@article {pmid42867924,
year = {2026},
author = {Truong, TD and Shi, H and Pena, C and Chinnappan, B and Savani, E and Cheema, A and Pandya, N and Klimas, NG and Theoharides, TC and Kempuraj, D},
title = {Emerging hydrogel platforms for disease modeling, diagnosis, and imaging of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261495937},
doi = {10.1177/13872877261495937},
pmid = {42867924},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the presence of amyloid plaques, neurofibrillary tangles, neurodegeneration, cognitive decline, and dementia. The exact pathogenesis is not well understood, as appropriate pathological and therapeutically relevant disease models remain limited. Hydrogels are hydrophilic, three-dimensional (3D) polymer networks composed of synthetic or natural materials and have diverse neuroscience applications, including drug delivery, tissue engineering, and regenerative medicine. Currently, hydrogel in vitro platforms are becoming increasingly explored for AD pathogenesis, as brain extracellular matrix-mimicking biodegradable components, for delivery of growth factors for neurons and other brain cells, AD-specific peptide release, engineered multi-region brain organoids, and therapeutic drug delivery. Beyond disease modeling, hydrogels are being used to evaluate emerging AD diagnostic and therapeutic strategies, such as biomarker sensing and the integration of imaging. Recent AD diagnostic platforms have leveraged hydrogels as biomolecule-capture matrices and signal-transduction elements to detect AD-associated biomarkers via minimally invasive or implantable systems. Hydrogels have also been harnessed in magnetic resonance imaging, ultrasound, computed tomography, and positron emission tomography imaging modalities to support imageable vehicles for therapeutic delivery. Such platforms hold promise for bridging physiologically relevant neurobiological investigation with more accessible, efficient clinical tools for AD. This review highlights recent advances in hydrogel-based disease models, diagnostic tools, and imaging technologies and their potential to integrate with brain organoids, artificial intelligence, and 3D printing to enhance mechanistic and translational applications for AD.},
}

@article {pmid42867929,
year = {2026},
author = {Zantis, A and Uliassi, E and Pallara, C and Li, X},
title = {Integrative analysis of Alzheimer's disease molecular networks with circadian regulators for prioritization of drug repurposing candidates.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261497407},
doi = {10.1177/13872877261497407},
pmid = {42867929},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by complex molecular mechanisms. Growing evidence indicates that circadian rhythm disruption contributes to disease progression and interacts with pathogenic pathways. Although multi-omics resources, compound perturbation profiles, and pharmacological bioactivity data are increasingly available, their integrative use for drug repurposing prioritization in AD, particularly with explicit consideration of circadian rhythm, remains limited.ObjectiveThis study aimed to prioritize drug repurposing candidates for AD, by integrating heterogeneous biological and pharmacological data.MethodsWe applied an integrative, systems-level computational analysis to prioritize drug repurposing and repositioning candidates for AD by combining network-based gene prioritization, functional transcriptomic similarity analysis, and target-level bioactivity prediction. Disease-associated molecular modules were identified within the human protein-protein interaction network, with circadian rhythm regulators incorporated as an additional disease relevant biological context. These modules were represented using functional gene embeddings to rank compound perturbation signatures. Candidate compounds were subsequently refined through ligand-based bioactivity prediction across AD associated targets to support polypharmacological prioritization.ResultsThe analysis prioritized compounds supported by convergent network-level disease relevance, transcriptomic similarity, and predicted target engagement. Several drugs previously investigated in dementia-related clinical trials were recovered. Novel repositioning candidates, including PF-562271, MGCD-265, and BMS-777607, were identified, converging on focal adhesion kinase (FAK), PI3K-AKT, and receptor tyrosine kinase (RTK) signaling pathways enriched in AD-associated genes and implicated in circadian regulation and neuroinflammation.ConclusionsThis integrative analysis identifies mechanistically coherent repurposing candidates, associated with circadian and inflammatory pathways, supporting systems-based strategies for therapeutic prioritization in complex neurodegenerative diseases.},
}

@article {pmid42867945,
year = {2026},
author = {David, C and Hendriks, S and Damsgaard, L and Köhler, S and de Vugt, M and , },
title = {A scoping review on the time to diagnosis, early symptoms, and the barriers and facilitators of diagnosis in young-onset dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261495145},
doi = {10.1177/13872877261495145},
pmid = {42867945},
issn = {1875-8908},
abstract = {BackgroundYoung-onset dementia (YOD) occurs when symptoms start before age 65 and affects about 3.9 million people globally. Variability in first symptoms, the young age, and prevalent non-cognitive symptoms pose challenges in recognizing YOD, leading to diagnostic delays. Better awareness and recognition of warning signs in primary care is essential for early YOD diagnosis, facilitating access to appropriate services and informal care arrangements.ObjectiveTo gain insights into the prediagnostic phase of YOD by exploring literature on early symptoms and factors influencing a timely diagnosis.MethodsA literature search was conducted across PubMed, Embase, Web of Science, and PsycInfo. Two independent reviewers screened 5862 titles and abstracts and assessed 790 full texts. Data extraction used a standardized form, including time to diagnosis, early symptoms, barriers, and facilitators to YOD diagnosis. Review reporting followed PRISMA-ScR guidelines. Focus group discussions with people with YOD, caregivers, and healthcare professionals (HCPs) contextualized the review findings.ResultsWe included 225 studies. Time to diagnosis ranged from 4 months to 15 years across dementia subtypes. Early symptoms included memory problems, language difficulties, disorientation, personality changes, delusions, hallucinations, apathy, and depression. HCPs, people with YOD, and their caregivers often lacked awareness of YOD, which hindered diagnosis. However, persistence in seeking medical care, YOD-related services, and couples' agreements to seek professional help were essential facilitators.ConclusionsEarly signs of YOD include cognitive, behavioral, and affective symptoms. Lack of YOD awareness hinders diagnosis, highlighting the need to raise awareness among HCPs and the community to promote early identification.},
}

@article {pmid42868017,
year = {2026},
author = {Zhu, T and Deng, X and Lu, J and Zhou, X and Wang, Y and Xu, D and Song, J and Xie, X and Chen, C},
title = {The ferroptosis-lipid metabolism-neuroinflammation axis in Alzheimer's disease: A review of mechanistic interplay and therapeutic implications.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261495962},
doi = {10.1177/13872877261495962},
pmid = {42868017},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) involves multiple pathological pathways, with ferroptosis and lipid metabolic dysregulation forming a coupled mechanism across the disease course, and neuroinflammation acting as a key mediator. While existing reviews often focus on isolated processes, they frequently lack an integrative analysis of the "ferroptosis-lipid-neuroinflammation axis" as a systemic pathological core. This review specifically addresses this gap by proposing a unified mechanistic framework for neuronal injury, synaptic dysfunction, and immunometabolic remodeling in AD, centered on this tripartite axis. We comprehensively summarize how key pathways involving glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), coenzyme Q10 (CoQ10), the cystine/glutamate antiporter system Xc[-], solute carrier family 7 member 11 (SLC7A11), AMP-activated protein kinase (AMPK), nuclear factor erythroid 2-related factor 2 (NRF2), and N6-methyladenosine (m[6]A) regulation shape neuroinflammation within this context. Furthermore, we explore how advanced methodologies, including spatial omics, single-cell transcriptomics, organoid models, and engineered exosome methods, are instrumental in elucidating regional specificity, optimal intervention windows, and targeted delivery strategies for modulating this iron-lipid-inflammation interplay. This axis functions as a pathological amplifier, linking metabolic, oxidative, immune, and structural dysfunctions. Its systemic reprogramming offers a new paradigm for AD subtyping, biomarker discovery, and multitarget interventions, thereby overcoming the limitations of traditional amyloid-β/tau-centric approaches. This review integrates literature published up to the submission date, ensuring the inclusion of the latest mechanistic insights and translational advances in the ferroptosis-lipid metabolism-neuroinflammation axis.},
}

@article {pmid42868033,
year = {2026},
author = {Yang, Y and Zhang, Y and Meliker, JR and Richmond, LL and Smith, DM and Clouston, SAP},
title = {Education as a proxy for cognitive reserve, and its moderating role in the amyloid-cognition relationship across the Alzheimer's disease continuum: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261496419},
doi = {10.1177/13872877261496419},
pmid = {42868033},
issn = {1875-8908},
abstract = {BackgroundEducational achievement is widely used as a proxy for cognitive reserve-the capacity to sustain cognition despite accumulating neuropathology. Nevertheless, the impact of education on the neuropathology-cognition association has not been assessed in a meta-analytical manner.ObjectiveTo meta-analyze studies reporting an education × neuropathology interaction term on cognition by pathology, and to determine whether the interaction effect differs by cognitive domains, age, participants' cognitive diagnosis, and gender.MethodsFollowing PRISMA guidelines, we searched PubMed, EMBASE, PsycINFO, and Web of Science through March 2026. Seventeen cross-sectional articles contributing 82 effect sizes were pooled using random-effects models with robust variance estimation across four pathology classes (amyloid, phosphorylated tau [pTau], vascular, and structural). All analyses were corrected for multiple comparisons using the Benjamini-Hochberg false-discovery rate (FDR).ResultsHigher education significantly attenuated the amyloid-cognition association (r = 0.114, adjusted-p = 0.012), a trend concentrated in the global cognitive domain (r = 0.108, adjusted-p = 0.060) and in studies with mixed cognitively unimpaired and cognitively impaired participants (r = 0.130, adjusted-p = 0.020). No significant interaction was found for pTau, vascular, or structural pathology (all adjusted-p > 0.100). Funnel plot and Egger's regression showed no evidence of publication bias.ConclusionsEducation moderated the amyloid-cognition association across the Alzheimer's disease continuum in full-spectrum (mixed-diagnosis) samples. Confirmation in adequately powered, longitudinal designs is warranted.PROSPERO Registration: CRD42023390544.},
}

@article {pmid42868043,
year = {2026},
author = {Yuan, Y and Xing, S and Ren, P and Chen, Z and Fu, Y},
title = {Gamma transcranial alternating current stimulation prevents scopolamine-induced damage to EEG activity and spatial memory.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261497298},
doi = {10.1177/13872877261497298},
pmid = {42868043},
issn = {1875-8908},
abstract = {BackgroundDementia is a serious public health concern, primarily caused by Alzheimer's disease (AD). Transcranial alternating current stimulation (tACS) can improve cognitive function by modulating neural oscillations. While tACS shows therapeutic potential for dementia, its preventive effects remain unknown. Because tACS has long-lasting modulatory effects, we propose that these offline effects may help prevent dementia.ObjectiveThis study aims to determine whether pre-administered 40 Hz tACS prevents scopolamine-induced impairment of electroencephalogram (EEG) activity and spatial cognition. Scopolamine induces cholinergic dysfunction in animal models, mimicking AD-related behavioral and EEG abnormalities.MethodsScopolamine (3 mg/kg, i.p.) was administered to induce a mouse model of dementia. Prior to induction, tACS targeting the prefrontal cortex (PFC) and/or hippocampus (Hip) was performed for five days (40 Hz, 300 μA, 20 min/day). EEG activity was recorded from the PFC and Hip during spontaneous and task-related (Y-maze) states. In addition, spatial memory was evaluated using the Barnes maze test, and general activity including locomotion and anxiety was evaluated using the open field test.ResultsScopolamine reduced spontaneous EEG activity in gamma frequency band and task-related PFC EEG activity across multiple frequency bands. Prior Hip tACS prevented these EEG reductions. Behaviorally, scopolamine induced spatial memory deficits and increased locomotion and anxiety-like behaviors. Notably, dual-site tACS reversed memory impairment and PFC tACS reduced locomotion. In addition, tACS had little effect on anxiety.ConclusionsPrior gamma tACS exerts region-specific protection against scopolamine-induced EEG and behavioral impairments, providing first evidence for its potential as a preventive strategy for dementia-related deficits.},
}

@article {pmid42868044,
year = {2026},
author = {Liu, R and Chen, J and Xue, S and Dong, Y and Xue, X},
title = {Effects of aerobic exercise on learning and memory function and inflammatory markers in animal models of Alzheimer's disease: A meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261496469},
doi = {10.1177/13872877261496469},
pmid = {42868044},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. Aerobic exercise (AE) may improve learning and memory function and modulate neuroinflammation in AD animal models, although evidence remains inconsistent.ObjectiveTo evaluate the effects of AE on learning and memory function and hippocampal inflammatory cytokines in AD animal models.MethodsThis systematic review and meta-analysis followed the PRISMA statement. We searched PubMed, Scopus, Embase, Web of Science, and the Cochrane Library, and included 19 animal studies. We used random-effects models to calculate standardized mean differences (SMD). We conducted subgroup analyses by AD modeling methods, exercise modality, AD pathological stage, and intervention duration. We also evaluated oxidative stress-related markers reported in the included studies as supplementary outcomes.ResultsAE significantly improved spatial memory (platform crossings, SMD = 1.82), spatial learning (escape latency, SMD = -1.48), and recognition memory (novel object recognition, SMD = 2.80). AE reduced hippocampal interleukin-1β (IL-1β) levels (SMD = -3.17); AE showed a trend toward reducing tumor necrosis factor-α (TNF-α) levels, but the effect did not reach statistical significance (SMD = -1.20, 95% CI: -2.44 to 0.04). Supplementary analyses showed that AE increased superoxide dismutase (SOD) activity (SMD = 2.05) and reduced malondialdehyde (MDA) content (SMD = -3.20). Moderate-to-high heterogeneity was observed across studies.ConclusionsAE improves learning and memory function and modulates hippocampal inflammation in AD animal models, particularly IL-1β. Supplementary analyses suggest potential benefits for oxidative stress, with increased SOD and reduced MDA.},
}

@article {pmid42868046,
year = {2026},
author = {Lv, C and Luo, Q and Jin, F and Shao, Q and Qiu, Y and Ni, J and Liu, J and Qing, H and Quan, Z},
title = {Intermittent hypoxia training alleviates cerebral hypoperfusion and amyloid-β deposition in a mixed dementia model established by bilateral common carotid artery stenosis in early-stage 5xFAD mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261497235},
doi = {10.1177/13872877261497235},
pmid = {42868046},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is the most common form of dementia and often coexists with vascular pathology in clinical settings, resulting in mixed dementia with more severe symptoms and more rapid progression.ObjectiveTo investigate whether chronic cerebral hypoperfusion aggravates early AD-related pathology, we established a mixed dementia-like model by inducing bilateral common carotid artery stenosis (BCAS) in early-stage 5xFAD mice and evaluated the effects of intermittent hypoxia treatment (IHT).MethodsEarly-stage 5xFAD mice were subjected to BCAS to induce chronic cerebral hypoperfusion. Cognitive performance, cerebral perfusion, amyloid-β (Aβ) deposition, glial reactivity, tight-junction transcripts, and perivascular astrocyte-vascular organization were assessed. The therapeutic effects of IHT were then evaluated in this mixed dementia-like model.ResultsBCAS-induced hypoperfusion aggravated cognitive impairment in early-stage 5xFAD mice and accelerated pathological changes, including increased Aβ burden and stronger glial reactivity. These changes were accompanied by altered tight-junction transcripts and impaired perivascular astrocyte-vascular organization. IHT mitigated several features of the mixed dementia phenotype, including cerebral hypoperfusion, Aβ accumulation, glial reactivity, and altered perivascular AQP4/CD31 organization, while partially improving cognitive performance.ConclusionsChronic cerebral hypoperfusion can exacerbate early AD-related pathological and cognitive changes. IHT may alleviate mixed dementia-like phenotypes by improving cerebral perfusion, with accompanying changes in perivascular AQP4/CD31 organization and tight-junction transcripts.},
}

@article {pmid42868172,
year = {2026},
author = {Otsuka, S and Nakamura, Y and Ito-Ishida, A and Suzuki, K and Ishikawa, A and Matsuda, K and Suyama, S and Contractor, A and Yuzaki, M},
title = {Operant House: A versatile open-source platform for automated operant conditioning testing of mice in home cages.},
journal = {PloS one},
volume = {21},
number = {10},
pages = {e0360626},
pmid = {42868172},
issn = {1932-6203},
mesh = {Animals ; *Conditioning, Operant/physiology ; Mice ; Memory, Short-Term/physiology ; Male ; Alzheimer Disease/physiopathology/genetics ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics ; Housing, Animal ; Mice, Inbred C57BL ; },
abstract = {Operant conditioning is a powerful method for probing cognitive functions, yet its widespread use is constrained by low throughput, labor-intensive procedures, and high costs. Here, we developed "Operant House," a low-cost, programmable device equipped with a touchscreen, retractable levers, and a water-reward port, designed to enable automated operant conditioning with minimal experimenter intervention in individually housed mice within their home cages. Although individual home-cage testing requires careful attention to animal welfare, the system permits continuous monitoring through live camera observation and recorded videos. As proof of concept, we implemented two cognitive protocols: a delayed non-match-to-position (DNMTP) test for assessing working memory and a two-choice spatial discrimination (TCSD) test involving working-memory-related processes and behavioral flexibility. Because working memory impairment is one of the earliest clinical features of Alzheimer's disease (AD), we further applied these protocols to a knock-in mouse model carrying familial AD-associated amyloid precursor protein mutations (AppNL-G-F mice). Using this model, we detected significant working memory deficits as early as 5 months of age. At this age, we also detected subtle and spatially heterogeneous synaptic alterations in the prefrontal cortex, whereas conventional electrophysiological measures were largely preserved. Together, these findings highlight the Operant House as a cost-effective, scalable platform for assessing higher cognitive functions in mice, offering an accessible tool for investigating neurological and neuropsychiatric disease models.},
}

Animals
*Conditioning, Operant/physiology
Mice
Memory, Short-Term/physiology
Male
Alzheimer Disease/physiopathology/genetics
Mice, Transgenic
Amyloid beta-Protein Precursor/genetics
Housing, Animal
Mice, Inbred C57BL

@article {pmid42868522,
year = {2026},
author = {Hwangbo, H and Han, DW and Lee, EH and Jeong, SJ and Choi, YH and Kim, SO},
title = {Cordycepin Attenuates Lipopolysaccharide-Induced Inflammation by Regulating the TLR4 Signaling Pathway in BV2 Microglia Cells.},
journal = {International journal of medicinal mushrooms},
volume = {28},
number = {5},
pages = {63-76},
doi = {10.1615/IntJMedMushrooms.2026063597},
pmid = {42868522},
issn = {1940-4344},
mesh = {*Microglia/drug effects/metabolism ; Animals ; Lipopolysaccharides/adverse effects ; *Deoxyadenosines/pharmacology ; *Signal Transduction/drug effects ; *Toll-Like Receptor 4/metabolism/genetics ; Mice ; Cell Line ; Nitric Oxide/metabolism ; *Inflammation/chemically induced/drug therapy ; *Anti-Inflammatory Agents/pharmacology ; *Cordyceps/chemistry ; Tumor Necrosis Factor-alpha ; Molecular Docking Simulation ; },
abstract = {Excessive neuroinflammation caused by activated microglia contributes to the progression of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Microglia, the immune cells of the central nervous system, play vital roles in brain development, immune defense, and maintaining the neural environment. Cordycepin from Cordyceps militaris exhibits diverse biological activities, including anti-inflammatory, antioxidant, and hypoglycemic effects. This study investigated the effects of ethanol extract of C. militaris fermented from Gryllus bimaculatus (EECM) and cordycepin on lipopolysaccharide (LPS)-induced neuroinflammation in BV2 microglial cells. EECM significantly reduced the levels of nitric oxide (NO), interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) elevated by LPS. Similarly, cordycepin decreased the secretion of NO, TNF-α, and IL-6. Additionally, LPS-induced expression of toll-like receptor 4 (TLR4) and inflammatory proteins (iNOS, COX-2, TNF-α, and IL-6) was significantly suppressed by cordycepin. Molecular docking revealed that cordycepin binds to the TLR4/MD2 complex (-6.2 kcal/mol) at Lys341, Ser364, and Phe365, suggesting competitive inhibition at the LPS-binding site. These findings indicate that cordycepin attenuates LPS-induced neuroinflammation by modulating the TLR4 signaling pathway, highlighting its therapeutic potential for neuroinflammatory conditions.},
}

*Microglia/drug effects/metabolism
Animals
Lipopolysaccharides/adverse effects
*Deoxyadenosines/pharmacology
*Signal Transduction/drug effects
*Toll-Like Receptor 4/metabolism/genetics
Mice
Cell Line
Nitric Oxide/metabolism
*Inflammation/chemically induced/drug therapy
*Anti-Inflammatory Agents/pharmacology
*Cordyceps/chemistry
Tumor Necrosis Factor-alpha
Molecular Docking Simulation

@article {pmid42868585,
year = {2026},
author = {Gu, L and Sun, D and Sun, L and Ma, T and Wang, Q and Hou, X and Cheng, H},
title = {JMJD6 Inhibits the Ferroptosis of Neurons in Alzheimer's Disease through Driving H4R3 Symmetrical Dimethylation of GPX4.},
journal = {Critical reviews in eukaryotic gene expression},
volume = {36},
number = {3},
pages = {47-57},
doi = {10.1615/CritRevEukaryotGeneExpr.2026064685},
pmid = {42868585},
issn = {2162-6502},
mesh = {*Alzheimer Disease/metabolism/genetics/pathology ; *Ferroptosis/genetics ; *Neurons/metabolism/pathology ; Animals ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism/genetics ; *Jumonji Domain-Containing Histone Demethylases/metabolism/genetics ; Humans ; Amyloid beta-Peptides ; Mice ; Methylation ; *Histones/metabolism ; Peptide Fragments ; },
abstract = {Histone methylation is a key hallmark of Alzheimer's disease (AD). JMJD6 functions in a neuro-protective role. The purpose of this study is to explore the role of JMJD6 in AD. Neurons are exposed to Aβ1-42 to establish in vitro AD model. Neurons are treated with RSL3 to induce neuronal ferroptosis. mRNA expression is detected using qRT-PCR. Protein expression is determined using Western blot. The levels of ROS, GSH, MDA, ferrous iron, and C11-BODIPY are analyzed. Neuronal death is detected using PI staining. H4R3 symmetrical dimethylation of GPX4 is analyzed using ChIP and luciferase assays. We found that Aβ1-42 exposure promotes iron overload and lipid peroxidation, driving neuronal ferroptosis. Aβ1-42 exposure inhibits the expression of JMJD6. However, overexpression of JMJD6 reverses Aβ1-42 exposure-induced neuronal ferroptosis. Moreover, JMJD6 promotes H4R3 symmetrical dimethylation and upregulation of GPX4, driving the release of anti-oxidant GSH. Furthermore, JMJD6 overexpression alleviated cognitive impairment and neuronal ferroptosis in AD mouse models. However, downregulation of GPX4 mediates neuronal ferroptosis. In conclusion, JMJD6 protects against neuronal ferroptosis in AD via upregulating GPX4.},
}

*Alzheimer Disease/metabolism/genetics/pathology
*Ferroptosis/genetics
*Neurons/metabolism/pathology
Animals
*Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism/genetics
*Jumonji Domain-Containing Histone Demethylases/metabolism/genetics
Humans
Amyloid beta-Peptides
Mice
Methylation
*Histones/metabolism
Peptide Fragments

@article {pmid42868894,
year = {2026},
author = {Mao, J and Luo, Y and Dai, Y and Wang, S and Jiang, T and Wu, K and Sun, J},
title = {Multifunctional SERS substrate of PDMS@UiO-66-NH2@Ag for direct detection of p-tau217 protein in different biofluids.},
journal = {Colloids and surfaces. B, Biointerfaces},
volume = {270},
number = {},
pages = {116246},
doi = {10.1016/j.colsurfb.2026.116246},
pmid = {42868894},
issn = {1873-4367},
abstract = {The sensitive and reliable detection of phosphorylated tau at threonine 217 (p-tau217) in Alzheimer's disease is important for early diagnosis and clinical intervention. However, conventional surface-enhanced Raman scattering (SERS) substrates often suffer from insufficient molecular enrichment and limited electromagnetic enhancement in complex biofluids. Herein, we developed a flexible SERS platform of UiO-66-NH2@Ag supported by polydimethylsiloxane (PDMS) for the label-free and ultrasensitive detection of p-tau217. Specifically, the porous UiO-66-NH2 framework enriched target molecules and potentially promoted interfacial charge transfer, whereas the densely packed Ag nanoparticles (NPs) generated abundant electromagnetic "hotspots" through localized surface plasmon resonance. The optimized substrate exhibited a remarkable enhancement factor of 5.4 × 10[10]. Benefiting from the superior near-field confinement assisted by charge transfer, the enrichment capability of the UiO-66-NH2 framework, and the signal uniformity afforded by the PDMS substrate, a quantitative detection of p-tau217 was enabled over a wide concentration range of 10[-11] - 10[-6] mg/mL. Notably, the platform also achieved reliable and reproducible performance in complex biological matrices, including serum, cerebrospinal fluid, and tear fluid. These results demonstrate that the proposed strategy offers an effective approach to combine molecular enrichment with plasmonic amplification in a flexible sensing system, which is benefit for trace biomarker detection.},
}

@article {pmid42868904,
year = {2026},
author = {Chen, W and Huang, Q and Wang, F and Hao, Z and Cai, R},
title = {Causal discovery from nonstationary subsample time series.},
journal = {Neural networks : the official journal of the International Neural Network Society},
volume = {206},
number = {Pt A},
pages = {109731},
doi = {10.1016/j.neunet.2026.109731},
pmid = {42868904},
issn = {1879-2782},
abstract = {Causal discovery from nonstationary subsample time series is a fundamental yet challenging problem in many scientific domains. In such data, observations are often recorded at a coarse time scale (subsampling). At the same time, the underlying data-generating mechanisms may change over time (nonstationarity), making standard methods that assume a single, fixed causal model unreliable. To address these challenges, we propose a local-to-global causal graph reconstruction framework for nonstationary subsample time series. Specifically, we first identify key latent variables via a pure-child-anchored strategy to recover boundary structures. We then infer contemporaneous causal relations through one-sided reduction and redundant-edge elimination. Finally, we reconstruct the full-time causal directed acyclic graph using recursive blocking and coefficient-invariant transfer, enabling consistent integration across nonstationary segments. We further provide theoretical guarantees for the correctness of the proposed method under mild conditions. Extensive experiments on synthetic datasets demonstrate the effectiveness of our method in recovering the underlying causal structure under both subsampling and nonstationarity. Moreover, an application to the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset reveals interpretable, stage-dependent causal pathways from mild cognitive impairment (MCI) to Alzheimer's disease (AD), highlighting the practical utility of our approach.},
}

@article {pmid42868934,
year = {2026},
author = {Knox, S and Johnson, J and Dooley, M and Cutty, M and Maldonado, L and Ward, R and Simpson, KN},
title = {Home Health Pathways Relevant to Patient-Driven Groupings Model Classification Among Medicare Beneficiaries With and Without Dementia.},
journal = {Journal of the American Medical Directors Association},
volume = {27},
number = {12},
pages = {106497},
pmid = {42868934},
issn = {1538-9375},
abstract = {OBJECTIVES: To characterize admission-source and episode timing pathways among Medicare Home Health (HH) beneficiaries with and without Alzheimer's disease and related dementias (ADRD) immediately prior to the Patient-Driven Groupings Model (PDGM) implementation, which incorporated these factors into HH payment.

DESIGN: Retrospective secondary analysis of national Medicare claims data from 2019, with propensity score matching of beneficiaries classified as ADRD highly likely and ADRD unlikely.

