@article {pmid42764825,
year = {2026},
author = {Chen, HW},
title = {Operator-Driven Active Craniospinal Tensioning (ACT) Device for Non-ambulatory Application.},
journal = {Cureus},
volume = {18},
number = {8},
pages = {e114854},
pmid = {42764825},
issn = {2168-8184},
abstract = {Active craniospinal tensioning (ACT) is an upright-posture axial spinal traction maneuver hypothesized to couple two mechanisms: dural pull-recoil, a cerebrospinal fluid (CSF) pressure-gradient effect shared with the supine technique pelvis-stabilized axial spinal traction (PSAST), and suboccipital venous occlusion-rebound, proposed to promote central nervous system (CNS) venous and lymphatic drainage, and as a distinct modality for cerebral venous preconditioning (CVPC). The CVPC mechanism depends on upright posture. In the upright position, cerebral venous return preferentially routes through the suboccipital venous plexus rather than the internal jugular veins, allowing the ACT strap to transiently occlude this outflow pathway during the hold and produce a hemodynamic rebound upon release. This CVPC-based rationale for choosing ACT over PSAST, along with the full biomechanical model, was developed in prior papers and is not re-derived here. In its originally described form, ACT is participant-driven: the participant voluntarily squats against a fixed overhead strap secured by a simple anchor, and the participant's own hands close the strap loop as a fail-safe. This report refers to that form, and the strap-and-anchor apparatus that delivers it, as active craniospinal tensioning, self-administered (ACT-SA). ACT-SA's delivered craniocervical junction (CCJ) tension depends on the participant fully relaxing into the maneuver. It categorically excludes non-ambulatory participants with advanced neurodegenerative disease, e.g., Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), who cannot generate or safely control a voluntary squat, yet who may stand to benefit most from craniospinal tensioning and CVPC given their disease-associated glymphatic impairment. This report describes active craniospinal tensioning, operator-driven (ACT-OD), a device that reproduces ACT-SA's anchor geometry, target force range, and hold duration while substituting the source of tensioning force. Rather than gravity acting on a squatting participant's own body mass, tension is generated by a practitioner operating a pulley-and-lever mechanism against a stationary, seated participant, with the strap confined near the forehead by a polyvinyl chloride (PVC) pipe rather than closed by the participant's own hands. Because the participant does nothing and the seated default state carries no CCJ tension, the fail-safe ACT-SA requirement becomes unnecessary; disengagement, not engagement, is ACT-OD's default. Freed from managing the strap, the practitioner can devote full attention to the lever and to continuous observation of the participant's response, a substitution that matters because non-verbal or cognitively impaired participants cannot reliably self-report the presyncopal symptoms that serve as ACT-SA's real-time safety signal. The design is offered without patent restrictions for research and clinical replication. This report presents device design and mechanism only, with no clinical outcome or efficacy data.},
}

@article {pmid42764861,
year = {2026},
author = {Qin, F and Zhang, N and Jiang, Y and Xu, K and Xiong, Y and Liu, Y and Ouyang, Q and Liu, H and Dai, Y and Jiang, L and Zhao, Y and Li, H and Wang, L and Chen, Y and Hu, L and Bu, Q and Zhao, Y and Kuang, W and Qin, M and Cen, X},
title = {Neutrophil-mediated BDNF delivery for the treatment of moderate to severe Alzheimer's disease.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {9},
pages = {6185-6202},
pmid = {42764861},
issn = {2211-3835},
abstract = {Alzheimer's disease (AD), especially its moderate-to-severe stage (MSAD), remains a global health challenge with no disease-modifying therapies. Here, we identified a dual pathological signature in MSAD patients and murine models: a systemic pro-inflammatory milieu and critically reduced brain-derived neurotrophic factor (BDNF) levels in both the hippocampus and serum. To mitigate the decrease in BDNF, we developed an engineered neutrophil capsule, in which neutrophils carrying lipid nanoparticles encapsulating BDNF penetrated the brain and ameliorated cognitive capacity deficits in MSAD mice. The pro-inflammatory state in the MSAD brain facilitated neutrophil passage through the blood-brain barrier, and inflammatory mediators triggered the release of BDNF from the engineered neutrophils. Collectively, our findings show that engineered neutrophil-mediated brain delivery of BDNF efficiently reduces the amyloid-β plaque deposition in the hippocampus, leading to significantly improved learning and memory in MSAD mice. This study establishes neutrophil-mediated delivery as a paradigm strategy for MSAD, merging cell biology with nanotechnology to reverse neurodegeneration.},
}

@article {pmid42764944,
year = {2026},
author = {Heidarian, S and Faizi, M and Alemi, M and Garmabdari, A and Nikray, N and Khoramjouy, M and Hajimahdi, Z and Zarghi, A},
title = {Design, Synthesis, Molecular Dynamics Analysis, and Biological Evaluation of New Urea Derivatives in an Animal Model of Alzheimer Disease.},
journal = {Iranian journal of pharmaceutical research : IJPR},
volume = {25},
number = {1},
pages = {e172672},
pmid = {42764944},
issn = {1726-6890},
abstract = {BACKGROUND: Alzheimer disease (AD), first described by Alois Alzheimer more than a century ago, remains a major global health challenge. Glycogen synthase kinase-3β (GSK-3β) plays an important role in AD pathophysiology. Dysregulation of GSK-3β is associated with beta-amyloid accumulation, tau hyperphosphorylation, neurodegeneration, and cognitive impairment.

OBJECTIVES: This study aimed to design and synthesize 17 arylalkyl urea derivatives as GSK-3β inhibitors and evaluate them in an animal model of AD.

METHODS: New arylalkyl derivatives were designed on the basis of the pharmacophores of GSK-3β inhibitors. Molecular docking and molecular dynamics simulations were used to evaluate the interactions of the designed compounds within the ATP-binding pocket of GSK-3β. The compounds were then synthesized by reacting substituted anilines with benzyl isocyanate, and their structures were confirmed by infrared spectroscopy, nuclear magnetic resonance spectroscopy, and liquid chromatography-mass spectrometry. The radial arm water maze was used to assess the effects of a selected compound on learning and memory deficits in an intracerebroventricular streptozotocin-induced rat model of sporadic Alzheimer-like disease.

RESULTS: Structure-activity relationship analysis indicated that variations in the R1 and R2 substituents played a crucial role in modulating GSK-3β inhibitory activity. Docking studies demonstrated that all novel derivatives fit well within the active site, with Val135 and Lys85 contributing prominently to ligand stabilization. On the basis of the docking results, compound 3b was selected for behavioural testing. Compound 3b significantly ameliorated spatial learning and memory deficits in a rat model of AD.

CONCLUSIONS: Compound 3b emerged as a promising lead in this series, combining favorable GSK-3β binding properties with robust cognition-enhancing effects in vivo. These findings may inform therapeutic design, clinical translation, and strategic development in the evolving field of AD drug discovery.},
}

@article {pmid42764999,
year = {2026},
author = {D'Amelio, C and Autelitano, S and Natale, F and Rinaudo, M and Fusco, S and Grassi, C},
title = {Differences in retroactive interference response reveal sex-specific memory resilience in pre-symptomatic triple transgenic Alzheimer's disease mice.},
journal = {Brain communications},
volume = {8},
number = {5},
pages = {fcag345},
pmid = {42764999},
issn = {2632-1297},
abstract = {Alzheimer's disease is a neurodegenerative disorder characterized by memory loss dependent on hippocampal and parahippocampal cortex dysfunction. However, recent evidence shows that patients with mild cognitive impairment progressing to Alzheimer's disease can exhibit early symptoms when assessed with more nuanced memory tests, such as those evaluating memory vulnerability to interference. Here, we characterize how sex and genotype shape the response to retroactive interference in triple-transgenic Alzheimer's disease mice at an early stage of the phenotype, when overt memory deficits are not yet present. Wild-type females were the only group resisting interference: transgenic females failed to discriminate despite normal recognition memory, irrespective of the moment during which retroactive interference was experienced, and males of both genotypes were similarly impaired at every time point tested. Both context change and increased memory strength restored discrimination in transgenic females and wild-type males, suggesting that their susceptibility depends on overlapping hippocampal representations. Transgenic males, by contrast, remained impaired when interference occurred in a different context and showed only a limited improvement after multiple training, pointing to a larger contribution of interference-induced memory decay. Overall, our data characterize the response to retroactive interference as a sex-dependent behavioural readout of early memory instability in a preclinical model of Alzheimer's disease.},
}

@article {pmid42765029,
year = {2026},
author = {Hyun, J and Jung, S and Noh, Y and Cho, Y and Saido, TC and Nah, J and Kim, KW and Jung, YK},
title = {eNAMPT-IFITM3 axis links neuroinflammation to γ-secretase activation.},
journal = {iScience},
volume = {29},
number = {10},
pages = {117496},
pmid = {42765029},
issn = {2589-0042},
abstract = {Amyloid-β (Aβ) accumulation and neuroinflammation are central features of Alzheimer's disease (AD), yet the molecular link connecting inflammatory signaling to γ-secretase activation remains poorly understood. Here, using a cell-based gain-of-function screen with a cDNA library, we identify nicotinamide phosphoribosyltransferase (NAMPT) as a positive regulator of γ-secretase activity. We demonstrate that extracellular NAMPT (eNAMPT) acts as a paracrine factor binding to cell-surface interferon-induced transmembrane protein 3 (IFITM3), enhancing its protein stability and promoting γ-secretase complex assembly to heighten amyloidogenic processing, independently of its NAD+ biosynthetic function. Pathologically, NAMPT levels are elevated in patients with AD and mouse models. Furthermore, systemic inflammation induced by lipopolysaccharide (LPS) enhances NAMPT expression and promotes the NAMPT-IFITM3 interaction and γ-secretase complex assembly in vivo, whereas NAMPT neutralization with an antibody suppresses LPS-induced γ-secretase activation. These findings establish the eNAMPT-IFITM3 axis as a key molecular link bridging neuroinflammation and γ-secretase-mediated AD pathology.},
}

@article {pmid42765175,
year = {2026},
author = {Liu, H and Yin, Z and Ye, Z and Xu, H},
title = {Identification of Gene Signatures and Molecular Mechanisms Underlying the Comorbidity of Alzheimer's Disease and Crohn's Disease Using Machine Learning.},
journal = {Psychiatry investigation},
volume = {},
number = {},
pages = {},
doi = {10.30773/pi.2026.0214},
pmid = {42765175},
issn = {1738-3684},
abstract = {OBJECTIVE: Alzheimer's disease (AD) and Crohn's disease (CD) both involve inflammation and immune dysregulation, yet the potential molecular mechanisms underlying their comorbidity remain unclear.

METHODS: We integrated transcriptomic data from AD and CD patients and applied differential expression analysis, weighted gene coexpression network analysis, protein-protein interaction networks, and multiple machine learning approaches to identify key comorbidity genes. Functional enrichment, single-cell sequencing validation, and virtual knockout analyses were used to explore their biological roles. Molecular docking was performed to evaluate the binding affinity of candidate small-molecule drugs to the identified core genes.

RESULTS: CXCL1 and IGFBP5 were identified as core comorbidity genes. CXCL1 was associated with inflammatory signaling, including cytokine receptor binding, neutrophil migration, and NOD-like receptor signaling. IGFBP5 was linked to growth factor binding, smooth muscle cell proliferation, and extracellular matrix-receptor interactions. Single-cell and virtual knockout analyses indicated that these genes play pivotal roles in inflammation, immune regulation, cell migration, and tissue remodeling, potentially bridging central and peripheral inflammation via the gut-brain axis and IgSF CAM signaling. Candidate drug prediction and molecular docking suggested that small molecules such as Dasatinib, Mifepristone, and Retinoic acid may modulate these pathways.

