomarker data and at least one follow-up assessment within 775 days were classified as biomarker-negative (BMs-neg; n = 7) or biomarker-positive (BMs-pos; n = 15). Group comparisons were performed using Mann-Whitney U tests and Fisher's exact tests.

RESULTS: The BMs-pos group showed older onset age and lower memory scores than the BMs-neg group. Dementia progression was more frequent in the BMs-pos group than in the BMs-neg group, although the difference was not statistically significant (8/15 [53.3%] vs. 1/7 [14.3%]; p = 0.165; odds ratio 6.31; 95% CI 0.55-353.18). Five of eight participants with AD biomarker positivity progressed to AD dementia. Three of seven participants with LBD biomarker positivity progressed to dementia, including two diagnosed with dementia with Lewy bodies. Follow-up MMSE, CDR, and CDR-SB scores differed significantly between groups.

CONCLUSIONS: AD and/or LBD biomarker-positive VLOSLP may be associated with greater dementia progression and cognitive decline, although findings should be interpreted cautiously given the small sample size and retrospective design. These results support the clinical value of considering neurodegenerative biomarkers when evaluating the prognosis and underlying pathology of VLOSLP.},
}

Humans
Disease Progression
*Lewy Body Disease/diagnosis/psychology
Retrospective Studies
Female
Biomarkers/blood
Male
*Alzheimer Disease/diagnosis/psychology
*Schizophrenia/diagnosis
Aged
*Psychotic Disorders/diagnosis
Age of Onset
Aged, 80 and over
*Dementia/diagnosis
Japan

@article {pmid42575917,
year = {2026},
author = {Jacob, T and Schützmann, MP and Gerhards, L and Hruby, L and Leprivier, G and Tamgüney, G and Hoyer, W},
title = {Liquid-liquid phase-separated tau colocalizes with and stabilizes Aβ oligomers.},
journal = {Communications chemistry},
volume = {9},
number = {1},
pages = {},
pmid = {42575917},
issn = {2399-3669},
support = {726368//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; },
abstract = {Protein aggregation is a hallmark of neurodegenerative diseases, where misfolded proteins accumulate into insoluble deposits. Emerging studies indicate that liquid-liquid phase separation (LLPS) may serve as a transient stage in the transition from monomers to amyloid fibrils for several proteins implicated in neurological disorders. In this study, we investigated the interplay between tau and off-pathway oligomers of amyloid-beta (Aβ), the two key proteins in Alzheimer's disease (AD). Our findings demonstrate that tau condensates act as reservoirs for Aβ oligomers under LLPS conditions. Inside the tau condensates, Aβ oligomers reduced tau dynamics and formed discrete puncta, indicating a conducive environment for Aβ oligomer clustering. In contrast, in the absence of LLPS conditions, tau and Aβ oligomers formed solid-like co-aggregates with distinct morphologies. Tau significantly affected the kinetics of Aβ assembly, stabilizing off-pathway oligomers and inhibiting their replacement by amyloid fibrils. Our results highlight interactions between higher-order assemblies of tau and Aβ that may contribute to AD pathology.},
}

@article {pmid42575945,
year = {2026},
author = {Keil, J and Hernandez-Urbina, V and Doherty, L and Bahmani, H and Holtkamp, M and Steinbart, D and Diall, AD and Hebel, JM and Brandt, C and Cloppenborg, T and Doll, A and Müschenich, M},
title = {High-frequency visual stimulation can increase medial temporal lobe ripple oscillation density.},
journal = {Communications medicine},
volume = {6},
number = {1},
pages = {},
pmid = {42575945},
issn = {2730-664X},
abstract = {BACKGROUND: Flickering visual stimulation can evoke neural oscillations, which can influence ongoing brain activity. Electrophysiological recordings of neural oscillations in the ripple band (80-180 Hz) show that these high-frequency oscillations occur in the neocortex and the hippocampus, that they phase-synchronize across long distances, and that ripple oscillations in the neocortex often precede those in the hippocampus during wakefulness. It is therefore possible that the neocortical ripple oscillations propagate beyond sensory areas to the hippocampus, inducing ripple oscillations.

METHODS: To test the hypothesis that neocortical ripple oscillations induced by visual stimulation induce hippocampal ripple oscillations, we conduct an exploratory experiment (N = 8) in humans, using ultra-high frequency visual stimulation to induce ripple oscillations recorded through electrodes implanted in or near the hippocampus. Although hippocampal ripple oscillations, so-called sharp-wave-ripples, mostly occur during quiet rest or slow-wave sleep, we aim to increase their abundance using visual stimulation during wakefulness in this exploratory study. We hypothesize that ultra-high frequency visual stimulation increases the number of sharp-wave-ripples relative to an eyes-open resting-state baseline.

RESULTS: In this exploratory and preliminary study, we observe significantly more sharp-wave-ripples per second during periods of stimulation compared to a resting-state baseline before and after the stimulation.

CONCLUSIONS: The increased number of sharp-wave ripples during stimulation suggests that ultra-high-frequency visual stimulation can be used as a safe noninvasive tool to influence sharp-wave ripples, which offers the potential to improve memory.},
}

@article {pmid42576087,
year = {2026},
author = {Oyedokun, PA and Gbadero, JO and Ajao, DI and Olorunsesan, MD and Oyesiji, AI and Ayilara, GO and Ogunsina, MK and Justus, BS and Ademola, FM and Adetunji, EA and Okodio, PS and Amedu, NO},
title = {The Amino Acid-Neurodegeneration Axis: Excitotoxicity and Oxidative Stress as Context-Dependent Amplifiers of Metabolic Dysfunction.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42576087},
issn = {1559-1182},
mesh = {*Oxidative Stress/physiology ; Humans ; Animals ; *Amino Acids/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; *Nerve Degeneration/metabolism/pathology ; Mitochondria/metabolism ; },
abstract = {Homeostasis of amino acids is essential for the integrity of the CNS, and is maintained by a tightly regulated transport and metabolic circuit that ensures efficient neurotransmission, mitochondrial bioenergetics and redox homeostasis. Disruption of this equilibrium is associated with the pathogenesis of the major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Excessive glutamatergic stimulation and impaired glycine or homocysteine metabolism result in pathological Ca[2][+] influx, loss of mitochondrial membrane potential and production of reactive oxygen species, which are hallmarks of these disorders. It also limits cysteine availability and causes glutathione depletion, which affects antioxidant defence, and disrupts tryptophan-kynurenine metabolism, further affecting neurotoxic and neuroprotective signalling. Though there are disease-specific molecular triggers, the convergent pathogenesis of metabolic disruption makes neurons susceptible to disease. The convergent pathways link amino acid dysregulation to the reinforcement of each other's mechanisms of excitotoxicity, oxidative stress, mitochondrial dysfunction, and protein aggregation. Correcting the amino acid balance has clear translational potential for developing new therapies, such as glutathione augmentation, modulation of NMDA receptors, targeting of transporters, and regulation of metabolic enzymes. In addition, the use of metabolic biomarkers alongside neuroprotective endpoints in clinical trials could improve detection rates, patient stratification, and therapeutic precision. The concept of amino acid metabolism as a mechanism of neurodegeneration, therefore, provides a systems-level perspective and targets potential areas for continued neuroprotection and disease modification.},
}