SETTING AND PARTICIPANTS: A total of 129,429 ADRD-highly likely HH beneficiaries were matched 1:1 to 129,429 ADRD-unlikely HH beneficiaries.

METHODS: Outcomes included annual counts of community and institutional HH admissions and late HH episodes, as well as Health Insurance Prospective Payment System 1 classifications reflecting admission source and episode timing. Incidence rate ratios (IRRs) and odds ratios were estimated to compare HH utilization and classification patterns between matched groups.

RESULTS: The matched cohort included 129,429 beneficiary pairs. Compared with ADRD-unlikely beneficiaries, ADRD-highly likely beneficiaries had more community admissions (mean, 2.7 vs 2.4; IRR, 2.75; 95% CI, 2.73-2.76) and more late episodes (mean, 2.35 vs 2.05; IRR, 2.35; 95% CI, 2.34-2.37). ADRD status was not associated with the likelihood of any institutional admission (odds ratio, 1.00; 95% CI, 0.98-1.01). Among beneficiaries with at least 1 institutional admission, ADRD-highly likely beneficiaries had higher institutional admission rates (IRR, 1.12; 95% CI, 1.09-1.14). ADRD-highly likely beneficiaries also had higher odds of community early and community late classifications relative to institutional early episodes.

CONCLUSIONS AND IMPLICATIONS: Immediately before PDGM implementation, ADRD-highly likely beneficiaries were more likely to enter HH from the community and to experience later episodes of care. These findings establish a pre-PDGM benchmark for understanding how beneficiaries with ADRD were distributed across admission source and episode-timing pathways subsequently incorporated into HH payment. Future research should evaluate whether PDGM has differentially affected HH access, utilization, payment, and care delivery for beneficiaries with ADRD.},
}

@article {pmid42869027,
year = {2026},
author = {Yu, F and Wang, R and Di, R and Xu, K and Gao, J and Shang, H and Yuan, Z and Dai, R and Wu, W and Weng, D and Gao, X and Li, H and Yu, T and Zhang, Y and Wang, X and Luan, G and Zhao, F and Luo, M},
title = {A cross-species AAV platform for precise microglial interrogation.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.09.017},
pmid = {42869027},
issn = {1097-4199},
abstract = {Targeting microglia with adeno-associated viruses (AAVs) remains challenging because of inefficient transduction, off-target expression, and inconsistent payload performance. Here, we develop an integrated, Cre-independent AAV platform that combines a compact 446-bp microglia-specific regulatory element (MSRE), a high-yield AAV2/9.m capsid, microRNA-mediated neuronal de-targeting, and a microglia-tailored codon-optimization strategy. Following direct intracranial delivery, the optimized vector achieves robust, long-lasting transgene expression with greater than 90% microglial specificity across multiple mouse brain regions, including in an Alzheimer's disease model. With doxorubicin-assisted delivery, the platform also enables efficient and selective microglial targeting in rats, rhesus macaques, and human ex vivo brain slices. Codon optimization supports the expression of otherwise challenging functional payloads, enabling calcium imaging, chemogenetic manipulation, and CRISPR-Cas9-mediated genome editing. This cross-species toolkit provides a versatile resource for investigating microglial biology and developing microglia-directed therapeutic strategies.},
}

@article {pmid42869105,
year = {2026},
author = {Luo, B and Liu, S and Zheng, L and Zhang, B and Chen, B and Shang, T and Zheng, J and Kuang, B and Zhou, Y and Sun, Y and Zou, W},
title = {The mechanism of dietary intervention in delaying brain aging and neurodegenerative diseases.},
journal = {Ageing research reviews},
volume = {123},
number = {},
pages = {103417},
doi = {10.1016/j.arr.2026.103417},
pmid = {42869105},
issn = {1872-9649},
abstract = {With the global aging population, age-related neurodegenerative diseases and cerebrovascular diseases have become major public health challenges. As a modifiable lifestyle strategy, dietary intervention shows significant potential in delaying brain aging and reducing the risk of neurodegenerative and cerebrovascular diseases. Caloric restriction (CR) and dietary restriction (DR), two important nutritional intervention approaches, exhibit substantial neuroprotective potential through multiple mechanisms. This review systematically summarizes the mechanisms of CR and DR in brain aging and related diseases, focusing on: (1) modulating gene expression and epigenetic modifications; (2) regulating proteostasis and autophagy; (3) inhibiting neuroinflammation to delay inflammaging; (4) improving mitochondrial function and oxidative homeostasis; and (5) optimizing nutrient-sensing pathways and metabolism. Additionally, this review discusses the mechanistic evidence of CR and DR in disease models such as Alzheimer's Disease (AD), Parkinson's Disease (PD), stroke, and Vascular Dementia (VaD). Despite promising preclinical findings, their clinical translation faces challenges including individual variability, safety concerns, and uncertainty regarding mechanism prioritization. Future research should focus on conducting more high-quality clinical trials, integrating multi-omics technologies with precision nutrition strategies to promote the practical application of CR and DR in advancing healthy brain aging.},
}

@article {pmid42869138,
year = {2026},
author = {Dou, B and Chen, J and Zhao, H and Sun-Yan, A and Zhu, X and Xu, Y},
title = {Mitochondrial dysfunction in Alzheimer's disease: mechanisms, pathogenic interplay, and therapeutic opportunities.},
journal = {Pharmacology & therapeutics},
volume = {288},
number = {},
pages = {109130},
doi = {10.1016/j.pharmthera.2026.109130},
pmid = {42869138},
issn = {1879-016X},
abstract = {Alzheimer's disease (AD) remains a major cause of dementia, yet effective disease-modifying therapies are still limited. Although amyloid-β (Aβ) and tau pathology remain core features of AD pathogenesis, they do not fully explain how these pathological alterations drive progressive cellular dysfunction. Increasing evidence suggests that mitochondria are involved at this critical interface. In AD, mitochondrial abnormalities impair energy production, compromise organelle quality control, disrupt calcium (Ca[2+]) homeostasis, and alter communication with the endoplasmic reticulum and glial cells. As these defects accumulate, neurons and glia become less able to maintain metabolic stability, redox balance, and synaptic function. Mitochondrial dysfunction is therefore relevant to AD not as a single isolated lesion, but as a convergent process through which metabolic failure, oxidative stress, mitochondrial DNA damage, inflammatory signaling, and defective cellular maintenance reinforce one another. This perspective also helps explain why disease progression is difficult to reverse once mitochondrial homeostasis has been broadly compromised. At the same time, this framework also points to therapeutic opportunities, as the mechanisms driving the development and progression of mitochondrial dysfunction may be amenable to intervention. However, many mitochondria-centered strategies remain preclinical or have yielded inconsistent clinical benefit. Current evidence supports mitochondrial dysfunction as both a useful mechanistic basis for understanding AD progression and a biologically meaningful, though challenging, therapeutic target.},
}

@article {pmid42869229,
year = {2026},
author = {Cardona, CJ and Sigdel, R and Johnson, PR and Kim, Y and Montgomery, MR and Emerson, SR and Chowanadisai, W},
title = {Dietary heme iron intake and common hemochromatosis HFE polymorphisms have similar associations with brain MRI phenotypes: a UK Biobank cohort study.},
journal = {The Journal of nutrition},
volume = {},
number = {},
pages = {101890},
doi = {10.1016/j.tjnut.2026.101890},
pmid = {42869229},
issn = {1541-6100},
abstract = {BACKGROUND: Brain iron accumulation is associated with aging and neurodegeneration, but how individual genetics and dietary iron intake affect brain iron is not well understood. Hemochromatosis is a genetic disorder arising from single nucleotide polymorphisms (SNPs) in the HFE gene, causing iron overload and brain iron accumulation, and is associated with accelerated brain aging.

OBJECTIVE: This cross-sectional study examined how dietary iron intake and hemochromatosis-associated single nucleotide polymorphisms are associated with brain MRI phenotypes sensitive to iron.

METHODS: We used a subset of the UK Biobank (N=24,223 participants) to investigate associations between dietary heme and non-heme iron intake (dietary predictors), HFE SNPs rs1799945 and rs1800562 (genetic predictors), brain quantitative susceptibility mapping (QSM) and T2* MRI phenotypes (primary outcomes) using multiple regression. We also investigated associations of HFE SNPs and dietary intake with hemoglobin, anemia risk, and MRI-derived liver iron levels as markers of systemic iron status. We compared brain QSM for rs1799945 and rs1800562 homozygotes and rs1799945/rs1800562 compound heterozygotes relative to control genotype subjects without either HFE SNP using ANCOVA and Tukey-Kramer post-hoc testing. Significance was set at false discovery rate (FDR) <0.05.

RESULTS: Intake of dietary heme iron and both HFE SNPs were associated with increased QSM and decreased T2* MRI intensities (FDR<0.05), a pattern associated with increased brain iron levels. Non-heme iron intake was associated with a slight, but statistically significant, decrease in QSM and increase in T2* intensity, which is consistent with less brain iron. Both SNPs and heme iron intake were associated with higher hemoglobin and MRI-derived liver iron levels. Adjusted mean QSM intensity was generally highest for rs1800562 homozygotes and mostly higher in rs1799945 homozygotes and rs1799945/rs1800562 compound heterozygotes compared to control genotype.

CONCLUSIONS: Dietary heme iron intake and SNPs linked to hemochromatosis are associated with altered brain MRI intensities consistent with elevated brain iron.},
}

@article {pmid42869255,
year = {2026},
author = {Zhang, ZY and Qin, BQ and Wu, SZ and Zhang, H},
title = {Conformational allocation of mitofusin 2 in neuronal mitochondrial dynamics: Mechanisms and therapeutic targeting.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118545},
doi = {10.1016/j.bcp.2026.118545},
pmid = {42869255},
issn = {1873-2968},
abstract = {Neurons must sustain functional mitochondria far from the cell body. Mitofusin 2 (MFN2), a dynamin-like large guanosine triphosphatase (GTPase), coordinates outer mitochondrial membrane remodeling with axonal transport, bioenergetic support, inter-organelle communication, and stress-responsive quality control. Studying these activities separately obscures how disruption of one protein produces diverse neuronal phenotypes. We propose a testable conformational-allocation framework in which molecular state distributions and transition kinetics bias MFN2 participation across cellular outputs. Integrating structural and functional evidence, we distinguish experimentally resolved mechanisms from working models. Variants associated with Charcot-Marie-Tooth disease type 2A (CMT2A) are compared by the molecular step or functional output affected. Fusion loss alone does not capture this mechanistic diversity. Structure-guided docking supports local compatibility at a shallow, conformationally conditional C-terminal surface, without establishing native accessibility, affinity, or therapeutic response. CMT2A provides the strongest context for intervention, combining causal genetics, direct mitofusin engagement studies, and multiscale rescue. Amyotrophic lateral sclerosis (ALS) provides secondary preclinical evidence, whereas Alzheimer's and Parkinson's diseases remain exploratory. The mitofusin pathway is chemically tractable, but paralog selectivity and state-dependent target engagement remain unresolved. A state- and variant-informed strategy may better match intervention to the affected output than indiscriminate enhancement of fusion.},
}

@article {pmid42869308,
year = {2026},
author = {Srivastava, S and Santhoshkumar, P and Tender, T and Sharma, K},
title = {A protease-resistant D-amino acid αA-crystallin mini-chaperone with enhanced chaperone and antioxidant activities protects against amyloid-β proteotoxicity.},
journal = {Free radical biology & medicine},
volume = {257},
number = {},
pages = {397-408},
doi = {10.1016/j.freeradbiomed.2026.10.032},
pmid = {42869308},
issn = {1873-4596},
abstract = {Protein misfolding, aggregation, and oxidative stress contribute to aging and numerous neurodegenerative diseases, including Alzheimer's disease. Although the αA-crystallin-derived mini-chaperone peptide suppresses protein aggregation, its therapeutic potential is limited by susceptibility to proteolytic degradation. Here, we synthesized a protease-resistant analog composed entirely of D-amino acids (D-MC-αA) and compared its biochemical and biological properties with those of the parent peptide (MC-αA). Chaperone activity was assessed using two aggregation-prone model proteins, antioxidant activity by inhibition of Cu[2+]-mediated oxidation of ascorbic acid, and proteolytic stability by enzymatic digestion followed by reverse-phase HPLC. Cytoprotective and membrane-protective activities were evaluated using melittin-induced cytotoxicity in retinal pigment epithelial cells and hemolysis of human red blood cells. Peptide uptake, lifespan, thermotolerance, and protection against amyloid-β toxicity were evaluated in Caenorhabditis elegans (C. elegans). D-MC-αA exhibited approximately threefold greater chaperone activity than MC-αA, completely resisted enzymatic degradation, and more effectively inhibited Cu[2+]-mediated ascorbic acid oxidation. Both peptides protected retinal cells against melittin-induced injury and reduced red blood cell hemolysis. The mini-chaperone was efficiently taken up by C. elegans, and both peptides significantly extended lifespan, enhanced thermotolerance, delayed amyloid-β-induced paralysis, and prolonged survival without adversely affecting feeding behavior or reproduction. D-MC-αA provided greater protection than MC-αA against amyloid-β-induced paralysis and mortality. Collectively, these findings demonstrate that all-D-amino acid substitution confers proteolytic resistance, enhances chaperone and antioxidant activities, and preserves cytoprotective function, supporting further development of D-MC-αA for disorders associated with protein misfolding, oxidative stress, and amyloid toxicity.},
}

@article {pmid42869338,
year = {2026},
author = {Tao, C and Wan, K and Song, Y and Xu, X and She, M and Sun, Z and Zhu, J and Yu, Y},
title = {Parsing the relationships among gut microbiome, neurotransmitter metabolome, glymphatic function, and cognition across healthy elderly, mild cognitive impairment, and probable Alzheimer's disease.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {107067},
doi = {10.1016/j.bbi.2026.107067},
pmid = {42869338},
issn = {1090-2139},
abstract = {BACKGROUND: Evidence has suggested brain glymphatic dysfunction and gut microbial metabolic disturbance in Alzheimer's disease (AD), yet the relationships among gut microbiota, neurotransmitter metabolites, glymphatic function, and cognition across clinically defined groups of healthy elderly, mild cognitive impairment (MCI), and probable AD remain unclear.

METHODS: Using metagenomic sequencing, targeted metabolomics, and multi-modal magnetic resonance imaging, we measured the gut microbiome, neurotransmitter metabolome, and a variety of glymphatic markers in 30 patients with clinically diagnosed probable AD, 75 individuals with MCI, and 59 healthy controls (HC).

RESULTS: Although global microbial diversity showed no group difference, MCI and AD showed shared and unique species-level microbial alterations relative to HC. Despite the absence of overall metabolomic divergence, AD exhibited reduced levels of multiple neurotransmitter metabolites compared with MCI and HC. Prominent alterations in multiple glymphatic markers were present in AD rather than in MCI. Further integrated analyses revealed a wide range of associations among these multi-omics changes and established potential serial mediation pathways, manifesting as a pattern of gut microbiota → neurotransmitter metabolites → glymphatic function → cognition.

CONCLUSIONS: These findings could enrich our understanding of the biological mechanisms involved in cognitive impairment and clinically diagnosed probable AD, but also may inform future preventive and therapeutic interventions by targeting the established pathways.},
}

@article {pmid42869342,
year = {2026},
author = {Mikalauskaite, K and Veiveris, D and Smirnovas, V and Ziaunys, M},
title = {Effect of freeze-thaw cycle induced oligomers on alpha-synuclein liquid-liquid phase separation and aggregation.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {154845},
doi = {10.1016/j.ijbiomac.2026.154845},
pmid = {42869342},
issn = {1879-0003},
abstract = {Protein aggregation in the form of amyloid fibrils is linked with the onset and progression of several widespread and incurable disorders, including neurodegenerative Alzheimer's and Parkinson's diseases. Despite decades of research and countless attempts to discover potential aggregation-altering treatment modalities, there are still no effective cures for the majority of amyloid-related disorders. This is, in part, due to our incomplete understanding of the underlying factors that influence the phase separation and aggregation of these various disease-related proteins. Over the last few years, it has been shown that even factors such as storage conditions or sample preincubation times can affect the formation kinetics of amyloid fibrils. In the case of alpha-synuclein, even the protein purification procedure yielded different concentrations of oligomeric species, which altered the aggregation mechanism. In this work, we further explore the role of alpha-synuclein oligomers by inducing their formation via freeze-thaw cycles and analyzing their effect on liquid-liquid and liquid-solid phase transitions. Using real-time kinetic monitoring, brightfield microscopy, Fourier-transform infrared spectroscopy and atomic force microscopy, we show that the presence of freeze-thaw cycle induced alpha-synuclein oligomers has significant effects on its condensate assembly and subsequent aggregation, as well as the final structure of the formed aggregates.},
}

@article {pmid42869662,
year = {2026},
author = {Kashuk, E and Smirnov, D and Eremenko, E and Tsitrina, A and Kriukov, D and Golova, A and Kaluski-Kopatch, S and Khrameeva, E and Toiber, D},
title = {The divergent 3D genome landscapes of aging and neurodegenerative mouse models.},
journal = {Genome research},
volume = {},
number = {},
pages = {},
doi = {10.1101/gr.281732.125},
pmid = {42869662},
issn = {1549-5469},
abstract = {Chromatin structure is essential for gene regulation and genome stability, as neurons must preserve their 3D genome organization throughout life. This structure gradually deteriorates with aging and is further disrupted in neurodegenerative diseases. To investigate whether aging and neurodegeneration share early chromatin changes or diverge, we perform Hi-C on cortical neurons from adult, aged, and brain-specific SIRT6-knockout (S6-KO) mice and compare them to the previously published Hi-C data sets from a CK-p25 Alzheimer's disease model stratified by γH2AX levels. All models show early features such as weakened interactions between chromosomes in expanded nuclei, A- to B-compartment shifts, and loss of architectural loops. However, aged neurons retain TAD prominence, short-range interactions, and enhancer-promoter loops, whereas pathological models showed reduced TAD prominence, shorter loops, and disorganized A-B mixing. These changes correlate with increased DNA damage. Our findings suggest that aging represents a "primed" state, in which chromatin regulation begins to erode, but further stressors like DNA damage are associated with progression toward neurodegenerative breakdown.},
}

@article {pmid42869847,
year = {2026},
author = {Liu, X and de Boer, SCM and Tartaglia, MC and , },
title = {Sex-specific brain reserve and progression from mild cognitive impairment to Alzheimer's disease dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71913},
doi = {10.1002/alz.71913},
pmid = {42869847},
issn = {1552-5279},
support = {//Donald Weaver Postdoctoral Fellowship/ ; //Early Career Grant of Alzheimer Nederland/ ; //Brain Canada-Krembil/ ; //Canadian Institute of Health Research/ ; //Tanenbaum Institute of Research in Sports Science/ ; //Weston Family Foundation/ ; //Michael J. Fox Foundation for Parkinson's Research/ ; },
mesh = {Humans ; Female ; *Alzheimer Disease/pathology/diagnostic imaging/cerebrospinal fluid ; *Cognitive Dysfunction/pathology/diagnostic imaging/cerebrospinal fluid ; Male ; Disease Progression ; *Brain/pathology/diagnostic imaging ; tau Proteins/metabolism ; Aged ; Positron-Emission Tomography ; *Sex Characteristics ; Magnetic Resonance Imaging ; Atrophy ; Longitudinal Studies ; Aged, 80 and over ; Gray Matter/pathology/diagnostic imaging ; Biomarkers/cerebrospinal fluid ; },
abstract = {INTRODUCTION: Sex differences exist in Alzheimer's disease (AD) treatment response, but the role of sex in disease development and progression remains unclear.

METHODS: We performed multimodal analyses of AD biomarker-positive individuals with mild cognitive impairment (MCI) and AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI; MCI n = 593, AD n = 270) and National Alzheimer's Coordinating Center (MCI n = 436, AD n = 174). Baseline gray matter volume (GMV) was compared by sex. In ADNI, tau positron emission tomography burden and cerebrospinal fluid growth-associated protein 43 (GAP-43) were assessed. Longitudinal analyses examined atrophy and conversion from MCI to dementia.

RESULTS: Females with MCI exhibited greater baseline GMV than males primarily in the thalamus, caudate, cerebellum, postcentral gyrus, and middle cingulate gyrus, with no differences at the AD stage. Despite this, females exhibited higher baseline GAP-43, greater tau burden in temporal and parietal regions, and more rapid annual hippocampal atrophy. Conversion rates were similar.

DISCUSSION: Findings suggest that females may tolerate greater pathology at early stages but experience faster neurodegeneration later, supporting sex-specific disease trajectories and highlighting the need for sex-informed biomarkers.},
}

Humans
Female
*Alzheimer Disease/pathology/diagnostic imaging/cerebrospinal fluid
*Cognitive Dysfunction/pathology/diagnostic imaging/cerebrospinal fluid
Male
Disease Progression
*Brain/pathology/diagnostic imaging
tau Proteins/metabolism
Aged
Positron-Emission Tomography
*Sex Characteristics
Magnetic Resonance Imaging
Atrophy
Longitudinal Studies
Aged, 80 and over
Gray Matter/pathology/diagnostic imaging
Biomarkers/cerebrospinal fluid

@article {pmid42869850,
year = {2026},
author = {Devignes, Q and Pruitt, PJ and Petscavage, K and Koeppe, RA and Albin, RL and Peltier, SJ and Rahman-Filipiak, A and Giordani, B and Iordan, AD and Hampstead, BM},
title = {Brain microstructure mediates the relationship between Alzheimer's proteinopathies and memory.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71899},
doi = {10.1002/alz.71899},
pmid = {42869850},
issn = {1552-5279},
support = {R01AG058724/AG/NIA NIH HHS/United States ; R35AG072262/AG/NIA NIH HHS/United States ; P30AG072931/AG/NIA NIH HHS/United States ; UM1TR004404/TR/NCATS NIH HHS/United States ; S10OD034250//NIH Office of the Director/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/complications ; tau Proteins/metabolism ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; *Memory Disorders/diagnostic imaging/pathology/etiology ; *Brain/diagnostic imaging/pathology/metabolism ; Female ; Male ; Aged ; Magnetic Resonance Imaging ; *Gray Matter/pathology/diagnostic imaging/metabolism ; Neuropsychological Tests ; Aged, 80 and over ; },
abstract = {INTRODUCTION: We examined how amyloid beta (Aβ) and tau accumulation affected gray matter (GM) microstructural integrity and how such alterations impacted memory.

METHODS: We tested voxel-wise mediation models to examine the relationships between (1) positron emission tomography-derived Aβ and tau accumulation and GM microstructural integrity assessed with neurite orientation dispersion and density imaging, (2) GM microstructural integrity and memory controlling for Aβ and tau, and (3) the indirect effect of Aβ and tau on memory through GM microstructural integrity in 194 participants with memory impairments.

RESULTS: Tau had a greater impact on GM microstructure than did Aβ. GM microstructural alterations in posterior cortical regions were associated with worse memory when controlling for Alzheimer's proteinopathies. GM microstructural alterations mediated the relationship between Alzheimer's proteinopathies and memory.

DISCUSSION: GM microstructural alterations have functional ramifications given their mediating effect on the relationship between Alzheimer's proteinopathies and memory and their association with worse memory beyond Alzheimer's proteinopathies.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/complications
tau Proteins/metabolism
Positron-Emission Tomography
Amyloid beta-Peptides/metabolism
*Memory Disorders/diagnostic imaging/pathology/etiology
*Brain/diagnostic imaging/pathology/metabolism
Female
Male
Aged
Magnetic Resonance Imaging
*Gray Matter/pathology/diagnostic imaging/metabolism
Neuropsychological Tests
Aged, 80 and over

@article {pmid42869853,
year = {2026},
author = {Schweickart, A and Batra, R and Huynh, K and Blach, C and Kueider-Paisley, A and Reddy, JS and Bennett, DA and Meikle, PJ and Zhang, B and De Jager, PL and Heath, L and Beck, J and Scanlan, J and Seyfried, NT and Dickson, DW and Ertekin-Taner, N and , and Kaddurah-Daouk, R and Arnold, M and Krumsiek, J},
title = {Sphingolipid and ceramide associations with tau pathology vary across diverse ethnoracial groups in postmortem brain tissue.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71690},
doi = {10.1002/alz.71690},
pmid = {42869853},
issn = {1552-5279},
support = {AARFD-22-974775/ALZ/Alzheimer's Association/United States ; ZEN-22-969810/ALZ/Alzheimer's Association/United States ; U01AG046139/AG/NIA NIH HHS/United States ; U01AG046170/AG/NIA NIH HHS/United States ; U01AG061356/AG/NIA NIH HHS/United States ; U01AG061357/AG/NIA NIH HHS/United States ; U01AG061359/AG/NIA NIH HHS/United States ; U01AG061359-05S1/AG/NIA NIH HHS/United States ; U01AG088562/AG/NIA NIH HHS/United States ; U19AG063744/AG/NIA NIH HHS/United States ; U19AG074879/AG/NIA NIH HHS/United States ; R01AG061796/AG/NIA NIH HHS/United States ; R01AG067025/AG/NIA NIH HHS/United States ; R01AG069901/AG/NIA NIH HHS/United States ; R01AG081322/AG/NIA NIH HHS/United States ; RFAG051504/AG/NIA NIH HHS/United States ; P30AG062677/AG/NIA NIH HHS/United States ; T32AG000266/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; *Alzheimer Disease/pathology/metabolism/ethnology ; Black or African American ; *Brain/pathology/metabolism ; *Ceramides/metabolism ; Hispanic or Latino ; Metabolomics ; *Sphingolipids/metabolism ; *tau Proteins/metabolism ; White ; },
abstract = {INTRODUCTION: Metabolic dysregulation is a hallmark of Alzheimer's disease (AD), with numerous studies characterizing metabolic pathways associated with AD onset and progression. A limitation of these studies has been a focus on non-Hispanic white participants. Despite evidence that AD prevalence, progression, and biomarkers differ across ethnoracial groups, it remains unclear whether previously identified metabolic dysregulation in AD brains generalizes across populations.

METHODS: We analyzed metabolomics data from 547 postmortem brain tissue samples of Hispanic American, Non-Hispanic African American, and White subjects, providing the largest multiethnic AD brain cohort to date. A metabolome-wide association study examined how relationships between metabolite abundance and AD neuropathology varied by ethnoracial group.

RESULTS: Forty-eight metabolites exhibited significant heterogeneity with tau pathology (Braak stage), with enrichment in tricarboxylic-acid-cycle intermediates and sphingolipid-ceramide pathway lipids, and with metabolite-tau associations driven predominantly by the Hispanic American and non-Hispanic White groups.