CONCLUSION: This study reveals the critical roles of CXCL1 and IGFBP5 in AD-CD comorbidity, providing a theoretical basis for exploring gut-brain axis mechanisms and potential targeted interventions.},
}

@article {pmid42765448,
year = {2026},
author = {Koychev, I and Rowe, JB and Amin, J and Arsland, D and Archer, H and Barber, R and Burns, A and Coulthard, E and Deasy, C and Dunne, R and Fox, N and Humphrey, SH and Jenkinson, J and Jones, D and Kennelly, S and Khan, F and Krishnan, MSP and Malhotra, P and McFarlane, B and McGuinness, B and Mummery, C and Pennington, C and Perry, JR and Raczek, G and Rasmussen, J and Ritchie, C and Taylor, JP and Underwood, BR and Venkataraman, AV and Raymont, V},
title = {Interpreting Evolving Evidence in Alzheimer's Disease: Implications for Dementia Clincians - CORRIGENDUM.},
journal = {The British journal of psychiatry : the journal of mental science},
volume = {},
number = {},
pages = {1},
doi = {10.1192/bjp.2026.10807},
pmid = {42765448},
issn = {1472-1465},
}

@article {pmid42765453,
year = {2026},
author = {van Wetering, J and van Ingen, MM and Timmermans, E and In't Veld, SGJG and Berendse, HW and Teunissen, CE and van de Berg, WDJ},
title = {Lysosomal Expression Profile in Plasma Associates with Disease Severity in Parkinson's Disease.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.70542},
pmid = {42765453},
issn = {1531-8257},
support = {//Stichting Woelse Waard/ ; grant P30 AG066515//Stanford Alzheimer's Disease Research Center NIH/NIA/ ; },
abstract = {BACKGROUND: Parkinson's disease (PD) is a clinically and biologically heterogeneous neurodegenerative disorder, driven by multiple mechanisms among which are lysosomal and mitochondrial dysfunction. Here, we explored blood-based lysosomal and mitochondrial profiles in relation to PD diagnosis and severity.

METHODS: Plasma samples (n = 504) were analyzed using SomaScan, targeting 394 lysosomal and 502 mitochondrial proteins in a discovery (ProPARK: 145 PD, 73 controls) and a validation cohort (Alzheimer's Disease Research Center [ADRC]: 104 PD, 182 controls). Linear and LASSO regression were included to compare groups and select PD-predictive proteins. Associations with Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr, Montreal Cognitive Assessment (MoCA), levodopa equivalent daily dose (LEDD) and disease duration were assessed and age-, sex-, and false discovery rate (FDR)-adjusted.

RESULTS: In ProPARK, 29 dysregulated lysosomal and 46 mitochondrial proteins were identified in PD; upregulated lysosomal sulfatase-modifying factor 1 (SUMF1) (FC = 1.41) and arrestin domain containing 3 (ARRDC3) (1.36) survived correction. LASSO identified eight lysosomal proteins (area under the curve [AUC] train: 0.83, test: 0.75) and two mitochondrial proteins (AUC train: 0.66, test: 0.65). Lysosomal score associated with disease duration, LEDD, and UPDRS-IV, whereas mitochondrial score did not. SUMF1 associated with disease duration, LEDD, and UPDRS-IV; ARRDC3 only with disease duration. In ADRC, upregulation of SUMF1 and ARRDC3 in PD (FC = 1.72 and 1.36), their association with LEDD, discriminatory AUCs of lysosomal and mitochondrial scores (0.80 and 0.58), and the association between lysosomal score and LEDD replicated.

CONCLUSIONS: Lysosomal expression scores discriminated PD from controls and associated with disease severity. SUMF1 and ARRDC3 emerged as blood-based biomarkers for PD. These findings support the use of pathway-specific biomarkers for improving PD diagnostics and monitoring disease progression. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.},
}

@article {pmid42765733,
year = {2026},
author = {Sheng, F and Yu, JM and Yang, Q and Jipei, R and Xie, WQ and Zhan, G and Zhang, Y and Zhang, LL},
title = {Integrating network pharmacology and experimental validation to uncover the mechanisms of Ganoderma lucidum in ameliorating neuroinflammation in Alzheimer's disease.},
journal = {The Journal of pharmacy and pharmacology},
volume = {78},
number = {9},
pages = {},
doi = {10.1093/jpp/rgag105},
pmid = {42765733},
issn = {2042-7158},
support = {82675242//National Natural Science Foundation of China/ ; 82304749//National Natural Science Foundation of China/ ; 82204728//National Natural Science Foundation of China/ ; SKLTCM202506//Open Research Project of Chinese Medicine Germplasm Resources Innovation and Effective Uses Key Laboratory of Sichuan Province/ ; },
mesh = {Animals ; *Reishi/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; Janus Kinase 2/metabolism ; Amyloid beta-Peptides/metabolism ; STAT1 Transcription Factor/metabolism ; *Neuroprotective Agents/pharmacology ; Molecular Docking Simulation ; Network Pharmacology ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Male ; *Anti-Inflammatory Agents/pharmacology ; Hippocampus/drug effects/metabolism ; Disease Models, Animal ; Microglia/drug effects/metabolism ; Macrophages/drug effects/metabolism ; Peptide Fragments/metabolism ; Molecular Dynamics Simulation ; Signal Transduction/drug effects ; },
abstract = {OBJECTIVES: This study aimed to explore the anti-neuroinflammatory mechanism of Ganoderma lucidum against Alzheimer's disease (AD) using network pharmacology and molecular docking, and verify its neuroprotective and anti-neuroinflammatory effects in Aβ1-42-induced AD mice.

METHODS: Common targets were screened and analyzed by KEGG/GO enrichment. Core targets were evaluated by molecular docking and dynamics simulation. Aβ1-42-induced AD mice and LPS-stimulated macrophages were used. Cognitive function, Aβ deposition, tau phosphorylation, and inflammatory gene expression were measured.

KEY FINDINGS: Network analysis highlighted inflammation-related pathways. Molecular dynamics simulations confirmed stable binding between active components and targets like STAT1, STAT3, JAK2, and TNF. In vivo, G. lucidum extract suppressed abnormal activation of microglia and astrocytes, and reduced pro-inflammatory factors. Following G. lucidum administration, mRNA levels of Jak2 and Stat1 in hippocampal tissue were significantly reduced, suggesting potential regulation of neuroinflammation via the JAK2/STAT1 pathway. Concurrently, G. lucidum down-regulated transcription of key subunits (Ncstn, Aph-1, Pen-2) in the γ-secretase complex, thereby reducing Aβ1-42 production. In vitro experiments similarly confirmed G. lucidum's ability to inhibit LPS-induced IL-6 and TNF-α release from macrophages.

CONCLUSIONS: Ganoderma lucidum extract alleviates neuroinflammation in AD models, providing experimental evidence for its potential application in AD prevention or therapy.},
}

Animals
*Reishi/chemistry
*Alzheimer Disease/drug therapy/metabolism
Mice
Janus Kinase 2/metabolism
Amyloid beta-Peptides/metabolism
STAT1 Transcription Factor/metabolism
*Neuroprotective Agents/pharmacology
Molecular Docking Simulation
Network Pharmacology
*Neuroinflammatory Diseases/drug therapy/metabolism
Male
*Anti-Inflammatory Agents/pharmacology
Hippocampus/drug effects/metabolism
Disease Models, Animal
Microglia/drug effects/metabolism
Macrophages/drug effects/metabolism
Peptide Fragments/metabolism
Molecular Dynamics Simulation
Signal Transduction/drug effects

@article {pmid42766035,
year = {2026},
author = {Nabizadeh, A and Rafati, A and Karbalaei, N and Namavar, MR and Hosseinzadeh, S and Jahromi, HM and Rahimi, A and Naseh, M},
title = {Correction: Probiotic effects on cognitive performance, hippocampal oxidative stress, and structural damage induced by icv STZ in Alzheimer-like rat model.},
journal = {Brain structure & function},
volume = {231},
number = {8},
pages = {},
doi = {10.1007/s00429-026-03195-5},
pmid = {42766035},
issn = {1863-2661},
}

@article {pmid42766053,
year = {2026},
author = {Gualco, L and Montobbio, N and Losa, M and Costagli, M and Massa, F and Orso, B and Argenti, L and Peira, E and Chincarini, A and Morbelli, S and Raffa, S and Sofia, L and Sambuceti, G and Lorenzini, L and Pravatà, E and Caulo, M and Pulze, M and Arnaldi, D and Diociasi, A and Zacà, D and Piredda, GF and Hilbert, T and Kober, T and Bozzali, M and Sormani, MP and Pardini, M and Roccatagliata, L},
title = {T1 mapping in Alzheimer's disease: a quantitative MRI study with amyloid-PET correlation.},
journal = {European radiology experimental},
volume = {10},
number = {1},
pages = {},
pmid = {42766053},
issn = {2509-9280},
support = {PNRR-MCNT2-2023-12377527 - CUP C13C23001070006//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; Female ; *Positron-Emission Tomography/methods ; *Magnetic Resonance Imaging/methods ; Aged ; Male ; Retrospective Studies ; *Amyloid/metabolism ; Cognitive Dysfunction/diagnostic imaging ; Aged, 80 and over ; },
abstract = {OBJECTIVES: Quantitative T1 mapping (qT1) is a magnetic resonance imaging (MRI) biomarker of brain microstructural changes; however, its application in Alzheimer disease (AD) remains limited. We compared cortico-limbic qT1 values between patients with AD and healthy controls (HCs) and examined their relationship with amyloid burden measured by amyloid-positron emission tomography (PET).

MATERIALS AND METHODS: We retrospectively identified subjects with mild cognitive impairment due to AD and HCs who underwent 3-T MRI, including a compressed-sensing MP2RAGE sequence, generating three-dimensional T1-weighted images and qT1 maps. Amyloid-PET was available for 16 patients. Hippocampal qT1 and volume were compared between groups, adjusting for age and sex; analyses were repeated after stratifying patients by Mini-Mental State Examination (MMSE). Voxel-wise group comparison was performed using SPM 12. The qT1-standardized uptake value ratio (SUVr) association was assessed with a linear mixed-effects model applied to voxel-level data, accounting for partial volume effects.

RESULTS: Thirty-three AD subjects, aged 69.3 ± 8.2 years (mean ± standard deviation), 18 females, and 22 HCs aged 70.5 ± 13.3 years, 15 females, were evaluated. Regional hippocampal qT1 was higher in AD (1,398 ± 53.0 ms versus 1,349 ± 53.4 ms; p = 0.002), without difference across cognitive subgroups stratified by MMSE. AD subjects exhibited increased qT1 in mesial temporal gray matter and temporo-parieto-occipital cortices (1,448 ± 55.7 ms versus 1,344 ± 51.6 ms; p < 0.001). Voxel-level modelling revealed a positive association between qT1 and amyloid-PET SUVr (p < 0.001; d = 0.223).

CONCLUSION: qT1 mapping can be sensitive to changes related to brain amyloidosis, supporting its role as a promising, noninvasive imaging biomarker in AD.