*Oxidative Stress/physiology
Humans
Animals
*Amino Acids/metabolism
*Neurodegenerative Diseases/metabolism/pathology
*Nerve Degeneration/metabolism/pathology
Mitochondria/metabolism

@article {pmid42576162,
year = {2026},
author = {Park, JH and Kim, B and Al-Amin, MM and Tate, MD and Sharify, AD and John, SK and Karahan, H and Lu, HC and Dabin, LC and Kim, J},
title = {Unique transcriptomic alterations in 5XFAD;PS19 mouse model identify glial lipid dysregulation and coordinated microglial-oligodendrocyte responses.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71742},
doi = {10.1002/alz.71742},
pmid = {42576162},
issn = {1552-5279},
support = {R01NS086794/NH/NIH HHS/United States ; R01AG077829/NH/NIH HHS/United States ; RF1AG074543/NH/NIH HHS/United States ; U01AG076804/NH/NIH HHS/United States ; },
mesh = {Animals ; Mice ; *Microglia/metabolism/pathology ; *Transcriptome ; Disease Models, Animal ; *Alzheimer Disease/genetics/metabolism/pathology ; *Oligodendroglia/metabolism/pathology ; *Lipid Metabolism/genetics ; Mice, Transgenic ; Humans ; Brain/metabolism/pathology ; Female ; *Neuroglia/metabolism ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) features amyloid beta (Aβ) plaques and tau tangles, yet how their coexistence reshapes brain transcriptomic programs remains unclear.

METHODS: We performed high-quality, sex-balanced single-nucleus RNA sequencing of 5XFAD (Aβ), PS19 (tau), and combined 5XFAD;PS19 mice.

RESULTS: We identified transcriptional programs that emerged most prominently under combined pathology. These programs included disruption of glial lipid metabolism and immune pathways at the network level, alongside immune and synaptic alterations coordinated between microglia and oligodendrocytes. Cross-species analyses further revealed that the pathway-level alterations under combined pathology, particularly in immune, lipid, and cell cycle programs, exhibited the strongest concordance with human AD datasets, underscoring their translational relevance.

DISCUSSION: Beyond benchmarking mouse models, this study provides a high-quality transcriptomic resource to dissect multicellular disease mechanisms in AD and to prioritize therapeutic targets for a network-level systems pharmacology approach.},
}

Animals
Mice
*Microglia/metabolism/pathology
*Transcriptome
Disease Models, Animal
*Alzheimer Disease/genetics/metabolism/pathology
*Oligodendroglia/metabolism/pathology
*Lipid Metabolism/genetics
Mice, Transgenic
Humans
Brain/metabolism/pathology
Female
*Neuroglia/metabolism

@article {pmid42576167,
year = {2026},
author = {Uruk, G and Gatto, RG and Hossain, N and Whitwell, JL and Reichard, RR and Josephs, KA},
title = {Structural Heterogeneity of TDP-43 Fragments in Alzheimer's Disease and Primary Age-Related Tauopathy by Artificial Intelligence (AI)-Based 3D Segmentation.},
journal = {Neuropathology and applied neurobiology},
volume = {52},
number = {4},
pages = {e70096},
doi = {10.1111/nan.70096},
pmid = {42576167},
issn = {1365-2990},
support = {R01-AG37491/NH/NIH HHS/United States ; },
mesh = {Humans ; *DNA-Binding Proteins/metabolism ; *Alzheimer Disease/pathology/metabolism ; *Tauopathies/pathology/metabolism ; Female ; Male ; Aged ; *Artificial Intelligence ; Aged, 80 and over ; *Brain/pathology/metabolism ; Imaging, Three-Dimensional/methods ; },
abstract = {TAR DNA-binding protein 43 (TDP-43) inclusions are defining pathological features of frontotemporal lobar degeneration (FTLD) but are also often observed in Alzheimer's disease (AD) and primary age-related tauopathy (PART). TDP-43 in AD is either associated with cognitive impairment or a protective-life prolonging impact, and yet the localization, cellular and fragment characteristics of TDP-43 need to be determined. We investigated the relationships between TDP-43 volumetric inclusion burden in low likelihood AD (lAD) and definite PART by immunostaining against phosphorylated TDP-43 (pTDP-43), TDP-43 C terminal (TDP-C) and TDP-43 N-terminal (TDP-N) fragments combined with 3D confocal imaging taken from eight regions: amygdala (basolateral [amygdala-BL] and centromedial amygdala [amygdala-CM]), the hippocampus (Cornu Ammonis [CA]-1, CA2/3, CA4, dentate gyrus [DG] and subiculum [SUB]) and entorhinal cortex (ERC) and artificial intelligence (AI)-based segmentation via object recognition, reconstruction and quantification. We found amygdala-CM in lAD and PART to have the overall greatest burden of pTDP-43 whereas TDP-N burden in amygdala-BL of PART cases was greater than other TDP-43 fragments. There was no difference in TDP-43 burden in hippocampal subfields in PART. However, CA2/3 region showed greater pTDP-43 burden while TDP-N stood out in DG and SUB. Multiple comparisons among the groups revealed that TDP-C was the only fragment showing differences among PART and lAD in CA2/3, DG and SUB regions. Overall, unbiased AI-based volumetric burden analysis pipeline demonstrated unique fragment aggregation patterns in the neurodegenerative processes of PART and AD.},
}