DISCUSSION: These findings reveal ethnoracial-specific metabolic signatures of tau pathology and emphasize the need to evaluate emerging therapeutic targets across diverse groups.},
}

Aged
Aged, 80 and over
Female
Humans
Male
*Alzheimer Disease/pathology/metabolism/ethnology
Black or African American
*Brain/pathology/metabolism
*Ceramides/metabolism
Hispanic or Latino
Metabolomics
*Sphingolipids/metabolism
*tau Proteins/metabolism
White

@article {pmid42869856,
year = {2026},
author = {Khalvandi, F and Izadi, S and Chalechale, A},
title = {MRC-GAT: A meta-relational copula-based graph attention network for interpretable multimodal Alzheimer's disease diagnosis.},
journal = {Artificial intelligence in medicine},
volume = {183},
number = {},
pages = {103555},
doi = {10.1016/j.artmed.2026.103555},
pmid = {42869856},
issn = {1873-2860},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition necessitating early and precise diagnosis to provide prompt clinical management. Given the paramount importance of early diagnosis, recent studies have increasingly focused on computer-aided diagnostic models to enhance precision and reliability. However, most graph-based approaches still rely on fixed structural designs, which restrict their flexibility and limit generalization across heterogeneous patient data. To overcome these limitations, the Meta-Relational Copula-Based Graph Attention Network (MRC-GAT) is proposed as an efficient multimodal model for AD classification tasks. The proposed architecture, copula-based similarity alignment, relational attention, and node fusion are integrated as the core components of metric-based episodic meta-learning, such that the multimodal features, including risk factors (RF), cognitive test scores, and MRI attributes, are first aligned via a copula-based transformation in a common statistical space and then combined by a multi-relational attention mechanism. According to evaluations performed on the TADPOLE and NACC datasets, the MRC-GAT model achieved accuracies of 96.87% and 92.31%, respectively, demonstrating state-of-the-art performance compared to existing diagnostic models. Finally, the proposed model confirms the robustness and applicability of the proposed method by providing interpretability at various stages of disease diagnosis.},
}

@article {pmid42869898,
year = {2026},
author = {Liang, J and Xu, Z and Zhu, Z and Liang, F and Tang, S and Deng, Y and Zhang, X and Chen, H and Lin, Y and Zhou, J},
title = {Single-cell, spatial, and machine learning analyses identify ANKIB1 as an oligodendrocyte-anchored palmitoylation-associated candidate biomarker of Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {16},
number = {1},
pages = {},
pmid = {42869898},
issn = {2158-3188},
support = {2026A1515010026//Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)/ ; 2025A1515012719//Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)/ ; },
mesh = {*Alzheimer Disease/genetics/metabolism ; *Oligodendroglia/metabolism ; Humans ; Biomarkers/metabolism ; Machine Learning ; *Lipoylation ; *Ankyrins/metabolism/genetics ; Single-Cell Analysis ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive neurodegeneration and cognitive decline, yet most candidate therapies targeting amyloid-β have failed to robustly modify disease progression, underscoring an incomplete mechanistic understanding. Oligodendrocytes (ODCs) have recently emerged as active contributors to AD pathology, but the cell-type-specific role of protein S-palmitoylation - a reversible lipid post-translational modification regulating membrane targeting and trafficking - in AD remains uncharacterized. Here we performed an integrated multi-omics analysis combining single-cell RNA sequencing (GSE233208; 48,714 cells), five bulk transcriptomic cohorts (769 samples), and 10× Visium spatial transcriptomic data from 16 brain sections. Palmitoylation activity was quantified at single-cell resolution using a curated 46-gene set; machine learning frameworks (LASSO, random forest, and XGBoost) were used to distil a parsimonious biomarker panel; and four complementary metrics (Jaccard index, overlap coefficient, colocalization percentage, and odds ratio) were applied to evaluate spatial gene-cell colocalization. Oligodendrocytes emerged as the cell population most strongly enriched for palmitoylation activity in the AD brain, supported by per-cell-type scoring, odds ratio enrichment, and an ODC-anchored 658-gene palmitoylation module. Intersection with AD-associated differentially expressed genes yielded 89 candidate genes, from which machine learning identified a seven-gene biomarker panel (ANKIB1, SPAG9, HBP1, SLC25A29, FAM171A1, ATXN10, and NDUFV1). ANKIB1 consistently topped every layer of analysis, with the highest AUC for AD discrimination (0.813, 95% CI 0.782-0.844) and persistent spatial colocalization with ODC-enriched regions across early AD and AD. Network pharmacology nominated AHR and TRIM11 as candidate upstream regulators and catalogued compounds with reported gene interactions. These findings identify the ODC-palmitoylation axis as a previously underappreciated dimension of AD biology and position ANKIB1 as a leading candidate biomarker of ODC dysfunction in AD.},
}

*Alzheimer Disease/genetics/metabolism
*Oligodendroglia/metabolism
Humans
Biomarkers/metabolism
Machine Learning
*Lipoylation
*Ankyrins/metabolism/genetics
Single-Cell Analysis

@article {pmid42869903,
year = {2026},
author = {Mao, Y and Pan, B and Liu, X},
title = {Global brain activity links subcortical degeneration to cortical tau progressively across Braak regions over early Alzheimer's disease stages.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42869903},
issn = {2041-1723},
support = {1R01NS113889-01A1//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U01 AG024904/AG/NIA NIH HHS/United States ; RF1 MH123247/MH/NIMH NIH HHS/United States ; W81XWH-12-2-0012//DOD/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/diagnostic imaging/physiopathology ; *tau Proteins/metabolism ; Female ; Aged ; Male ; Cognitive Dysfunction/pathology/metabolism/diagnostic imaging ; Aged, 80 and over ; Magnetic Resonance Imaging ; *Brain/pathology/diagnostic imaging/metabolism ; *Basal Nucleus of Meynert/pathology/diagnostic imaging/metabolism ; Disease Progression ; Neuroimaging ; },
abstract = {Alzheimer's disease (AD) is characterized by early tau pathology in subcortical neuromodulatory nuclei, followed by progressive cortical tau accumulation; however, the mechanisms linking subcortical dysfunction to cortical tau pathology remain unclear. Using multimodal neuroimaging data from the ADNI cohort, we examined how infra-slow (< 0.1 Hz) global brain (i.e., gBOLD) activity is related to the volume of the nucleus basalis of Meynert (NbM) and cortical tau accumulation in the early stages of AD. NbM degeneration was associated with reduced gBOLD activity and spatially co-localized tau accumulation, appearing in early Braak regions during the preclinical stage, i.e., cognitively unimpaired participants with abnormal CSF markers, and extending to more advanced Braak areas during the prodromal stage, i.e., mild cognitive impairment (MCI) subjects. Our findings suggest that infra-slow gBOLD activity serves as a functional neural mediator linking subcortical degeneration to cortical tau pathology, highlighting a potential functional pathway linking subcortical and cortical pathology in early AD.},
}

Humans
*Alzheimer Disease/pathology/metabolism/diagnostic imaging/physiopathology
*tau Proteins/metabolism
Female
Aged
Male
Cognitive Dysfunction/pathology/metabolism/diagnostic imaging
Aged, 80 and over
Magnetic Resonance Imaging
*Brain/pathology/diagnostic imaging/metabolism
*Basal Nucleus of Meynert/pathology/diagnostic imaging/metabolism
Disease Progression
Neuroimaging

@article {pmid42870189,
year = {2026},
author = {Zhao, S and Zhang, X and Zhong, S and Li, K and Yan, Y and Zhang, B and Chen, Y},
title = {Early cerebral hypoperfusion promotes spatially biased tau pathology in tau-seeded PS19 mice.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42870189},
issn = {2509-2723},
support = {82371190//National Natural Science Foundation of China/ ; LY24H090007//Natural Science Foundation of Zhejiang Province/ ; ZCLQN26C0901//Natural Science Foundation of Zhejiang Province/ ; },
abstract = {Growing evidence has demonstrated a significant association between reduced cerebral blood flow and Alzheimer's disease (AD)-related cognitive impairment. Chronic cerebral hypoperfusion (CCH) has been reported to exacerbate tau hyperphosphorylation and behavioral deficits in rodents, but whether CCH promotes tau pathology at the initial stage of tauopathy remains unclear. Here we show, using a tau-seeded PS19 mouse model with unilateral common carotid artery occlusion, that early CCH exacerbates spatially biased tau pathology, inducing ipsilateral enrichment of insoluble tau in the hippocampus and, in the cortex, an ipsilateral increase that was dependent on the presence of tau seeds. Early CCH also induces myelin loss in the cortex and dorsal fornix, although no synergistic interaction was detected between tau seeds and CCH. Additionally, early CCH promotes microglial activation and IL-1β elevation, and increases hippocampal neuronal loss. In the Morris water maze, early CCH-exposed mice display a marginal trend toward reduced spatial memory performance that did not reach statistical significance. These findings indicate that early CCH facilitates tau pathology and neuroinflammation at the early stage of tauopathy, with only a marginal trend toward early cognitive changes, providing experimental evidence that vascular hypoperfusion may act as a disease modifier in the initial phase of tau pathology, with potential implications for early detection and therapeutic targeting of vascular contributions to tauopathies.},
}

@article {pmid42870221,
year = {2026},
author = {Lee, GY and Han, SN},
title = {The Receptor for Advanced Glycation End Products: Regulation and Implications in Metabolic Diseases.},
journal = {IUBMB life},
volume = {78},
number = {10},
pages = {e70137},
doi = {10.1002/iub.70137},
pmid = {42870221},
issn = {1521-6551},
support = {NRF-RS-2024-00353119//National Research Foundation (NRF) of Korea/ ; },
mesh = {Humans ; *Receptor for Advanced Glycation End Products/metabolism/genetics ; Signal Transduction ; Animals ; Glycation End Products, Advanced/metabolism ; *Metabolic Diseases/metabolism ; Alzheimer Disease/metabolism ; },
abstract = {Receptor for advanced glycation end-products (RAGE) was originally identified as a receptor for advanced glycation end-products; however, it can also bind a broader range of damage-associated molecular patterns, including S100 proteins, high mobility group box 1, and amyloid-β. Ligand-induced RAGE activation promotes receptor oligomerization and recruitment of diaphanous-related formin-1, which activates several intracellular cascades, leading to the production of inflammatory mediators and reactive oxygen species. RAGE expression is upregulated in disease-associated tissues, including adipose tissue in diabetes and microglia and neurons in Alzheimer's disease, and the mechanisms by which RAGE activation contributes to pathogenesis are disease-specific. The review summarizes the expression and activation of RAGE, and the potential mechanisms through which RAGE contributes to disease pathogenesis. We further discuss current and emerging strategies for modulating RAGE signaling and highlight their therapeutic potential in the prevention and treatment of RAGE-associated diseases.},
}

Humans
*Receptor for Advanced Glycation End Products/metabolism/genetics
Signal Transduction
Animals
Glycation End Products, Advanced/metabolism
*Metabolic Diseases/metabolism
Alzheimer Disease/metabolism

@article {pmid42870385,
year = {2026},
author = {Bindra, S and Rangarajan, TM and Parambi, DGT and Kumar, S and Anal, JMH and Mathew, B},
title = {Beyond Single-Target Therapy: Dual-Acting Cannabinoid Type-2 Receptor Modulation in Neurological Disorders.},
journal = {ChemMedChem},
volume = {21},
number = {20},
pages = {e70521},
doi = {10.1002/cmdc.70521},
pmid = {42870385},
issn = {1860-7187},
mesh = {Humans ; *Receptor, Cannabinoid, CB2/metabolism/antagonists & inhibitors ; *Nervous System Diseases/drug therapy/metabolism ; Structure-Activity Relationship ; Ligands ; Animals ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; *Neuroprotective Agents/chemistry/pharmacology ; *Cannabinoids/chemistry/pharmacology ; Molecular Structure ; },
abstract = {Neurological disorders such as Alzheimer's disease, Parkinson's disease, and neuroinflammatory conditions involve complex, interconnected mechanisms, including neuroinflammation, oxidative stress, cholinergic dysfunction, and synaptic impairment. The cannabinoid type-2 receptor (CB2R), primarily expressed in immune and glial cells, has emerged as a promising therapeutic target due to its role in modulating neuroinflammation and providing neuroprotection without the psychoactive effects associated with CB1R activation. Recent research highlights the potential of dual-acting CB2R ligands that also modulate CB1R, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), offering a multitarget approach to neurological disorders. Although CB1R expression was identified in 1993, significant progress in designing receptor modulators began in the 2000s, with recent focus expanding to autoimmune, metabolic, and cancer-related applications. This review summarizes advances in the design, synthesis, and structure-activity relationships of CB2R-targeting ligands, emphasizing dual- or multitarget agents with cholinesterase inhibitory activity. Key chemical scaffolds include synthetic cannabinoids, heterocyclic compounds, and hybrid molecules integrating cholinesterase pharmacophores. Molecular docking and in silico studies are discussed to elucidate ligand-receptor interactions, binding modes, and determinants of selectivity. Overall, CB2R-centric dual-acting ligands represent a promising strategy for addressing multifactorial neurological disorders.},
}

Humans
*Receptor, Cannabinoid, CB2/metabolism/antagonists & inhibitors
*Nervous System Diseases/drug therapy/metabolism
Structure-Activity Relationship
Ligands
Animals
*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis
*Neuroprotective Agents/chemistry/pharmacology
*Cannabinoids/chemistry/pharmacology
Molecular Structure

@article {pmid42870413,
year = {2026},
author = {Saengsomsuan, N and Sangkakit, L},
title = {Low-Volume Superior Trunk and Superficial Cervical Plexus Block With Sedation as the Sole Regional Anesthetic for Proximal Humerus Fracture Fixation in a Patient With Alzheimer Disease.},
journal = {The American journal of case reports},
volume = {27},
number = {},
pages = {e954296},
doi = {10.12659/AJCR.954296},
pmid = {42870413},
issn = {1941-5923},
mesh = {Humans ; Female ; Aged ; *Cervical Plexus Block/methods ; *Fracture Fixation, Internal ; *Alzheimer Disease/complications ; *Shoulder Fractures/surgery/complications ; Bupivacaine/administration & dosage ; Hypnotics and Sedatives ; Geriatric Anesthesia ; Anesthetics, Local/administration & dosage ; },
abstract = {BACKGROUND Proximal humerus open reduction and internal fixation (ORIF) is usually performed under interscalene brachial plexus block (ISB) or general anesthesia (GA). ISB causes ipsilateral phrenic nerve paresis in nearly all patients, and GA may raise the risk of postoperative neurocognitive disorders in elderly patients with cognitive impairment. We report the feasibility of a low-volume regional technique, used as the sole regional anesthetic with sedation, in a patient in whom GA avoidance was desirable. CASE REPORT A 68-year-old woman (American Society of Anesthesiologists physical status II) with Alzheimer's disease underwent ORIF of a closed right proximal humerus fracture via a deltopectoral approach under superior trunk block (STB) with 5 mL of 0.5% bupivacaine, combined with superficial cervical plexus block (SCPB) with 3 mL of 0.5% bupivacaine, totaling 8 mL, with propofol and dexmedetomidine sedation. Surgery lasted 174 minutes without intraoperative rescue analgesia. Heart rate ranged from 48 to 68 beats/min during dexmedetomidine infusion without anticholinergic treatment, and oxygen saturation remained at 100% with spontaneous ventilation preserved. The block provided analgesia for about 12 hours, with pain score 1/10 at rest at 24 hours, and satisfaction 10/10. No clinically evident respiratory compromise, Horner's syndrome, or postoperative delirium was observed, although diaphragmatic and cognitive function were not formally assessed. The patient was discharged on postoperative day 2. CONCLUSIONS In this single patient, low-volume STB combined with SCPB was a feasible sole regional anesthetic technique, supported by sedation, for proximal humerus ORIF, completed without conversion to GA or clinically evident respiratory compromise. Respiratory and cognitive outcomes were clinically uneventful but not formally measured; broader utility remains to be established.},
}

Humans
Female
Aged
*Cervical Plexus Block/methods
*Fracture Fixation, Internal
*Alzheimer Disease/complications
*Shoulder Fractures/surgery/complications
Bupivacaine/administration & dosage
Hypnotics and Sedatives
Geriatric Anesthesia
Anesthetics, Local/administration & dosage

@article {pmid42870580,
year = {2026},
author = {Wang, S and Hu, T and He, M and Qin, M and Hu, Y and Zhao, L and Qin, Z},
title = {Cross-tissue graph attention networks for semi-supervised gene expression prediction.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {5},
pages = {},
doi = {10.1093/bib/bbag557},
pmid = {42870580},
issn = {1477-4054},
mesh = {Graph Neural Networks ; Humans ; *Alzheimer Disease/genetics/metabolism ; *Gene Expression Profiling/methods ; Algorithms ; *Gene Expression ; *Computational Biology/methods ; Brain/metabolism ; },
abstract = {High-throughput biotechnologies have significantly advanced precision medicine by enabling the exploitation of global gene expression patterns to enhance our understanding of disease etiology, progression, and treatment options. However, the tissue-specific nature of gene expression presents a challenge, particularly for less accessible tissues such as the brain, underscoring the need for computational methods to accurately impute gene expression in these critical but hard-to-reach tissues. While several attempts to impute gene expression in tissue-specific contexts have shown promising results, their reliance on regression analysis faces limitations due to the inability to capture complex, nonlinear relationships in gene expression patterns. In contrast, modern machine learning techniques, particularly graph neural networks, have demonstrated superior performance by efficiently modeling the intricate interactions among genes across different tissues. Therefore, we introduce gene expression imputation with graph attention networks (gemGAT), a novel approach leveraging GATs to enhance gene expression prediction across different tissues. gemGAT distinguishes itself by predicting the expression of all genes simultaneously, utilizing the full spectrum of genomic data to account for gene coexpressions and nonlinear relationships. Validated through extensive experiments with Genotype-Tissue Expression data and a case study from the Alzheimer's Disease Neuroimaging Initiative, gemGAT demonstrates superior performance over existing methods by efficiently capturing nonlinear gene coexpressions. This advancement underscores gemGAT's potential to significantly contribute to precision medicine, showcasing its utility in advancing our understanding of gene expression in less accessible tissues.},
}

Graph Neural Networks
Humans
*Alzheimer Disease/genetics/metabolism
*Gene Expression Profiling/methods
Algorithms
*Gene Expression
*Computational Biology/methods
Brain/metabolism

@article {pmid42870592,
year = {2026},
author = {Li, W and Ma, HX and Song, Q and Wang, PC},
title = {Immune Dysregulation and Metabolic Dysfunction in Alzheimer's Disease.},
journal = {Biomedical and environmental sciences : BES},
volume = {39},
number = {9},
pages = {1027-1029},
doi = {10.3967/bes2026.096},
pmid = {42870592},
issn = {2214-0190},
}

@article {pmid42870594,
year = {2026},
author = {Song, Q and Li, W and Liu, Y and Li, SG and Ju, LY and Cao, JR and Gao, S and Liao, ZC and Wang, YQ and Hou, YL and Ma, HX and Zhang, YX and Chen, DD and Yang, WS and Yang, X and Li, QL and Wang, PC},
title = {LDH-related Metabolic Alterations in Alzheimer's Disease: Evidence from Clinical and Transcriptomic Analyses.},
journal = {Biomedical and environmental sciences : BES},
volume = {39},
number = {9},
pages = {1042-1062},
doi = {10.3967/bes2026.083},
pmid = {42870594},
issn = {2214-0190},
mesh = {*Alzheimer Disease/genetics/metabolism/blood ; Humans ; *L-Lactate Dehydrogenase/metabolism/blood/genetics ; Female ; Male ; Gene Expression Profiling ; Retrospective Studies ; Aged ; *Transcriptome ; *Cognitive Dysfunction/genetics/metabolism/blood ; Brain/metabolism ; Case-Control Studies ; },
abstract = {OBJECTIVE: Reduced brain energy metabolism is a key feature of Alzheimer's disease (AD); however, lactate dehydrogenase (LDH)-related metabolic changes in AD are not fully understood. This study aimed to evaluate serum LDH activity in patients with mild cognitive impairment (MCI) and AD. We used public transcriptomic datasets to explore the features of LDHA and LDHB across brain regions, cell types, and co-expression networks.

METHOD: In a retrospective clinical cohort of 132 healthy controls (HC), 87 patients with MCI, and 103 patients with AD, we compared serum LDH activity after adjusting for major clinical covariates. Next, we used public transcriptomic datasets [AlzData, Agora, CELLxGENE, and genotype-tissue expression (GTEx)] to evaluate regional and cell-type-specific expression patterns of LDHA and LDHB. We also characterized LDH-associated functional networks using GTEx normal brain data for baseline co-expression analysis and AD-related weighted gene co-expression network analysis (WGCNA).

RESULTS: Clinical cohort analysis showed that serum LDH activity was significantly decreased in patients with MCI and AD. Serum LDH activity did not significantly correlate with mini-mental state examination (MMSE) or montreal cognitive assessment (MoCA) scores. Brain transcriptomic analysis revealed that LDHA expression was significantly downregulated in AD-related regions (entorhinal cortex, hippocampus, and temporal cortex), whereas LDHB showed a downward trend in several AD-related regions. Both genes were detectable across multiple brain cell types with relatively prominent expression in neurons. Functional analysis showed that, under normal conditions, LDHA-correlated genes were broadly involved in glycolysis, vesicle trafficking, autophagy, and proteostasis, whereas LDHB-correlated genes were highly concentrated in mitochondrial oxidative phosphorylation and the citric acid (TCA) cycle. AD-related WGCNA showed region-dependent organization of LDHA- and LDHB-containing modules, with repeated enrichment in synaptic vesicle-related processes, mitochondrial respiration, autophagy, and proteostasis-related pathways.

CONCLUSION: This study provides clinical and transcriptomic evidence of LDH-related metabolic alterations in patients with AD. Reduced serum LDH activity in MCI and AD, together with decreased LDHA/LDHB expression in AD-related brain regions and region-dependent LDH-associated co-expression networks, supports a potential link between LDH-related metabolism and mitochondrial energy metabolism, synaptic function, and proteostasis in AD. These findings should be interpreted as exploratory, and require validation through paired prospective and mechanistic studies.},
}

*Alzheimer Disease/genetics/metabolism/blood
Humans
*L-Lactate Dehydrogenase/metabolism/blood/genetics
Female
Male
Gene Expression Profiling
Retrospective Studies
Aged
*Transcriptome
*Cognitive Dysfunction/genetics/metabolism/blood
Brain/metabolism
Case-Control Studies

@article {pmid42870749,
year = {2026},
author = {Vossberg, DAF and Rolfes, V and Fangerau, H and Haupt, M},
title = {Medical Decision-Making Capacity in Early-Stage Alzheimer Patients: Comparison With Healthy Controls and Benefit of Assistive Information.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {6},
pages = {e70227},
doi = {10.1111/psyg.70227},
pmid = {42870749},
issn = {1479-8301},
support = {2020-1061//Alzheimer Society of Germany (Deutsche Alzheimer Gesellschaft)/ ; },
mesh = {Humans ; *Alzheimer Disease/psychology/diagnosis ; Female ; Male ; *Decision Making ; Aged ; *Mental Competency/psychology ; *Informed Consent/psychology ; Aged, 80 and over ; Case-Control Studies ; Neuropsychological Tests ; *Audiovisual Aids ; },
abstract = {BACKGROUND: Early-stage Alzheimer Disease (AD) may lead to restricted decision-making capacity and without standardized instruments, there is great variability in determining patients' ability to give consent. This study aimed to assess decision-making capacity of AD patients in comparison to a healthy control group and investigated the usefulness of visual aids.

METHODS: A group of 30 ad patients and 30 healthy controls were compared using the MacArthur Competence Assessment Tool for Treatment (MacCAT-T). Additionally, we implemented a modified version of the MacCAT-T with visual aids.

RESULTS: Results revealed a significant difference in the MacCAT-T domain of Understanding between the AD and control group after adjustment for age, sex, and education. No significant differences were found for Appreciation, Reasoning, or Expression of Choice. Adding visual aids led to no significant improvements.

CONCLUSIONS: Standardized assessments can be valuable tools for determining the decision-making capacity of patients with early-stage AD. The efficacy of visual aids should be further investigated.},
}

Humans
*Alzheimer Disease/psychology/diagnosis
Female
Male
*Decision Making
Aged
*Mental Competency/psychology
*Informed Consent/psychology
Aged, 80 and over
Case-Control Studies
Neuropsychological Tests
*Audiovisual Aids

@article {pmid42870956,
year = {2026},
author = {Seifallahi, M and Galvin, JE and Ghoraani, B},
title = {Curve walking gait analysis using depth camera and machine learning for detecting cognitive impairment.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1777635},
pmid = {42870956},
issn = {1664-2295},
mesh = {Humans ; *Machine Learning ; *Cognitive Dysfunction/diagnosis/physiopathology ; *Gait Analysis/methods ; Dual-Task Tests ; Female ; Aged ; Male ; *Alzheimer Disease/diagnosis/physiopathology ; Motion Capture ; *Walking/physiology ; Aged, 80 and over ; Gait/physiology ; },
abstract = {INTRODUCTION: Early detection of cognitive impairment (CI), including MCI and Alzheimer's disease (AD), remains limited by the invasiveness and cost of current diagnostic tools. While gait analysis is a promising alternative, most studies focus on straight-path walking, which may miss subtle motor-cognitive deficits. We hypothesized that curve walking-especially under dual-task (DT) conditions-would better expose early CI-related changes. Combined with machine learning, this approach offers a low-cost, non-invasive tool to distinguish healthy controls (HC), MCI, and AD.

METHODS: Seventy-three older adults (HC, MCI due to Alzheimer's disease, and mild AD) performed curve walking along a 10-m oval path under single-task (ST) and DT conditions (counting backward from 100 by ones) while 3D body joint motion was captured using a Kinect v.2 depth camera. Comprehensive macro- and micro-level gait markers were extracted using signal processing and statistical analysis, followed by gait marker selection and machine learning-based classification of CI vs. HC and AD vs. MCI.

RESULTS: Out of 156 extracted gait markers, statistical analysis identified 22 ST and 34 DT markers-including macro, micro-temporal, spatial, and symmetry markers-as selected significantly discriminative markers. CI participants showed slower, less stable gait, with greater variability and asymmetry, particularly under DT conditions. Machine learning models combining ST and DT markers achieved 89.04% accuracy for CI vs. HC and 93.02% for AD vs. MCI, confirming that curved walking under dual-task conditions provides richer discriminative gait information than single-task curved walking alone, and supporting curved dual-task gait analysis as a promising paradigm for early cognitive impairment detection and staging.

DISCUSSION: Curve walking under cognitive load revealed subtle gait deficits linked to CI, enabling accurate, low-cost, and non-invasive detection and staging using depth camera data and machine learning-supporting its potential as a screening approach for supervised clinical and community settings, subject to validation in less-controlled environments.},
}

Humans
*Machine Learning
*Cognitive Dysfunction/diagnosis/physiopathology
*Gait Analysis/methods
Dual-Task Tests
Female
Aged
Male
*Alzheimer Disease/diagnosis/physiopathology
Motion Capture
*Walking/physiology
Aged, 80 and over
Gait/physiology

@article {pmid42871035,
year = {2026},
author = {Omidian, H and Cubeddu, LX},
title = {Intranasal hydrogels for Alzheimer's disease: from nasal-interface engineering to brain targeting and translational readiness.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1960603},
pmid = {42871035},
issn = {1663-9812},
abstract = {Intranasal hydrogels offer a strategy to address rapid mucociliary clearance, limited nasal residence, difficult payload properties, and insufficient brain exposure in Alzheimer's disease (AD). This Review evaluates hydrogel and hydrogel-associated systems across formulation architecture, nasal-interface performance, brain pharmacokinetics, pharmacodynamics, safety, and translation. Selected systems improved deposition or retention, controlled release, permeation, and central exposure relative to relevant comparators, with some also showing convergent behavioral and disease-relevant biological effects in preclinical models. The strongest evidence comes from matched comparisons that distinguish route effects from the incremental contributions of carriers and hydrogels. However, rheology, deposition, targeting metrics, statistical reporting, complete-product stability, repeated-dose safety, device performance, and human reproducibility remain inconsistently characterized. Overall, the evidence supports intranasal hydrogels as a credible preclinical platform for brain-directed AD drug delivery, but not as clinically validated therapy, and favors standardized, device-integrated, comparator-resolved development.},
}

@article {pmid42871063,
year = {2026},
author = {Tan, Z and Li, S and Li, T and Liu, L and Xue, X and Li, X and Ren, H},
title = {Muscle quality index combined with plasma metabolomics: enhancing risk stratification for post-stroke dementia.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1837030},
pmid = {42871063},
issn = {1663-4365},
abstract = {OBJECTIVE: Post-stroke dementia is a severe long-term stroke complication with heavy medical burdens, and early risk identification is critical. This study explored the association of muscle quality index (MQI) and plasma metabolomics with dementia among stroke survivors.