KEY POINTS: Question Can qT1 mapping detect AD-related microstructural changes in the cortico-limbic gray matter? Findings Participants with AD showed increased cortico-limbic qT1 values. A subtle yet consistent positive association was observed between cortical qT1 values and amyloid-PET SUVr. Relevance statement qT1 mapping captures microstructural tissue alterations related to amyloid pathology in Alzheimer's disease, supporting its role as a potential non-invasive imaging biomarker in this condition.},
}

Humans
*Alzheimer Disease/diagnostic imaging
Female
*Positron-Emission Tomography/methods
*Magnetic Resonance Imaging/methods
Aged
Male
Retrospective Studies
*Amyloid/metabolism
Cognitive Dysfunction/diagnostic imaging
Aged, 80 and over

@article {pmid42766082,
year = {2026},
author = {Reyes-Bueno, JA and Paredes-Pacheco, J and Muñoz-García, JB and Alfaro-Rubio, F and Ramos-Rodríguez, JR and Ariza, MJ and Rioja, J and García-Arnés, JA and García-Casares, N},
title = {White matter microstructural alterations associated with type-2 diabetes mellitus and mild cognitive impairment.},
journal = {Brain imaging and behavior},
volume = {20},
number = {5},
pages = {},
pmid = {42766082},
issn = {1931-7565},
support = {19/01375//Instituto de Salud Carlos III/ ; },
mesh = {Humans ; *Diabetes Mellitus, Type 2/diagnostic imaging/complications/psychology/pathology ; Female ; *Cognitive Dysfunction/diagnostic imaging/psychology/pathology ; Male ; Cross-Sectional Studies ; *White Matter/diagnostic imaging/pathology ; Neuropsychological Tests ; Aged ; *Brain/diagnostic imaging/pathology ; Middle Aged ; Diffusion Tensor Imaging ; Magnetic Resonance Imaging ; Anisotropy ; },
abstract = {Diabetes is one of the main risk factors for developing amnesic mild cognitive impairment and Alzheimer's disease. Several studies have found differences between the microstructural abnormalities that appear in the brains of patients with type 2 diabetes and amnesic mild cognitive impairment (T2DM-aMCI). To compare the microstructural differences between the brains of subjects with T2DM-aMCI and the brains of healthy controls. In addition, to correlate the cognitive decline of subjects with T2DM-aMCI with microstructural alterations. A cross-sectional study was conducted with a sample size of 54 patients. The participants were divided into two groups: T2DM-aMCI and healthy controls. All the participants underwent a wide range of neuropsychological tests assessing different cognitive domains. 47 subjects had MRI session. An exploratory analysis showed that the T2DM-aMCI group had a reduced fractional anisotropy in the white matter compared to the healthy controls group (p < 0.15). The most affected areas were the body of the corpus callosum and the right and left superior corona radiata. T2DM-aMCI had significant positive correlations (p < 0.05) between cerebral regions and Mini Mental State Examination, Montreal Cognitive Assessment, Rey Auditory Verbal Learning Test immediate recall and recognition, Verbal Fluency Test total words and animals. Persons with T2DM-aMCI showed less cerebral white matter integrity in different brain areas when compared to healthy controls. Positive correlations between white matter microstructural alterations and functional cognition (general cognition, memory and language) in T2DM-aMCI group were found.},
}

Humans
*Diabetes Mellitus, Type 2/diagnostic imaging/complications/psychology/pathology
Female
*Cognitive Dysfunction/diagnostic imaging/psychology/pathology
Male
Cross-Sectional Studies
*White Matter/diagnostic imaging/pathology
Neuropsychological Tests
Aged
*Brain/diagnostic imaging/pathology
Middle Aged
Diffusion Tensor Imaging
Magnetic Resonance Imaging
Anisotropy

@article {pmid42766267,
year = {2026},
author = {Kania, J and Zawar, I and Reyes, A and Williams, V and Sarkis, R and Punia, V and Williams, M and Ferguson, L and Arrotta, K and Busch, RM and Jones, J and Hermann, BP and McDonald, CR},
title = {Diagnostic accuracy of the ADAS-Cog-13 as a cognitive screening tool in older adults with focal epilepsy: A multicenter cross-sectional study.},
journal = {Epileptic disorders : international epilepsy journal with videotape},
volume = {},
number = {},
pages = {},
doi = {10.1002/epd2.70415},
pmid = {42766267},
issn = {1950-6945},
support = {R01NS120976/NH/NIH HHS/United States ; },
abstract = {OBJECTIVE: Cognitive impairment is common among older adults with epilepsy, and although the Montreal Cognitive Assessment (MoCA) has demonstrated validity as a screening tool in this population, additional efficient screening options are needed. Here we examine, for the first time, the diagnostic accuracy of the Alzheimer's Disease Assessment Scale-Cognitive-13 Item Subscale (ADAS-Cog-13) as a screening tool to identify cognitive impairment in older adults with focal epilepsy.

METHODS: Participants included 83 adults (ages ≥55) with focal epilepsy from the Brain, Aging, and Cognition in Epilepsy (BrACE) study and 83 age-, sex-, and education-matched cognitively healthy controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI-3). All completed the ADAS-Cog-13 and a comprehensive neuropsychological battery that was analyzed through the International Cognitive Disorders in Epilepsy (IC-CoDE) system to identify cognitive phenotypes (intact vs. impaired). Performance on the individual ADAS-Cog-13 total score and items was assessed, clinical and sociodemographic features characterized, and diagnostic efficiency statistics determined and compared with MoCA performance.

RESULTS: Focal epilepsy participants (mean age = 66.4 years) performed significantly worse across the ADAS-Cog-13 total score and 8 of the 13 individual test items compared with controls. The largest effect sizes were observed on verbal learning and memory tasks, particularly word recall (d = .87) and delayed word recall (d = 1.06). An ADAS-Cog-13 total score of ≥15 yielded optimal diagnostic efficiency (67.5% accuracy, 68.8% sensitivity, 66.7% specificity) for identifying cognitive impairment-similar to MoCA performance.

SIGNIFICANCE: The ADAS-Cog-13 is sensitive to detecting cognitive impairment in older adults with focal epilepsy and may represent a scalable screening option in this population. Additional comparative studies in older epilepsy populations are needed to determine the sensitivity of this measure to longitudinal change, cross-cultural applicability, and availability across languages.

PLAIN LANGUAGE SUMMARY: Cognitive decline is common among older adults with epilepsy. Although the Montreal Cognitive Assessment (MoCA) has been shown to be a valid screening tool in this population, additional options are needed. The ADAS-Cog-13 may be a useful screening option in epilepsy research and clinical care, although additional studies are needed to compare it with other cognitive screening tests and to confirm its applicability for clinical care and across healthcare settings and cultures.},
}

@article {pmid42766299,
year = {2026},
author = {Ruppert, E and Vermeiren, MR and Scop Medeiros, M and Povala, G and Soares, C and Rocha, A and de Oliveira Franco, A and Scarpatto Rodrigues, M and Oliveira, M and Mroué, R and Ferreira, PCL and Bauer-Negrini, G and Lussier, FZ and Amaral, L and Bellaver, B and Tissot, C and Masdeu, J and Tudorascu, DL and Karikari, T and Soleimani-Meigooni, DN and Fortea, J and Lowe, VJ and Oh, H and Pascual, B and Gordon, BA and Rosa-Neto, P and Baker, S and Ossenkoppele, R and van de Giessen, E and Pascoal, TA and , },
title = {A Harmonized Visual Reading Framework for Tau PET Staging in Alzheimer Disease.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
pmid = {42766299},
issn = {2168-6157},
abstract = {IMPORTANCE: Tau positron emission tomography (PET) can detect and stage Alzheimer disease pathology; however, current binary regulatory-approved visual interpretation focuses on advanced disease, limiting early detection and patient stratification.

OBJECTIVE: To develop and validate a harmonized tau PET visual reading framework across radiotracers that stages tau burden into 5 classes: negative, low, moderate, high, and atypical.

This prospective multicenter cross-sectional study among a cohort with head-to-head tau PET acquisitions was conducted from March 2022 to August 2025 and data analyzed from February to June 2026, with blinded visual reads performed by clinicians. The study was conducted at 9 sites across North America and Europe. Of those individuals enrolled in the HEAD (Head-to-Head Harmonization of Tau Tracers in Alzheimer's Disease) study, a proportion of participants aged 50 to 90 years who completed multitracer tau PET (2-4 scans) and cognitive assessments were included, spanning cognitively unimpaired to dementia.

EXPOSURES: Tau PET with 18F-MK-6240 (TAUKLARIFY, n = 681), 18F-flortaucipir (Tauvid, n = 644), 18F-RO948 (n = 150), and 18F-PI-2620 (n = 149); all participants underwent amyloid-β (Aβ) PET and magnetic resonance imaging.

MAIN OUTCOMES AND MEASURES: The primary outcomes were interrater and intertracer agreement for 5-class tau classification; prevalence ratio (PR) vs the regulatory-approved 18F-flortaucipir framework; and associations with cognition, Aβ burden, and plasma phosphorylated tau 217 (p-tau217).

RESULTS: Of 822 individuals enrolled in the HEAD study, 681 participants spanning cognitively unimpaired to dementia were included. Mean (SD) age was 69.3 (8.4) years, and 367 participants (53.9%) were female. The harmonized 5-class framework achieved excellent interrater agreement (κ = 0.77-0.85) and good to excellent intertracer agreement, highest between 18F-MK-6240 and 18F-flortaucipir (κ = 0.88). Compared with the regulatory-approved framework, the harmonized classification identified more tau-positive cognitively unimpaired participants (regulatory-approved binary: 26 of 364 participants; harmonized 18F-flortaucipir: 49 of 364 [PR = 1.89; 95% CI, 1.31-2.70; P = .001]; harmonized 18F-MK-6240: 71 of 364 [PR = 2.73; 95% CI, 1.95-3.83; P < .001]) and those with mild cognitive impairment (regulatory-approved binary: 100 of 223; harmonized 18F-flortaucipir: 123 of 223 [PR = 1.23; 95% CI, 1.12-1.35; P < .001]; harmonized 18F-MK-6240: 142 of 223 [PR = 1.42; 95% CI, 1.27-1.59; P < .001]), with convergence in dementia. Tau burden classes showed stepwise worsening of cognition, Aβ PET burden, and plasma p-tau217, with 1.4-fold, 3.2-fold, and 2.5-fold differences between the low and high tau classes, respectively.

CONCLUSIONS AND RELEVANCE: In this prospective multitracer cross-sectional study, a 5-class harmonized tau PET visual reading framework showed high interrater and intertracer agreement and detected more early-stage tau pathology than the regulatory-approved binary approach, with tau burden classes tracking stepwise with cognition and biomarkers. These findings support a standardized, tracer-agnostic framework for diagnostic categorization, therapeutic window identification, and clinical trial stratification.},
}

@article {pmid42766599,
year = {2026},
author = {Agbavor, F and Liang, H},
title = {Multimodal Dementia Prediction With Large Language Models: Cross-Attention Over Text, Audio, and Image.},
journal = {JMIR aging},
volume = {9},
number = {},
pages = {e93279},
pmid = {42766599},
issn = {2561-7605},
mesh = {Humans ; *Attention ; *Alzheimer Disease/diagnosis ; Large Language Models ; Female ; *Dementia/diagnosis ; Aged, 80 and over ; },
abstract = {BACKGROUND: Alzheimer disease (AD) is a leading cause of dementia, and there is growing interest in scalable approaches for early screening using speech-based tasks. While prior work has demonstrated promising results using either transcript-based language features or acoustic cues, most approaches remain unimodal or rely on simple fusion strategies that do not explicitly consider interactions across modalities.

OBJECTIVE: In this study, we propose an attention-based trimodal fusion framework that integrates text, audio, and image representations of the Cookie Theft picture, which serves as the shared visual stimulus in the picture-description task.

METHODS: Our method uses a new bidirectional cross-attention mechanism to achieve a unified multimodal embedding for downstream tasks. We evaluate the approach on 2 tasks: AD detection by classifying whether the participant has AD or not, and AD severity assessment by predicting Mini-Mental Status Examination cognitive scores.

RESULTS: On the AD detection task, trimodal fusion achieves the best overall performance (F1-score=0.8667, area under the receiver operating characteristic curve=0.9032), outperforming unimodal baselines, bimodal fusion, and conventional early or late fusion methods. For AD severity assessment, the proposed multimodal representation reduces prediction error of root mean squared error to about 4.20, improving over both unimodal and bimodal fusion settings. We further perform the ablation analysis to show that bidirectional cross-attention consistently outperforms conventional unidirectional cross-attention.

CONCLUSIONS: These results demonstrate that attention-based multimodal fusion can enhance dementia prediction from picture-description responses and provide a strong foundation for developing multimodal cognitive screening pipelines.},
}

Humans
*Attention
*Alzheimer Disease/diagnosis
Large Language Models
Female
*Dementia/diagnosis
Aged, 80 and over

@article {pmid42766920,
year = {2026},
author = {Liu, P and Harrison, TM and Snyder, HM and DeCarli, C and Maillard, P and Vemuri, P and Harvey, D and Koeppe, R and Jagust, W and Baker, LD and Landau, SM and , },
title = {Are the factors associated with cognitive performance generalizable across cohorts?.},
journal = {NeuroImage. Clinical},
volume = {52},
number = {},
pages = {104064},
doi = {10.1016/j.nicl.2026.104064},
pmid = {42766920},
issn = {2213-1582},
abstract = {OBJECTIVE: To examine whether vascular risk and brain atrophy account for cohort differences in the associations between tau burden and cognition across cognitive domains in U.S. POINTER and ADNI.