Humans
*DNA-Binding Proteins/metabolism
*Alzheimer Disease/pathology/metabolism
*Tauopathies/pathology/metabolism
Female
Male
Aged
*Artificial Intelligence
Aged, 80 and over
*Brain/pathology/metabolism
Imaging, Three-Dimensional/methods

@article {pmid42576170,
year = {2026},
author = {Wan, L and Kang, C and Harrison, R and Solis-Urra, P and Sewell, KR and Oberlin, LE and Jain, S and Huang, H and Grove, G and Kamboh, MI and Sutton, BP and Snitz, BE and Kramer, AF and McAuley, E and Burns, JM and Hillman, CH and Vidoni, ED and Marsland, AL and Karikari, TK and Morris, J and Erickson, KI},
title = {Neurobiological markers across joint profiles of subjective cognitive decline and objective cognitive function in older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71743},
doi = {10.1002/alz.71743},
pmid = {42576170},
issn = {1552-5279},
support = {R01 AG053952/NH/NIH HHS/United States ; R35 AG072307/NH/NIH HHS/United States ; },
mesh = {Humans ; Aged ; Male ; Female ; Biomarkers/blood ; Neurofilament Proteins/blood ; Magnetic Resonance Imaging ; *Cognitive Dysfunction/blood/diagnostic imaging/psychology ; Glial Fibrillary Acidic Protein/blood ; *Cognition/physiology ; tau Proteins/blood ; Brain/pathology/diagnostic imaging ; Neuropsychological Tests ; Aging ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Subjective cognitive concerns frequently diverge from objective cognitive performance in cognitively unimpaired (CU) older adults, yet the neurobiological basis of this mismatch remains unclear.

METHODS: In 648 participants from the Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE), we defined four profiles by integrating subjective and objective cognitive status. We examined associations with plasma neurofilament light chain (NfL), phosphorylated tau 217 (p-tau217), glial fibrillary acidic protein (GFAP), a magnetic resonance imaging-based volumetric Alzheimer's disease (AD) signature reflecting atrophy, and brain-predicted age difference (brain-PAD).

RESULTS: Joint profiles were differentially associated with NfL (P = 0.0427) and brain-PAD (P = 0.0296). Follow-up contrasts further indicated higher NfL and lower volumetric AD signature in the concordant lower functioning profile, and higher brain-PAD in discordant profiles. p-tau217 and GFAP did not differ across profiles.

DISCUSSION: Joint subjective-objective cognitive profiles may capture biologically meaningful heterogeneity relevant to neurodegeneration and brain aging in older adults.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT02875301.},
}

Humans
Aged
Male
Female
Biomarkers/blood
Neurofilament Proteins/blood
Magnetic Resonance Imaging
*Cognitive Dysfunction/blood/diagnostic imaging/psychology
Glial Fibrillary Acidic Protein/blood
*Cognition/physiology
tau Proteins/blood
Brain/pathology/diagnostic imaging
Neuropsychological Tests
Aging
Aged, 80 and over

@article {pmid42576193,
year = {2026},
author = {Saifullah, K and Ridwan, AR and Evia, AM and Leurgans, SE and Wagner, M and Bennett, DA and Schneider, JA and Arfanakis, K},
title = {Brain morphometry patterns in the presence of Alzheimer's disease and/or LATE neuropathologic changes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71719},
doi = {10.1002/alz.71719},
pmid = {42576193},
issn = {1552-5279},
support = {R01AG064233/AG/NIA NIH HHS/United States ; R01AG067482/AG/NIA NIH HHS/United States ; R01AG017917/AG/NIA NIH HHS/United States ; R01AG015819/AG/NIA NIH HHS/United States ; RF1AG022018/AG/NIA NIH HHS/United States ; R01AG056405/AG/NIA NIH HHS/United States ; R01AG052200/AG/NIA NIH HHS/United States ; P30AG010161/AG/NIA NIH HHS/United States ; P30AG072975/AG/NIA NIH HHS/United States ; UH2-UH3NS100599//Institute of Neurological Disorders and Stroke (NINDS)/ ; U01NS100599//Institute of Neurological Disorders and Stroke (NINDS)/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; *Brain/pathology/diagnostic imaging ; Aged ; Female ; Male ; Aged, 80 and over ; Image Processing, Computer-Assisted ; },
abstract = {INTRODUCTION: Alzheimer's disease neuropathologic change (ADNC) and limbic-predominant age-related transactive response DNA-binding protein 43 kDa (TDP-43) encephalopathy neuropathologic change (LATENC) are common in older adults, yet differences in brain morphometry patterns when one or both pathologies are present remain unclear.

METHODS: We used deformation-based morphometry on ex-vivo MRI from 912 community-based older adults to compare groups with or without ADNC and/or LATENC.

RESULTS: AD+LATE- and AD-LATE+ groups showed less tissue in the medial temporal lobe than AD-LATE-. The AD+LATE+ group had less tissue in temporal, frontal, and parietal lobes. The AD-LATE+ group exhibited smaller anterior hippocampi than the AD+LATE- group. These findings were less pronounced in individuals without dementia. Increments in LATENC stages were associated with smaller hippocampi than increments in ADNC severity, independent of the severity of comorbid ADNC or LATENC, respectively.

DISCUSSION: These findings reveal distinct and overlapping brain morphometry patterns associated with ADNC and/or LATENC, with possible implications for diagnosis in older adults.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging
Magnetic Resonance Imaging
*Brain/pathology/diagnostic imaging
Aged
Female
Male
Aged, 80 and over
Image Processing, Computer-Assisted

@article {pmid42576197,
year = {2026},
author = {Um, YJ and Cho, IY and Koo, HY and Park, YM and Kim, KM and Lee, CE and Han, K},
title = {Intellectual disabilities and risk of dementia: A Korean population-based cohort study.},
journal = {Journal of intellectual disabilities : JOID},
volume = {},
number = {},
pages = {17446295261476476},
doi = {10.1177/17446295261476476},
pmid = {42576197},
issn = {1744-6309},
abstract = {This retrospective cohort study assessed the risk of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD) in individuals with intellectual disabilities compared to those without. Using data from the Korean National Disability Registry and National Health Insurance Service, individuals over 40 who underwent health examinations in 2009 were followed until 2020. Cox proportional hazards models estimated hazard ratios (HRs) for dementia outcomes, adjusting for confounders. Over a mean 8-year follow-up, 161 dementia, 111 AD, and 22 VaD cases occurred among individuals with intellectual disabilities. Adjusted HRs for all-cause dementia, AD, and VaD were 5.75, 5.23, and 4.66, respectively, compared to those without intellectual disabilities. The risk was especially elevated among those aged 40-64 years (P for interaction <0.01). In conclusion, individuals with intellectual disabilities have a significantly higher risk of dementia, particularly at younger ages, highlighting the need for increased awareness and targeted healthcare strategies.},
}