METHODS: This study included 7,047 UK Biobank participants with a history of stroke who were free of dementia at the baseline assessment. MQI was defined as dominant handgrip strength (HGS) divided by corresponding arm fat-free mass. Plasma metabolomics was analyzed via high-throughput nuclear magnetic resonance (NMR). Metabolomics risk scores (MRS-ACD, MRS-AD, and MRS-VaD) were constructed using metabolite features screening with LASSO regression and XGBoost algorithms. Statistical analyses included Cox proportional hazards models, time-dependent receiver operating characteristic (TD-ROC), restricted cubic spline (RCS) regression, interaction analyses, Mendelian randomization (MR), and several sensitivity analyses.

RESULTS: Higher MQI was associated with lower risks of all-cause dementia (ACD), Alzheimer's disease (AD) and vascular dementia (VaD) (all p for trend <0.05). Each 1-SD increment in MRS was associated with a higher risk of ACD (HR = 1.63, 95% CI: 1.36-1.96), AD (HR = 2.40, 95% CI: 1.74-3.31), and VaD (HR = 1.92, 95% CI: 1.46-2.54). Individuals with high MRS and lowest MQI had the highest ACD (HR = 3.29, 95% CI: 1.91-5.68), AD (HR = 5.83, 95% CI: 1.75-19.37), and VaD (HR = 4.57, 95% CI: 2.28-9.14) risk. MQI was linearly negatively associated with ACD (p for non-linear = 0.240) and VaD (p for non-linear = 0.665), and non-linearly associated with AD (p for non-linear = 0.013). Two-sample MR using genetically proxied grip strength and lean mass provided suggestive genetic evidence for muscle-dementia relationships: higher genetically predicted lean mass reduced AD risk (OR = 0.92, 95% CI 0.86-0.99, p = 0.027), while grip strength showed an independent protective effect on VaD after accounting for lean mass (OR = 0.16, 95% CI 0.04-0.64, p = 0.009). Extensive sensitivity analyses confirmed the robustness of the main findings.

CONCLUSION: Joint assessment of MQI and plasma metabolomics provides suggestive evidence for stratifying post-stroke dementia risk and may assist early risk screening in stroke survivors.},
}

@article {pmid42871078,
year = {2026},
author = {Ma, T and Li, Y and Ding, Y and Liu, S and Gao, C and Li, X and Tong, Z and Lv, Y},
title = {New insight into Alzheimer's disease: small molecule-Aβ in the brain transport and peripheral organ clearance.},
journal = {Frontiers in aging},
volume = {7},
number = {},
pages = {1921485},
pmid = {42871078},
issn = {2673-6217},
abstract = {Alzheimer's disease (AD) represents one of the most prevalent neurodegenerative disorders without approved disease-modifying therapies. A major contributing factor is that, for decades, drug development has focused almost exclusively on repairing or removing lesions within the brain itself. Yet a growing body of work now points to AD as a systemic disorder, rooted in a breakdown of whole-body Aβ homeostasis. Nevertheless cerebral Aβ transport and peripheral Aβ clearance are commonly investigated as independent processes, and the coordinated interplay… remains insufficiently characterized. This review bridges the current research gap by systematically elaborating the full trafficking cascade of brain-derived Aβ from intracerebral drainage to peripheral elimination. Four major intracranial clearance pathways are comprehensively summarized, including the blood-brain barrier, blood-cerebrospinal fluid barrier, arachnoid granulation venous outflow, and meningeal lymphatic/glymphatic system. The peripheral clearance processes of circulating Aβ in the blood, liver, kidney, and gastrointestinal tract are further illustrated. A broad spectrum of emerging therapeutic strategies targeting Aβ transport and clearance is also reviewed, including specific pathway modulators, microglia regulators, Aβ aggregation inhibitors, natural multi-target compounds, ultrasound-mediated blood-brain barrier opening, and exosome-based intervention approaches. When we compare the relative contributions of central versus peripheral clearance, Comparative analysis of central and peripheral Aβ clearance indicates that the liver appears to dominate the peripheral elimination of Aβ, yet the real driver of cerebral Aβ deposition is not the failure of any single route, but rather the loss of synergy among multiple pathways. This mechanistic framework explains why purely brain-centric therapeutics are unlikely to correct a systemic Aβ imbalance. Instead, future translational efforts should give higher priority to combination regimens that simultaneously facilitate intracerebral drainage and bolster peripheral organ clearance. This review further discusses current hurdles and emerging opportunities in systemic AD drug discovery, with the aim of offering a unified conceptual framework-one that providing a unified conceptual framework for understanding AD pathogenesis and facilitating the exploration of novel therapeutic paradigms.},
}

@article {pmid42871154,
year = {2026},
author = {Liang, Y and Li, P and Liu, L and Dong, C and Wang, X},
title = {Multimodal neuroimaging and electrophysiological signatures in amnestic mild cognitive impairment with different amyloid-β deposition status: correlations with cognitive function and diagnostic value.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1896908},
pmid = {42871154},
issn = {1663-4365},
abstract = {BACKGROUND: Amnestic mild cognitive impairment (aMCI) is a heterogeneous transitional cognitive state between normal aging and dementia. Aβ positivity elevates dementia conversion risk but does not equate to prodromal Alzheimer's disease (AD), and not all Aβ-positive aMCI individuals progress to clinical AD dementia. Distinguishing Aβ-positive from Aβ-negative aMCI facilitates pathological subtyping rather than definitive early AD diagnosis. This cross-sectional study aimed to characterize scalp-level resting-state EEG and structural MRI signatures specific to Aβ-positive aMCI, explore their covariate-adjusted correlations with cognitive performance and regional Aβ burden, and develop an internally validated multimodal auxiliary classification model for Aβ stratification.

METHODS: Fifty enrolled aMCI participants (30 Aβ-positive, 20 Aβ-negative) and 35 cognitively normal controls (NC) completed unified 20-min eyes-closed resting-state scalp EEG, 3.0 T structural MRI, [18]F-AV45 amyloid PET and [18]F-FDG cerebral metabolism PET examinations. Artifact-free scalp EEG spectral power and regional θ/α ratio were calculated via Welch spectral analysis; voxel-based morphometry (VBM) was adopted to quantify whole-brain gray matter volume. Covariate-controlled partial correlation corrected for multiple comparisons was applied to evaluate cross-modal associations among cortical Aβ SUVR load, cerebral glucose metabolism and domain-specific cognitive scores. A binary logistic regression classification model combining screened EEG and MRI markers was established, with DeLong test for ROC curve comparison and 1,000-bootstrap internal validation.

RESULTS: (1) Relative to Aβ-negative aMCI and NC groups, the Aβ-positive subgroup presented significantly elevated whole-scalp θ relative power and scalp θ/α ratio, decreased scalp α and β relative power (all q < 0.05, FDR-corrected), with predominant scalp oscillatory alterations distributed over temporal, parietal and occipital scalp electrode clusters. The temporal scalp θ/α ratio yielded optimal classification performance for Aβ stratification (AUC = 0.875). (2) The Aβ-positive subgroup showed significant gray matter atrophy across 13 AD-vulnerable brain regions including bilateral fusiform gyrus, inferior parietal lobule, parahippocampal gyrus, precuneus and right entorhinal cortex (all q < 0.05), with the maximum effect size identified in the right precuneus (partial η [2] = 0.477, AUC = 0.778). (3) Within the Aβ-positive subgroup, the temporal scalp θ/α ratio was positively correlated with medial temporal Aβ SUVR (r = 0.501, 95% CI [0.146, 0.732], q = 0.030); right precuneus gray matter volume was negatively correlated with multi-region cortical Aβ burden (q < 0.05). Left parahippocampal gyrus volume was positively correlated with MoCA memory subscores (r = 0.479, 95% CI [0.118, 0.709], q < 0.05). No significant associations between scalp EEG metrics and FDG glucose metabolism survived FDR correction. (4) The multimodal logistic regression model integrating temporal scalp θ/α ratio and right precuneus gray matter volume achieved favorable classification efficacy for Aβ-positive aMCI differentiation (AUC = 0.852, 95% CI [0.748, 0.955]), with good calibration and clinical net benefit based solely on internal bootstrap validation.

CONCLUSION: The temporal scalp θ/α ratio and right precuneus gray matter volume are promising candidate non-invasive auxiliary biomarkers for Aβ pathological stratification in aMCI, rather than validated clinical diagnostic biomarkers. The multimodal model provides supplementary subtyping value within this single-center cohort, while external multicenter validation is mandatory before clinical application. This cross-sectional dataset cannot support prediction of longitudinal progression to AD dementia.},
}

@article {pmid42871217,
year = {2026},
author = {Ruesga Mundo, S},
title = {Persistent Alzheimer-related molecular dysregulation after cerebral ischemia: a hierarchical-circular hypothesis of impaired allostatic recovery.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1938670},
pmid = {42871217},
issn = {1663-4365},
abstract = {INTRODUCTION: Growing evidence suggests a consistent association between brain ischemia and the subsequent development of Alzheimer's disease (AD)-related molecular changes. Experimental and clinical studies have demonstrated that ischemic episodes trigger the overexpression of genes associated with AD pathology, including amyloid precursor protein (APP), β-secretase (BACE1), presenilin 1 and 2 (PSEN1, PSEN2), and MAPT (tau). However, the mechanisms by which transient or chronic ischemic events convert transient gene dysregulation into sustained neurodegenerative pathology remain poorly understood. We acknowledge that current evidence, largely derived from animal models, does not establish that ischemia alone is sufficient to initiate AD as defined by the 2024 NIA-AA biological criteria (core amyloid and tau biomarkers); rather, ischemia may act as a significant contributor that accelerates or exacerbates AD-related molecular changes in vulnerable individuals.

OBJECTIVE: To propose a multilevel reconceptualization of the ischemic contribution to AD within the hierarchical-circular model of biological memory and the construct of allostatic integrity, integrating recent evidence on post-ischemic gene expression, neuroinflammation, oxidative stress, and epigenetic mechanisms.

HYPOTHESIS AND SYNTHESIS: We propose that cerebral ischemia acts as a high-intensity allostatic challenge that may "freeze" biological memory into a pathological configuration. Within this framework, ischemic episodes are not merely transient vascular events but rather serve as biological "programmers" that dysregulate AD-associated genes across multiple levels of biological organization: genetic-epigenetic (DNA methylation, microRNA dysregulation), cellular-mitochondrial (oxidative stress, mitophagy failure), synaptic-neurotrophic (loss of plasticity), neuroimmune-proteostatic (chronic neuroinflammation, protein misfolding), and behavioral-cognitive (progressive dementia). The persistent overexpression of APP, BACE1, PSEN1, PSEN2, and MAPT represents a failure of the system's capacity to restore adaptive circular information flow after an ischemic insult.

IMPLICATIONS: This model reframes the ischemic contribution to AD from a linear cause-effect relationship to a dynamic, multilevel failure of allostatic adaptation. It provides a conceptual roadmap for understanding why ischemic events may predispose to sporadic AD and suggests that therapeutic strategies should target the restoration of allostatic integrity across multiple levels rather than single molecular pathways.

TESTABLE PREDICTIONS: The framework generates falsifiable predictions, including: (1) composite indices of allostatic integrity will predict post-ischemic AD progression better than single biomarkers; (2) interventions that restore allostatic integrity (e.g., anti-inflammatory agents, epigenetic modulators, neuroprotective strategies) will attenuate AD-associated gene dysregulation; and (3) patients with higher allostatic load prior to an ischemic event will show more severe AD-associated gene expression changes and worse clinical outcomes.},
}

@article {pmid42871277,
year = {2026},
author = {Wang, Y and Liu, MX and Zhu, JL and Li, GX and Yu, H and Wang, CH and Zong, Q and Wang, WS},
title = {Gastrodin alleviates mild cognitive impairment and Alzheimer's disease via candidate targeting of ACHE, S1PR5, SERPINE1, and TOP2A: an integrative computational and cellular study.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1937359},
pmid = {42871277},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's disease (AD) and its prodromal mild cognitive impairment (MCI) lack effective disease-modifying therapeutic strategies. Gastrodin (GAS), the major bioactive compound of Gastrodia elata, exhibits pronounced neuroprotective effects. However, the precise candidate molecular targets and systematic mechanisms by which GAS protects against AD and MCI remain poorly clarified; target engagement is inferred from computational simulation rather than direct biochemical validation.

METHODS/RESULTS: This study adopted an integrated approach of network pharmacology, transcriptome-based machine learning, molecular simulation, and in vitro cellular validation to explore the therapeutic mechanisms of GAS against AD/MCI. A total of 127 overlapping therapeutic targets of GAS, AD, and MCI were identified, which were mainly enriched in synaptic transmission and calcium signaling pathways. Four core hub genes (ACHE, S1PR5, SERPINE1, and TOP2A) were further screened by intersecting candidate targets with AD differentially expressed genes from the GSE329677 dataset. The ensemble Logistic + SVM machine learning model exhibited optimal diagnostic efficiency with an AUC value of 0.897. Molecular docking and 50 ns molecular dynamics simulations confirmed that GAS stably bound to the four target proteins and maintained stable binding states under physiological conditions. In an Aβ1-42 oligomer-injured N2a neuronal model, GAS showed no significant cytotoxicity at concentrations ranging from 0.1 to 100 μM. Notably, 25 μM GAS markedly reversed Aβ1-42-induced neuronal death and excessive intracellular ROS accumulation.

CONCLUSION: This study identifies four novel candidate core therapeutic targets of GAS against AD/MCI and provides computational evidence for their stable atomic-level binding characteristics. GAS exerts prominent neuroprotective effects through anti-apoptotic and antioxidant mechanisms in Aβ-injured neurons. These findings provide a novel theoretical basis and preclinical evidence for the development of GAS as a natural candidate agent for AD intervention.},
}

@article {pmid42871397,
year = {2026},
author = {Chen, Y and Lian, T and Luo, D and Wang, R and Li, A and Gao, D and Du, T and Xu, Q and Wang, A and Meng, F and Yang, A and Zhang, W and Zhang, J},
title = {A pilot study of invasive vagus nerve stimulation in Chinese patients with Alzheimer's disease: preliminary results on safety, cognition, and biomarkers.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1934496},
pmid = {42871397},
issn = {1662-4548},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with no curative therapies, and vagus nerve stimulation (VNS) has emerged as a promising neuromodulatory approach. This prospective, open-label pilot study aimed to evaluate the feasibility, safety, and preliminary cognitive, psychological, inflammatory, and AD biomarker effects of invasive VNS (iVNS) in Chinese AD patients.

METHODS: Five AD patients (mean age: 62.4 ± 4.0 years) underwent iVNS implantation, with assessments at baseline, 3, and 6 months postoperatively (one patient did not complete the 6-month follow-up). Cognitive function (MMSE, CDR, VFT, BNT), psychological/behavioral symptoms (CMAI, HAMA, HAMD), sleep/daily-living status (ESS, ADL), serum inflammatory factors, and AD biomarkers were measured.

RESULTS: Among cognitive outcomes, MMSE increased by 1 point at both follow-ups and VFT rose by 5.2 and 4.25 points at 3 and 6 months, respectively, although none of these changes reached statistical significance; global CDR remained unchanged. HAMA and HAMD scores decreased, and ESS scores declined by 25-27%, without reaching significance. Serum pro-inflammatory Eotaxin and CCL5 were significantly reduced (p = 0.026 and p = 0.045, respectively), whereas CXCL10 levels showed a non-significant numerical increase. Although the Aβ42 and Aβ42/Aβ40 ratio showed numerical increases (by 126.4% and 75.3%) and pTau181, pTau217, and NfL showed numerical decreases, these changes were not statistically significant. Only transient hoarseness was reported.

DISCUSSION: These preliminary findings suggest that iVNS is feasible and associated with early signals of cognitive, psychological, inflammatory, and biomarker changes in AD patients, which warrant confirmation in larger, randomized, sham-controlled trials.},
}

@article {pmid42871474,
year = {2026},
author = {Wang, S and Zhang, J and Sun, S and Xiao, R and Zhang, Z and Yao, J},
title = {Global research trends and hotspots in blood-based biomarkers for Alzheimer's disease: a bibliometric analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1886781},
pmid = {42871474},
issn = {1663-4365},
abstract = {BACKGROUND: Blood-based biomarkers (BBMs) are rapidly reshaping the diagnostic and translational landscape of Alzheimer's disease (AD), offering a scalable alternative to cerebrospinal fluid (CSF) assays and positron emission tomography (PET). This paper aims to conduct bibliometric analysis on the hotspots and trends in this field.

METHODS: Publications addressing AD-related blood/plasma/serum biomarkers from 1 January 2011 to 29 November 2025 were retrieved from the Web of Science Core Collection (WoSCC) and Scopus. Only English-language articles and reviews were included. VOSviewer, CiteSpace, and the R package bibliometrix were used to evaluate publication trends, collaboration networks (countries, institutions, authors), co-cited journals and references, and keyword evolution.

RESULTS: A total of 1,771 publications with 53,568 citations were included. Annual output rose steadily and accelerated after 2018, while 2025 records covered approximately the first 11 months of the year. The USA (795 publications) and China (478) were the most productive countries, whereas the UK and Sweden showed strong citation impact and collaboration intensity. The University of Gothenburg (263) and Sahlgrenska University Hospital (237) were the leading institutions. Henrik Zetterberg (218) and Kaj Blennow (185) were the most prolific authors. Co-citation analysis identified the NIA-AA biological research framework and validation studies of plasma amyloid-beta (Aβ) and plasma phosphorylated tau (p-tau) as the intellectual base. Keyword and burst analyses indicated a clear shift from early themes (e.g., proteomics and oxidative stress) toward clinically oriented topics, including plasma p-tau217/p-tau181, diagnostic performance, and implementation recommendations.

CONCLUSION: Research on AD BBMs has entered a phase of rapid growth and clinical translation. Plasma phosphorylated tau (especially p-tau217) is the leading biomarker for detecting AD-specific pathology. Plasma Aβ ratios play a supportive role in amyloid triage, while neurodegeneration (NfL) and astroglial (GFAP) markers provide complementary information for prognosis and monitoring. Future priorities include real-world implementation, assay standardization, and integration of multi-marker panels into biological diagnostic/staging frameworks.},
}

@article {pmid42871649,
year = {2026},
author = {Shah, KB and Xiang, L and Shah, SK and Adler, MRR and Weissman, JS},
title = {Complex or multivessel PCI is associated with higher 1-year mortality but better patient-centered outcomes when compared to CABG in patients with dementia.},
journal = {Journal of geriatric cardiology : JGC},
volume = {23},
number = {9},
pages = {602-608},
pmid = {42871649},
issn = {1671-5411},
abstract = {OBJECTIVES: To compare outcomes of coronary revascularization with coronary artery bypass grafting (CABG) or complex or multivessel percutaneous coronary intervention (MV PCI) in patients with dementia.

METHODS: We compared outcomes of Medicare fee-for-service (FFS) beneficiaries 66 years or older with Alzheimer's disease and related dementias (ADRD) who underwent coronary artery bypass grafting (CABG) or MV PCI from January 1, 2017 to December 31, 2019. The primary clinical outcome was 1-year mortality, and secondary clinical outcomes were inpatient and 90-day complications and 90-day readmissions. Patient-centered outcomes were time-at-home ratio and discharge to higher level of care.

RESULTS: 8,939 patients with ADRD undergoing revascularization with CABG MV PCI met study criteria. Of these, 3,510 (39.3%) underwent CABG and 5,429 (60.7%) underwent MV PCI. Patients with ADRD who underwent MV PCI were more likely to be older (81.0 vs. 76.7, P < 0.001), women (44.1% vs. 29.4%, P < 0.001), frail (82.4% vs. 75.0%, P < 0.001), and have moderate to severe dementia (64.4% vs. 54.6%, P < 0.001). One-year mortality was higher among patients undergoing MV PCI (OR = 2.0, 95% CI: 1.8-2.3) but inpatient and 90-day major complications were lower (OR = 0.3, 95% CI: 0.3-0.3 and OR = 0.5, 95% CI: 0.4-0.5, respectively). Patients with ADRD undergoing MV PCI were less likely to be discharged to a higher level of care (OR = 0.2, 95% CI: 0.2-0.2) and had higher time-at-home ratios (Mean Difference 4.2, 95% CI: 2.4-6.0).

CONCLUSIONS: Patients with ADRD undergoing MV PCI demonstrate higher 1-year mortality but lower short-term complications. Patient-centered outcomes of time-at-home ratio and risk for discharge to a higher level of care were more favorable with MV PCI compared to CABG. These data should be used by patients, their families, and physicians to facilitate goal-concordant care especially when optimization of patient-centered outcomes is desired.},
}

@article {pmid42872064,
year = {2026},
author = {Cai, W and Yi, Y and Zeng, R and Yin, Y and Zhao, J and Zhang, J and Fu, G and Xu, H},
title = {HMGB1 functional plasticity in neurodegenerative diseases and its translational implications.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1928641},
pmid = {42872064},
issn = {1664-3224},
mesh = {Humans ; *HMGB1 Protein/metabolism/genetics ; *Neurodegenerative Diseases/metabolism ; Animals ; Translational Research, Biomedical ; Signal Transduction ; Alarmins/metabolism ; Biomarkers ; },
abstract = {High mobility group box 1 (HMGB1) is a chromatin-associated protein that can be redistributed and released during cellular stress, when it acts as an extracellular alarmin within the broader family of damage-associated molecular patterns (DAMPs). Its functions depend on subcellular localization, redox and post-translational modification state, cellular source, mode of release, and molecular partners. This critical narrative review examines how these variables shape HMGB1 biology in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar ataxias (SCAs), frontotemporal dementia (FTD), and related disorders, and considers their implications for biomarker and therapeutic development. Intracellular HMGB1 contributes to chromatin organization, DNA repair, mitochondrial genome maintenance, and proteostasis. After redistribution and release, extracellular HMGB1 signals through receptors including the receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4), interacts with disease-associated proteins, and links proteostatic stress with glial activation, neuronal dysfunction, and blood-brain barrier impairment. Across disease models, two recurrent patterns emerge: loss or sequestration of intracellular HMGB1 in models of polyglutamine disorders, including HD and SCAs, and extracellular HMGB1 signaling as a progression-associated inflammatory amplifier in AD, PD, and ALS models. Central-peripheral inflammatory communication and cell-specific HMGB1 release further shape these responses. Clinical studies have associated total HMGB1 or anti-HMGB1 autoantibodies with clinical features, but current assays do not resolve redox form, cellular source, or biological activity. Most therapeutic studies remain preclinical, while available human intervention studies involve drugs with multiple molecular actions. Clinical translation requires redox-resolved and standardized assays, longitudinal human sampling, compartment- and cell-specific causal studies, and interventions with documented target engagement, central nervous system exposure, and long-term safety. HMGB1 is best understood as a context-dependent mediator rather than a uniformly pathogenic factor or a single treatment target.},
}

Humans
*HMGB1 Protein/metabolism/genetics
*Neurodegenerative Diseases/metabolism
Animals
Translational Research, Biomedical
Signal Transduction
Alarmins/metabolism
Biomarkers

@article {pmid42872112,
year = {2026},
author = {Amiri, M and Kakavand Hamidi, A and Farkas, DL and Buyalos, RP and Azziz, R},
title = {Potential links between PCOS/PMOS and Alzheimer disease and related dementias.},
journal = {Journal of the Endocrine Society},
volume = {10},
number = {11},
pages = {bvag206},
pmid = {42872112},
issn = {2472-1972},
abstract = {BACKGROUND: Polycystic ovary syndrome/polyendocrine metabolic ovarian syndrome (PCOS/PMOS) is a common endocrine disorder with significant metabolic and reproductive implications. Increasing attention has focused on its potential long-term neurological consequences, including possible links to cognitive impairment and Alzheimer disease (AD), through overlapping biological pathways.

METHODS: We conducted a comprehensive PubMed search, from inception through October 2025, identifying studies on cognitive performance, brain structure and function, neurodegenerative biomarkers, and dementia risk in PCOS/PMOS patients.

RESULTS: Evidence supports multiple potential mechanistic pathways that could connect PCOS/PMOS to AD-relevant biology, such as insulin resistance (IR), chronic inflammation, hormonal dysregulation, and cardiovascular dysfunction. These pathways converge on neurodegeneration processes such as impaired Aβ clearance, tau hyperphosphorylation, oxidative stress, and cerebral metabolic deficits. Clinically, PCOS/PMOS patients exhibit mild but reproducible impairments in executive function and memory, alongside structural and functional brain alterations, including hippocampal and white matter changes, and altered network connectivity. However, these findings are influenced by coexisting metabolic dysfunction, and direct epidemiological evidence linking PCOS/PMOS to increased dementia incidence remains limited and inconsistent.

CONCLUSION: Current evidence indicates that any association between PCOS/PMOS and AD risk is likely mediated by metabolic comorbidities, particularly IR and obesity, rather than an independent effect of PCOS/PMOS itself. However, clinical evidence for increased PCOS/PMOS risk for cognitive vulnerability and dementia remain inconsistent and cognitive benefits from PCOS/PMOS-specific interventions are lacking. Clinical focus should therefore remain on optimizing metabolic health, while longitudinal and interventional studies are required to clarify long-term neurological relationships and outcomes.},
}

@article {pmid42872207,
year = {2026},
author = {Wang, M and VanderVeen, B and Xu, ZA and Xu, Y and Mintzer, J and Murphy, A and Zhang, Q and Xu, P},
title = {Reverse the progression of Alzheimer's disease through Nano-ERASER-based adult neuroregeneration.},
journal = {Cell biomaterials},
volume = {},
number = {},
pages = {},
pmid = {42872207},
issn = {3050-5623},
abstract = {Alzheimer's disease (AD) remains irreversible largely because the adult brain cannot replace lost neurons. Here, we present a Nano-ERASER-based Trim-Away system (TN-PTBP1) that enables adult neuroregeneration in the AD brain, offering a new strategy to counteract AD progression. TN-PTBP1 penetrates the blood-brain barrier, delivers anti-PTBP1 antibodies into astrocytes, and triggers rapid TRIM21-mediated PTBP1 degradation. This non-genomic protein depletion induces astrocyte-to-neuron conversion, generates functional neurons in vitro and in human brain organoids, and restores hippocampal neurogenesis in AD mice. Importantly, TN-PTBP1 treatment significantly improves cognition, learning, and memory, demonstrating true functional reversal of AD-associated deficits. By resolving the long-standing controversy surrounding PTBP1 reprogramming and establishing a translational biomaterials-based platform for in situ neuronal regeneration, this work introduces a transformative therapeutic paradigm aimed not only at slowing AD but at rebuilding the neuronal circuitry it destroys.},
}

@article {pmid42872444,
year = {2026},
author = {Altaf, A and Arif, M and Inam, W and Abbas, G and Mahmood, W},
title = {Sulfamethoxazole Attenuates Aluminum-induced Cognitive Impairment: In silico Evidence for BACE1 Interaction and In vivo Behavioral Assessment.},
journal = {Current drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113894501509464261006043242},
pmid = {42872444},
issn = {1873-5592},
abstract = {INTRODUCTION/OBJECTIVE: BACE1 (Beta-Site Amyloid precursor protein-cleaving enzyme is a rate-limiting aspartic protease responsible for beginning Amyloid-β (Aβ) peptide synthesis, the major neurotoxic characteristic of Alzheimer's Disease (AD). Repurposing drugs with known safety profiles and Blood-Brain Barrier (BBB) permeability is a practical approach to treating AD. The current work combined in silico and in vivo approaches to investigate Sulfamethoxazole (SMZ) as a potential BACE1-interacting compound.