METHODS: We analyzed baseline data from 775 U.S. POINTER and 405 ADNI participants without significant cognitive impairment and matched on age, sex, clinical status, and APOE ε4 status. Cognitive outcomes included global cognition, verbal memory, and executive function. Regional tau (entorhinal and meta-temporal), vascular risk biomarkers, and structural MRI measures (entorhinal cortical thickness and hippocampal volume) were examined using linear regression models stratified by amyloid status and adjusted for age, sex, education, and average number of prior cognitive test exposures. Interaction terms (biomarker × cohort) were used to assess cohort differences. False discovery rate (FDR) correction was applied.

RESULTS: Greater tau burden was associated with poorer cognitive performance across global cognition, verbal memory, and executive function in ADNI compared to U.S. POINTER, particularly among Aβ + individuals (corrected p < .05). Unexpectedly, vascular risk biomarkers contributed minimally to cognitive variability in either cohort. Finally, brain atrophy, particularly hippocampal volume, made a tau-independent contribution to verbal memory in ADNI but not in U.S. POINTER, especially among Aβ + individuals (corrected p < .05).

CONCLUSIONS: Tau pathology in the presence of Aβ was a stronger predictor of cognition in ADNI than in U.S. POINTER, and this discrepancy was not explained by increased vascular risk or brain atrophy in U.S. POINTER. The drivers of cognition differed between cohorts in a way that is not easily attributable to clinical characteristics.},
}

@article {pmid42766994,
year = {2026},
author = {Xie, Z and Hong, YR and Armstrong, MJ and Wang, X and Jacobs, M},
title = {Dementia and End-of-Life Shared Decision-Making Among Older US Adults.},
journal = {Journal of the American Medical Directors Association},
volume = {27},
number = {11},
pages = {106490},
doi = {10.1016/j.jamda.2026.106490},
pmid = {42766994},
issn = {1538-9375},
abstract = {OBJECTIVES: To examine whether dementia is associated with differences in advance directive completion, decision-making needs near death, surrogate involvement, and concordance between expressed preferences for care and care received among older US adults.

DESIGN: Retrospective, nationally representative observational study using Health and Retirement Study Exit Interview data from 2010 to 2022.

SETTING AND PARTICIPANTS: The study included 5,389 decedents aged 50 years or older with complete information on dementia status, end-of-life decision-making outcomes, and selected covariates, representing approximately 22.2 million US decedents. Of these, 1,010 (weighted 17.7%) had dementia prior to death.

METHODS: Dementia status was identified from proxy reports of Alzheimer's disease or another form of dementia before death. Primary outcomes were advance directive completion and the occurrence of important medical decisions during the final days of life. Secondary outcomes included the decedent's ability to participate in decision-making, the primary decision-maker, and concordance between preferences for comfort-focused care and care received. Analyses incorporated Health and Retirement Study sampling weights, strata, and primary sampling units. Survey-weighted descriptive analyses and modified Poisson regression with robust variance estimation were used to compare decedents with and without dementia and estimate adjusted risk ratios (aRRs) and 95% CIs.

RESULTS: Decedents with dementia were more likely than those without dementia to have completed an advance directive (81.3% vs 69.1%; P < .001; aRR, 1.11; 95% CI, 1.07-1.15) and to have important medical decisions requiring resolution during the final days of life (54.3% vs 47.2%; P < .001; aRR, 1.09; 95% CI, 1.01-1.19). They were also substantially more likely to be unable to participate in end-of-life medical decision-making (78.9% vs 48.0%; P < .001), with children or grandchildren more frequently serving as the primary decision-makers (63.9% vs 45.6%; P < .001). Among decedents with documented advance directives, preferences for and receipt of comfort-focused care were high in both groups, with no significant differences by dementia status.

CONCLUSIONS AND IMPLICATIONS: Decedents with dementia experienced a distinct end-of-life shared decision-making pattern characterized not only by greater advance care planning but also greater decisional needs and reliance on surrogate decision-makers. These findings suggest that advance directives should be viewed as one component of an ongoing shared decision-making process rather than a substitute for it. Health care systems should complement advance care planning with early and ongoing caregiver engagement, structured decision support, and integration of palliative care across the dementia trajectory to help patients and families navigate evolving end-of-life decisions.},
}

@article {pmid42767135,
year = {2026},
author = {Alemdağ, B and Siyah, B and Alemdağ, İN and Berber, T and Güdük, ÖF},
title = {Elucidating the molecular nexus between dental developmental anomalies and chronic inflammatory diseases: A computational systems biology analysis of genomic sequence homology using matrix factorization.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 1},
pages = {109395},
doi = {10.1016/j.compbiolchem.2026.109395},
pmid = {42767135},
issn = {1476-928X},
abstract = {This entirely in silico, exploratory study investigates potential sequence-level links between periodontal disease, developmental dental anomalies such as molar-incisor hypomineralization (MIH), and selected systemic conditions including leukemias, amyotrophic lateral sclerosis, and Alzheimer's disease. To identify annotation-independent signatures, we applied Non-negative Matrix Tri-Factorization (NMTF) to k-mer/tf-idf representations of disease-associated gene and protein sequences compiled from OMIM, GeneCards, and PubMed for eleven curated disease groups; similarity values denote the proportion of the total between-cluster interaction (S-matrix) captured by a cluster. To guard against trivial explanations, we applied a composition-preserving sequence-shuffling test of the similarity magnitude and a degree-preserving (curveball) permutation test of the disease co-clustering that accounts for the dependence introduced by isoform records and shared genes, repeating the latter across a 1890-configuration parameter grid. At the gene level the dominant cluster was governed by the largest disease group (MIH) rather than by disease identity, whereas at the protein level periodontitis, dental anomalies, and leukemia subtypes co-clustered. The magnitude of the shares did not exceed a composition-preserving null (gene p=0.66; protein p=0.082), and under the degree-preserving null co-clustering was not significant at the gene level (p=0.36) but was significant, modest, and grid-robust at the protein level (p=0.033); canonical k-mer and coding-sequence controls confirmed that the gene-level weakness is intrinsic to nucleotide k-mers. These results delineate the protein level as the informative scale for annotation-independent cross-disease screening and identify the dental-leukemia axis as the candidate relationship for targeted follow-up. The findings are hypothesis-generating: the disease-associated gene sets were compiled with a non-systematic, literature-guided procedure, magnitudes do not exceed composition baselines, neither experimental or clinical validation nor quantitative benchmarking against alternative computational frameworks was performed, and any translational implication requires future validation.},
}

@article {pmid42767712,
year = {2026},
author = {Brandalise, F and Lorenzi, E and Melis, M},
title = {Vulnerability in the womb: Charting the effects of prenatal cannabinoid exposure to mitigate developmental actions on dopamine metabolic capacities and circuits.},
journal = {International review of neurobiology},
volume = {190},
number = {},
pages = {1-15},
doi = {10.1016/bs.irn.2026.08.020},
pmid = {42767712},
issn = {2162-5514},
mesh = {*Prenatal Exposure Delayed Effects/metabolism/chemically induced ; Humans ; Pregnancy ; Animals ; *Cannabinoids/adverse effects ; *Dopamine/metabolism ; Female ; *Brain/metabolism/drug effects ; *Dopaminergic Neurons/metabolism/drug effects ; Mesolimbic System ; },
abstract = {Prenatal cannabis exposure (PCE) is increasingly recognized as a major public health concern as cannabis use during pregnancy continues to rise worldwide. While early studies focused on cannabinoid receptor-mediated alterations in neurotransmission, emerging evidence indicates that PCE induces long-lasting developmental reprogramming affecting neural circuits, metabolism, and endocrine regulation. In this roadmap, we propose a shift from viewing PCE as a discrete synaptic disturbance to considering it a disorder of developmental coordination. We discuss how prenatal cannabinoid exposure may alter mesolimbic dopamine circuit maturation through the interaction of neuronal excitability, mitochondrial bioenergetics, and stress-related hormonal signaling. Particular attention is given to mitochondrial-circuit coupling in dopaminergic neurons and the potential role of mitochondrial cannabinoid receptors (mtCB1) in shaping long-term neuronal function. We further highlight the contribution of astrocytes, microglia, and neuroimmune processes in determining vulnerability or resilience trajectories. We propose that PCE generates latent neurobiological vulnerabilities that may emerge during adolescence or later life when challenged by environmental or physiological stressors. This framework provides new opportunities for early intervention, and prevention, while also offering insights into how early-life metabolic and mitochondrial dysfunction may contribute to lifelong brain vulnerability, including increased susceptibility to age-related neurodegenerative disorders such as Alzheimer's disease.},
}

*Prenatal Exposure Delayed Effects/metabolism/chemically induced
Humans
Pregnancy
Animals
*Cannabinoids/adverse effects
*Dopamine/metabolism
Female
*Brain/metabolism/drug effects
*Dopaminergic Neurons/metabolism/drug effects
Mesolimbic System

@article {pmid42767717,
year = {2026},
author = {Maiese, K},
title = {Running out the clock: Circadian rhythm dysfunction in cognitive disease.},
journal = {International review of neurobiology},
volume = {190},
number = {},
pages = {231-306},
doi = {10.1016/bs.irn.2026.08.015},
pmid = {42767717},
issn = {2162-5514},
mesh = {Humans ; Animals ; *Chronobiology Disorders/metabolism/physiopathology ; *Circadian Rhythm/physiology ; *Cognitive Dysfunction/metabolism/physiopathology ; *Cognition Disorders/physiopathology/metabolism ; },
abstract = {Lifespan is increasing such that within a few decades approximately twenty percent of the world's population is expected to be greater than sixty years of age. In concert with global aging of the population, neurodegenerative disorders have become the leading cause of disability with dementia now the seventh leading cause of death worldwide. Despite multi-faceted treatment approaches for disorders of cognition that include Alzheimer's disease and multiple sclerosis, present therapies ultimately cannot halt disease progression and eventually cognitive impairment continues unabated. Furthermore, co-morbidities, such as metabolic disorders with diabetes mellitus, also lack strategies to prevent disease progression. Given these clinical challenges for cognitive loss, innovative avenues of investigation that involve mammalian chronobiology with circadian rhythm clock genes and related pathways of aging, cellular senescence, oxidative stress, metabolic dysfunction, sleep fragmentation, apolipoprotein E, programmed cell death, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae), nicotinamide adenine dinucleotide, the gut microbiota, and glucagon-like peptide-1 receptor agonism may offer exceptional promise for forging new strategies for cognitive disease treatment. These pathways are intimately linked to circadian rhythm processes, are complex in generating biological outcomes, can broadly influence clinical translation of both short- and long-term considerations for cognitive disease care, and necessitate dissection of their precise regulatory mechanisms with the benefit from early diagnostic platforms as well as artificial intelligence and machine learning applications to foster translation of these pathways into effective clinical treatments.},
}

Humans
Animals
*Chronobiology Disorders/metabolism/physiopathology
*Circadian Rhythm/physiology
*Cognitive Dysfunction/metabolism/physiopathology
*Cognition Disorders/physiopathology/metabolism

@article {pmid42767917,
year = {2026},
author = {Zhang, W and Smith, N and Veliz, EA and Zhao, B and Kandel, N and Joji, A and Chen, J and Ferreira, BCLB and Perez, M and Claure, X and Zhou, Y and Mintz, KJ and Zhang, F and Wang, C and Leblanc, RM},
title = {Nanoconjugation of chalcone derivatives and carbon nitride dots for the inhibition of tau aggregation.},
journal = {Colloids and surfaces. B, Biointerfaces},
volume = {},
number = {},
pages = {116175},
doi = {10.1016/j.colsurfb.2026.116175},
pmid = {42767917},
issn = {1873-4367},
abstract = {Tau aggregation is a pathological hallmark of Alzheimer's disease, yet small-molecule inhibitors targeting this process often face limitations in solubility, selectivity, and bioavailability. In this study, we engineered a library of hybrid nanostructures by covalently conjugating eleven structurally diverse chalcone derivatives to carbon nitride dots (CNDs), aiming to enhance their physicochemical stability and therapeutic efficacy. The resulting CND-chalcone conjugates exhibited favorable aqueous dispersibility and minimal cytotoxicity in HEK293 and HeLa cells. In vitro aggregation assays revealed that the conjugates modulated tau fibrillization in a structure-dependent manner, with several hybrids, particularly those containing hydroxyl or selectively positioned methoxy groups, showing strong inhibitory effects. Thioflavin-T fluorescence assays confirmed that the most active conjugates disrupted both nucleation and elongation phases of fibril formation. Notably, one hybrid (CNDs-S6) outperformed its free chalcone counterpart, suggesting synergistic interactions between the nanoparticle platform and ligand. These findings highlight the potential of CND-chalcone architectures as multifunctional nanoinhibitors and offer a rational approach to designing aggregation-targeting nanotherapeutics for neurodegenerative disease intervention.},
}