@article {pmid42576199,
year = {2026},
author = {Zheng, F and Guan, R and Yu, X and Yang, J and Zhao, H and Yang, F},
title = {ADAR-mediated RNA editing in CNS disorders: from pathogenic mechanisms to therapeutic opportunities.},
journal = {Cellular & molecular biology letters},
volume = {31},
number = {1},
pages = {},
pmid = {42576199},
issn = {1689-1392},
mesh = {Humans ; *RNA Editing/genetics ; *Adenosine Deaminase/metabolism/genetics ; *Central Nervous System Diseases/genetics/therapy/pathology/metabolism ; Animals ; *RNA-Binding Proteins/metabolism/genetics ; },
abstract = {The adenosine deaminases acting on RNA (ADAR) family of enzymes (ADAR1 and ADAR2) catalyze adenosine-to-inosine (A-to-I) RNA editing. This post-transcriptional change is remarkably prevalent in the central nervous system (CNS). ADAR-mediated editing is critical for proper brain development, synaptic plasticity, and immunological homeostasis in the central nervous system (CNS) via recoding neurotransmitter receptors and ion channels. Conversely, a wide range of CNS disorders, such as neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis), neuropsychiatric conditions (schizophrenia, bipolar disorder, and major depression), cerebrovascular diseases, and gliomas, are now linked to dysregulation of ADAR activity, whether through loss-of-function mutations, altered expression, or mislocalization. To address the main question of whether altered RNA editing is a fundamental driver of pathogenesis, a compensatory response, or a context-dependent modulator, this review critically synthesizes existing evidence. The basic processes of ADAR enzymes and their regulation throughout neurodevelopment are first described. Next, we thoroughly assess the unique molecular fingerprints of ADAR dysregulation across several CNS disorders, emphasizing recurring themes such as Alu RNA hypo-editing, induction of innate immunity, and GRIA2 editing, which can cause excitotoxicity. Lastly, we examine new treatment approaches that use or reinstate ADAR activity, such as small-molecule modulators and site-directed RNA editing tools (leveraging endogenous ADAR for programmable editing of RNA [LEAPER], clustered ADAR-recruiting guide RNAs (gRNAs) for effective RNA editing [CLUSTER], and mimicking inverted repeats to recruit ADARs using engineered oligoribonucleotides [MIRROR]). We summarize by reviewing key obstacles to clinical translation, including crossing the blood-brain barrier, the risks of off-target editing, and the challenges of achieving spatiotemporal accuracy. We also list important open topics for further investigation.},
}

Humans
*RNA Editing/genetics
*Adenosine Deaminase/metabolism/genetics
*Central Nervous System Diseases/genetics/therapy/pathology/metabolism
Animals
*RNA-Binding Proteins/metabolism/genetics

@article {pmid42576501,
year = {2026},
author = {Li, D and Li, Y and Yang, X and Wang, Y and Qu, Y},
title = {[Association between 473 gut microbiota and Alzheimer's disease: a Mendelian randomization mediation analysis of 233 circulating metabolites].},
journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University},
volume = {46},
number = {8},
pages = {1926-1935},
doi = {10.12122/j.issn.1673-4254.2026.08.20},
pmid = {42576501},
issn = {1673-4254},
mesh = {*Alzheimer Disease/microbiology/genetics ; *Mendelian Randomization Analysis ; Humans ; *Gastrointestinal Microbiome ; Genome-Wide Association Study ; },
abstract = {OBJECTIVES: To investigate the causal associations between gut microbiota (GM) and Alzheimer's disease (AD) and the mediating role of circulating metabolites using Mendelian randomization (MR) analysis.

METHODS: A two-sample MR analysis was conducted based on genome-wide association study (GWAS) summary data. Valid instrumental variables for 473 GM taxa and 233 circulating metabolites were selected, and the inverse-variance weighted (IVW) method was used as the primary analytical approach, with MR-Egger regression and weighted median method as the complementary analyses. Multiple sensitivity analyses were conducted to assess the robustness of the results, and reverse MR analyses were used to verify the direction of causality. Mediation MR analyses were performed to determine the mediating effects of the circulating metabolites.

RESULTS: A positive causal association was identified between the abundance of Negativibacillus massiliensis and the risk of AD (OR=1.204, 95% CI: 1.020-1.421,P=0.028), and the results were stable and reliable as confirmed by sensitivity analyses (P>0.05). Reverse MR analysis revealed no significant causal effect of AD on the abundance of Negativibacillus massiliensis (P=0.678). Mediation MR analysis showed that the indirect effect mediated by free cholesterol to total lipid ratio in very small very-low-density lipoprotein (v-VLDL FC/TL) accounted for 6.63% of the total effect of Negativibacillus massiliensis on AD.

CONCLUSIONS: From a genetic causal inference perspective, Negativibacillus massiliensis is likely associated with an increased risk of AD, and v-VLDL FC/TL may partially mediate this association, suggesting their potential as targets for AD prevention and treatment.},
}

*Alzheimer Disease/microbiology/genetics
*Mendelian Randomization Analysis
Humans
*Gastrointestinal Microbiome
Genome-Wide Association Study