METHODS: Molecular docking of sulfamethoxazole to the BACE1 crystal structure (PDB: 1FKN) was done using AutoDock Vina. Female Sprague-Dawley rats (n = 6/group) received AlCl3 (500 mg/kg, i.g.) for 30 days to induce cognitive impairment, while SMZ (0.5, 1.0, and 1.5 mg/kg) was coadministered with AlCl3 for 30 days. On Days 31-36, locomotor activity assessments and the Morris Water Maze (MWM) were used to measure neurocognitive function.

RESULTS: Docking revealed prominent hydrogen-bond interactions between SMZ's sulfonamide oxygen atoms and the Tyr71, Asp228, and Thr72 residues, with the isoxazole ring occupying the hydrophilic S2 pocket of BACE1. Molecular docking analysis indicated a favorable interaction between SMZ and BACE1, suggesting BACE1 as a potential molecular target. In vivo, SMZ dosedependently reversed AlCl3-induced cognitive decline: reduced escape latency (F(1,27) = 117.0; p < 0.0001) and increased time spent in the platform quadrant (F(13.21; 6,6) = p < 0.05). Locomotor activity was unaffected (F(1.150; 3.24); p > 0.05), confirming the absence of CNS stimulation.

DISCUSSION: The findings provide preliminary computational and behavioral evidence supporting further investigation of SMZ in cognitive dysfunction. However, docking predictions do not establish direct BACE1 inhibition, and biochemical validation was not performed.

CONCLUSION: SMZ attenuated AlCl3-induced cognitive impairment in rats and demonstrated a favorable predicted interaction with BACE1. Further studies are required to validate the proposed molecular mechanism and determine the therapeutic relevance of SMZ in cognitive dysfunction.},
}

@article {pmid42872450,
year = {2026},
author = {Kang, K},
title = {Bilateral Lower Extremity Edema During Donepezil Treatment: A Case Report.},
journal = {Current drug safety},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115748863527540260928113823},
pmid = {42872450},
issn = {2212-3911},
abstract = {Introduction/ Background: Acute bilateral lower-extremity edema is uncommon and often results from medication side effects, acute heart failure, nephrotic syndrome, or bilateral deep vein thrombosis. Drugs such as dihydropyridine calcium channel blockers, corticosteroids, thiazolidinediones, and nonsteroidal anti-inflammatory agents are known to cause edema. Donepezil, a widely used acetylcholinesterase inhibitor for Alzheimer's disease, has not been previously linked to leg edema. Recognizing rare adverse reactions is essential for patient safety, as edema may indicate serious conditions. Case Presentation: A 75-year-old woman with Alzheimer's disease developed bilateral pitting lower leg edema six months after starting treatment with donepezil. She had no history of cardiac, renal, hepatic, or venous diseases. Laboratory tests, electrocardiography, chest X-ray, and computed tomography venogram were normal, except for mild anemia and a slightly reduced estimated glomerular filtration rate. The edema resolved three weeks after discontinuation and did not recur after the administration of rivastigmine. Conclusion: The temporal association and resolution upon drug cessation suggest a probable association. Possible mechanisms may include cholinergic-induced vasodilation, which increases capillary permeability.},
}

@article {pmid42872554,
year = {2026},
author = {Vilor-Tejedor, N and Rodríguez-Fernández, B and Genius, P and Fernández-Bonet, A and González-Escalante, A and Brugulat-Serrat, A and Sanchez-Benavides, G and Cumplido-Mayoral, I and Minguillón, C and Cirach, M and Nieuwenhuijsen, M and Kollmorgen, G and Quijano-Rubio, C and Zetterberg, H and Blennow, K and Navarro, A and Suárez-Calvet, M and Gispert, JD and , },
title = {Air pollution is associated with sex-specific longitudinal changes in astrocytic and neuroinflammatory processes linked to cognitive decline in Alzheimer's disease at-risk individuals.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71837},
doi = {10.1002/alz.71837},
pmid = {42872554},
issn = {1552-5279},
support = {PID2022-143106OA-I00//Agencia Estatal de Investigación/ ; FJC2018-038085-I//Agencia Estatal de Investigación/ ; RYC2022-038136-I//Ramón y Cajal Programme/ ; 23S06083-001//Ajuntament de Barcelona-La Caixa Foundation/ ; //Alzheimer Nederland/ ; //Alzheimer's Disease Data Initiative/ ; },
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/cerebrospinal fluid ; *Air Pollution/adverse effects ; Longitudinal Studies ; *Astrocytes ; *Cognitive Dysfunction/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Middle Aged ; *Neuroinflammatory Diseases/cerebrospinal fluid ; Particulate Matter ; *Environmental Exposure/adverse effects ; Sex Factors ; Aged ; Glial Fibrillary Acidic Protein/cerebrospinal fluid ; },
abstract = {INTRODUCTION: Air pollution is associated with dementia risk, but its role during preclinical Alzheimer's disease (AD) remains unclear.

METHODS: We examined long-term residential exposure to traffic-related air pollution in 226 cognitively unimpaired middle-aged individuals at increased risk of AD from the ALzheimer's and FAmilies ALFA+ cohort (a nested longitudinal cohort within the ALzheimer's and Families parent cohort). Participants underwent baseline and 3-year follow-up cerebrospinal fluid (CSF) assessment of AD, neurodegeneration, astrocytic, microglial, and inflammatory biomarkers. Exposure to nitrogen dioxide (NO2), particulate matter (PM)10, PM2.5, and PM2.5 absorbance was estimated using land-use regression models. Sex-interaction and stratified analyses were performed. Mediation analyses evaluated cognitive and brain-age outcomes.

RESULTS: Sex-dependent associations were observed between air pollution exposure and CSF inflammatory and astrocytic biomarkers. Higher exposure was associated with longitudinal increases in glial fibrillary acidic protein (GFAP) and interleukin (IL) -6, primarily in women. GFAP partially mediated associations between air pollution exposure and worsening executive and attentional performance.

DISCUSSION: Findings support sex-specific astroglial and neuroinflammatory susceptibility to traffic-related air pollution in preclinical AD.

TRIAL REGISTRATION: The ALFA+ study has been registered at ClinicalTrials.gov (10-06-2015, identifier: NCT02485730).},
}

Humans
Male
Female
*Alzheimer Disease/cerebrospinal fluid
*Air Pollution/adverse effects
Longitudinal Studies
*Astrocytes
*Cognitive Dysfunction/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
Middle Aged
*Neuroinflammatory Diseases/cerebrospinal fluid
Particulate Matter
*Environmental Exposure/adverse effects
Sex Factors
Aged
Glial Fibrillary Acidic Protein/cerebrospinal fluid

@article {pmid42872589,
year = {2026},
author = {Martin, KS and Obst, J and Ibarra, S and Murphy, EJ and Gospodinova, KO and Mead, E},
title = {SHIP1 regulates TREM2 signalling and macrophage functions in a hiPSC-derived model.},
journal = {The FEBS journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/febs.70752},
pmid = {42872589},
issn = {1742-4658},
support = {ARUK-2020DDI-OX//Alzheimer's Research UK/ ; },
abstract = {Genetic and functional studies strongly implicate microglia in the pathology of Alzheimer's disease. The Triggering Receptor Expressed on Myeloid cells 2 (TREM2) pathway is an important functional regulator of microglia, promoting phagocytosis of apoptotic cells, debris and pathogenic proteins. Genome-wide association studies have identified risk-bearing polymorphisms in several members of the pathway including INPP5D, encoding the inositol phosphatase SHIP1. Recent studies utilising in vitro and in vivo disease-relevant models have identified a role for SHIP1 in modulating TREM2 signalling and neurotoxic microglial activation. In this study, we characterised the role of SHIP1 in regulating TREM2 signalling and myeloid functions using human-induced pluripotent stem cell (hiPSC)-derived macrophages. Characterisation of isogenic SHIP1 knockout (SHIP1 KO) macrophages showed decreased expression of the lipopolysaccharide (LPS) coreceptor CD14, which translated to lower secretion of pro-inflammatory cytokines. Additionally, loss of SHIP1 in this macrophage model attenuated TREM2 signalling, which was further reflected in a reduced level of phagocytosis of apoptotic neurons compared to the parental line. The observed effects on TREM2 signalling did not correspond to changes in total protein levels or shedding. Further examination of macrophage scavenger receptor expression revealed reduced cell surface levels of CD163 and CD206 involved in resolution of inflammation, but increased levels of the phagocytic receptor MerTK. Morphological analysis revealed a less amoeboid-activated phenotype and increased adhesion in the SHIP1 KO macrophages. Taken together, our data indicate that SHIP1 plays a key role in modulating TREM2 signalling, inflammation and phagocytosis.},
}

@article {pmid42872643,
year = {2026},
author = {Patel, R and Sinha, S and Shukla, KS and Singh, B and Ved, A and Kumar, A and Yadav, N and Singh, V},
title = {Therapeutic Significance of Natural vs. Synthetic Coumarins in Alzheimer's Disease.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575482030261005073306},
pmid = {42872643},
issn = {1875-5607},
abstract = {INTRODUCTION/OBJECTIVE: Coumarin, a naturally occurring aromatic compound bearing a benzopyrone scaffold, represents a versatile motif in synthetic drug design. Recent therapeutic developments have highlighted its potential as a privileged pharmacophore for neurodegenerative disorders (NDs), with particular efficacy targeting Alzheimer's disease (AD). This study presents a critical, comparative review of natural versus synthetic coumarins, evaluating their neuroprotective mechanisms across various preclinical, non-transgenic models of sporadic Alzheimer's disease (sAD).

METHODS: Natural coumarins (e.g., umbelliferone, esculetin, and scopoletin) exert potent antioxidant, anti-inflammatory, and moderate enzyme-inhibitory activities, particularly against acetylcholinesterase (AChE) and β-amyloid (Aβ) aggregation. These phytochemicals attenuate neurodegeneration by modulating oxidative stress and neuroinflammatory pathways across various cellular and rodent models, including 5xFAD mice, as well as streptozotocin (STZ)-and scopolamine (SCOP)- induced Alzheimer's disease (AD) rat models. However, their clinical utility remains constrained by poor bioavailability and modest potency. To address these limitations, synthetic coumarin derivatives, including coumarin-pyrrolidine, coumarin-triazole, coumarin-chalcone, and coumarin-donepezil hybrids, as well as hydroxycoumarins, have been developed. These heterocyclic hybrid architectures exhibit superior therapeutic potency, enhanced blood-brain barrier (BBB) permeability, and synergistic inhibition of core pathological targets, including AChE activity and Aβ aggregation.

RESULT: Both in vivo preclinical models and in silico docking simulations substantiate the neuroprotective capacity of coumarin-based frameworks, demonstrating substantial cognitive rescue, restored synaptic plasticity, and favorable safety margins. Moving beyond the baseline safety of naturally derived coumarins, structural optimization and hybrid design strategies serve as a compelling framework for developing potent, multi-target therapeutics for neurodegenerative diseases.

DISCUSSION: According to the review, Alzheimer's disease treatment is shifting from natural coumarins to multi-target-directed ligands (MTDLs) because natural compounds, such as esculetin, scopoletin, and daphnetin, are often limited by narrow target specificity and lower potency than synthetic coumarin derivatives.

CONCLUSION: Herein, the authors review the biological activities of natural coumarins and their synthetic analogs as potential therapeutics for Alzheimer's disease (AD). This study systematically compared and evaluated the therapeutic efficacy and structural scaffold variations of both natural and synthetic derivatives. To support their translational potential, this study also summarizes current ADMET profiles and pharmacokinetic evaluations, which represent key prerequisites for clinical advancement.},
}

@article {pmid42862306,
year = {2026},
author = {Sahu, S and Jain, P and Dharme, KK and Yadav, K},
title = {CRISPR/Cas9-based nanodelivery systems for precision gene editing in neuroinflammation.},
journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]},
volume = {75},
number = {1},
pages = {},
pmid = {42862306},
issn = {1420-908X},
support = {Probecell/Res/2026/124//Probecell Scientific Pvt. Ltd./ ; },
mesh = {Humans ; Animals ; *Neuroinflammatory Diseases/genetics/therapy ; *Gene Editing/methods ; *CRISPR-Cas Systems ; Nanoparticles/administration & dosage ; },
abstract = {BACKGROUND: Neuroinflammation is a characteristic feature of many neurological diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Uncontrolled activation of microglia and astrocytes results in the production of proinflammatory mediators that contribute to neuronal dysfunction and degeneration.

PURPOSE: CRISPR/Cas9 genome-editing technology provides highly precise targeting of genes involved in these pathways, enabling the deletion, correction, or modulation of disease-associated genetic alterations. Nonetheless, effective delivery of CRISPR components to the central nervous system (CNS) remains a major challenge because of protective barriers such as the blood-brain barrier (BBB), as well as concerns regarding genomic instability and immunogenicity.

METHODS: Nanotechnology-guided delivery platforms, such as lipid nanoparticles, liposomes, dendrimers and polymeric carriers, have been developed as promising strategies to address these challenges. These nanosystems can improve biodistribution, pharmacokinetic behavior, and cellular uptake, while potentially reducing off-target effects and systemic toxicity.

RESULTS: The preclinical studies demonstrate successful modulation of key neuroinflammatory targets, including the NLRP3 inflammasome, triggering receptor expressed on myeloid cells 2 (TREM2), Janus kinase (JAK) signaling, and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, with potential therapeutic relevance to neurodegenerative diseases. In addition, novel techniques, such as mitochondrial base editing, prime editing, and epigenetic modulation, expand the scope of CRISPR-mediated therapeutic strategies. Although outcomes from animal models are promising, translation to the clinical setting requires careful consideration of safety, ethical concerns, and long-term efficacy.

CONCLUSIONS: This review highlights the potential of integrating CRISPR/Cas9 with nanodelivery systems to advance precision medicine for neuroinflammatory disorders, while emphasizing their potential for therapeutic applications in complex CNS conditions. Ongoing studies aimed at optimizing delivery and reducing off-target effects will be essential for advancing these approaches toward clinical practice.},
}

Humans
Animals
*Neuroinflammatory Diseases/genetics/therapy
*Gene Editing/methods
*CRISPR-Cas Systems
Nanoparticles/administration & dosage

@article {pmid42862409,
year = {2026},
author = {Singh, S and Ayaz, A and Ansari, O and Farooqi, H and Narang, J},
title = {Multiplexed impedimetric zinc oxide nanorods-modified aptasensor on carbon ink-inscribed paper electrodes for the specific and sensitive co-detection of Alzheimer's and Parkinson's disease.},
journal = {Biomedical microdevices},
volume = {28},
number = {4},
pages = {},
pmid = {42862409},
issn = {1572-8781},
mesh = {Humans ; *Carbon/chemistry ; *Paper ; *Parkinson Disease/diagnosis ; *Biosensing Techniques/instrumentation ; *Alzheimer Disease/diagnosis ; *Aptamers, Nucleotide/chemistry ; Electrodes ; *Nanotubes/chemistry ; Amyloid beta-Peptides/analysis ; *Zinc Oxide/chemistry ; Limit of Detection ; *Ink ; *Electrochemical Techniques/instrumentation ; alpha-Synuclein ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), represent a growing health burden, while early diagnosis remains challenging because established diagnostic approaches, including cerebrospinal fluid analysis and neuroimaging, are invasive, expensive, and unsuitable for decentralized point-of-care testing. Recent progress in electrochemical and paper-based biosensors has enabled low-cost, portable, and multiplexed biomarker analysis. However, their clinical translation remains limited by low biomarker concentrations, matrix interference, nonspecific adsorption, sensor-to-sensor variability, storage stability, and the need for validation using clinical samples. Herein, a paper-based multiplex electrochemical aptasensor was developed for simultaneous impedimetric detection of amyloid beta-42 (Aβ-42) and alpha synuclein-60 (αS-60), biomarkers associated with AD and PD, respectively. The device comprised screen-printed carbon and silver electrodes on a cellulose substrate, two independently functionalized working electrodes, zinc oxide nanorods (ZnO-NRs) as electroactive signal-amplification layers, and target-specific DNA aptamers as biorecognition elements. Electrochemical impedance spectroscopy was used for label-free measurement of target-induced changes in charge-transfer resistance. The sensor exhibited a linear response from 0.1 ng/mL to 10 µg/mL for both biomarkers, with limits of detection of 4.41 ng/mL for Aβ-42 and 2.62 ng/mL for αS-60. The platform further detected both analytes in artificial cerebrospinal fluid and artificial saliva, demonstrating that the paper-based sensing interface remains responsive in physiologically mimicked matrices. Overall, this study provides a low-cost, disposable, label-free, and multiplexed proof-of-concept platform for simultaneous AD- and PD-associated biomarker detection. Although the system demonstrates promising performance in artificial matrices, further optimization of sensitivity, surface immobilization, antifouling behaviour, long-term storage, and validation using real clinical saliva and CSF samples will be required before practical diagnostic deployment.},
}

Humans
*Carbon/chemistry
*Paper
*Parkinson Disease/diagnosis
*Biosensing Techniques/instrumentation
*Alzheimer Disease/diagnosis
*Aptamers, Nucleotide/chemistry
Electrodes
*Nanotubes/chemistry
Amyloid beta-Peptides/analysis
*Zinc Oxide/chemistry
Limit of Detection
*Ink
*Electrochemical Techniques/instrumentation
alpha-Synuclein

@article {pmid42862481,
year = {2026},
author = {de Oliveira Maciel, VCB and de Moura Arruda, J and Silva, RC and da Rosa, MM},
title = {PPARγ Signaling in the Central Nervous System: A Review of the Implications in Synaptic Plasticity, Neuroinflammatory and Neoplastic Processes.},
journal = {Neurochemical research},
volume = {51},
number = {5},
pages = {},
pmid = {42862481},
issn = {1573-6903},
mesh = {Humans ; *Neuronal Plasticity/physiology ; Animals ; *PPAR gamma/metabolism ; *Signal Transduction/physiology ; *Neuroinflammatory Diseases/metabolism ; *Central Nervous System/metabolism ; PPAR-gamma Agonists ; },
abstract = {Peroxisome proliferator activated receptor gamma (PPARγ) is a ligand activated nuclear receptor traditionally associated with lipid and glucose metabolism. Emerging evidence, however, identifies PPARγ as a central immunometabolic regulator in the central nervous system (CNS), coordinating mitochondrial function, neuroinflammation, synaptic plasticity, and neurovascular integrity. Beyond its classical metabolic actions, PPARγ regulates microglial activation, astrocytic inflammatory responses, oxidative stress, and mitochondrial biogenesis, thereby influencing neuronal resilience and circuit stability. This narrative review synthesizes knowledge of PPARγ structure, activation, CNS distribution, endogenous ligands, and synthetic agonists, including thiazolidinediones and selective modulators. We highlight how PPARγ controls transcriptional programs related to energy homeostasis, inflammatory signaling, including NF κB dependent pathways, and blood brain barrier function. Attention is devoted to synaptic remodeling and plasticity, positioning PPARγ as a molecular bridge between metabolic state and neuronal adaptability. We propose that PPARγ signaling dysregulation represents a convergent mechanism in neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and adrenoleukodystrophy; psychiatric conditions, such as depression and anxiety; and neurooncological processes. Integrating evidence across these conditions supports PPARγ as a master regulator of neuroimmune metabolic coupling in the brain. Finally, we discuss translational challenges and opportunities, including brain penetrant, functionally selective ligands, clarification of cell type specific signaling, and expansion of rigorous clinical trials. Integrating mechanistic, preclinical, and clinical trial evidence, this review critically examines the therapeutic potential of PPARγ across neurodegenerative, psychiatric, and neurooncological CNS conditions, while identifying priorities for future therapeutic development in diverse brain disorders.},
}

Humans
*Neuronal Plasticity/physiology
Animals
*PPAR gamma/metabolism
*Signal Transduction/physiology
*Neuroinflammatory Diseases/metabolism
*Central Nervous System/metabolism
PPAR-gamma Agonists

@article {pmid42862512,
year = {2026},
author = {Geng, C and Chen, C},
title = {Plasma p-tau217 and neurodegeneration-related biomarkers predict incident cognitive impairment in obstructive sleep apnea: a prospective cohort study.},
journal = {Sleep & breathing = Schlaf & Atmung},
volume = {30},
number = {6},
pages = {},
pmid = {42862512},
issn = {1522-1709},
mesh = {Humans ; *Sleep Apnea, Obstructive/blood/complications/epidemiology ; Biomarkers/blood ; Prospective Studies ; Female ; Male ; *Cognitive Dysfunction/blood/diagnosis/etiology/epidemiology ; *tau Proteins/blood ; Middle Aged ; Neurofilament Proteins/blood ; Amyloid beta-Peptides/blood ; Polysomnography ; Cohort Studies ; Aged ; Adult ; Incidence ; },
abstract = {BACKGROUND: Obstructive sleep apnea (OSA) is associated with cognitive decline, but biomarkers for identifying cognitively unimpaired patients at increased future risk remain limited. We evaluated the prognostic value of plasma biomarkers associated with neuroaxonal injury and Alzheimer's disease-related biology in OSA.

METHODS: In this prospective cohort study, 286 cognitively unimpaired adults with polysomnography-confirmed OSA underwent baseline measurement of plasma NfL, GFAP, p-tau181, p-tau217, Aβ42, and Aβ40 and were followed for incident cognitive impairment. Cox regression, predictive performance analyses, and linear mixed-effects models were used.

RESULTS: During a median follow-up of 4.18 years, 68 participants (23.78%) developed incident cognitive impairment. In fully adjusted Cox models, each 1-SD increase in NfL was associated with a 46% higher risk of incident cognitive impairment (HR = 1.46, 95% CI 1.17-1.83, P = 0.001), and each 1-SD increase in p-tau217 was associated with a 58% higher risk (HR = 1.58, 95% CI 1.25-2.00, P < 0.001). When modeled jointly, both NfL (HR = 1.34, 95% CI 1.06-1.69, P = 0.014) and p-tau217 (HR = 1.47, 95% CI 1.14-1.89, P = 0.003) remained associated with incident cognitive impairment. In longitudinal analyses, higher baseline NfL and p-tau217 were also associated with faster annual declines in MoCA scores when modeled jointly (NfL × time: β = -0.10, 95% CI - 0.18 to - 0.02, P = 0.014; p-tau217 × time: β = -0.16, 95% CI - 0.25 to - 0.07, P = 0.001). Adding both biomarkers to the clinical model increased the C-index from 0.72 to 0.81 and the 4-year time-dependent AUC to 0.81; the optimism-corrected C-index was 0.79.

CONCLUSIONS: Higher plasma NfL and p-tau217 levels were independently associated with incident cognitive impairment and faster longitudinal cognitive decline in cognitively unimpaired patients with OSA.},
}

Humans
*Sleep Apnea, Obstructive/blood/complications/epidemiology
Biomarkers/blood
Prospective Studies
Female
Male
*Cognitive Dysfunction/blood/diagnosis/etiology/epidemiology
*tau Proteins/blood
Middle Aged
Neurofilament Proteins/blood
Amyloid beta-Peptides/blood
Polysomnography
Cohort Studies
Aged
Adult
Incidence

@article {pmid42862590,
year = {2026},
author = {Molina-Henry, DP and Liu, A and Langford, O and Raman, R and Dass, D and Clark, E and Day, GS and Okhravi, HR and Joshi, P and Cazares, P and Turner, RS and Braunstein, JB and Verghese, P and Venkatesh, V and West, T and Dhadda, S and Irizarry, M and Johnson, K and Rissman, RA and Grill, JD and Aisen, P and Sperling, RA},
title = {Plasma Phosphorylated Tau 217 Percentage by Race and Ethnicity in Preclinical Alzheimer Disease.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.3598},
pmid = {42862590},
issn = {2168-6157},
abstract = {IMPORTANCE: In trials targeting preclinical Alzheimer disease (AD), defined as amyloid pathology without cognitive symptoms, racial and ethnic differences in plasma phosphorylated tau 217 percentage (%p-tau217) may influence screening eligibility.

OBJECTIVE: To characterize racial and ethnic differences in %p-tau217 and determine whether associations between %p-tau217, cognition, and amyloid positron emission tomography (PET) differ across groups.

This was a cross-sectional analysis of AHEAD 3-45 screening participants conducted from July 2020 to October 2024 at 106 sites across 4 world regions. Adults aged 55 to 80 years with %p-tau217 measured before medical and cognitive exclusions (N = 15 612) were included.

EXPOSURES: Self-reported race (Asian, Black, and White) and ethnicity (Hispanic and non-Hispanic) and apolipoprotein E ε4 (APOE ε4) carrier status.

MAIN OUTCOMES AND MEASURES: %p-tau217 levels and associations of %p-tau217 with Preclinical Alzheimer Cognitive Composite 5 (PACC5) score and amyloid PET were evaluated across racial and ethnic groups using multivariable linear regression.

RESULTS: Among 15 612 participants, the mean (SD) age was 68.4 (6.2) years; 9941 (63.7%) were female and 5755 (36.9%) were APOE ε4 carriers. %p-tau217 levels were lower among Asian, Black, and Hispanic participants than among White and non-Hispanic participants. APOE ε4 status was associated with higher %p-tau217 across all groups. The association between APOE ε4 status and %p-tau217 differed by race (APOE ε4 × race: F2,14 973 = 10.06; P < .001) and ethnicity (APOE ε4 × ethnicity: β, 0.042; 95% CI, 0.017 to 0.067; P = .005) (Asian: β, 0.05; 95% CI, 0.02 to 0.08; P = .01; Black: β, 0.05; 95% CI, 0.03 to 0.08; P = .002; Hispanic: β, 0.04; 95% CI, 0.02 to 0.07; P = .005). The %p-tau217-PACC5 association showed no pairwise differences across racial groups but differed by ethnicity (β, -0.53; 95% CI, -0.85 to -0.21; P = .008) and APOE ε4 × ethnicity (β, 0.78; 95% CI, 0.26 to 1.30; P = .02). The %p-tau217-PET association showed no significant pairwise differences across racial groups but differed by ethnicity (β, -6.30; 95% CI, -9.10 to -3.51; P < .001) and APOE ε4 × ethnicity (β, 7.12; 95% CI, 2.52 to 11.73; P = .01).