@article {pmid42767982,
year = {2026},
author = {López-González, FJ and Nemy, M and Jerele, C and Jiménez-Pérez, A and López-Martínez, MJ and Jonkman, L and Rábano, A and Sánchez-Juan, P and Grothe, MJ and Ferreira, D},
title = {Post mortem MRI of cholinergic white matter pathways across neurodegenerative diseases.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71851},
pmid = {42767982},
issn = {1552-5279},
support = {//Next Generation funding UE/Mecanismo de Recuperación y Resiliencia/ ; PMP22/00022//ISCIII/ ; PI23/01314//ISCIII/ ; PI20/01011//ISCIII/ ; TED2021-131676B-100//ISCIII/ ; 101155955//European Union's Horizon Europe research and innovation programme/ ; 25-18359 M//Czech Science Foundation/ ; 2022-00916//Swedish Research Council/ ; 2025-02984//Swedish Research Council/ ; 20200505//Center for Innovative Medicine/ ; FoUI-988826//Center for Innovative Medicine/ ; FoUI-962240//regional agreement on medical training and clinical research of Stockholm Region/ ; FoUI-987534//regional agreement on medical training and clinical research of Stockholm Region/ ; FoUI-1023640//regional agreement on medical training and clinical research of Stockholm Region/ ; FO2021-0131//Swedish Brain Foundation/ ; FO2022-0175//Swedish Brain Foundation/ ; FO2023-0261//Swedish Brain Foundation/ ; FO2025-0214//Swedish Brain Foundation/ ; AF-968032//Swedish Alzheimer Foundation/ ; AF-980580//Swedish Alzheimer Foundation/ ; AF-994058//Swedish Alzheimer Foundation/ ; AF-1010553//Swedish Alzheimer Foundation/ ; AF-1031740//Swedish Alzheimer Foundation/ ; RYC2023-043746-I//Ramón and Cajal" fellowship/ ; CNS2024-154295//Spanish Ministry of Science, Innovation and Universities/ ; //European Social Fund (ESF)/ ; PI24/00089//Institute of Health Carlos III - European Regional Development Fund/ ; //Reina Sofia Foundation/ ; },
mesh = {Humans ; *White Matter/pathology/diagnostic imaging ; Female ; Male ; *Magnetic Resonance Imaging/methods ; Aged ; *Alzheimer Disease/pathology/diagnostic imaging ; *Neurodegenerative Diseases/pathology/diagnostic imaging ; Aged, 80 and over ; *Lewy Body Disease/pathology/diagnostic imaging ; Diffusion Tensor Imaging ; *Brain/pathology/diagnostic imaging ; Autopsy ; Neural Pathways/pathology/diagnostic imaging ; Middle Aged ; },
abstract = {INTRODUCTION: Cholinergic white matter pathway (CWMP) degeneration is central in Alzheimer's disease (AD) and Lewy body disease (LBD). CWMP degeneration can be assessed in vivo using magnetic resonance imaging (MRI) proxies, but neuropathological validation is limited.

METHODS: We studied post mortem in situ 3T MRIs of 55 brain donors with standardized neuropathologic assessment (AD, LBD, AD+LBD, other dementias, controls). CWMP integrity was assessed quantitatively using diffusion tensor imaging and visually using the Cholinergic Pathways Hyperintensities Scale (CHIPS) on fluid-attenuated inversion recovery MRI.

RESULTS: CWMP diffusivity was strongly associated with CHIPS (p < 0.001), independent of global white matter damage. AD and AD+LBD showed greater CWMP degeneration than LBD, other dementias, and controls (p < 0.05). Multivariate analyses across neuropathological variables identified hippocampal sclerosis and vascular co-pathology as strongest predictors for CWMP degeneration.

DISCUSSION: CWMP degeneration is pronounced in AD and mixed AD+LBD pathology and is additionally affected by vascular co-pathology and hippocampal sclerosis. CHIPS may serve as a clinically accessible MRI-based proxy of CWMP integrity.},
}

Humans
*White Matter/pathology/diagnostic imaging
Female
Male
*Magnetic Resonance Imaging/methods
Aged
*Alzheimer Disease/pathology/diagnostic imaging
*Neurodegenerative Diseases/pathology/diagnostic imaging
Aged, 80 and over
*Lewy Body Disease/pathology/diagnostic imaging
Diffusion Tensor Imaging
*Brain/pathology/diagnostic imaging
Autopsy
Neural Pathways/pathology/diagnostic imaging
Middle Aged

@article {pmid42768129,
year = {2026},
author = {Xu, Y and Wang, Q and Tang, H and Ji, G and Yang, R and Wu, D and Gui, Y},
title = {A multi-omics insight into the sex-specific burden of tobacco-associated neurodegeneration: trends, projections, and mechanistic clues from the TH gene.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42768129},
issn = {1590-3478},
support = {22ZR1449800//Shanghai Science and Technology Program/Natural Science Foundation of Shanghai/ ; 81401038//National Natural Science Foundation of China/ ; 2020KY602//Zhejiang Province Medicine Health General Research Program/ ; },
mesh = {Humans ; Male ; Female ; *Parkinson Disease/genetics/epidemiology/etiology ; *Alzheimer Disease/genetics/epidemiology ; Global Burden of Disease/trends ; Sex Factors ; *Sex Characteristics ; Nicotine/metabolism ; *Neurodegenerative Diseases/genetics/epidemiology ; },
abstract = {BACKGROUND: Tobacco exposure significantly influences neurological health, yet its specific associations with Parkinson's disease (PD) and Alzheimer's disease and other dementias (ADOD), including mechanisms, require clarification.

METHODS AND MATERIALS: Using data from the Global Burden of Disease (GBD) 2021 study, multidimensional stratified comparisons of global PD and ADOD attributable to tobacco exposure were performed across dimensions including sex, socio-demographic index (SDI) quintiles, GBD sub-regions, and national levels. Furthermore, autoregressive integrated moving average and exponential smoothing models were incorporated to project trends until 2050. Bioinformatics analysis was conducted to identify key genes linking nicotine metabolism and sex differences.

RESULTS: Tobacco exposure exerted a negative modulatory effect on PD burden but increased ADOD risk. Marked sex-specific differences existed, with males more affected. Regional heterogeneity was pronounced: PD impact was strongest in East Asia, while ADOD burden was highest in high-SDI regions. Projections showed rising ASRs for males but a decline for females. Mechanistically, the TH gene was a key nexus connecting PD, nicotine pathways, and sex differences, potentially explaining the stronger effect in males.

CONCLUSIONS: Tobacco exposure differentially influences PD and ADOD, with distinct patterns by sex and region. It is detrimental for ADOD but may negatively modulate PD. The burden is projected to increase over the next three decades with persistent sex disparities. The TH gene may provides a mechanistic clue for the sex-heterogeneous effect against PD.},
}

Humans
Male
Female
*Parkinson Disease/genetics/epidemiology/etiology
*Alzheimer Disease/genetics/epidemiology
Global Burden of Disease/trends
Sex Factors
*Sex Characteristics
Nicotine/metabolism
*Neurodegenerative Diseases/genetics/epidemiology

@article {pmid42768165,
year = {2026},
author = {Simkhada, B and Liang, TY and Cui, X and Adeyosoye, M and Simkhada, B and Cabrerizo, M and Cid, RC and Burke, SL and Barreto, A and Rishe, N and Loewenstein, DA and Adjouadi, M},
title = {Multimodal prediction of MCI-to-dementia conversion over a two-year window.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42768165},
issn = {2509-2723},
support = {CNS-1920182//National Science Foundation/ ; CNS-2018611//National Science Foundation/ ; NIA/NIH 1P30AG066506-01/NH/NIH HHS/United States ; NIA/NIH 5R01AG061106-02/NH/NIH HHS/United States ; 5R01AG047649-05/NH/NIH HHS/United States ; R01AG077677-04/NH/NIH HHS/United States ; },
abstract = {Mild cognitive impairment (MCI) represents a heterogeneous clinical state where some individuals remain stable while others progress to dementia. Identification of patients who are at high risk for near-term conversion remains a critical challenge for timely intervention. We developed an explainable multimodal machine-learning framework to predict progression from MCI to dementia within a clinically meaningful two-year period. We analyzed 2008 samples from 828 unique MCI subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitive/functional assessments, demographic/genetic variables, and structural MRI features. Subjects were classified as stable MCI (sMCI, n = 1306) or progressive MCI (pMCI, n = 702) based on two-year outcomes. Machine learning algorithms were evaluated on unimodal and multimodal using nested cross-validation, and explainability was assessed using SHapley Additive exPlanations (SHAP) and permutation feature importance. The combination of cognitive assessments, demographics/risk factors and structural MRI features outperformed individual modalities, highlighting the complementary relationship between cognitive-functional decline and neuroanatomical degeneration. The best-performing model, a calibrated XGBoost, achieved a balanced accuracy of 81.28% ± 2.56% during cross-validation and 81.99% (bootstrap mean 81.97%, 95% CI: [78.22%-85.51%]) on an independent held-out test set. Explainable AI analyses identified functional impairment measures (Functional Activities Questionnaire, Clinical Dementia Rating - Sum of Boxes), cognitive performance scores (Alzheimer's Disease Assessment Scale - Cognitive Subscale 11-item version, Alzheimer's Disease Assessment Scale - Cognitive Subscale 13-item version, Mental State Examination), APOE ε4 status, and structural abnormalities within the hippocampus, lateral ventricle, parietal and temporal regions, and amygdala, as the most influential predictors of conversion. Short-term progression from MCI to dementia can be predicted with high accuracy using multimodal information obtained from a single clinical visit. The convergence of cognitive impairment and region-specific neurodegeneration emerged as the strongest indicator of conversion risk.},
}

@article {pmid42768200,
year = {2026},
author = {Wang, J and Meng, C and Xie, Y and Wang, S and Hu, Z and Jie, H and Mu, J and Duan, F and Huang, L},
title = {Tinosinenside A ameliorates Alzheimer's disease-related pathology in APP/PS1 mice, accompanied by reduced neuroinflammation and altered microglial phenotype-associated marker expression.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42768200},
issn = {1432-1912},
abstract = {Tinospora sinensis (Lour.) Merr. has traditionally been used for its anti-inflammatory properties. Tinosinenside A (Tis A), a major sesquiterpene glycoside isolated from this plant, has shown neuroprotective activity; however, its effects on Alzheimer's disease (AD)-related neuroinflammation remain unclear. This study evaluated the effects of Tis A on behavioral impairment, neuroinflammation, and amyloid-β (Aβ) pathology in APPswe/PSEN1dE9 (APP/PS1) mice. APP/PS1 mice received oral Tis A for 6 months and were evaluated at 11 months of age using behavioral, histopathological, biochemical, and molecular analyses. Tis A partially improved behavioral performance, reduced Aβ plaque burden and pro-inflammatory cytokine levels, attenuated microglial overactivation, shifted microglial phenotype-associated marker expression toward a less pro-inflammatory profile, and alleviated neuronal apoptosis and histopathological damage. These effects were accompanied by reduced TLR4 and NLRP3 inflammasome-related protein expression and decreased phosphorylation of NF-κB p65 and IκBα. Collectively, these findings indicate that Tis A attenuates neuroinflammation and AD-related neuropathology while providing partial behavioral benefits in APP/PS1 mice, supporting its further investigation as a natural-product-derived therapeutic lead for AD.},
}