@article {pmid42576518,
year = {2026},
author = {Shakya, M and Patel, SK and Singh, M and Rao, H and Moorthy, NHN and Tiwari, A},
title = {An Overview of 1,2,4-Triazole-5-Thiol and 3-Thione Derivatives as Promising Scaffolds for Anti-Neuroinflammatory Drug Discovery.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575433269260710072055},
pmid = {42576518},
issn = {1875-5607},
abstract = {Neuroinflammation is a major complex reaction that causes Neurodegenerative Diseases (ND) and cognitive behavioural disorders such as Alzheimer's Disease (AD), Parkinson's disease, multiple sclerosis, and traumatic brain injury. Neuroinflammation can be regulated by different types of enzymes and proteins, including acetyl- and butyrylcholinesterases, cyclooxygenases, kinases, and the accumulation of Amyloid-beta (Aβ) plaques and hyperphosphorylated tau protein. Due to the complex physiology of enzymes and proteins, ND cannot be cured permanently yet. Therefore, we need to design and synthesise novel small molecules with high selectivity and inhibitory properties against enzymes and proteins associated with neuroinflammation. In recent decades, researchers have examined a range of different heterocyclic scaffolds for their ability to fight neuroinflammation. The 1,2,4-triazole scaffold, especially its 5-thiol and 3-thione derivatives, is a chemically flexible heterocyclic scaffold that has attracted significant attention due to its wide range of biological activities and promising drug-like properties. As a review methodology, comprehensive literature searches of the PubMed, Scopus, Web of Science (WoS), ScienceDirect, and DOAJ databases were conducted using keywords to gather information on synthesis, in vitro (IC50 values), in vivo biology, and in silico approaches related to the 1,2,4-triazole-targeted scaffold. This literature review highlights 1,2,4-triazole scaffold 5-thiol and 3-thione derivatives, potent compounds from the synthesised derivatives, presenting synthetic schemes, biological activity data, and in silico studies. Molecular docking, in silico predictions, and preclinical experiments are summarised in detail to show how they can be used in medicinal drug discovery. The goal of this review is to provide a source of information that will help with future efforts to design new neuroprotective agents based on the 1,2,4-triazole scaffold.},
}

@article {pmid42576561,
year = {2026},
author = {Kara, S and Özandaç, S and Sencar, L and Akillioglu, K and Polat, S},
title = {Transforming Growth Factor Beta-1 Alleviates Neurodegeneration by Regulating Aβ42 and VDAC1 Expression in the Temporal Lobe and Cerebellum in an Alzheimer's Disease-Like Model.},
journal = {Current molecular medicine},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115665240501722260724103809},
pmid = {42576561},
issn = {1875-5666},
abstract = {BACKGROUND: Alzheimer's Disease (AD) has a critical pathology that causes neurodegeneration and mitochondrial dysfunctions via the amyloid deposition. The temporal lobe plays a role in converting sensory input into derived meanings for appropriate processing of visual memory, language comprehension, and emotional association. The cerebellum plays a critical role in the control of motor systems, cognitive, and emotional functions. Aβ42 accumulates between nerve cells in the brain, disrupting synaptic functions and negatively affecting memory and other cognitive functions. VDAC1 is a protein located in the cell membrane that facilitates energy transport to the mitochondria. TGF-β1 is a cytokine that plays a role in many biological functions, including cell growth, differentiation, and tissue repair.

OBJECTIVE: The aim of the study was to investigate the effect of TGF-β1 on scopolamine-induced neurodegeneration of the temporal lobe and cerebellum in experimental AD.

METHODS AND RESULTS: The evaluation showed that, according to light and electron microscopic results, edema areas, cytoplasmic vacuolization, and cellular damage were increased in the scopolamine group, while these changes were significantly reduced in the treatment group. According to immunohistochemical findings, the expression levels of Aβ42 and VDAC1 were significantly higher in the scopolamine group than in the control and TGF-β1 groups, while in the treatment group, a low expression was observed compared to the scopolamine group.

CONCLUSION: When all these results are considered together, it has been concluded that TGF-β1 application may regulate the expression of Aβ42 and VDAC1 in critical control centers such as the temporal lobe and cerebellum in a Scopolamin-induced neurodegeneration model, potentially alleviating cellular damage.

DISCUSSION: Previous studies have reported that TGF-β1 exerts both antineurodegenerative and neuroprotective effects. In our study, evaluation of the effects of TGF-β1 demonstrated beneficial effects on both mitochondrial damage and amyloid accumulation. Nevertheless, further detailed investigations of these effects may provide valuable insights for future studies.},
}

@article {pmid42576562,
year = {2026},
author = {Kumar, D and Ashesh, AM and Gupta, S and Kumar, A and Lohidasan, S and Tosaramandani, TJ},
title = {WNT Signaling in Alzheimer's Disease: Mechanisms, Pathological Implications, and Therapeutic Potential.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273455895260722103746},
pmid = {42576562},
issn = {1996-3181},
abstract = {The WNT signaling pathway plays a significant role in various biological processes during embryonic development, childhood, and adulthood. It is involved in neurogenesis, synapse formation, and such cognitive processes as learning and memory in the CNS. Dysregulated WNT signaling is associated with cognitive decline, synaptic dysfunction, neuronal loss, and has been associated with diseases like leukemia and colorectal cancer. The studies show that WNT/β-catenin signaling affects the cellular, molecular, and metabolic mechanisms that promote disease progression. The WNT pathway is a potential therapeutic target because it helps maintain neuronal survival, supports the growth of new nerve cells, and enhances synaptic plasticity. WNT signaling is important for stem cell selfrenewal and differentiation. Research is being conducted on therapeutic methods targeting WNT signaling to treat neurological diseases and cancer. This review explores the connection between WNT signaling and the pathology of Alzheimer's disease. This review explores the role of WNT signaling in AD pathogenesis, with a focus on the Wnt/β-catenin pathway as a therapeutic target. It summarizes existing findings to demonstrate that WNT signaling is a context-dependent regulatory network in which a shift from protective canonical activity to dysregulated non-canonical and inflammatory pathways contributes to disease progression.},
}

@article {pmid42576583,
year = {2026},
author = {Ahmed, A and Fu, X and Khan, H and Li, P},
title = {A Narrative Review: Suvorexant's Role in Sleep Deprivation and Neurodegenerative Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X468876260722063322},
pmid = {42576583},
issn = {1875-6190},
abstract = {Sleep loss is a major risk factor for neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD), accelerating cognitive impairment with neuropathology. Cumulative sleep loss impairs the glymphatic system, reduces amyloid-β clearance, and enhances the neuroinflammatory response, all of which contribute to the development of neurodegeneration. Given the orexin system's essential role in modulating sleep-wake rhythms, orexin receptor antagonists such as Suvorexant are potent candidates for treating sleep disturbances and cognitive decline associated with neurodegenerative conditions. Suvorexant promotes sustained sleep without the side effects commonly associated with sleep-inducing drugs, such as drowsiness and cognitive impairment, potentially offering a neuroprotective approach by selectively antagonizing orexin receptors. By inhibiting excessive orexin signaling in the brain, Suvorexant may benefit other neurodegenerative diseases. Preclinical studies support the idea that improving sleep quality, as seen with Suvorexant, can normalize sleep architecture, leading to reduced tau phosphorylation and amyloid plaque deposition, both of which are pathological hallmarks of AD. Furthermore, enhanced sleep quality may bolster synaptic plasticity and aid in memory consolidation, potentially counteracting cognitive deterioration. Although most research has been conducted in AD, the putative applications of Suvorexant in PD and other tauopathies are worth exploring, especially given the common involvement of sleep disturbances in these diseases. Animal studies show that Suvorexant not only promotes sleep but also prevents neuronal damage, suggesting its dual therapeutic potential. Long-term clinical trials are necessary, however, to prove its effectiveness in humans, especially in populations at risk for sleep disorders and early neurodegenerative alterations. Suvorexant could be a novel approach to slow cognitive decline and improve quality of life in patients with AD, PD, and related diseases, highlighting the vital interplay between sleep and brain health.},
}