CONCLUSIONS AND RELEVANCE: In this cross-sectional study, plasma %p-tau217 varied across racial and ethnic groups. Consistent %p-tau217-PACC5 score and %p-tau217-PET associations across racial groups support plasma-based screening before PET confirmation, while ethnicity-related findings warrant further investigation.},
}

@article {pmid42862637,
year = {2026},
author = {Gupta, A},
title = {Using Alzheimer's Disease Cerebrospinal Fluid Biomarkers in CKD: A Caution for Clinicians.},
journal = {Journal of the American Society of Nephrology : JASN},
volume = {},
number = {},
pages = {},
pmid = {42862637},
issn = {1533-3450},
}

@article {pmid42862642,
year = {2026},
author = {Lin, Y and Garcia Ptacek, S and Eriksdotter, M and Xu, H},
title = {Authors' Reply: Using Alzheimer's Disease Cerebrospinal Fluid Biomarkers in CKD: A Caution for Clinicians.},
journal = {Journal of the American Society of Nephrology : JASN},
volume = {},
number = {},
pages = {},
pmid = {42862642},
issn = {1533-3450},
}

@article {pmid42862762,
year = {2026},
author = {Howe, MD and Zide, BS and Hayes, K and Ross, D and Barker, MS and Kunicki, ZJ and Rudolph, J and Huey, E},
title = {Symptom-Guided Blood Biomarker Testing for Alzheimer's Disease.},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1},
doi = {10.1159/dem/aciag010},
pmid = {42862762},
issn = {1421-9824},
abstract = {Introduction Blood-based biomarkers can accurately detect Alzheimer's disease (AD) pathology, but symptom-guided testing approaches are understudied. This study evaluated the utility of early symptom and biomarker changes in predicting cognitive decline due to AD. Methods We analyzed data from the Alzheimer's Disease Neuroimaging Initiative-2 (development, n=603) and -3 (validation, n=378). The primary outcome was 4-year progression to mild cognitive impairment or dementia associated with amyloid-beta neuropathology. Machine learning estimated baseline symptom burden from subjective ratings. Logistic regression calculated area under the curve (AUC), relative risk, and time-to-event. Results Symptom burden predicted clinical progression (AUC=0.79), which further improved with blood biomarkers (AUC=0.90). Participants with elevated symptoms and biomarkers had a progression incidence of 72.1% and a 19-fold higher progression risk. Findings replicated in validation. Conclusion Findings underscore the potential of pairing symptoms and biomarkers to more efficiently and accurately detect AD cases at risk of clinical progression. Trial Parent study registrations: NCT01231971; NCT02854033.},
}

@article {pmid42862765,
year = {2026},
author = {Cihák, M and Bezdicek, O and Horáková, H and Motýl, J and Vyhnálek, M and Nikolai, T},
title = {Uniform Dataset 3 Neuropsychological Battery: Czech Normative Study of a Battery assessing cognitive functioning in older adults.},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1},
doi = {10.1159/dem/aciag011},
pmid = {42862765},
issn = {1421-9824},
abstract = {INTRODUCTION: The Uniform Data Set Neuropsychological Battery, version 3 (UDSNB 3), is a comprehensive, non-proprietary tool designed to assess cognitive domains relevant to neurodegenerative disorders, particularly Alzheimer's disease. This study aimed to establish Czech norms for the UDSNB 3, including the Lewy body disease module, using continuous norming methods.

METHODS: A normative sample of 171 cognitively healthy adults aged 50 - 95 years was recruited. Participants completed the Czech adaptation of the UDSNB 3. Continuous norming was performed using a semi-parametric approach. Education and age effects were examined, and selected scores were compared with previous Czech normative studies.

RESULTS: Cognitive performance generally declined with age across measures. Compared to previous Czech normative studies, differences were small and inconsistent across tests.

DISCUSSION: The present study provides the first Czech normative data for UDSNB 3 using continuous norming approach, supporting its clinical applicability. Continuous norming appears to be a viable approach for developing norms in contexts of countries with limited resources or smaller populations, where collecting large stratified samples of older adults can be difficult.},
}

@article {pmid42862793,
year = {2026},
author = {Ffrench-Constant, C},
title = {Does perturbed adaptive myelination contribute to cognitive dysfunction in Alzheimer's disease?.},
journal = {PLoS biology},
volume = {24},
number = {10},
pages = {e3004033},
pmid = {42862793},
issn = {1545-7885},
mesh = {*Alzheimer Disease/physiopathology/pathology/metabolism ; Humans ; Oligodendroglia/metabolism/pathology/physiology ; *Myelin Sheath/pathology/metabolism/physiology ; Animals ; *Cognition Disorders/physiopathology/pathology ; Gray Matter/pathology/metabolism ; },
abstract = {The consequences of oligodendrocyte involvement in Alzheimer's disease are poorly understood. Could a key role of gray-matter oligodendrocytes-activity-dependent adaptive myelination to sustain changes in activity-be perturbed, leading to cognitive loss?},
}

*Alzheimer Disease/physiopathology/pathology/metabolism
Humans
Oligodendroglia/metabolism/pathology/physiology
*Myelin Sheath/pathology/metabolism/physiology
Animals
*Cognition Disorders/physiopathology/pathology
Gray Matter/pathology/metabolism

@article {pmid42863052,
year = {2026},
author = {Zussy, C and Mathias, M and Vitalis, M and Moujellil-Legagneur, T and Malhaire, F and Canet, G and Desrumaux, C and Claeysen, S and Gómez-Santacana, X and Goudet, C and Llebaria, A and Givalois, L},
title = {Shedding light on left hippocampal mGlu5 in Alzheimer's disease.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {42},
pages = {e2535413123},
doi = {10.1073/pnas.2535413123},
pmid = {42863052},
issn = {1091-6490},
support = {MND202003011477-OPA//Fondation pour la Recherche Médicale (FRM)/ ; MUSE-AAP20REC-FRS09-GAiA//Université de Montpellier (UM)/ ; ANR-22-CE14-0042-EpiNeurAge//Agence Nationale de la Recherche (ANR)/ ; ANR-11-LABEX-0021-LipSTIC//Agence Nationale de la Recherche (ANR)/ ; 10.13039/501100011033//Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación/ ; PID2020-120499RB-I00//EC | European Regional Development Fund (ERDF)/ ; 2021 SGR 00508//Catalan government/ ; ANR-22-CE36-0003-DENTALCOG//Agence Nationale de la Recherche (ANR)/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology/genetics/pathology ; *Receptor, Metabotropic Glutamate 5/metabolism/genetics ; *Hippocampus/metabolism/physiopathology ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Signal Transduction ; Humans ; Glycogen Synthase Kinase 3 beta/metabolism ; Male ; },
abstract = {Metabotropic glutamate receptor 5 (mGlu5) is essential for synaptic plasticity and memory, making it a potential therapeutic target in Alzheimer's disease (AD). While hemispheric asymmetries in hippocampal function have been observed in AD patients, the lateralized contribution of mGlu5 signaling to cognitive decline remains unclear. Here, we show a physiological left-right asymmetry in hippocampal mGlu5 expression in wild-type mice, with higher levels in the left hemisphere, consistent with previous reports. This physiological asymmetry is lost in two distinct mouse models of AD, the J20 and 5xFAD mice, revealing a hemisphere-specific disruption of hippocampal mGlu5 regulation. Using the light-controllable negative allosteric modulator Alloswitch-1, we show that selective inhibition of left, but not right, hippocampal mGlu5 restores working and short-term memory in AD mice. This finding indicates that altered mGlu5 expression does not simply reflect receptor loss, but rather a dysregulated signaling state that remains functionally relevant and pharmacologically targetable. Left-specific modulation also normalizes pathological downstream signaling, including aberrant Pyk2 and GSK-3β activation and tau hyperphosphorylation, across both hemispheres, indicating a widespread impact of hemisphere-selective intervention. These findings establish a functional lateralization of hippocampal mGlu5 signaling and identify the left hippocampus as a critical site for mGlu5-dependent memory dysfunction in AD. They also highlight the therapeutic potential of region-specific photopharmacology for precise intervention in early AD pathology, providing a strategy for spatially targeted modulation of pathological synaptic signaling in neurodegenerative disease.},
}

Animals
*Alzheimer Disease/metabolism/physiopathology/genetics/pathology
*Receptor, Metabotropic Glutamate 5/metabolism/genetics
*Hippocampus/metabolism/physiopathology
Mice
Mice, Transgenic
Disease Models, Animal
Signal Transduction
Humans
Glycogen Synthase Kinase 3 beta/metabolism
Male

@article {pmid42863225,
year = {2026},
author = {Basavaraju, KC and Priyadarshini, P},
title = {Targeting tau acetylation in Alzheimer's disease: Molecular mechanisms, pathological consequences, and therapeutic opportunities of dietary phytochemicals.},
journal = {Biochemical and biophysical research communications},
volume = {839},
number = {},
pages = {154717},
doi = {10.1016/j.bbrc.2026.154717},
pmid = {42863225},
issn = {1090-2104},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline, synaptic dysfunction, and neuronal loss. Emerging evidence identifies tau acetylation as a crucial post-translational modification that contribute significantly to tauopathies associated pathology in AD. Aberrant tau acetylation results in autophagy dysregulation, DNA damage, altered lipid metabolism, endoplasmic reticulum (ER) stress, and neuroinflammation ultimately leading to cognitive decline and neuronal death. Dysregulation of acetyltransferases such as p300/CBP and reduced deacetylase activity, including sirtuins, further promote pathological tau accumulation and propagation. Dietary phytochemicals have emerged as promising multi-targeted neuroprotective agents due to their antioxidant, anti-inflammatory, and epigenetic regulatory properties. Notably, studies investigating dietary phytochemicals that directly regulate tau acetylation remain very limited, making this an important and promising area for future research. Nevertheless, several dietary phytochemicals have been reported to modulate the activities of SIRT1 and EP300 across a range of experimental models and various disease conditions. Future investigations should focus on incorporating these dietary phytochemicals into experimental models of AD to elucidate their potential to modulate tau acetylation and associated pathogenic mechanisms. Such studies will provide critical insights into their therapeutic potential and may facilitate the development of novel phytochemical-based interventions for tau acetylation in AD. This review provides a comprehensive overview of the mechanisms by which tau acetylation contributes to AD pathology and highlights therapeutic opportunities of dietary phytochemicals.},
}

@article {pmid42863333,
year = {2026},
author = {Zhu, W and Tang, R and Wu, F and Yi, L and Ouyang, Y and Zhang, Z},
title = {Structure-activity relationship of uronic acid oligosaccharides as potential anti-Alzheimer's disease agents.},
journal = {Carbohydrate research},
volume = {570},
number = {},
pages = {110126},
doi = {10.1016/j.carres.2026.110126},
pmid = {42863333},
issn = {1873-426X},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder and the primary cause of dementia. Although natural polysaccharides exhibit significant therapeutic potential against AD due to their multi-target activities, the structure-activity relationship (SAR) of uronic acid oligosaccharides-particularly the influence of specific glycosidic linkages and monosaccharide compositions-remains insufficiently characterized. To address this, we utilized a highly selective TEMPO oxidation system to prepare four structurally distinct uronic acid oligosaccharides (α1,4-G, β1,4-G, β1,3-G, and β1,4-M/G) from diverse natural polysaccharides. NMR spectroscopy showed that the resulting oligosaccharides retained the major glycosidic linkage characteristics of their parent polysaccharides, while oxidation and depolymerization also occurred during the reaction. Comprehensive in vitro and in vivo evaluations demonstrated that the β-1,4-glycosidic linkage is a critical structural determinant for neuroprotective activity against Aβ-induced neuronal damage and cognitive impairment, while β1,4-M/G and β1,4-G showed different effects under the present experimental conditions. Mechanistic studies revealed that both β1,4-G and β1,4-M/G ameliorated Aβ-induced cognitive impairment and were associated with alterations in the gut microbiota and related metabolites. Importantly, fermentation products generated from these oligosaccharides by the AD microbiota were associated with enhanced Treg differentiation, which may potentially contribute to the observed neuroprotective effects. These findings provide systematic insights into the SAR of uronic acid oligosaccharides and support the further investigation of β-1,4-linked uronic acid oligosaccharides as potential neuroprotective candidates.},
}

@article {pmid42863347,
year = {2026},
author = {Zhao, J and Qu, L and Guan, H and Che, H and Shi, F and Yang, Y},
title = {Immunosenescence as a modifiable driver of neurodegenerative diseases: Pathways and multidimensional emerging strategies for Alzheimer's and Parkinson's diseases.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {6},
pages = {e01096},
doi = {10.1016/j.neurot.2026.e01096},
pmid = {42863347},
issn = {1878-7479},
abstract = {Immunosenescence represents a core upstream driver of Alzheimer's disease (AD) and Parkinson's disease (PD), exerting its pathological effects through four mechanistically interconnected cascades: chronic inflammatory imbalance mediated by the senescence-associated secretory phenotype (SASP), oxidative stress arising from immune-metabolic reprogramming, protein homeostasis dysfunction caused by autophagy-lysosomal failure, and disrupted neuro-immune crosstalk secondary to breakdown of central nervous system (CNS) immune privilege. Current clinical practice remains largely constrained to neurotransmitter-based symptomatic management, which can neither arrest upstream pathological progression nor restore lost neuronal populations. Emerging intervention strategies targeting immunosenescence, including senolytic agents, antioxidant and metabolic modulators, autophagy restoration, and precision-targeted nanocarrier delivery, have demonstrated substantial capacity to delay disease progression in preclinical and early clinical investigations. These strategies act through selective clearance of senescent immune cells, remodeling of the neuroinflammatory microenvironment, and restoration of cellular quality-control mechanisms. The multidimensional treatment strategy approaches from the perspectives of artificial intelligence (AI) guided target discovery, nanocarrier engineering, and gut microbiota intervention to simultaneously address multiple nodes in the immunosenescence network, thereby overcoming the inherent limitations of single-target strategies. This review consolidates current mechanistic evidence and translational data to establish immunosenescence as an actionable therapeutic target and to provide a conceptual framework for precision disease-modifying therapy in AD and PD.},
}

@article {pmid42863362,
year = {2026},
author = {Zhou, Z},
title = {Uncovering the mechanism of gastrodin in treating Alzheimer's disease through bioinformatics, machine learning, and virtual gene knockout technology.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 2},
pages = {109464},
doi = {10.1016/j.compbiolchem.2026.109464},
pmid = {42863362},
issn = {1476-928X},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Gastrodin is a natural compound with neuroprotective activity; however, the precise molecular mechanisms underlying its therapeutic effects on human AD remain unclear. This study employed bioinformatics approaches to systematically elucidate the therapeutic mechanisms of gastrodin in AD. Pharmacokinetic analysis showed that gastrodin exhibited favorable drug-like properties (bioavailability score: 0.55; LogP: -0.85) and an acceptable overall toxicity profile, although predicted nephrotoxicity (0.71) and ototoxicity (0.908) scores suggest potential safety concerns warranting further investigation. Next, differentially expressed genes (DEGs) associated with AD were screened from GEO datasets, yielding 13 core targets that overlapped with gastrodin-responsive genes. Functional enrichment analysis indicated significant enrichment of these targets in signaling pathways closely related to neuroinflammation and cell survival, including the Ras-proximate 1 (Rap1), Ras, mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) pathways. The Ridge model achieved AUCs of 0.898 in the training set and 0.859 in the GSE37263 cohort, but showed modest generalizability in the GSE138260 cohort (AUC = 0.684), highlighting the heterogeneity of external datasets. Further single-cell transcriptomic analysis revealed specific upregulation of insulin-like growth factor 1 receptor (IGF1R) in brain endothelial cells of AD patients. Virtual gene knockout simulations demonstrated that IGF1R knockout substantially disrupted core networks associated with endothelial functions and neurovascular homeostasis, including focal adhesion and calcium signaling pathways. Finally, molecular docking and molecular dynamics (MD) simulations revealed stable binding conformations of gastrodin to EGFR and MET, while the gastrodin-IGF1R complex exhibited a more dynamic binding behavior with conformational flexibility, suggesting an induced-fit binding mechanism. MM/PBSA calculations revealed favorable enthalpic contributions (ΔH = -17.43, -13.63, and -10.41 kcal/mol for EGFR, IGF1R, and MET, respectively) for gastrodin-target binding. In conclusion, this study suggests that gastrodin exerts multi-target effects via coordinated regulation of multiple signaling pathways. Notably, gastrodin targets IGF1R in brain endothelial cells, modulating focal adhesion/calcium signaling networks, thus providing a novel mechanistic hypothesis for AD treatment by restoring neurovascular unit homeostasis.},
}

@article {pmid42863472,
year = {2026},
author = {Hategan, LA and Luo, JQ and Creighton, SD and Pirri, F and McLean, TAB and Hua, S and Dahi, TA and Jin, Z and Winston, SM and Reeves, IL and Johnston, K and Fahnestock, M and Brimble, MA and Walters, BJ and Murphy, PJ and Zovkic, IB},
title = {The histone variant H2A.Z regulates sex differences in Alzheimer's disease pathophysiology.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.09.019},
pmid = {42863472},
issn = {1097-4199},
abstract = {Alzheimer's disease (AD) disproportionately affects women, yet mechanisms underlying this sex difference remain unclear. Histone variants are overrepresented components of aging neuronal chromatin, but their contribution to AD is unknown. Here, we identify the histone variant H2A.Z as a sex-specific regulator of AD in the postmortem human hippocampus and in 5xFAD mice. H2A.Z occupancy decreased in female but increased in male AD patients. In females, reduced H2A.Z occupancy at the transcription start site (TSS) occurred despite increased total H2A.Z, indicating that H2A.Z is redistributed to sites of lower H2A.Z occupancy. Similar sex-dependent alterations were observed in 5xFAD mice over disease progression. Whereas H2A.Z.1 depletion improved memory and AD pathology in females at early and late disease stages, it impaired memory in male mice at early stages and improved memory in late stages. Together, these data identify H2A.Z as a regulator of sex- and stage-dependent AD outcomes, with implications for the sex-specific therapeutic targeting of chromatin factors.},
}

@article {pmid42863578,
year = {2026},
author = {Said, G and Ramos da Silva, AS and da Silva Rodrigues, G},
title = {EXERCISE, DNA METHYLATION, AND ALZHEIMER'S DISEASE: MECHANISTIC LINKS AND FUTURE DIRECTIONS IN INTERGENERATIONAL RESEARCH.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103415},
doi = {10.1016/j.arr.2026.103415},
pmid = {42863578},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia and remains without a cure; recently introduced disease-modifying therapies provide only modest slowing in selected patients. Physical exercise is associated with better cognitive and functional outcomes, but the molecular mechanisms underlying these benefits remain incompletely understood. DNA methylation is a potential interface linking environmental stimuli to gene regulation and neural function. This narrative review examines evidence connecting exercise, DNA methylation, and AD, with emphasis on AD-related loci and on the possible intergenerational implications of parental exercise. We examine methylation findings involving amyloid precursor protein (APP) and presenilin-1 (PSEN1), which are relevant to amyloid-β production; microtubule-associated protein tau (MAPT), which encodes tau; and apolipoprotein E (APOE), which influences lipid transport and amyloid-β clearance. These findings suggest potential epigenetic contributions to AD-related biology, although their direction and functional significance vary across studies. We also discuss exercise-responsive pathways involved in energy sensing, autophagy, and redox signaling. We also evaluate whether exercise-associated epigenetic remodeling could influence amyloid-β accumulation, Tau homeostasis, and neuronal function. Evidence that exercise modifies DNA methylation is growing, whereas studies that integrate exercise interventions, genome-wide methylation, and AD-related outcomes remain scarce. Evidence for an inherited reduction in AD susceptibility is even more limited and currently supports a hypothesis rather than an established mechanism. Future studies integrating behavioral, neuropathological, cell-type-resolved epigenomic, and other multi-omic outcomes are needed to determine whether exercise-induced DNA methylation changes mediate neuroprotection in AD or primarily reflect broader physiological adaptation.},
}

@article {pmid42863610,
year = {2026},
author = {Xu, Q and Zhao, H and Zhang, H and Zhao, Y and Ju, A and Chen, H and Liu, H},
title = {Microplastics detection in freshly harvested human brain tissues of northeast Chinese postmortem donors and their correlation with Alzheimer's disease- related pathological proteins.},
journal = {Neurotoxicology},
volume = {},
number = {},
pages = {103588},
doi = {10.1016/j.neuro.2026.103588},
pmid = {42863610},
issn = {1872-9711},
abstract = {Microplastics (MPs) and nanoplastics (NPs) (MNPs) have been linked to various health risks, but their presence in the human brain and association with Alzheimer's disease (AD)-related pathological proteins remain poorly understood. In this study, superior temporal gyrus tissues of 16 northeast Chinese postmortem donors were analyzed via pyrolysis-gas chromatography-mass spectrometry (Py-GC/MS) and laser direct infrared spectroscopy (LDIR) to characterize MNPs, while AD-related pathological proteins Aβ and p-tau levels in the hippocampus were detected by immunohistochemical staining and quantified by H-score. Py-GC/MS quantification revealed polymers corresponding to polyethylene (PE), polyvinyl chloride (PVC), polystyrene (PS) and polypropylene (PP) in all samples, with PE as the dominant type (63.3% of total polymers concentrations). The overall mean concentration of these four polymers was 105.70μg/g ranging from 24.69μg/g to 184.77μg/g. LDIR of four selected samples further identified 17 additional types of MPs besides the aforementioned four; additionally, 80.8% of MPs had diameters smaller than 60 μm, and 84.7% were spherical and irregular in shape. Exploratory multiple linear regression suggested positive associations of PE and PS with Aβ levels. This study provided evidence of plastic polymers in fresh human brain tissue and established a preliminary association between polymers burden and AD-related pathological proteins, might provide a valuable basis for future studies investigating the association between MNPs and AD.},
}

@article {pmid42863691,
year = {2026},
author = {Urano, Y and Maeda, W and Noguchi, N},
title = {Inhibition of glycan sialylation reduces amyloid-β secretion via suppression of amyloid-β exocytosis.},
journal = {Biochimie},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biochi.2026.10.016},
pmid = {42863691},
issn = {1638-6183},
abstract = {Among nutrient-sensitive regulatory mechanisms, protein glycosylation is a key post-translational modification that links metabolism to protein function. Amyloid-β (Aβ) peptides play a crucial role in the pathogenesis of Alzheimer's disease (AD). Because excessive accumulation of Aβ is believed to drive AD progression, approaches that reduce Aβ production and secretion remain of considerable therapeutic interest. Accumulating evidence suggests that protein glycosylation influences the processing and trafficking of amyloid-β precursor protein (APP) and other proteins involved in Aβ metabolism. However, while N-linked protein glycosylation has been shown to affect Aβ production, the specific contribution of protein terminal glycan sialylation remains incompletely understood. In this study, we investigated the effects of inhibiting glycan sialylation on Aβ production using CHO cells stably expressing human APP. Treatment with the sialyltransferase inhibitor P-3Fax-Neu5Ac (P-3Fax) significantly reduced extracellular Aβ levels, while intracellular Aβ levels were increased. Importantly, P-3Fax treatment did not alter β-secretase- or γ-secretase-mediated cleavage of their substrates, indicating that changes in secretase activity do not account for the reduction in extracellular Aβ. In addition, P-3Fax treatment markedly reduced plasma membrane levels of lysosome-associated membrane protein 1 (LAMP1), consistent with impaired lysosomal exocytosis. Taken together, these results indicate that inhibition of sialylation by P-3Fax reduces extracellular Aβ levels independently of secretase activity, potentially through impaired lysosomal exocytotic pathways. Our findings identify glycan sialylation as a key regulatory factor in Aβ trafficking and provide new insight into the cellular mechanisms controlling Aβ homeostasis.},
}

@article {pmid42863694,
year = {2026},
author = {Tanahashi, M and Kozuka, A and Sasakawa, N and Niikura, T},
title = {Humanin attenuates neuronal cellular senescence and preserves neurotransmitter release in differentiated PC12 cells.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.10.017},
pmid = {42863694},
issn = {1873-7544},
abstract = {Cellular senescence, characterized as a permanent arrest of cell proliferation, is triggered by various types of stress. Senescent cells are identified by markers, including senescence-associated β-galactosidase (SA-β-gal) activity and the secretion of senescence-associated secretory phenotype (SASP) factors. These senescent phenotypes have been observed in neurons, suggesting that cellular senescence may contribute to the pathogenesis of neurodegenerative diseases. Humanin (HN), an endogenous short peptide, mitigates Alzheimer's disease-associated pathologies, including amyloid β-induced neuronal cell death. Overexpression of HN extends the lifespan of nematodes, suggesting a potential anti-aging role for this peptide. Here, we first investigated the effect of HN on cellular senescence in mouse primary cortical neurons. Chronic treatment with HNG, a highly potent HN derivative, attenuated prolonged culture-induced senescence. To further determine whether this anti-senescent effect is associated with preserved exocytotic function, we employed a glutamate-induced senescence model in neuronal-differentiated PC12 cells. In this system, HNG mitigated changes in senescence-associated markers, including increases in SA-β-gal activity, Ki67 expression, and SASP factor expression. In addition, acetylcholine-induced dopamine release was reduced in senescent PC12 cells, whereas chronic HN treatment sustained the expression levels of synapsin 1 and synaptophysin and attenuated the senescence-associated decrease in neurotransmitter release. These findings suggest that HN suppresses senescence and sustains exocytosis activity in neuronal cells, supporting an anti-aging function of HN at the cellular level.},
}

@article {pmid42863717,
year = {2026},
author = {Tukiran, N and Kolb, T and Maggioni, L and Rai, S and Rafath, Z and Borsini, A},
title = {Cytokine dysregulation and hippocampal neurogenesis: A shared mechanism underlying cognitive impairments across neuropsychiatric and neurodegenerative disorders.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {107069},
doi = {10.1016/j.bbi.2026.107069},
pmid = {42863717},
issn = {1090-2139},
abstract = {Neuropsychiatric and neurodegenerative disorders, such as major depressive disorder, bipolar disorder, schizophrenia, Alzheimer's disease, and Parkinson's disease, all show a neuroimmune signature with dysregulated inflammatory cytokine profile and cognitive impairment. Although these deficits are clinically relevant, the immunological mechanisms that cause cognitive dysfunction across these conditions remain poorly defined. Recent studies demonstrate that inflammatory cytokines actively modulate adult hippocampal neurogenesis, a process critical for learning, memory, and affective regulation. Here, we synthesise clinical evidence to characterise the disorder-specific inflammatory profile of each of these five disorders, representing each profile with three frequently dysregulated cytokines rather than a single cytokine signature shared across conditions. We also integrate preclinical data where cytokines induce behavioural, cognitive, and hippocampal-related deficits in animal and cellular models. Hence, this review develops a mechanistic framework that links brain-immune communication directly to cognitive impairment through hippocampal neurogenesis, thereby suggesting neuroimmune targets for therapeutic intervention.},
}

@article {pmid42863728,
year = {2026},
author = {Li, Y and Tang, ZL and Liu, FW and Chen, M and Chang, SQ and Ding, FM and Bian, QL and Pan, JP and Qiu, ZC and Kong, MW and Li, Y and Chen, JX},
title = {Si-Shen-San Attenuates Alzheimer's Disease Pathology and Cognitive Deficits Through Multi-Target Regulation of Astrocyte Function and Synaptic Plasticity.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122475},
doi = {10.1016/j.jep.2026.122475},
pmid = {42863728},
issn = {1872-7573},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by cognitive decline, amyloid-β (Aβ) deposition, tau hyperphosphorylation, synaptic dysfunction, and astrocyte dysregulation. The constituent herbs of the traditional Chinese medicine formula Si-Shen-San (SSS) have been used to ameliorate cognitive impairment. However, the comprehensive chemical profile, core bioactive constituents, and underlying mechanisms of action of SSS remain to be fully elucidated.