@article {pmid42768280,
year = {2026},
author = {Arcangeli, A and De Santi, LA and Santarelli, MF and Celi, S and Positano, V},
title = {Reject Option for Medical Image Classification Using CNN-Derived Latent-Space Neighbourhood Analysis.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10278-026-02318-y},
pmid = {42768280},
issn = {2948-2933},
abstract = {Reliable uncertainty estimation is a key requirement for the clinical adoption of convolutional neural networks (CNNs) in biomedical imaging. We propose a reject option framework that assesses prediction reliability by leveraging the local structure of the latent space. The method is based on three latent-space features: Simple Data Point Target Density (DPTD S), defined as the proportion of a sample's nearest neighbours sharing its label, a distance-weighted extension (DPTD W), and the k ∗ value. These metrics characterise local label agreement and intra-class consistency without relying on explicit parametric assumptions. A logistic regression rejector is trained post hoc using features derived from the latent representations of the base CNN. Experiments were conducted on two public neuroimaging datasets: ADNI (FDG-PET for Alzheimer's disease) and PPMI (DaTSCAN SPECT for Parkinson's disease). Using all three latent-space features, the rejector achieved AUC-ROC values of 0.843 (95% CI: 0.809-0.874) on ADNI and 0.884 (95% CI: 0.867-0.900) on PPMI, with corresponding eAURC values of 0.0278 (95% CI: 0.0193-0.0370) and 0.0169 (95% CI: 0.0133-0.0209), respectively. For the full-feature configuration, no significant difference from maximum softmax probability (MSP) was detected on ADNI for either AUC-ROC or eAURC, whereas MSP performed significantly better on PPMI for both metrics. The proposed framework provides a representation-based mechanism to assess prediction reliability through local latent-space structure. As a post-hoc approach, it can be integrated into existing CNN pipelines without modifying the underlying model, offering a practical tool for uncertainty-aware decision support in biomedical imaging.},
}

@article {pmid42768715,
year = {2026},
author = {Kinnunen, M and Vitikka, E and Krüger, J and Hoffmann, D and Haapasalo, A and Lleó, A and Belbin, O and Suhonen, NM and Borroni, B and Portaankorva, AM and Säisänen, L and Katisko, K and Solje, E},
title = {Non-motor symptoms questionnaire-based profiles in early-stage dementias: A prospective cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261487345},
doi = {10.1177/13872877261487345},
pmid = {42768715},
issn = {1875-8908},
abstract = {BackgroundCurrent knowledge regarding the nature and prevalence of non-motor symptoms across different types of dementia is limited. While Alzheimer's disease (AD), behavioral variant frontotemporal dementia (bvFTD), and dementia with Lewy bodies (DLB) are primarily characterized by cognitive and motor symptoms, several other features such as non-motor symptoms are also known to occur in all these conditions.ObjectiveTo assess non-motor symptoms in early-stage dementia and characterize symptom profiles across different neurodegenerative dementia diseases.MethodsA total of 64 AD, 38 bvFTD, and 17 DLB early-stage patients, along 63 cognitively healthy controls (HC), were prospectively recruited from Kuopio and Oulu University Hospitals. Non-motor symptoms were evaluated using the Non-Motor Symptoms Questionnaire (NMSQ), focusing on gastrointestinal, neuropsychiatric, cognitive, sleep-related and sensory-motor domains within three timeframes prior to the baseline visit.ResultsDLB patients exhibited the highest prevalence of non-motor symptoms across all domains. bvFTD and AD patients did not show disease group specific symptoms, but apathy and paranoidal thoughts appeared earlier in bvFTD than AD or DLB. Diplopia was reported by 14% of DLB patients (Fisher exact test, p = 0.035) one year before diagnosis. Neuropsychiatric and cognitive symptoms were more frequent in all dementia groups compared to HC (Fisher exact test, p < 0.01).ConclusionsNon-motor symptom profiles differ among these dementia subtypes even at early stages, suggesting their potential utility as early disease-specific indicators.},
}

@article {pmid42768750,
year = {2026},
author = {Jati, S and Kal, S and Munoz-Mayorga, D and Tang, K and Sahoo, D and Chen, X and Mahata, SK},
title = {Catestatin peptide ameliorates tauopathy and amyloidogenesis via adrenergic inhibition.},
journal = {Molecular therapy : the journal of the American Society of Gene Therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ymthe.2026.09.022},
pmid = {42768750},
issn = {1525-0024},
abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Corticobasal Degeneration (CBD), and Progressive Supranuclear Palsy (PSP) are characterized by tau aggregation, neuroinflammation, and progressive cognitive decline. Although metabolic dysregulation and neuropeptide imbalance have been linked to these disorders, the functional consequences of this imbalance and its reversal remain poorly understood. Our previous work identified chromogranin A (CgA), the gene encoding a pro-hormone for several metabolic peptides, as a key regulator of tau pathology. Here, we investigate Catestatin (CST), a CgA-derived peptide, for its role in modulating tauopathy. We report marked reductions in CST levels and an increase in Pancreastatin (PST) in the hippocampus and cortex of AD brains, as well as in the frontal cortex of CBD and the basal ganglia of PSP. CST-supplementation in cortical neuronal cultures and organotypic slice cultures (OTSC) reduced Tau phosphorylation and aggregation. In vivo, CST administration to PS19 tauopathy mice decreased pathological Tau species, attenuated gliosis, improved cognitive function, and reduced amyloid burden and neuroinflammation in 5xFAD mice. Mechanistically, CST reduced epinephrine levels in PS19 and 5xFAD mice, suppressed Protein Kinase A hyperactivation in PS19 and OTSC, and revealed a link between CST deficiency, adrenergic stress signaling, tauopathy-mediated neurodegeneration, and the therapeutic potential of CST supplement.},
}

@article {pmid42768846,
year = {2026},
author = {Gantenberg, JR and La Joie, R and Heston, MB and Ackley, SF and , },
title = {Do amyloid trajectories reach a ceiling? Evidence from iterative approximation and simulation.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71781},
pmid = {42768846},
issn = {1552-5279},
support = {//NIH/NIA/ ; },
mesh = {Humans ; Positron-Emission Tomography ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology ; Algorithms ; *Amyloid beta-Peptides/metabolism ; *Brain/diagnostic imaging/metabolism/pathology ; Computer Simulation ; *Amyloid/metabolism ; },
abstract = {INTRODUCTION: Qualitative models of Alzheimer's disease (AD) pathology often posit that amyloid accumulation follows a sigmoid curve, indicating that the rate of deposition wanes over time. Longitudinal positron emission tomography (PET) data now allow us to investigate amyloid accumulation trajectories with greater detail and over longer follow-up periods.

METHODS: We combine inferences from simulated amyloid trajectories, empirical PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), and the sampled iterative local approximation algorithm (SILA) to assess whether amyloid accumulation reaches a physiologic ceiling.

RESULTS: SILA reliably detects a ceiling in simulated scenarios that impose a sigmoid shape. Fit to ADNI, SILA does not appear to indicate the presence of a ceiling.

DISCUSSION: Amyloid trajectories may not reach a physiologic ceiling during the stages of AD typically observed while patients remain under follow-up in cohort studies. Illustrative models of biomarker cascades, while useful for conceptualizing pathologic processes, may not represent amyloid trajectory shapes accurately.},
}

Humans
Positron-Emission Tomography
*Alzheimer Disease/diagnostic imaging/metabolism/pathology
Algorithms
*Amyloid beta-Peptides/metabolism
*Brain/diagnostic imaging/metabolism/pathology
Computer Simulation
*Amyloid/metabolism

@article {pmid42768849,
year = {2026},
author = {Sun, H and Xin, X and Yan, J and Huang, T},
title = {Comparative Risk of Nonarteritic Anterior Ischemic Optic Neuropathy Among Glucagon-Like Peptide-1 Receptor Agonists: An Integrated Safety and Mechanistic Analysis.},
journal = {Diabetes, obesity & metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1111/dom.71358},
pmid = {42768849},
issn = {1463-1326},
support = {//Young Clinical Scientist Training Program at Shanghai Medical College of Fudan University/ ; },
abstract = {AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for Type 2 diabetes (T2DM) and obesity, but emerging evidence links them to nonarteritic anterior ischemic optic neuropathy (NAION). Whether this risk differs across agents and the underlying mechanisms remains unclear. We aimed to compare the risks of NAION associated with different GLP-1RAs and to explore the potential molecular mechanisms underlying this adverse reaction.

MATERIALS AND METHODS: A network meta-analysis was performed to quantitatively compare the differences in NAION risk. Real-world pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS) were used for validation. Network toxicology was further applied to identify central hub targets and signalling pathways. Molecular docking was conducted to evaluate the binding capacity of GLP-1RAs to central hub targets.

RESULTS: The network meta-analysis revealed significant differences in NAION risk across GLP-1RAs. Compared with non-GLP-1RA treatments, semaglutide showed the highest risk (HR = 1.538, 95% CI: 1.305-1.816), followed by liraglutide (HR = 1.251, 95% CI: 1.080-1.450). FAERS pharmacovigilance analysis suggested a strong disproportionate signal for semaglutide (ROR = 94.534, 95% CI: 83.093-107.552) and a statistically significant but weaker signal for liraglutide (ROR = 4.519, 95% CI: 2.617-7.802). Network toxicology identified CASP3 as the central hub target, and pathway enrichment analysis revealed that the underlying mechanisms were primarily related to Alzheimer's disease, neurodegeneration pathways, and lipid and atherosclerosis pathways. Molecular docking suggested that semaglutide and liraglutide had high binding affinity to CASP3.

CONCLUSIONS: The combined strategy of network meta-analysis, pharmacovigilance, network toxicology and molecular docking provides insights into possible risk differences and potential mechanisms, and may guide future research on the safety profile of GLP-1RAs.},
}

@article {pmid42768864,
year = {2026},
author = {Scodari, BT and Brown, R and Jiang, X and Shen, C and Ferber, K and Wu, S and Gao, F and Bullain, S and Millen, B},
title = {Enhancing early Alzheimer's disease clinical trials through prognostic score covariate adjustment.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71849},
pmid = {42768864},
issn = {1552-5279},
support = {//Biogen/ ; },
mesh = {*Alzheimer Disease/diagnosis ; Humans ; Prognosis ; Disease Progression ; Female ; *Machine Learning ; Male ; Aged ; *Randomized Controlled Trials as Topic ; Mental Status and Dementia Tests ; *Clinical Trials as Topic ; },
abstract = {INTRODUCTION: A prognostic score (PS) summarizes a patient's expected disease progression and can increase the statistical efficiency of clinical trials when included as an analysis covariate.

METHODS: We pooled patient data from observational studies and randomized trials for early Alzheimer's disease (AD) and trained PS candidates to predict 18-month changes in the Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) score. The efficiency gains achieved through covariate adjustment were evaluated in a held-out trial (N = 650).

RESULTS: A machine learning PS achieved a Pearson correlation of 0.48 between predicted and observed CDR-SB changes in an internal test set (N = 398). Adjusting for this PS in the held-out trial increased power from 80% to 87.9% (95% confidence interval [CI]: 85.5%-90.2%) with the original sample size. Alternatively, this approach could reduce the required sample size by 19.7% (95% CI: 13.7%-25.7%) while maintaining 80% power.