@article {pmid42576592,
year = {2026},
author = {Jeeru, TR and Palathoti, N and Swaminathan, G},
title = {The Multifaceted Role of the P2X7 Receptor in Alzheimer's Disease: A Unifying Pathological Link.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273460900260724035926},
pmid = {42576592},
issn = {1996-3181},
abstract = {Alzheimer's Disease (AD) is a neurodegenerative disorder that characterizes depletion of memory, cognition, and a change in behavioural patterns. There is no standard treatment that completely cures this prevalent disease. This review delves into the existing pathologies of AD, which include the Aβ plaques accumulation, neurofibrillary tangles and Lewy bodies formation, and the influence of the P2X7 receptor on cellular mechanisms of neuronal cells like microglial cells, astrocytes and oligodendrocytes and also its influence on pathways such as JAK2/STAT3, NGF signalling, (Transactive response DNA binding protein) TDP-43 Proteinopathy, Wnt/β-Catenin signalling, and FGF7/FGFR2/PI3K/Akt causing AD. It discusses the unifying role of the P2X7 receptor mediating these pathways that link to the occurrence and progression of AD. The role of the Purinergic receptor (P2X7 receptor), a ligand-gated ion channel activated by extracellular ATP, was examined across existing cellular mechanisms and possible pathways involved in AD, as well as the co-pathologies encompassed and their hypothetical relationship with the P2X7 receptor. Additionally, the current P2X7 receptor antagonists treating neurotoxicity are discussed along with existing pre-clinical and clinical data. This may further advance drug development by targeting the P2X7 receptor to mitigate AD across multiple mechanisms.},
}

@article {pmid42576595,
year = {2026},
author = {Maghsoudlou, F and Esteki, A},
title = {Audio‒Visual Gamma Stimulation for Alzheimer's Disease: Current Evidence and Future Directions.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050478693260720114427},
pmid = {42576595},
issn = {1875-5828},
abstract = {INTRODUCTION/OBJECTIVE: Alzheimer's Disease (AD) is characterized by progressive cognitive decline and disrupted neural oscillations. Recently, 40 Hz gamma stimulation has emerged as a potential non-invasive therapy. This review evaluates the safety, tolerability, and clinical outcomes of this intervention based on evidence from the past decade.

METHODS: A literature search was conducted across PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov for studies published during the last ten years. Registered and ongoing studies were also identified through ClinicalTrials.gov. Extracted data included stimulation modality, stimulation parameters, safety and tolerability outcomes, and reported effects on functional connectivity, brain atrophy, cognitive performance, and sleep-related measures.

RESULTS: Thirty studies were identified, comprising eight sensory-based 40-Hz gamma stimulation approaches, 12 40-Hz transcranial Alternating Current Stimulation (tACS) protocols, and 10 ongoing clinical trials. Among the 20 completed studies, 40-Hz gamma stimulation was reported to be safe and well-tolerated. The synthesized evidence from these completed trials suggests potential beneficial effects on functional connectivity, brain atrophy progression, cognitive outcomes, and sleep-related measures.

DISCUSSION: Gamma stimulation may represent a promising approach for modulating neural network activity and cognitive function in AD. Nevertheless, current evidence remains limited by small sample sizes, methodological heterogeneity, differences in stimulation protocols, and short follow-up periods. These factors limit the ability to draw definitive conclusions regarding therapeutic efficacy.

CONCLUSION: 40-Hz gamma stimulation is a feasible and generally well-tolerated non-invasive intervention with potential relevance for AD treatment. Further large-scale, randomized, and controlled studies are required to establish standardized stimulation protocols, determine long-term efficacy, and clarify its clinical utility.},
}

@article {pmid42576606,
year = {2026},
author = {Ioakeimidis, V and Palombo, M and Casella, C and Layland, L and McNabb, C and Schubert, R and Pallmann, P and Busse, M and Drew, C and Alusi, S and Harrower, T and Davies, J and Rosser, A and Metzler-Baddeley, C},
title = {In vivo mapping of striatal neurodegeneration in Huntington's disease with Soma and Neurite Density Imaging.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
doi = {10.7554/eLife.107661},
pmid = {42576606},
issn = {2050-084X},
support = {NIHR-FS(A)-2022/HCRW_/HCRW_/United Kingdom ; MR/T020296/2//UKRI/ ; 10.35802/204005/WT_/Wellcome Trust/United Kingdom ; 10.35802/104943/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Humans ; *Huntington Disease/pathology/diagnostic imaging/physiopathology ; Female ; Male ; *Neurites/pathology ; Middle Aged ; *Corpus Striatum/pathology/diagnostic imaging ; Adult ; Diffusion Magnetic Resonance Imaging/methods ; Basal Ganglia/pathology/diagnostic imaging ; Aged ; },
abstract = {Huntington's disease (HD) is an inherited neurodegenerative disorder characterised by progressive cognitive and motor decline driven by basal ganglia (BG) atrophy. Clinical trials of novel disease-modifying therapies are ongoing, creating a need for sensitive non-invasive imaging biomarkers. Soma and Neurite Density Imaging (SANDI) is a multi-shell diffusion MRI model that estimates intracellular signal fractions from sphere-shaped soma and shows promise as a marker of neurodegeneration. The objectives of this study were to characterise HD-related microstructural abnormalities in the BG using SANDI and to examine relationships between SANDI and volumetric measurements and motor performance. T1- and diffusion-weighted images (b-values 200-6000 s/mm[2]) were acquired on a 3T Siemens Connectom scanner (300 mT/m) in 56 individuals with HD and 57 age- and sex-matched controls. HD participants completed Quantitative Motor (Q-Motor) tasks, summarised using principal component analysis. SANDI estimated apparent soma and neurite density, apparent soma size, and extracellular signal fraction. Microstructural and volumetric indices were extracted from bilateral caudate, putamen, pallidum and thalamus regions, compared between groups, and correlated with Q-Motor performance. HD was associated with reduced apparent soma density and increased apparent soma size and extracellular signal fraction in the BG but not the thalami. No group differences were present for apparent neurite density. SANDI metrics correlated with Q-Motor performance and explained up to 63% of striatal atrophy in HD. SANDI indices detected HD-related striatal neurodegeneration, explained atrophy, and correlated with motor impairments, demonstrating its potential as an in vivo biomarker and surrogate clinical outcome measure for HD and other neurodegenerative diseases.},
}