AIM OF THE STUDY: This study aims to systematically investigate the therapeutic potential of SSS against AD and to clarify its multi-faceted mechanisms of action, with a focus on astrocyte-mediated neuroprotection, synaptic repair, and modulation of core AD pathologies.

MATERIALS AND METHODS: Ultra-high performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UHPLC-Q/TOF-MS) was used to characterize the chemical constituents of SSS extract and SSS-containing serum. In vivo, 3×Tg-AD mice were orally administered SSS. And cognitive function, AD-related pathology, synaptic integrity, and astrocyte-associated molecular changes were evaluated using behavioral, histological, biochemical, ultrastructural, and electrophysiological approaches. In vitro, an astrocyte-conditioned medium paradigm was used to examine whether SSS-induced changes in astrocytes were associated with protection of HT22 neurons against glutamate-induced injury.

RESULTS: UHPLC-Q/TOF-MS tentatively annotated 525 and 318 compounds in the SSS extract and drug-containing serum. In 3×Tg-AD mice, SSS improved cognitive performance, reduced hippocampal 6E10- and ThS-positive Aβ-like immunoreactivity and tau phosphorylation at Thr231 and Ser404, and preserved synaptic structure and function. The reduction in tau phosphorylation was accompanied by changes in GSK-3β signaling. SSS treatment was also associated with reduced astrocyte reactivity, increased GLT-1 expression, and restoration of astrocyte-associated homeostatic markers. In vitro, conditioned medium derived from SSS-treated C8-D1A astrocytes alleviated glutamate-induced injury in HT22 neurons and was accompanied by activation of neuronal CREB-BDNF signaling.

CONCLUSION: SSS ameliorated cognitive deficits and multiple AD-related pathological alterations in 3×Tg-AD mice. These effects were associated with restoration of astrocyte-related homeostatic features, improved glutamate regulation, preservation of synaptic integrity, and activation of CREB-BDNF signaling. These findings provide an experimental foundation for SSS as a potential therapeutic strategy for AD and highlight astrocyte homeostasis as a promising target for future drug development.},
}

@article {pmid42864178,
year = {2026},
author = {Ko, JS and Jung, W and Suh, PS and Heo, H and Shim, WH and Kim, DH and Lee, SH and Kim, M and Lee, N and Kim, S and Kim, SJ and Suh, CH},
title = {Automated Structured Reporting of Neurodegenerative Imaging Markers Using Quantitative MRI and Large Language Models.},
journal = {Academic radiology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.acra.2026.09.056},
pmid = {42864178},
issn = {1878-4046},
abstract = {RATIONALE AND OBJECTIVES: To evaluate the feasibility of a quantitative magnetic resonance imaging (MRI)-to-structured reporting pipeline that integrates quantitative MRI software with large language models (LLMs) for structured drafting of neurodegenerative imaging markers and generating clinician-facing report conclusions.

MATERIALS AND METHODS: A total of 192 patients with 3D T1 and 2D or 3D FLAIR MRI images from the Alzheimer's Disease Neuroimaging Initiative database were randomly selected. A deep-learning model generated structured report findings based on nine indices related to brain atrophy, white matter hyperintensities, and cerebrospinal fluid (CSF) space abnormalities, and compared with neuroradiologist-generated reference reports. Four LLMs (GPT-OSS 20B, MedGemma 4B, Phi-3, and Llama 3.1 8B) generated clinician-facing conclusions from the structured findings. Generated conclusions were evaluated using a five-point Likert scale across four metrics (accuracy, relevance, clarity, and satisfaction). Output errors were assessed across four categories: language, omission, addition, and numeric errors.

RESULTS: Structured report findings demonstrated high accuracy for CSF space analysis (77.6%-97.9%). Performance for ordinal visual scales was lower under strict matching (27.1%-57.8%) but improved with a one-grade tolerance (91.7%-97.4%). Among LLMs, GPT achieved the highest scores across most metrics (median score 5) and exhibited the lowest output error rates. Smaller models (Phi-3 and Llama 3.1 8B) showed overall lower performance, with more language, omission, and addition errors. MedGemma demonstrated intermediate performance, but the highest rate of numeric errors.

CONCLUSION: Our quantitative MRI-to-structured reporting pipeline, integrating quantitative MRI software with LLM-based conclusion generation, might be feasible for automated structured drafting of neurodegenerative imaging markers.},
}

@article {pmid42864446,
year = {2026},
author = {Cao, H and Fu, Y and Zhou, X and Duan, Y and Ip, FCF and Chen, Y and Hu, S and Liu, SC and Kwok, TCY and Mok, KY and Cheung, TH and Hardy, J and Fu, AKY and Ip, NY},
title = {Genome-wide analysis of common structural variants in Alzheimer's disease identifies a risk-associated regulatory CCG repeat in FAM193B.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42864446},
issn = {1546-1726},
support = {C6027-19GF//Research Grants Council, University Grants Committee (RGC, UGC)/ ; T13-605/18W//Research Grants Council, University Grants Committee (RGC, UGC)/ ; AoE/M-604/16//University Grants Committee (UGC)/ ; InnoHK, ITCPD/17-9, ITS/207/18FP, MRP/042/18X//Innovation and Technology Commission (ITF)/ ; },
abstract = {Although Alzheimer's disease (AD) has a polygenic architecture, with numerous associated single-nucleotide polymorphisms (SNPs) identified, the contribution of structural variants (SVs) is unclear. In this study, using long-read (n = 11) and short-read (n = 3,190) sequencing data from the Chinese population, we show that common SVs contribute to AD heritability beyond common SNPs. We identify an expanded CCG repeat in the FAM193B promoter that shows a genome-wide significant association with increased AD risk (odds ratio = 2.20 per 10-repeat increase, P = 5.5 × 10[-13]). The expanded FAM193B-CCG repeat increases FAM193B expression and mediates the pleiotropic association between brain FAM193B expression and AD risk. Analyses of postmortem human brains and cultured neuronal cells show that elevated neuronal FAM193B expression is associated with DNA damage and cell death-related pathways. These findings establish the common FAM193B-CCG repeat as an AD risk genetic factor and highlight the contribution of common SVs to AD heritability.},
}

@article {pmid42864510,
year = {2026},
author = {Zhang, C and Bai, L and Shi, D and Li, W and Ai, L and Ao, F and Bai, Y and Bai, Y and Bao, H and Cai, Q and Cao, J and Chai, L and Chen, F and Chen, F and Chen, K and Chen, Y and Cheng, D and Cole, J and Cui, Z and Dai, H and Deng, D and Du, X and Du, Y and Duan, X and Fu, Y and Gao, Z and Gou, L and Guo, C and Guo, M and Guo, Y and Han, X and He, H and Hou, Y and Hu, B and Hu, J and Hua, T and Huang, C and Huang, P and Lei, J and Li, H and Li, J and Li, J and Li, K and Li, K and Li, S and Li, X and Li, Y and Li, Y and Li, Y and Li, Y and Liang, P and Liao, H and Liao, L and Lin, B and Lin, CP and Liu, J and Liu, J and Liu, W and Liu, Y and Lu, S and Luo, J and Luo, Y and Lui, S and Ma, H and Mao, N and Meng, L and Meng, L and Qiu, J and Shao, J and Shen, Q and Shi, Y and Shu, Z and Tian, D and Tu, Y and Wang, F and Wang, J and Wang, J and Wang, J and Wang, W and Wang, X and Wang, Y and Wang, Y and Wang, Y and Wang, Z and Weng, J and Wu, F and Wu, Y and Wu, Y and Wu, H and Xia, X and Xu, C and Xu, J and Xu, J and Xu, R and Yang, R and Yin, S and Yin, X and Yin, Y and Yu, R and Yuan, Z and Zhang, F and Zhang, H and Zhang, J and Zhang, N and Zhang, R and Zhang, T and Zhang, Y and Zhang, Z and Zhang, Z and Zhao, J and Zhao, L and Zhao, X and Zhao, X and Zhao, X and Zhe, X and Zhou, F and Zhu, J and Zhu, L and Zhuo, Z and Fan, G and Qian, Y and Wang, J and Duan, Y and Liu, Y},
title = {Normative Modeling of Amygdala Subfields and Disease-Specific Vulnerabilities Across Neurological Disorders.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {42864510},
issn = {1995-8218},
abstract = {As an integrative center of the limbic system, the amygdala and its subfields participate in diverse neural functions and demonstrate heterogeneous structural changes in various neurological disorders. In this study, three-dimensional T1-weighted MRI data from 22,258 healthy participants were analyzed using normative modeling to establish normative references for the volumes of the amygdala and its subfields. These models elucidated the developmental and aging curves of the amygdala and identified distinct ages at peak volume across subfields, ranging from 24.6 to 43.7 years. Based on these references, individual centile scores were calculated for 4132 patients with mild cognitive impairment, Alzheimer's disease, Parkinson's disease, cerebral small vessel disease, multiple sclerosis, and neuromyelitis optica spectrum disorder. These centile scores not only captured disease-specific deviation patterns of the amygdala subfields but also demonstrated utility in disease classification. Moreover, the centile scores correlated with clinical measures of cognitive function, emotional state, and motor performance across disorders. These findings suggest that normative references of the amygdala subfields provide insights into cross-disease alteration patterns and offer potential neuroimaging biomarkers to aid differential diagnosis and clinical assessment.},
}

@article {pmid42864517,
year = {2026},
author = {Miao, G and Gao, C and Yu, L and Yang, J and Li, Y and Grodstein, F and Schneider, JA and Barnes, LL and De Jager, PL and Yao, B and Bennett, DA and Zhao, J},
title = {Brain DNA methylation, APOE genotype and Alzheimer's disease neuropathology in a large postmortem cohort.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {42864517},
issn = {2662-8465},
support = {RF1AG052476//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG10161//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG72975//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG15819//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG17917//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01DK091369//U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)/ ; R01MH097018//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; },
abstract = {DNA methylation (DNAm) plays a critical role in Alzheimer's disease (AD). Previous epigenome-wide association studies using 450K arrays captured limited CpG coverage and often focused on a single neuropathological measure. Here we profiled DNAm in 1,250 postmortem prefrontal cortex samples from the Rush Alzheimer's Disease cohorts using the Infinium MethylationEPIC v2 array (~930,000 CpGs) and performed epigenome-wide association studies of multiple neuropathologic measures, including AD diagnosis, amyloid-β and tau tangles. We identified 107 differentially methylated probes associated with AD neuropathology, 38 of which were replicated in an independent cohort (n = 139). DNAm also partially mediated the effect of APOE genotype on AD diagnosis (proportion mediated: 8.6%, P = 2 × 10[-6]). Moreover, 39 identified genes (for example, RIN3, LGMN, LHPP) were differentially expressed across major brain cell types, including neurons and astrocytes. These findings expand the epigenetic landscape of AD neuropathology and reveal DNAm as a mediator of APOE-related genetic risk.},
}

@article {pmid42864705,
year = {2026},
author = {Hacker, K and Nickelson, PF and Kansagra, SM and Alongi, J},
title = {The Future of Chronic Disease and the Role of Governmental Public Health.},
journal = {Journal of public health management and practice : JPHMP},
volume = {},
number = {},
pages = {},
pmid = {42864705},
issn = {1550-5022},
abstract = {Chronic diseases have accounted for the leading causes of morbidity and mortality in the United States for decades. Today, the shape and context of chronic disease is changing. Therapeutic advances have transformed fatal conditions like HIV/AIDS and cancer into chronic conditions. Depression and Alzheimer disease are emerging as leading chronic conditions. Biomarkers are helping individuals determine their risk of certain cancers long before they appear, and technological devices like wearables, mobile applications, and self-administered tools are placing prevention in the hands of individuals. It is imperative that governmental public health redefine its role and look at new opportunities in primary prevention and early intervention of chronic disease. To assist the field, the authors offer recommendations and examples of health department-led initiatives that are meeting the moment in data and surveillance, education and communication, relationships with the health care and policy, environment, and systems efforts.},
}

@article {pmid42864795,
year = {2026},
author = {Ramalakshmi, N and Dibenthiran, S and Arunkumar, S and Amuthalakshmi, S and Indrakumar, S and Nalini, CN},
title = {Mechanistic Insights into the Neuroprotective Potential of Luteolin: An Overview.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249434117260910074306},
pmid = {42864795},
issn = {1875-6166},
abstract = {Neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, are characterized by pathologies such as oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein aggregation. Luteolin, a natural flavonoid, is known for its neuroprotective properties, targeting key pathological mechanisms. This review highlights the multi-target effects of luteolin, as demonstrated by in vitro and in vivo studies. Luteolin reduces oxidative damage by scavenging ROS, enhancing antioxidant enzymes, such as SOD, CAT, and GPx, and activating the Nrf2/ARE pathway. It reduces neuroinflammation by inhibiting NF-κB, AP-1, and JNK signalling and by lowering pro-inflammatory cytokines such as TNF-α and IL-1β. Luteolin maintains mitochondrial membrane potential, modulates apoptotic pathways via Bcl-2/Bax and PI3K/Akt signalling, and promotes autophagy by upregulating LC3-II and modulating the p62-Keap1-Nrf2 axis. It disrupts amyloidogenic and tau hyperphosphorylation pathways, inhibits AChE activity, enhances cholinergic transmission, and improves cognitive function by upregulating CREB, BDNF, and synaptic proteins. Although promising, these effects have been observed mainly in preclinical models, with limited clinical evidence. Future research should focus on the clinical validation and improvement of delivery systems to enhance brain bioavailability. This review provides a foundation for the development of luteolin as a therapeutic candidate for neurodegenerative diseases.},
}

@article {pmid42864883,
year = {2026},
author = {Li, J and Ling, C and Peng, Y and Yu, Y and Feng, G and Du, W and Chen, R},
title = {An EEG-based framework for Alzheimer's disease diagnosis via single-channel multi-entropy fusion and ensemble learning.},
journal = {Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine},
volume = {},
number = {},
pages = {9544119261496349},
doi = {10.1177/09544119261496349},
pmid = {42864883},
issn = {2041-3033},
abstract = {Alzheimer's Disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline, and its early diagnosis is vital for timely intervention. However, most existing EEG-based diagnostic methods rely on multi-channel devices confined to hospital settings, limiting their accessibility for community screening. To address this gap, this study aims to develop a lightweight processing approach for portable, low-cost devices to support early AD diagnosis using single-channel EEG data, integrating signal purification with complementary entropy-based feature extraction and ensemble learning. Specifically, EEG signals are first decomposed into five brain rhythms (δ, θ, α, β, γ) using Discrete Wavelet Transform (DWT). Empirical Mode Decomposition (EMD) is then applied to extract Intrinsic Mode Functions (IMFs) from the selected rhythm. Four entropy measures, including Differential Entropy (DE), Singular Spectral Entropy (SSE), Fuzzy Entropy (FE), and Sample Entropy (SE), are subsequently extracted from each IMF to construct the Multi-IMF Entropy Matrix (MIMFEM). After that, an ensemble learning framework combining five classifiers is designed to discriminate AD patients from healthy controls (HCs). The proposed method is evaluated on two public datasets using Leave-One-Out Cross-Validation (LOOCV). Using single-channel EEG data, our approach achieves classification accuracies of 97.92% on the Florida-based dataset and 81.54% on the AHEPA dataset, with corresponding F1-scores of 97.87% and 82.86%, respectively. These results, achieved with limited data sources, show that our approach provides an effective, practical solution for single-channel wearable AD screening and addresses the critical need for low-cost, accessible early diagnostic tools, advancing Artificial Intelligence (AI) in healthcare through a lightweight model.},
}

@article {pmid42864910,
year = {2026},
author = {Polzer, O and Salette, L and van Wijhe, M and Siva, TL and Tsonkova, A and Swildens, A and Randoe, RE and Ayyildiz, D and Chameau, P and Lucassen, PJ and Salta, E and Fitzsimons, CP},
title = {miR-124 delivery to the hippocampus reduces excitability, enhances neurogenesis and affects microglia in a model of Alzheimer's disease.},
journal = {Molecular therapy : the journal of the American Society of Gene Therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ymthe.2026.10.001},
pmid = {42864910},
issn = {1525-0024},
abstract = {MicroRNA-124 (miR-124) has been proposed as therapeutic candidate for Alzheimer's disease (AD), given its regulation of gene networks governing synaptic function, neurogenesis and inflammation. However, its functional role during early disease stages, and the cellular context-dependence of its effects, remain unclear. Here, we investigated the effects of targeted neuronal miR-124 delivery to the hippocampal dentate gyrus (DG) of App[NL-G-F] mice. At an earlier 'presymptomatic' stage, miR-124 reduced intrinsic excitability of mature granule neurons and induced subtle changes in dendritic architecture. Integrative transcriptomic analyses revealed that predicted miR-124 targets were enriched among downregulated genes involved in synapse organization and cell junction assembly. At the same time, miR-124 increased the number of immature neurons and microglia, indicating structural and functional remodeling of the DG. At a later 'symptomatic' disease stage, where AD pathology is established, neuronal miR-124 supplementation reduced DG Aβ40 and Aβ42 levels and decreased local amyloid plaque burden, while also altering the plaque-associated microglial response. Together, these findings identify neuronal miR-124 as a context- and disease-stage-dependent regulator of the DG microenvironment and demonstrate effects extending from neuronal function to other cellular populations and local AD-associated pathology.},
}

@article {pmid42864926,
year = {2026},
author = {Bhardwaj, A and Parveen, N and Singh, R and Bhushan, B},
title = {Unraveling Shared Molecular Mechanisms in Alzheimer's, Parkinson's, and Neuropathic Pain: Targeting p38 MAPK and Wnt/β-Catenin Pathways.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273492918261001111401},
pmid = {42864926},
issn = {1996-3181},
abstract = {Neurodegenerative disorders, including Alzheimer's Disease (AD), Parkinson's Disease (PD), and Neuropathic Pain (NP), share overlapping molecular and cellular mechanisms that contribute to progressive neuronal dysfunction, neuroinflammation, and impaired neural repair. Although these conditions present with distinct clinical manifestations, accumulating evidence indicates that dysregulation of the p38 mitogen-activated protein kinase (p38 MAPK) and Wnt/β-catenin signaling pathways represents a common pathogenic axis underlying disease initiation and progression. Activation of p38 MAPK amplifies inflammatory signaling, mitochondrial dysfunction, oxidative stress, neuronal apoptosis, and glial activation, whereas suppression of Wnt/β-catenin signaling disrupts synaptic plasticity, blood-brain barrier integrity, neurogenesis, and neuronal survival. The reciprocal interaction between these pathways further exacerbates amyloid-β accumulation, dopaminergic neuronal degeneration, tau hyperphosphorylation, central sensitization, and persistent neuroimmune activation, thereby linking cognitive decline, motor impairment, and chronic pain. This review comprehensively examines the molecular crosstalk between p38 MAPK and Wnt/β-catenin signaling across AD, PD, and NP, highlighting their roles in regulating neuroinflammation, oxidative stress, mitochondrial homeostasis, and neuronal resilience. In addition, it summarizes emerging pharmacological agents, natural bioactive compounds, and targeted therapeutic strategies designed to inhibit p38 MAPK activation or restore Wnt/β-catenin signaling to promote neuroprotection and functional recovery. Particular emphasis is placed on the translational potential of dual-pathway modulation as a disease-modifying approach that addresses shared pathological mechanisms rather than isolated disease- specific manifestations. By integrating current experimental and clinical evidence, this review provides a unified mechanistic perspective, identifies promising therapeutic opportunities for developing more effective interventions against neurodegenerative disorders and neuropathic pain, and outlines the remaining challenges for future translational research.},
}

@article {pmid42865106,
year = {2026},
author = {Kogularasu, S and Kumar, H and Liang, CK and Kung, HC and Sriram, B and Wang, SF and Huang, BW and Chang-Chien, GP and Lin, YT},
title = {Amino-functionalized MIL-101(Fe)-confined Au nanostructures for advanced electrochemical detection of H2O2 in Alzheimer's disease research.},
journal = {Nanoscale},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6nr01767c},
pmid = {42865106},
issn = {2040-3372},
abstract = {Oxidative stress is a fundamental pathological contributor to Alzheimer's disease and is closely linked to amyloid-beta-mediated toxicity, tau dysregulation, mitochondrial impairment, and progressive neuronal degeneration. Among the associated reactive oxygen species, hydrogen peroxide (H2O2) is a mechanistically relevant redox intermediate and an important oxidative stress biomarker. Herein, an Au@NH2-MIL-101(Fe) hybrid was rationally engineered as an electrocatalytically active sensing interface for H2O2 determination. The hybrid was constructed by integrating conductive Au nanodomains with an amino-functionalized Fe-based metal-organic framework, thereby combining the high surface area, porous architecture, and accessible coordination environment of NH2-MIL-101(Fe) with the superior conductivity and catalytic activity of Au. Electrochemical investigations revealed that Au@NH2-MIL-101(Fe)/SPCE exhibited substantially enhanced interfacial electron-transfer kinetics and electrocatalytic reduction of H2O2 relative to bare SPCE, MIL-101(Fe), and NH2-MIL-101(Fe). Under optimized conditions, the sensor delivered a linear range of 0.01 to 429.7 μM and a limit of detection of 0.063 µM. In addition, the platform showed good selectivity, operational stability, reproducibility, and satisfactory performance in H2O2-spiked serum and urine samples, highlighting its promise for oxidative stress-related electroanalysis relevant to Alzheimer's disease.},
}

@article {pmid42865133,
year = {2026},
author = {Lv, Y and Shi, M and Zhao, Y and Yu, Y and Lv, J and Zhao, H},
title = {Context-dependent TREM2 signalling in myeloid cells: Molecular mechanisms and immunotherapeutic divergence in neurodegeneration and cancer.},
journal = {Clinical and translational medicine},
volume = {16},
number = {10},
pages = {e70863},
doi = {10.1002/ctm2.70863},
pmid = {42865133},
issn = {2001-1326},
support = {ZR2022QH372//Shandong Province Natural Science Foundation/ ; },
mesh = {Humans ; *Receptors, Immunologic/metabolism ; *Membrane Glycoproteins/metabolism ; *Signal Transduction ; *Myeloid Cells/metabolism/immunology ; *Neoplasms/therapy/immunology ; Animals ; *Immunotherapy/methods ; *Neurodegenerative Diseases/therapy/immunology ; },
abstract = {BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) is a pivotal lipid-sensing receptor that governs the functional plasticity and metabolic fitness of mononuclear phagocytes, including microglia, osteoclasts, dendritic cells and tissue-resident macrophages. While originally identified as a genetic risk factor for Alzheimer's disease (AD), TREM2 functions as a context-dependent immunometabolic checkpoint rather than a uniform phenotypic driver, exerting divergent biological outputs dictated by distinct tissue microenvironments and ligand repertoires.

SUMMARY OF KEY CONTENTS: This review provides a comprehensive synthesis of TREM2 immunobiology, detailing how ligand engagement-including cell-surface phospholipids and apolipoprotein E (ApoE)-activates the DAP12/DAP10-SYK-PI3K-mTOR signalling axis. This coordinated intracellular cascade instructively drives myeloid adaptation towards metabolically competent disease-associated microglia (DAM) and lipid-associated macrophage (LAM) states, sustaining bioenergetics and debris clearance under pathological stress. Across neurodegenerative proteinopathies and acute cerebral ischemia, TREM2 signalling is predominantly neuroprotective by promoting aggregate compaction and mitigating secondary excitotoxicity, although chronic dysregulated activation may drive stage-dependent neuroinflammation. In peripheral inflammatory pathologies such as rheumatoid arthritis and sepsis, TREM2 fine-tunes macrophage efferocytosis and systemic metabolic thresholds. In oncology, TREM2 displays a complex, microenvironment-dependent divergence: in central nervous system malignancies such as glioblastoma (GBM), TREM2 exerts controversial, stage-dependent effects, spanning microglial tumour containment in early stages versus pro-tumoural myelin recycling and immunosuppression by monocyte-derived macrophages in post-treatment recurrence; conversely, in peripheral solid tumours, monocyte-derived TREM2+ tumour-associated macrophages (TAMs) predominantly orchestrate an immunosuppressive, nutrient-deprived niche that impairs cytotoxic T-cell function. Furthermore, we synthesise emerging paradigms along the bidirectional microbiome-gut-brain-tumour axis, elucidating how commensal and intra-tumoural microbial cues dynamically calibrate myeloid signalling tone and therapeutic susceptibility.

CONCLUSION: We address translation bottlenecks-including blood-brain barrier (BBB) shuttles, human trial scarcity and soluble TREM2 (sTREM2) biomarker harmonisation-outlining a biomarker-guided, context-tailored precision therapeutic framework for targeting the TREM2 axis.},
}

Humans
*Receptors, Immunologic/metabolism
*Membrane Glycoproteins/metabolism
*Signal Transduction
*Myeloid Cells/metabolism/immunology
*Neoplasms/therapy/immunology
Animals
*Immunotherapy/methods
*Neurodegenerative Diseases/therapy/immunology

@article {pmid42865136,
year = {2026},
author = {Pinheiro, CN and Song, X and Brock, KE and Harp, JP and Karr, JE},
title = {Measurement of subjective cognitive decline and prediction of longitudinal clinical outcomes in older adults: a systematic review.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-30},
doi = {10.1080/13803395.2026.2743151},
pmid = {42865136},
issn = {1744-411X},
abstract = {Subjective cognitive decline (SCD) is a preclinical risk factor for Alzheimer's disease and may represent one of the earliest clinical indicators of underlying neurodegeneration. Prevalence estimates vary but suggest that between 20 and 30% of cognitively unimpaired older adults report some form of subjective decline (Rohr et al. 2020). Longitudinal studies indicate that individuals with SCD are at approximately twice the risk of progressing to mild cognitive impairment (MCI) or dementia compared to those without complaints. While not every older adult reporting decline will progress, early detection allows for timely intervention and risk stratification for clinical trials of dementia prevention. The current review examined longitudinal studies of adults aged ≥ 60 to assess and highlight the heterogeneity in operational definitions of SCD and risk of incident MCI or dementia. Among the 26 studies reviewed, 24 distinct definitions of SCD were used, highlighting the need for standardized measurement to improve comparability and generalizability. Of the studies reporting hazard ratios, all nine found that SCD was associated with a significantly higher risk of incident MCI or dementia compared to cognitively healthy older adults not reporting SCD; with the exception that no significant association between SCD and risk of vascular dementia was observed. The consistent association between SCD and risk of progression to MCI and dementia in these studies strengthens the evidence that suggests SCD may not be a benign complaint of aging or psychiatric conditions, but a potentially early clinical indicator of possible underlying neurodegenerative changes. These findings highlight the need for standardization in measurement tools and definitions to refine this pre-MCI construct.},
}

@article {pmid42865229,
year = {2026},
author = {Xiang, X and Li, T and Feng, Z and Yang, J and Gong, Z and Wang, L and Wang, L and Zhang, W},
title = {MAFG as a Redox-Sensitive Node Linking Peripheral Immune Reprogramming to Cognitive Risk in the Sepsis-to-Alzheimer's Disease Continuum: Single-Cell Dissection and Adoptive-Transfer Validation.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {10},
pages = {e71201},
doi = {10.1002/cns.71201},
pmid = {42865229},
issn = {1755-5949},
support = {82173262//National Natural Science Foundation of China/ ; 2024NSFSC1536//Sichuan Province Science and Technology Support Program/ ; },
mesh = {Animals ; Humans ; *Alzheimer Disease/immunology/metabolism/genetics/psychology ; *Sepsis/immunology/metabolism/genetics ; Male ; *Adoptive Transfer/methods ; Mice ; Oxidation-Reduction ; *Repressor Proteins/genetics/metabolism/immunology ; Mice, Transgenic ; Female ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Sepsis survivors face an elevated long-term risk of Alzheimer's disease (AD), yet the peripheral pathways linking systemic immune activation to chronic neurodegeneration remain undefined. We mapped peripheral immune reprogramming across sepsis and AD and tested a candidate regulatory node.