DISCUSSION: Our findings support the use of PS adjustment for enhancing the efficiency of early AD trials.},
}

*Alzheimer Disease/diagnosis
Humans
Prognosis
Disease Progression
Female
*Machine Learning
Male
Aged
*Randomized Controlled Trials as Topic
Mental Status and Dementia Tests
*Clinical Trials as Topic

@article {pmid42768866,
year = {2026},
author = {Wang, Y and Chen, Y and Kong, H and Chen, W and Su, F and Zheng, Y and Fang, Y and Lin, L and Zhou, J and Li, Y and Zhang, Y and Huang, A and Bergeron, MF and Jr, JOC and Ashford, JW and Zhou, X and Dai, Z and Sheng, W and Pei, Z},
title = {Unmasking preclinical Alzheimer's pathology: auditory distraction cost and occupational reserve jointly discriminate amyloid positivity in subjective cognitive decline.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71874},
pmid = {42768866},
issn = {1552-5279},
support = {82271266//the National Natural Science Foundation of China/ ; c250130//Shenzhen Medical Research Fund/ ; 2022YFA1104904//the National Key Research and Development Program of China/ ; K0601902//Shanghai Medical Innovation and Development Foundation Project/ ; 2020B1212060017//Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases/ ; 2020B1111170002//Guangdong Provincial Clinical Research Center for Neurological Diseases/ ; 2015B050501003//Southern China International Joint Research Center for Early Intervention and Functional Rehabilitation of Neurological Diseases/ ; 2020A0505020004//Southern China International Joint Research Center for Early Intervention and Functional Rehabilitation of Neurological Diseases/ ; //Guangdong Provincial Engineering Center for Major Neurological Disease Treatment/ ; //Guangdong Provincial Translational Medicine Innovation Platform for Diagnosis and Treatment of Major Neurological Disease/ ; 201604020010//Guangzhou Clinical Research and Translational Center for Major Neurological Diseases/ ; },
mesh = {Humans ; Female ; Male ; *Cognitive Dysfunction/diagnosis/metabolism/pathology ; Aged ; *Alzheimer Disease/pathology/diagnosis/metabolism ; Positron-Emission Tomography ; *Amyloid beta-Peptides/metabolism ; *Cognitive Reserve/physiology ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Conventional cognitive instruments exhibit limited efficacy in detecting insidious cognitive decline in subjective cognitive decline (SCD) due to neural compensation. We hypothesized that auditory distraction during a visual memory task would unmask preclinical amyloid beta (Aβ) vulnerability.

METHODS: We evaluated 112 participants (SCD and mild cognitive impairment [MCI]) using the MemTrax test under quiet and noisy conditions to quantify distraction costs (d-MTxc). Aβ status and cognitive reserve were assessed via positron emission tomography and the Cognitive Reserve Index questionnaire (CRIq).

RESULTS: Aβ-positive SCD individuals performed normally in quiet but showed higher d-MTxc than Aβ-negative peers (11.17 ± 5.762 vs 6.67 ± 5.096). Higher CRIq-WorkingActivity (CRIW) scores identified Aβ positivity and moderated performance. The combination of d-MTxc and CRIW accurately classified Aβ positivity (AUC = 0.836), whereas MCI individuals exhibited metabolic network fragmentation.

DISCUSSION: Auditory distraction taxes cognitive capacity to expose compensatory failures coupled with Aβ burden. This paradigm, interacting with occupational reserve, offers a promising digital biomarker framework for preclinical Alzheimer's screening.},
}

Humans
Female
Male
*Cognitive Dysfunction/diagnosis/metabolism/pathology
Aged
*Alzheimer Disease/pathology/diagnosis/metabolism
Positron-Emission Tomography
*Amyloid beta-Peptides/metabolism
*Cognitive Reserve/physiology
Neuropsychological Tests

@article {pmid42768868,
year = {2026},
author = {Cervantes González, A and Morcillo-Nieto, AO and Serrano, S and Benejam, B and Videla, L and Barroeta, I and Fernández, S and Del Hoyo Soriano, L and Hernandez, AS and Maure-Blesa, L and Vaqué-Alcázar, L and Arranz, J and Rodríguez-Baz, Í and Aranha, MR and Perlaza, D and Lidón, L and Alcolea, D and Bejanin, A and Carmona-Iragui, M and Fortea, J and Lleó, A and Otto, M and Oeckl, P and Belbin, O},
title = {Changes in serum β-synuclein precede blood biomarkers of Alzheimer pathology in Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71860},
pmid = {42768868},
issn = {1552-5279},
support = {23-PPG-674-2//ALS Association/ ; SFB1279//Deutsche Forschungsgemeinschaft/ ; FTLDc//Bundesministerium für Forschung und Technologie/ ; 01GI1007A//Bundesministerium für Forschung und Technologie/ ; R01AG061566/AG/NIA NIH HHS/United States ; FI22/00241//Instituto de Salud Carlos III/ ; 2021 SGR 00979//Departament de Salut, Generalitat de Catalunya/ ; AARG-22-923680/ALZ/Alzheimer's Association/United States ; 101156566//HORIZON EUROPE Health/ ; },
mesh = {Humans ; *Down Syndrome/blood/complications/pathology ; Female ; *Alzheimer Disease/blood/pathology/complications ; Biomarkers/blood ; Male ; *beta-Synuclein/blood ; Cross-Sectional Studies ; Middle Aged ; Adult ; tau Proteins/blood ; Neurofilament Proteins/blood ; Glial Fibrillary Acidic Protein/blood ; Aged ; Brain/pathology ; },
abstract = {INTRODUCTION: There is a need for early, objective markers of Alzheimer's disease (AD)-related synapse dysfunction in adults with Down syndrome (DS). The presynaptic protein β-synuclein is elevated in the blood of adults with DS. This study evaluates the positioning of these changes relative to changes in pathophysiological blood biomarkers along the AD continuum.

METHODS: We quantified serum β-synuclein using immunoprecipitation-mass spectrometry in a cross-sectional cohort (n = 131) spanning the AD continuum in adults with DS (n = 88) and cognitively unimpaired euploid controls (n = 43).

RESULTS: β-synuclein levels were elevated in individuals with DS (p < 0.001), preceding symptom onset by two decades and changes in other blood biomarkers (tau phosphorylated at threonine 217, neurofilament light, glial fibrillary acidic protein) by several years. Higher β-synuclein was associated with cortical atrophy (p < 0.001) and hypometabolism (p < 0.001) in AD-vulnerable regions and reduced episodic memory (p < 0.009).

DISCUSSION: These findings consolidate β-synuclein as an early blood-based biomarker of synaptic dysfunction and provide insight into early AD-related mechanisms.},
}

Humans
*Down Syndrome/blood/complications/pathology
Female
*Alzheimer Disease/blood/pathology/complications
Biomarkers/blood
Male
*beta-Synuclein/blood
Cross-Sectional Studies
Middle Aged
Adult
tau Proteins/blood
Neurofilament Proteins/blood
Glial Fibrillary Acidic Protein/blood
Aged
Brain/pathology

@article {pmid42768871,
year = {2026},
author = {Yetim, E and Ayhan, Y and Yildirim, MA and Volkan-Salanci, B and Ergün, EL and Çakmakli, GY},
title = {The Diagnostic Role of FDG-PET in Dementias Presenting with Language and Behavioral Symptom.},
journal = {Turk psikiyatri dergisi = Turkish journal of psychiatry},
volume = {37},
number = {},
pages = {77-82},
doi = {10.5080/u27876},
pmid = {42768871},
issn = {2651-3463},
mesh = {Humans ; *Positron-Emission Tomography ; Female ; Fluorodeoxyglucose F18 ; Male ; Biomarkers/cerebrospinal fluid ; Aged ; *Alzheimer Disease/diagnostic imaging/cerebrospinal fluid ; Middle Aged ; Neuropsychological Tests ; Radiopharmaceuticals ; Diagnosis, Differential ; Amyloid beta-Peptides/cerebrospinal fluid ; *Frontotemporal Lobar Degeneration/diagnostic imaging/cerebrospinal fluid ; },
abstract = {OBJECTIVE: This study aimed to assess the diagnostic contribution of Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) in neurodegenerative dementias presenting with language-predominant symptoms, with or without accompanying behavioral changes, and to evaluate the correspondence between PET-derived metabolic patterns and cerebrospinal fluid (CSF) biomarkers.

METHODS: Sixteen patients with language-predominant onset were categorized into two groups: Alzheimer’s disease (AD) spectrum (n=8) and the frontotemporal lobar degeneration (FTLD) spectrum (n=8). All participants underwent clinical evaluation, neuropsychological testing, and FDG-PET imaging. Cerebrospinal fluid biomarkers [Amyloid Beta (Aβ42), total tau, and phosphorylated tau] were analyzed in eligible individuals (n=6). The two groups were compared across demographic, clinical, and neuroimaging parameters.

RESULTS: FDG-PET revealed pronounced posterior temporoparietal hypometabolism in AD-spectrum patients, whereas FTLD-spectrum patients demonstrated frontal, insular, and anterior temporal metabolic involvement. Cerebrospinal fluid biomarker profiles consistently supported Alzheimer-type pathology among AD-spectrum cases. In the FTLD group, one patient exhibited borderline-low Aβ42; however, the corresponding FDG-PET pattern was characteristic of FTLD.

CONCLUSION: FDG-PET demonstrates a supportive role in differentiating AD from FTLD among patients presenting with language-predominant neurodegenerative syndromes. In scenarios where CSF biomarkers are unavailable or yield borderline values, FDG-PET-based metabolic signatures may offer additional guidance and can contribute to strengthening multimodal diagnostic frameworks in geropsychiatry settings.},
}

Humans
*Positron-Emission Tomography
Female
Fluorodeoxyglucose F18
Male
Biomarkers/cerebrospinal fluid
Aged
*Alzheimer Disease/diagnostic imaging/cerebrospinal fluid
Middle Aged
Neuropsychological Tests
Radiopharmaceuticals
Diagnosis, Differential
Amyloid beta-Peptides/cerebrospinal fluid
*Frontotemporal Lobar Degeneration/diagnostic imaging/cerebrospinal fluid

@article {pmid42768912,
year = {2026},
author = {Williams, CA and Rose, SE and Stamenkovic, V and Reid, AN and Travaglini, KJ and Smith, SEP and Young, JE},
title = {The Alzheimer's disease risk gene SORL1 is a regulator of excitatory neuronal function.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71862},
pmid = {42768912},
issn = {1552-5279},
support = {P01AG079787//NIH/ ; T32AG52354/AG/NIA NIH HHS/United States ; MH113545//National Institute of Mental Health and Neurosciences/ ; //Cure Alzheimer's Fund/ ; 23AARG-1022491/ALZ/Alzheimer's Association/United States ; },
mesh = {*LDL-Receptor Related Proteins/genetics/metabolism ; Humans ; *Neurons/metabolism/physiology ; *Alzheimer Disease/genetics/metabolism ; *Membrane Transport Proteins/genetics/metabolism ; Animals ; Cells, Cultured ; Cerebral Cortex ; },
abstract = {INTRODUCTION: Synaptic dysfunction is an early feature of Alzheimer's disease (AD) and proper localization of proteins involved in pre- and post-synaptic composition is dependent on endosomal recycling and trafficking, cellular processes involving the AD risk gene sortilin-related receptor 1 (SORL1).

METHODS: We examined SORL1's role in synaptic protein composition and neuronal function in human excitatory cortical neurons. Synaptic protein interactions were analyzed using a mesoscale proteomics assay. Immunocytochemistry was used to visualize synaptic proteins and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits. Neuronal function was measured with multi-electrode arrays.

RESULTS: Loss of SORL1 expression significantly changes many synaptic protein-protein interactions and patterns of expression. SORL1-deficient neurons exhibit hyperactivity that is primarily amyloid beta independent. SORL1-deficient neurons also have impaired network plasticity.

DISCUSSION: These findings further support a growing body of literature implicating early endosomal recycling defects as drivers of AD pathogenesis.},
}

*LDL-Receptor Related Proteins/genetics/metabolism
Humans
*Neurons/metabolism/physiology
*Alzheimer Disease/genetics/metabolism
*Membrane Transport Proteins/genetics/metabolism
Animals
Cells, Cultured
Cerebral Cortex

@article {pmid42769145,
year = {2026},
author = {Li, J and Liu, G and Wang, X and Song, Z and Chen, H and Hou, H and Hu, Q},
title = {Adult-onset hippocampal α7 nicotinic acetylcholine receptor loss rapidly drives Alzheimer-like neuropathology in mice.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1929468},
pmid = {42769145},
issn = {1663-9812},
abstract = {INTRODUCTION: The reduction of α7 nicotinic acetylcholine receptor (nAChR) in the hippocampus con-stitutes one of the neuropathological features observed in the brains of individuals with Alzheimer's disease (AD), and α7 nAChR is crucial to cognitive process. However, studies involving α7 nAChR knockout mice have not demonstrated any abnormal brain structure or damage to hippocampal neurons, a discrepancy likely driven by widespread developmental compensatory signaling reprogramming triggered by permanent whole-body α7 nAChR deletion from embryonic stages. This limitation renders traditional knockout lines unable to recapitulate the adult-onset, hippocampus-restricted α7 nAChR insufficiency characteristic of human AD, creating an unaddressed knowledge gap regarding whether isolated α7 nAChR loss in mature hippocampal neurons independently drives AD-related neurodegeneration and cognitive dysfunction.