Humans
*Huntington Disease/pathology/diagnostic imaging/physiopathology
Female
Male
*Neurites/pathology
Middle Aged
*Corpus Striatum/pathology/diagnostic imaging
Adult
Diffusion Magnetic Resonance Imaging/methods
Basal Ganglia/pathology/diagnostic imaging
Aged

@article {pmid42576610,
year = {2026},
author = {Yang, Y and Yang, Y and Tang, Y and Yang, W},
title = {Myokines, Microbiota, and Neuroinflammation: Physical Activity Modulates the Gut-Brain Axis.},
journal = {Immunological investigations},
volume = {},
number = {},
pages = {1-28},
doi = {10.1080/08820139.2026.2689670},
pmid = {42576610},
issn = {1532-4311},
abstract = {BACKGROUND: Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are increasingly recognized as disorders influenced not only by intrinsic neural pathology but also by systemic physiological networks, including the gut-brain axis. Emerging evidence highlights physical activity as a potent modulator of this bidirectional communication system, with muscle-derived signals particularly myokines, metabolites, and extracellular vesicles playing a central role.

METHODS: This narrative review synthesizes current knowledge on how exercise-induced molecular mediators influence gut microbiota composition, intestinal barrier integrity, immune signaling, and neuroinflammatory pathways. Findings were integrated across the disciplines of neuroscience, microbiology, and exercise physiology to evaluate mechanistic links between muscle-secreted factors and gut-mediated responses.

RESULTS: Mechanistic links exist between muscle-secreted factors such as irisin, cathepsin B, BDNF-inducing pathways, and lactate with microbial metabolites including short-chain fatty acids. These interacting pathways demonstrate a combined impact on neuroprotection, synaptic plasticity, and the modulation of disease progression in neurodegenerative conditions.

CONCLUSION: Physical activity represents a promising non-pharmacological strategy for modulating the gut-brain axis in neurodegenerative conditions. Understanding the interplay between muscle-derived signals and gut-mediated pathways may open new avenues for targeted interventions aimed at slowing or preventing neurodegenerative decline.},
}

@article {pmid42576612,
year = {2026},
author = {Carrier, T and Rouleau, I and St-Georges, MA and Afrooz, P and Montembeault, M},
title = {Deficits in the knowledge of social norms and their correlates in Alzheimer's disease.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/13854046.2026.2712921},
pmid = {42576612},
issn = {1744-4144},
abstract = {Objective: Compared to other components of social cognition, knowledge of social norms has received less attention in the scientific literature. While social cognitive and semantic memory deficits appear early in the course of Alzheimer's disease (AD), no study has examined knowledge of social norms at earlier stages of the disease. In addition, it is unclear whether the knowledge of social norms in AD is associated with socioemotional deficits, as may be seen in the behavioral variant of frontotemporal dementia (bvFTD). Method: This study included 136 participants with amnestic mild cognitive impairment (aMCI), 134 with AD, most of whom were younger than 65 years, 280 with bvFTD, and 361 older healthy controls (HC). All participants were selected from the National Alzheimer's Coordinating Center (NACC). They completed the Social Norms Questionnaire (SNQ), which assesses the tendency to break or overadhere to social norms. They also completed tests assessing executive, semantic, and socioemotional functions. Results: Between-group comparisons showed that individuals with AD and aMCI made significantly more Break and Overadhere errors than HC, while they demonstrated better social norms knowledge than individuals with bvFTD. In aMCI and AD, social norms overadherence errors were most consistently associated with executive functioning. In bvFTD, semantic memory was the most consistent correlate across all SNQ variables. Conclusions: These findings may help clinicians and researchers better understand social cognitive changes in patients, support the inclusion of social norms knowledge assessment within broader neuropsychological evaluations, and provide complementary insight into the cognitive correlates of social knowledge loss in major neurocognitive disorders.},
}

@article {pmid42576814,
year = {2026},
author = {Singh, N and Guha, L and Kumari, A},
title = {Exosome-based nanomedicine for neurological disorders: mechanisms, engineering, and therapeutic potential.},
journal = {Therapeutic delivery},
volume = {},
number = {},
pages = {1-40},
doi = {10.1080/20415990.2026.2715878},
pmid = {42576814},
issn = {2041-6008},
abstract = {Exosomes are naturally occurring extracellular vesicles that have emerged as promising bio-inspired nanocarriers for the treatment of neurological disorders owing to their intrinsic biocompatibility, low immunogenicity, and ability to cross the blood-brain barrier. This review highlights recent advances in exosome biology, cargo-sorting mechanisms, and engineering strategies designed to enhance therapeutic delivery and targeting within the central nervous system. Particular emphasis is placed on the application of engineered exosomes in neurodegenerative diseases, stroke, spinal cord injury, neuropathic pain, and neuroinflammatory disorders. In addition, we discuss how exosomes compare with conventional delivery platforms and critically examine the major barriers limiting their clinical translation, including heterogeneity, scalability, reproducibility, purity, and regulatory standardization. By integrating mechanistic insights with translational perspectives, this review provides a framework for the rational design and future clinical implementation of exosome-based nanomedicines for neurological disorders. Relevant literature was identified through searches of PubMed, Scopus, Web of Science, and Google Scholar. Publications available from database inception through [Month Year] were screened using combinations of keywords including "exosomes," "extracellular vesicles," "neurological disorders," "brain-targeted delivery," "exosome engineering," "drug delivery," and "clinical trials." Additional relevant articles were identified through manual searches of reference lists from selected studies and recent reviews.},
}