METHODS: A single-cell atlas of peripheral immunity was built by integrating scRNA-seq from human sepsis and AD cohorts, using clustering, SCENIC regulatory-network inference and an exploratory pseudotime ordering. The resulting signature was validated in two clinical cohorts (ROC and survival analysis). MAFG-associated subpopulations and redox status were profiled in APP/PS1, cecal ligation and puncture (CLP) and composite models, and causality was tested by lentiviral MAFG knockdown and adoptive transfer into APP/PS1 recipients.

RESULTS: Peripheral immunity was myeloid-skewed in sepsis and lymphoid-dominated in AD, with APP-expressing common myeloid progenitors (CMPs), dendritic cells (DCs), and platelets forming an APP-enriched compartment. A core transcription-factor network differed between disease states, yielding a four-gene signature (MAFG, NFIL3, RGS10, FOXO3) with cross-cohort diagnostic and prognostic value. MAFG was upregulated in septic patients and associated with poorer survival, subpopulation expansion, and systemic oxidative stress. Superimposed CLP aggravated amyloid deposition, microglial activation, and memory deficits in APP/PS1 mice, whereas MAFG silencing restored Aβ uptake and, on adoptive transfer, reduced amyloid burden, attenuated microgliosis, and preserved cognition.

CONCLUSIONS: Peripheral immune states differ across the sepsis-to-AD spectrum and are captured by a MAFG-centered signature. Independent of any trajectory assumption, loss-of-function and adoptive-transfer experiments identify MAFG as a causal, redox-sensitive node constraining peripheral Aβ clearance and a candidate biomarker and therapeutic target in sepsis survivors.},
}

Animals
Humans
*Alzheimer Disease/immunology/metabolism/genetics/psychology
*Sepsis/immunology/metabolism/genetics
Male
*Adoptive Transfer/methods
Mice
Oxidation-Reduction
*Repressor Proteins/genetics/metabolism/immunology
Mice, Transgenic
Female
Mice, Inbred C57BL

@article {pmid42865340,
year = {2026},
author = {Kamonnat, C and Thongdechsri, S and Kraokaew, P and Niamnont, N and Sobhon, P and Meemon, K},
title = {Protective Role of Holothuria leucospilota Extract Against Amyloid-β Toxicity via Autophagy and Antioxidant Mechanisms in Caenorhabditis elegans Model.},
journal = {Oxidative medicine and cellular longevity},
volume = {2026},
number = {1},
pages = {e1471919},
doi = {10.1155/omcl/1471919},
pmid = {42865340},
issn = {1942-0994},
support = {//National Research Council of Thailand/ ; N42A660511//Mahidol University/ ; AN-KME-3-66-02//Central Instrument Facility (CIF)/ ; },
mesh = {Animals ; *Caenorhabditis elegans/drug effects/metabolism ; *Amyloid beta-Peptides/toxicity/metabolism ; *Autophagy/drug effects ; *Antioxidants/pharmacology ; *Holothuria/chemistry ; Oxidative Stress/drug effects ; Disease Models, Animal ; Reactive Oxygen Species/metabolism ; *Plant Extracts/pharmacology ; Caenorhabditis elegans Proteins/metabolism ; Alzheimer Disease/drug therapy ; Animals, Genetically Modified ; },
abstract = {Alzheimer's disease (AD) is a major global health challenge characterized by cognitive decline and neuronal degeneration driven by amyloid-β (Aβ) aggregation and oxidative stress. Given the limited efficacy and adverse effects of current pharmacological therapies, food-derived bioactive compounds have gained increasing attention as potential preventive strategies against neurodegenerative disorders. In this study, we investigated the neuroprotective effects of Holothuria leucospilota extracts using a transgenic Caenorhabditis elegans model of AD. Our results demonstrated that H. leucospilota hexane extract (HLHE) at 500 µg/mL significantly delayed Aβ-induced paralysis and improved chemotaxis behavior. Consistently, HLHE treatment reduced Aβ deposition and decreased both high- and low-molecular weights of Aβ oligomers, as determined by automated Western blot analysis. Additionally, HLHE also reduced reactive oxygen species (ROS) levels. Transcriptomic and RT-qPCR analyses revealed that HLHE enhanced autophagic activity through the upregulation of bec-1 (autophagy initiation) and lysosomal genes (cpr-1, cpr-2, and cpr-5). Furthermore, HLHE activated antioxidant defense pathways via the insulin/IGF-1 signaling (IIS) axis, specifically upregulating genes associated with SKN-1 pathway (pmk-1, skn-1, gst-4, and gst-10) and HSF-1 pathway (hsf-1, hsp-16.1, hsp-12.6, and mtl-1). HLHE also promoted nuclear localization of SKN-1 and increased expression of its downstream target gst-4. Chemical analysis revealed that HLHE contained arachidonic acid (21.12%) and other bioactive lipid compounds as major constituents, suggesting a synergistic role in promoting autophagy and antioxidant responses. Collectively, this study suggests that HLHE confers neuroprotection against Aβ-induced toxicity by activating autophagy and oxidative stress defense mechanisms, supporting its potential development as a food-derived preventive or therapeutic agent for AD.},
}

Animals
*Caenorhabditis elegans/drug effects/metabolism
*Amyloid beta-Peptides/toxicity/metabolism
*Autophagy/drug effects
*Antioxidants/pharmacology
*Holothuria/chemistry
Oxidative Stress/drug effects
Disease Models, Animal
Reactive Oxygen Species/metabolism
*Plant Extracts/pharmacology
Caenorhabditis elegans Proteins/metabolism
Alzheimer Disease/drug therapy
Animals, Genetically Modified

@article {pmid42865478,
year = {2026},
author = {Li, L and Sun, N and Chen, S and Yang, S and Li, H and Li, Q and Zhong, K and Yan, J},
title = {Effect of age-friendly community degree on the cognitive function of older adults.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1927936},
pmid = {42865478},
issn = {1664-0640},
abstract = {INTRODUCTION: The relationship between individual environmental indicators and the physical and mental health of older adults has been widely studied. However, the holistic impact of age-friendly communities on the wellbeing of older adults has not beenclearly elucidated. This study aimed to explore the correlation between the degree of community friendliness and cognitive function of older adults and provide scientific evidence for healthy aging.

METHODS: This cross-sectional study enrolled 450 residents aged ≥60 years with cognitive impairment in Ningbo, Zhejiang Province, from June to September 2024. Participants provided personal demographic data, and their community's age-friendly status and cognitive function were assessed using the Age-Friendly Community (AFC) Evaluation Scale and the Alzheimer's Disease 8 Questionnaire. A multivariate logistic regression analysis was performed to examine the relationship between demographic characteristics and cognitive function of the older adults.

RESULTS: Among the five dimensions of the AFC evaluation scale, community participation scored the highest at 3.56 ±' 1.21 points. Multivariate linear regression analysis revealed that personal demographic factors (age, sex, education level, economic status, housing conditions, alcohol consumption, and chronic diseases) significantly infiuenced cognitive function (all P < 0.05). Furthermore, residential environment, transportation, and community environment were identified as significant predictors of cognitive impairment (all P < 0.05).

DISCUSSION: Low scores in residential environment, transportation, community environment, and social inclusion in AFC are independent risk factors for cognitive dysfunction. Measures to enhance community age-friendly environments could help improve the cognitive function of older adults.},
}

@article {pmid42865480,
year = {2026},
author = {Li, SY and Zhang, JX and Huang, LZ and Wu, HB and Ye, YB and Liu, A and Chen, J and Lai, S},
title = {Efficacy and safety of lecanemab monoclonal antibody in the treatment of mild to moderate Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1947129},
pmid = {42865480},
issn = {1663-9812},
abstract = {BACKGROUND: Lecanemab is a novel therapy for Alzheimer's disease (AD), but comprehensive evidence is lacking. This systematic review and meta-analysis evaluated the efficacy and safety in AD.

METHODS: Registered in PROSPERO (CRD420251146867). PubMed, Embase, Cochrane Library, Web of Science, and Scopus were searched for English-language RCTs. Efficacy and safety were evaluated using the risk difference with a Mantel-Haenszel fixed-effects model. Study quality and sensitivity were assessed using Cochrane risk-of-bias and leave-one-out methods. Primary outcomes: mean changes in Alzheimer's Disease Composite Score (ADCOMS), Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and amyloid burden on positron emission tomography (PET). Secondary: adverse events including amyloid-related imaging abnormalities with edema (ARIA-E), ARIA with hemorrhage (ARIA-H), death, treatment-emergent adverse events (TEAEs), headache, dizziness, and urinary tract infection.

RESULTS: A total of five articles involving 8 clinical trials were included. Based on the fixed-effect model, lecanemab treatment significantly improved cognitive performance on ADCOMS (SMD -0.1999, 95% CI [-0.2831, -0.1167], I[2] = 0%, P < 0.00001), CDR-SB (SMD -0.1853, 95% CI [-0.2683, -0.1024], I[2] = 0%, P < 0.0001), ADAS-Cog (SMD -0.1821, 95% CI [-0.2670, -0.0973], I[2] = 0%, P < 0.0001) and amyloid burden on PET (SMD -1.1872, 95% CI [-2.2474, -0.1270], I[2] = 96%, P = 0.03). Sensitivity analysis indicated stability. However, lecanemab was associated with an increased risk of TEAEs (MH RR 1.0730, 95% Cl [1.0296, 1.1183], I[2] = 0%, P = 0.0008) and an increased risk of headache (MH RR 1.3617, 95% Cl [1.0243, 1.8103], I[2] = 0%, P = 0.03). Sensitivity analysis indicated that both results were stable. The lecanemab group showed no significant differences in the risks of death, dizziness, or urinary tract infection compared with the control group. In addition, the lecanemab group showed a significantly increased risk of ARIA-E (MH RR 5.9948, 95% CI [3.9047, 9.2037], I[2] = 86%, P < 0.00001) and ARIA-H (MH RR 1.7490, 95% CI [1.3896, 2.2014], I[2] = 41%, P < 0.00001). Sensitivity analyses confirmed the stability of the TEAE finding, while the headache result should be interpreted with caution due to the limited number of studies. After excluding Honig et al. (OLE) 2021 via leave-one-out, results became stable, likely due to its open-label design.

CONCLUSION: Lecanemab slowed cognitive decline versus placebo in mild-to-moderate AD by ADCOMS, CDR-SB, and ADAS-Cog. High heterogeneity in PET amyloid burden warrants future RCTs. Nevertheless, lecanemab was associated with an increased risk of TEAEs and headache.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251146867.},
}

@article {pmid42865534,
year = {2026},
author = {Li, J and Xiang, X and Long, S and Hu, F and Ding, F},
title = {Association of temporal and masseter muscle thickness with cognitive function and clinical severity in Alzheimer's disease: a retrospective study.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1905634},
pmid = {42865534},
issn = {1662-4548},
abstract = {BACKGROUND: Temporal muscle thickness (TMT) has emerged as an imaging marker of skeletal muscle status and may be associated with cognitive decline in Alzheimer's disease (AD). However, its relationship with AD severity remains unclear, and the clinical relevance of masseter muscle thickness (MMT) is unknown.

OBJECTIVE: To evaluate the associations of TMT and MMT with cognitive function and disease severity in AD.

METHODS: This retrospective study included 242 patients with AD between December 2023 and April 2025. TMT and MMT were measured on axial T1-weighted MRI, cognitive function was assessed using standardized neuropsychological tests, and disease severity was determined by Clinical Dementia Rating (CDR).

RESULTS: The intraclass correlation coefficients (ICC) for the mean TMT and MMT were 0.868 and 0.896, respectively, indicating good consistency. As the severity of AD progresses, TMT tends to be thinner in severe AD than in mild AD. Spearman's correlation analysis revealed that both TMT and MMT were correlated with the Mini-Mental State Examination (MMSE) and CDR. After adjusting for various confounding factors using ordered logistic regression and multiple linear regression, TMT was found to be independently associated with AD severity (OR: 0.424, 95% CI: 0.290-0.618, p < 0.001) and positively correlated with MMSE scores. MMT showed only a weak independent association with CDR staging (OR: 0.830, 95% CI: 0.724-0.952, p = 0.008), while no significant correlation was observed with the MMSE. Stratified analysis revealed that the TMT maintained a consistent association in both male and female patients, whereas the MMT achieved statistical significance only in females in ordered logistic regression; all other findings were not statistically significant.

CONCLUSION: Temporal muscle thickness is associated with cognitive impairment and clinical severity in patients with AD and may serve as a simple, noninvasive imaging marker; in contrast, the independent associations of MMT with disease severity were weak and sex-specific, suggesting that its clinical utility may be limited and requires further validation.},
}

@article {pmid42865621,
year = {2026},
author = {Tan, W and Han, X and Wang, X and Tang, M and Li, S and Liu, H and Zhang, J and Wang, J and Liu, G},
title = {Multimodal MRI to elucidate cross-organ coupling mechanisms of the heart-brain axis.},
journal = {Frontiers in cardiovascular medicine},
volume = {13},
number = {},
pages = {1914265},
pmid = {42865621},
issn = {2297-055X},
abstract = {Cardiovascular and cerebrovascular diseases (CCVDs) are leading causes of mortality and disability worldwide, and their development is closely linked to bidirectional interactions between the heart and the brain. The heart-brain axis, a systemic framework that integrates neural, humoral, and inflammatory pathways, provides an important theoretical basis for understanding heart-brain comorbidities. With continuous advances in magnetic resonance imaging(MRI), research in this field has progressively shifted from the traditional single-organ diagnostic model to cross-organ and system-oriented strategies for prevention and management. Centered on cardiac magnetic resonance (CMR) and brain MRI, and complemented by quantitative, diffusion, functional, ultra-high-field, and metabolic imaging techniques, multimodal MRI has become a powerful tool for comprehensively characterizing myocardial remodeling, alterations in brain networks, and their coupling relationships. These techniques have been widely applied in studies of representative heart-brain comorbidities, including cardiac dysfunction associated with acute brain injury, cognitive impairment related to heart failure, and cardiovascular abnormalities associated with neurodegenerative diseases, such as Alzheimer's disease (AD). Such studies have not only revealed structural and functional alterations in the heart and brain but have also provided important insights into potential mechanisms, including autonomic imbalance, neuroendocrine activation, and inflammatory responses. However, current heart-brain axis research remains largely based on correlational analyses, whereas causal inference and characterization of dynamic mechanisms remain insufficient. In addition, significant challenges persist in multimodal data integration and clinical translation. Overall, MRI is driving heart-brain axis research from structural characterization toward mechanistic investigation. In the future, integrating imaging, physiological, and genetic information may enable early identification, risk stratification, and precision intervention for heart-brain comorbidities, thereby promoting a transition in medical practice from single-organ management to systemic prevention and treatment.},
}

@article {pmid42865655,
year = {2026},
author = {Contreras, JA and Ortega, NE and Jones, R and Thorpe, RJ and Hayes, CA},
title = {Plasma p-tau181 moderates the association between ten-year atherosclerotic cardiovascular disease risk and mild cognitive impairment - HABS-HD.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1870150},
pmid = {42865655},
issn = {1663-4365},
abstract = {INTRODUCTION: This study examined cross-sectional associations between ten-year American Heart Association (AHA) atherosclerotic cardiovascular disease (ASCVD) risk and plasma Alzheimer's disease (AD) biomarkers in relation to cognitive outcomes and to determine whether ASCVD risk modifies biomarker-cognition relationships.

METHODS: Baseline data were analyzed from cognitively unimpaired and mild cognitive impaired (MCI) participants enrolled in the Health and Aging Brain Study-Health Disparities (HABS-HD), a large, community-based cohort enriched for racial and ethnic diversity. Plasma biomarkers included amyloid-β42/40 (Aβ42/Aβ40), phosphorylated tau (p-tau181 and p-tau217), and neurofilament light (NfL). Ten-year ASCVD risk was calculated using pooled cohort equations. Multivariable logistic regression models examined associations of ten-year ASCVD risk and plasma biomarkers with MCI, while multivariable linear regression models evaluated associations with Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) Sum of Boxes scores. Separate models were constructed for Aβ42/40, p-tau217, p-tau181, NfL, and apolipoprotein (APOE) ε4 carrier status, and analyses were stratified by race and ethnicity. ASCVD × biomarker interaction terms were tested to evaluate effect modification.

RESULTS: Increased ten-year ASCVD risk was consistently associated with increased odds of MCI, ranging from OR = 2.62 (95% CI: 1.31-5.17) to OR = 4.22 (95% CI: 2.04-8.64), lower MMSE scores, ranging from β = -1.90 (95% CI: -2.62 to -1.18) to β = -2.56 (95% CI: -3.30 to -1.82), and increased CDR Sum of Boxes scores, ranging from β = 0.28 (95% CI: 0.09-0.46) to β = 0.39 (95% CI: 0.20-0.58). The ASCVD × p-tau181 interaction was significant for MCI (OR = 1.91; 95% CI: 1.26-2.95) and CDR Sum of Boxes (β = 0.27; 95% CI: 0.16-0.39). ASCVD associations with CDR Sum of Boxes ranged from β = 0.11 (95% CI: -0.08 to 0.30) to β = 0.24 (95% CI: 0.04-0.43) among non-Hispanic White participants, β = 0.80 (95% CI: 0.10-1.51) to β = 1.17 (95% CI: 0.49-1.86) among non-Hispanic Black participants, and β = 0.36 (95% CI: 0.08-0.65) to β = 0.52 (95% CI: 0.25-0.80) among Hispanic participants.

CONCLUSION: Greater ten-year ASCVD risk was consistently associated with cognitive impairment independent of plasma AD biomarkers, with evidence that p-tau181 modifies these associations and that their magnitude varies across racial and ethnic groups.},
}

@article {pmid42865677,
year = {2026},
author = {Wahbeh, H and Cooley, S and Chamberlin, SR and Brophy, T and Hameroff, S},
title = {Home-administered unfocused transcranial ultrasound in subjective cognitive decline and dementia: an open-label, uncontrolled feasibility pilot study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1937897},
pmid = {42865677},
issn = {1663-4365},
abstract = {BACKGROUND: Memory and cognitive impairments remain disabling, with few effective treatments. Low-intensity transcranial ultrasound (TUS) is a non-invasive neuromodulation approach with a favorable safety profile and preliminary evidence of cognitive benefit, with one hypothesized but unproven mechanism involving microtubule resonance and reassembly.

OBJECTIVES: This open-label pilot study evaluated the safety and preliminary efficacy of the US Pro2000 unfocused ultrasound device in adults with memory or cognitive difficulties, a sample spanning subjective cognitive decline among self-administering participants to diagnosed dementia among caregiver-rated recipients, and described self-reported symptom trajectories.

METHODS: In a within-participant design, adults with self-reported cognitive impairment, or their caregivers, applied the device at the right temporal window for 5 min three times daily (target 15 min/day), in cycles of 3 weeks on and 1 week off. Outcomes (GAD-7, CESD-5, Inoue battery, and caregiver-rated MDS 3.0) and adverse events were collected online. Mixed-effects models with age and device-use covariates assessed change over time, with False Discovery Rate correction within aim.

RESULTS: Twenty-seven participants enrolled and 26 initiated treatment. Across 2,174 daily assessments, no serious or unanticipated adverse events occurred; only headache (15.4%) and transient jaw clenching (3.8%) were possibly related, and none caused discontinuation. Among self-administered participants, depression (CESD-5) declined significantly (p_FDR = 0.016) and five of eight monthly self-report symptoms improved, including memory, word-finding, and problem-solving (all p_FDR ≤ 0.040); anxiety trended downward, and the objective cognitive battery, near ceiling at baseline, did not change. Caregiver-rated outcomes were stable. Device use showed no dose response, and sensitivity analyses were consistent.

CONCLUSION: Home-based self-administered low-intensity TUS was well tolerated, with only mild transient events, although adverse-event ascertainment relied on unblinded self-report and relatedness judgments were made by unblinded investigators. Efficacy signals were confined to self-report, while objective cognition and caregiver ratings were unchanged. The uncontrolled design, small subgroups, and reliance on self-report preclude causal inference. These findings support the safety and feasibility of TUS and justify an adequately powered, double-blind, sham-controlled trial.},
}

@article {pmid42865723,
year = {2026},
author = {Pascual-Lucas, M and Sarasa, L and Fandos, N and Loscos, J and Romero, J and Sánchez, A and Terencio, J and Ortega-Madueño, I and Cárdenas, MC and Cava-Valenciano, F and Gil-Moreno, MJ and Matias-Guiu, JA and Allué, JA},
title = {Plasma biomarker strategies to reduce diagnostic uncertainty in p-tau217-based assessment of CSF amyloid positivity in secondary-care patients with MCI.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1918304},
pmid = {42865723},
issn = {1663-4365},
abstract = {INTRODUCTION: Plasma p-tau217 accurately reflects amyloid pathology, but dual-cutoff strategies leave a non-negligible grey zone requiring confirmatory testing. We evaluated whether integrating plasma Aβ measurements could reduce diagnostic uncertainty in patients with mild cognitive impairment (MCI).

METHODS: Plasma p-tau217 was measured using the Lumipulse platform, and plasma Aβ40 and Aβ42 were quantified by liquid chromatography-mass spectrometry (ABtest-MS) in 186 secondary-care MCI patients. CSF Aβ42/Aβ40 defined amyloid status. Logistic regression models were compared, and dual-cutoff strategies targeting 95% predictive values were applied.

RESULTS: p-tau217 was the strongest individual biomarker. Models incorporating plasma Aβ measures improved AUC, model fit, and reduced the grey zone from 27.4% with p-tau217 alone to 12.3%. A sequential two-step strategy restricted additional Aβ testing to p-tau217-indeterminate cases and reduced the final grey zone to 13.4%.

DISCUSSION: Plasma Aβ measurements complement p-tau217 by reducing the indeterminate results, with the potential to improve diagnostic efficiency and streamline diagnostic workflows.},
}

@article {pmid42865737,
year = {2026},
author = {Moreno, MDMM and Celis, K and Rajabli, F and Whitehead, PL and Hamilton-Nelson, KL and Dykxhoorn, DM and Nuytemans, K and Mesulam, MM and Bennett, DA and Schuck, T and Weintraub, S and Geula, C and Gearing, M and Alba, C and Dalgard, CL and Davis, DA and Scott, WK and Haines, JL and Pericak-Vance, MA and Griswold, AJ and Vance, JM and Young, JI},
title = {Unraveling changes in mitochondrial processes influenced by ancestry in APOEε4 carriers with Alzheimer disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1888862},
pmid = {42865737},
issn = {1663-4365},
abstract = {INTRODUCTION: The APOEε4 allele is the strongest known genetic risk factor for late-onset Alzheimer disease (AD). However, the risk effect of APOEε4 varies substantially by ancestry, with individuals of African ancestry (AF) demonstrating markedly lower risk compared to those of European ancestry (EU). This difference in risk is associated with distinct levels of APOE gene expression. Here, we investigate whether mitochondrial processes in brain cells are also influenced by ancestry in AD APOEε4 carriers, potentially contributing to the observed risk differences.

METHODS: Single nuclei RNA sequencing was performed on frontal cortex from 17 AD patients homozygous for APOEe4 with either African Local Ancestry (AF-LA; N = 7) or European Local Ancestry (EU-LA; N = 10). Differential gene expression was compared between AF and EU samples, with particular focus on mitochondrial pathways. Differential expression and functional enrichment analyses were performed using MAST and PathFindR, respectively. MitoXplorer was used to identify differential mitochondrial processes, while REACTOME facilitated the building of regulatory networks.

RESULTS: Multiple cell types and biological processes contribute to the differences in APOEe4 risk seen between individuals of AF and EU ancestry. AF astrocytes show a less reactive phenotype and L6 and L5/6 excitatory neurons appear to be less vulnerable in AF compared to EU samples. Mitochondrial alterations were more pronounced in EU-LA APOEe4 AD carriers relative to their AF counterparts. Cells highly expressing APOE (astrocytes, microglia, and vascular leptomeningeal cells) showed increased expression of mitochondrial genes, particularly in EU-LA samples. We observed increased expression of pro-apoptotic, oxidative phosphorylation, and mitophagy-related genes in EU samples. Regulatory network analysis identified the transcription factor PPARG as a potential mediator linking APOEε4 expression to mitochondrial gene programs in a cell-type- and ancestry-dependent manner.

CONCLUSION: Our snRNA-seq analysis demonstrates that ancestry-linked regulation of APOEε4 expression influences mitochondrial transcriptome and astrocyte activation in AD. The stronger APOE-PPARG-mitochondrial gene coupling in EU ancestry particularly in astrocytes may underlie increased AD risk, while AF ancestry confers partial decoupling of these pathways. These results underscore the importance of considering ancestry in AD research and suggest that precision therapeutic strategies targeting mitochondrial and glial pathways should account for APOE local ancestry.},
}

@article {pmid42865788,
year = {2026},
author = {Cacciotti, A and Fabbrocino, A and Pappalettera, C and Ginatempo, F and Loi, N and Sottana, D and Deriu, F and Rossini, PM and Vecchio, F},
title = {Electroencephalographic complexity and cognitive decline: Insights from approximate entropy across aging and dementia.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {4},
pages = {e70284},
pmid = {42865788},
issn = {2352-8737},
abstract = {INTRODUCTION: Physiological aging involves gradual modifications of brain activity patterns sometimes leading to pathological outcomes. Understanding changes in brain signal complexity from healthy aging to mild cognitive impairment (MCI) and Alzheimer's disease (AD) may provide insights into cognitive decline and support early diagnosis.

METHODS: Electroencephalography (EEG) data were collected from 269 participants divided into three groups: healthy elderly (HE, n = 109), MCI (n = 75), and AD (n = 85). Approximate entropy (ApEn) was computed for the total EEG spectrum and frequency bands. A random forest classifier with a one-versus-one strategy and recursive feature elimination (RFE) was used for group discrimination. Additionally, group comparisons and correlations with neuropsychological scores were performed to further investigate the functional relevance of these entropy changes by assessing their association with cognitive and functional performance.

RESULTS: Significant group differences in total ApEn were found, particularly in central brain regions, with progressive decreases from HE to MCI and AD. Frequency-specific patterns emerged: (1) delta ApEn was increased in those with AD across the scalp; (2) alpha 1 ApEn showed frontal decreases and occipital increases in the AD group, with an intermediate pattern in MCI; (3) gamma ApEn was markedly reduced in those with AD compared to both HE and MCI groups, with central and frontal localization, and extended occipital differences in those with MCI versus AD. The classifier achieved 66.55% accuracy, with sensitivities of 78.90% (HE), 49.33% (MCI), and 65.88% (AD). Positive correlations were found between ApEn and cognitive scores in both the total EEG spectrum and gamma band; conversely, delta and alpha 1 ApEn showed negative correlations with cognitive and functional scores.

DISCUSSION: The distinct entropy patterns observed across frequency bands and scalp/brain regions may help characterize electrophysiological changes associated with cognitive decline and AD.},
}