@article {pmid42577088,
year = {2026},
author = {Zheng, K and Tsitsos, FN and Konofagou, EE and Leong, KW},
title = {Focused ultrasound-mediated lipid nanoparticle delivery for brain gene editing.},
journal = {Molecular therapy. Nucleic acids},
volume = {37},
number = {3},
pages = {103012},
pmid = {42577088},
issn = {2162-2531},
abstract = {Efficient brain gene editing remains constrained by the lack of delivery platforms that combine efficacy, spatial precision, and translational potential. Compared with viral vectors, lipid nanoparticles (LNPs) offer larger cargo capacity and lower immunogenicity for repeat dosing. However, their brain delivery is restricted by the blood-brain barrier (BBB). Here, we show that focused ultrasound (FUS)-mediated BBB opening enables systemic delivery of CRISPR-encoding plasmid DNA (pDNA)-LNPs for brain gene editing. Using a pDNA construct containing astrocyte-targeting GfaABC1D promoter and dual guide RNAs targeting apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimer's disease, we achieved efficient APOE4 knockdown, with reduced APOE4 mRNA and apoE4 protein expression, and attenuated astrocytes and microglial activation. These results establish FUS-mediated pDNA-LNP delivery as a non-invasive, non-viral strategy for brain gene editing that provides spatial control and cell-type-specific expression, while accommodating large genetic payload and enabling repeatable dosing.},
}

@article {pmid42577096,
year = {2026},
author = {Gaborit, M and Arabi, A and Mariotti, L},
title = {The emerging role of astrocytes in spatial cognition, action and Alzheimer's disease.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1811370},
pmid = {42577096},
issn = {1662-5102},
abstract = {Astrocytes sense synaptic activity, neuromodulation, and metabolic signals, and respond by modulating neurotransmission, excitability, and plasticity in neural networks. Increasing evidence demonstrates that these processes contribute to information processing and encoding across brain areas, thereby influencing perception, memory, cognition, and goal-directed behaviours. Notably, impairments in these functions represent some of the earliest hallmarks of ageing and neurodegenerative disorders such as Alzheimer's disease. Here we review molecular, cellular, and computational insights into astrocyte-neuron interactions, framing their importance at the system and behavioural level; then, we discuss the role of these interactions in spatial cognition, goal-directed behaviour, and their impairment in Alzheimer's disease, and review the mouse models used to investigate spatial deficits and associated astrocyte activity. Finally, we highlight major open questions in the field, outline future research directions, and discuss emerging strategies to address astrocyte role in cognitive function in health and disease.},
}

@article {pmid42577185,
year = {2026},
author = {Highet, B and Singh-Bains, M and Eszes, M and Parker, R and McShane, E and Webb-Robinson, C and Hubbard, K and Biggins, F and Sharma, S and Bell, P and Burnett, O and Lehnert, K and Jacobsen, JC and Ryan, B and Hu, M and Turner, C and Faull, RLM and Curtis, MA},
title = {Operational, molecular, and cultural perspectives at the Neurological Foundation Human Brain Bank, New Zealand.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1900088},
pmid = {42577185},
issn = {1664-2295},
abstract = {Post-mortem human brain tissue is an irreplaceable resource for advancing understanding of the brain and neurological disease. Brain banks that collect, preserve, and distribute this tissue underpin discoveries across neuropathology, genomics, and emerging molecular disciplines. Yet brain banking is a resource-intensive enterprise that faces distinct operational, cultural, and scientific challenges depending on the national context in which it operates. Here, we present the perspective of the Neurological Foundation Human Brain Bank (NFHuBB) - New Zealand's sole post-mortem human brain bank, based at The University of Auckland. Operating as the only such facility in the country, the NFHuBB confronts a unique convergence of challenges: the logistical complexity of coordinating donation across a dispersed population, the scientific imperative to preserve tissue for molecular-era multi-omics technologies, and a multi-cultural population that needs culturally informed consent practices. We describe the growth of the bank's donor registry and collection over 45 years with specific emphasis on donations in the last five calendar years (2021-2025), outline recent advances in tissue processing, including the development of formalin-fixed paraffin-embedded (FFPE) RNA preservation protocols and integration of whole-genome sequencing from un-fixed cerebellar tissue. Finally, we discuss the community engagement strategies that have supported increasing donation rates in New Zealand.},
}

@article {pmid42577242,
year = {2026},
author = {Meera, B and Hiatt, M and Hays, A and Punshon, S and Christensen, JR and Fields, B},
title = {Implementation of Riding in the Moment™: the crucial role of implementer preparedness and satisfaction in an adaptive horseback riding program for older adults with dementia.},
journal = {Frontiers in health services},
volume = {6},
number = {},
pages = {1799552},
pmid = {42577242},
issn = {2813-0146},
abstract = {INTRODUCTION: Riding in the Moment™ (RM) is a community-based, standardized, evidence-informed equine-assisted service program designed to support individuals with Alzheimer's disease and related dementias and their caregivers through social connection, physical activity, and meaningful engagement. Delivered by trained non-clinical personnel, RM's long-term success depends on effective implementation and sustainability in real-world settings. This project explored implementation strategies used to deliver RM, focusing on staff and volunteer preparedness and satisfaction.

METHODS: A repeated measures survey design that included closed-ended items and open-ended questions, guided by the RE-AIM framework, was used to explore implementation strategies. Pre-and post-implementation surveys assessed training satisfaction, perceived preparedness, and delivery experience among RM staff and volunteers. Quantitative data were analyzed using descriptive statistics, while qualitative feedback was organized into key categories. Implementation and fidelity checklists were also completed.

RESULTS: Majority of the participants (95%; n = 21) reported overall satisfaction with training and felt prepared to deliver RM. All fidelity checklist items were met, indicating strong adherence to program protocols. Post-implementation, majority of the participants (74%; n = 11) were extremely satisfied with RM, and 100% (n = 15) stated they would recommend the program. Qualitative feedback emphasized the emotional impact of the experience, value of structured training, and opportunities to improve volunteer engagement and communication.

DISCUSSION: This program evaluation project contributes to understanding early-stage implementation considerations for community-based dementia-specific programs in real-world settings. Continued evaluation is needed to determine how these factors influence long-term implementation, program sustainability, and scalability across broader settings.},
}