METHODS: To resolve this limitation, we established a spatially and temporally restricted knockdown mouse model via stereotaxic intrahippocampal injection of adeno-associated virus encoding Chrna7-targeted short hairpin RNA (shRNA) in 4-month-old mice. We assessed behavioral performance via open field test, novel object recognition test, Y-maze and Barnes maze 1 month post-viral delivery to quantify cognitive function; 2 months after injection, we harvested brain tissues to measure Aβ deposition, tau hyperphosphorylation, neuronal loss, astrocytic and microglial activation using immunofluorescence staining, and performed transcriptome RNA sequencing to profile genome-wide transcriptional alterations.

RESULTS: The knockdown of α7 nAChR in the hippocampus of adult mice rapidly induced cognitive deficits, impairments in learning and memory, and led to the increase of amyloid-β levels, Tau protein aggregation, neuronal damage, and the activation of astrocytes and microglia. Transcriptomic analysis revealed that the differentially expressed genes were significantly enriched in pathways related to inflammatory signaling.

DISCUSSION: Our study demonstrates that selective depletion of hippocampal α7 nAChR in adult mice is sufficient to trigger a spectrum of AD-like pathological alterations. Importantly, our AAV-mediated region-specific knockdown paradigm fully eliminates the developmental compensatory bias inherent to constitutive global α7 nAChR knockout animals by restricting receptor suppression exclusively to mature hippocampal neurons in post-developmental mice, closely recapitulating the spatial-temporal pattern of α7 nAChR loss in human AD brains. Our work provides novel pharmacological insights into α7 nAChR as a promising therapeutic target for AD pathological intervention.},
}

@article {pmid42769165,
year = {2026},
author = {Yang, L and Yu, H and Hong, ZY and Liu, Z and Li, XJ and Ye, F},
title = {Resting-state EEG biomarkers of general and domain-specific cognitive impairment and plasma P-tau217 in patients with Alzheimer's disease and mild cognitive impairment.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1875216},
pmid = {42769165},
issn = {1664-2295},
mesh = {Humans ; *Alzheimer Disease/blood/physiopathology/diagnosis ; *Cognitive Dysfunction/physiopathology/blood/diagnosis ; Female ; *Electroencephalography ; Biomarkers/blood ; *tau Proteins/blood ; Male ; Aged ; Middle Aged ; Early Diagnosis ; },
abstract = {BACKGROUND: Early detection of Alzheimer's disease (AD)-related cognitive impairment remains challenging due to the lack of convenient, non-invasive screening tools.

OBJECTIVE: To explore the multidimensional utility of quantitative electroencephalography (EEG) as a complementary tool for early detection of AD-related cognitive impairment.

METHODS: Clinical data, electroencephalogram (EEG) records, cognitive scale scores and blood samples were collected. According to the established clinical diagnostic criteria, the participants were divided into three groups: cognitive normal group, mild cognitive impairment group (MCI) and Alzheimer's disease (AD) dementia group. Traditional statistical methods and machine learning algorithms were used to analyze the correlation between 200 EEG indexes and the severity of cognitive impairment, domain-specific cognitive impairment and plasma P-tau217 concentration.

RESULTS: A total of 360 participants (154 dementia patients with Alzheimer's disease, 116 mild cognitive impairment patients and 90 healthy controls) were included. The area under the curve (AUC) of EEG in 360 participants is 0.70-0.87, which can effectively distinguish cognitive dysfunction related to Alzheimer's disease. Among them, 102 participants improved the cognitive domain assessment scale, and the results showed that several EEG indexes were correlated with cognitive domain function score. The blood samples of 105 normal and MCI participants were tested for blood P-tau217 concentration. The relative power of right temporal lobe and right parietal lobe was negatively correlated with blood P-tau217 concentration, and the relative power of right parietal lobe was an independent influencing factor for the increase of blood P-tau217 level (AUC = 0.68).

CONCLUSION: Quantitative EEG indicators show potential as a complementary screening approach for AD-related cognitive impairment. Further validation in prospective, multicenter cohorts is needed before implementation in clinical practice.},
}

Humans
*Alzheimer Disease/blood/physiopathology/diagnosis
*Cognitive Dysfunction/physiopathology/blood/diagnosis
Female
*Electroencephalography
Biomarkers/blood
*tau Proteins/blood
Male
Aged
Middle Aged
Early Diagnosis

@article {pmid42769265,
year = {2026},
author = {Shen, L and Tong, W and Zhao, Y and Wu, B and Zhang, P and Kan, J},
title = {Explainable machine learning for Alzheimer's disease characterization using small-sample EEG data.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1900857},
pmid = {42769265},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is associated with progressive cognitive decline and altered brain functional activity, yet objective and interpretable electrophysiological indicators remain insufficiently established. Resting-state electroencephalography (EEG) offers a low-cost and clinically accessible candidate, provided that the analysis is validated at the subject level and remains interpretable. This study evaluated an interpretable resting-state EEG framework for distinguishing AD patients from healthy control (HC) subjects. A total of 63 participants (36 AD and 27 HC) from a publicly available dataset were included. Subject-level spectral and nonlinear complexity features were extracted from 19 preprocessed scalp channels; missing-value imputation, feature screening, redundancy pruning, scaling, and model fitting were carried out within each fold of leave-one-subject-out cross-validation. Four linear classifiers were compared, and Ridge Logistic regression was retained for out-of-fold SHAP interpretation because of its balanced hard-label performance and direct compatibility with Linear SHAP. Ridge Logistic regression achieved an exploratory AUC of 0.912 (accuracy = 0.857, sensitivity = 0.778, specificity = 0.963) under a non-nested validation design. Across 30 independently balanced epoch resamples, mean AUC was 0.887 ± 0.020; using all accepted epochs yielded AUC = 0.917. SHAP analysis indicated that the classifier drew jointly on posterior α activity, frontal and temporal θ power, the θ/α ratio, and slow/fast ratio features. A classifier-independent microstate analysis revealed reduced putative Class B occurrence, increased putative Class C and Class D duration, and six FDR-corrected off-diagonal transition differences in AD; the three temporal effects persisted across repeated K = 4 initializations and matched K = 3-6 solutions. These findings suggest that resting-state EEG can provide non-invasive and interpretable information about AD-related functional alterations, pending validation in larger, independent cohorts.},
}

@article {pmid42769274,
year = {2026},
author = {Schechter, M and Sehtman-Shachar, DR and Fishkin, A and Mosenzon, O and Cukierman-Yaffe, T and Sharon, R and Leibowitz, G and Arkadir, D and Aharon-Hananel, G},
title = {Dementia progression with GLP-1 receptor agonists in people with mild cognitive impairment and type 2 diabetes: target-trial emulation study.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70315},
pmid = {42769274},
issn = {2352-8737},
abstract = {INTRODUCTION: In people with type 2 diabetes (T2D) without dementia, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improved cardiovascular, kidney, and mortality outcomes, with multiple real-world studies suggesting reduced risk of dementia onset. However, the EVOKE/EVOKE+ randomized-controlled trials (RCTs) found that oral semaglutide did not slow cognitive decline in individuals with early Alzheimer's disease (AD), most (86%) without T2D. It is unclear whether GLP-1 RA therapy influences progression to dementia in people with both T2D and mild cognitive impairment (MCI).

METHODS: In a target-trial emulation hypothesis-generating study using TriNetX global collaborative network data, we compared incident dementia (including AD) in adults with MCI and T2D without dementia, who were new users of GLP-1 RAs versus dipeptidyl peptidase-4 inhibitors (DPP4i).

RESULTS: We included 1320 propensity-score-matched (1:1) individuals who initiated GLP-1 RAs or DPP4i in the period 2010 to 2021 (702 women; mean age 67.2 years). Over up to 5 years of follow-up, incident dementia occurred in 101 and 132 participants initiating GLP-1 RAs and DPP4i, respectively (Cox proportional hazard ratio 0.74 [95% confidence interval [CI]: 0.57 to 0.95]). At a mean follow-up of 3.9 years, the respective Kaplan-Meier-derived cumulative incidences were 15.5% and 20.4% (absolute difference -4.9% [95% CI -9.4 to -0.4], number needed to treat of 21 [11 to 234] individuals to prevent one event). Various sensitivity analyses supported the primary analysis: comparing GLP-1 RAs with basal insulin, using alternative outcome definitions, repeating the analyses across baseline subgroups, and using a negative control outcome.

CONCLUSION: In this hypothesis-generating study, initiation of GLP-1 RAs versus DPP4i in people with T2D and MCI without dementia was associated with a lower risk of incident dementia.},
}

@article {pmid42769492,
year = {2026},
author = {Dong, K and Lang, J and Fu, J and Lan, J and Xu, F and Cheng, T and Jin, T and Wang, H and Wu, X and Luo, F},
title = {Total intravenous anesthesia facilitates early cognitive recovery compared with inhalational anesthesia in Alzheimer's disease patients after cervical lymphatic-venous anastomosis: a randomized controlled trial.},
journal = {American journal of translational research},
volume = {18},
number = {8},
pages = {7320-7330},
pmid = {42769492},
issn = {1943-8141},
abstract = {BACKGROUND: The optimal anesthesia method for Alzheimer's disease (AD) patients undergoing cervical lymphatic-venous anastomosis remains unclear. This study compared the effects of three general anesthesia techniques on postoperative cognitive outcomes in AD patients.

METHODS: In this prospective randomized controlled trial, 132 AD patients were assigned (1:1:1) to receive total intravenous anesthesia (TIVA), total inhalation anesthesia (IH), or combined intravenous-inhalation anesthesia (CI). The primary outcome was cognitive function assessed by MMSE, MoCA and CDR at postoperative day 7 (P7), P90 and P180. The secondary outcome was ADL scores at P180.

RESULTS: A total of 123 patients completed the study. At P7, MMSE scores in the TIVA group significantly improved from baseline (P < 0.05) and were superior to the IH and CI groups, which showed no significant change. At P90, MMSE scores improved in all three groups (P < 0.05), but returned to baseline by P180. No significant differences were observed in MoCA, CDR, or ADL scores at any time point.

CONCLUSION: Among the three anesthesia methods, TIVA was associated with better early cognitive performance at P7 as measured by MMSE, compared with inhalational anesthesia. However, this benefit was not sustained to P180 and no significant changes were observed in MoCA or CDR scores at any time point. These findings suggest that TIVA may reduce early postoperative psychomotor disturbance rather than confer sustained neurocognitive recovery in this population.},
}

@article {pmid42769555,
year = {2026},
author = {Huang, L and Cheng, P and Liu, G and Xiang, Y and Hong, Z and Le, W},
title = {Myelin Impairment and Regeneration in the Central Nervous System: Molecular Mechanisms, Diseases, and Prospective Therapeutic Targets.},
journal = {MedComm},
volume = {7},
number = {10},
pages = {e71017},
pmid = {42769555},
issn = {2688-2663},
abstract = {Myelin plasticity is fundamental to the formation of neural networks and the optimization of neural functions, shaping circuits governing emotion, cognition, sensation, and motor control. Synthesized by oligodendrocytes, myelin undergoes lifelong remodeling that demands high metabolic activity; this renders the myelin-oligodendrocyte unit highly susceptible to metabolic stress, aging, and pathological insults. While demyelination is the core hallmark of various chronic neurological disorders, this review specifically highlights its emerging role in Alzheimer's disease (AD). Myelin impairment is increasingly recognized as an early pathological event in AD, potentially preceding the classic accumulation of amyloid plaques and neurofibrillary tangles. Here, we provide a comprehensive overview of myelin structure and function, evaluating the potential of tracking myelin changes as early diagnostic biomarker for AD. We further synthesize recent evidence regarding myelin pathology across a spectrum of central nervous system disorders including multiple sclerosis, leukodystrophies, cerebral small vessel disease, psychiatric disorders, and traumatic injury, highlighting the underlying pathological mechanisms. Furthermore, we examine emerging therapeutic strategies, ranging from pharmacological interventions to noninvasive stimulation, aimed at restoring oligodendroglial function and promoting remyelination. Finally, we offer a forward-looking perspective on myelin regeneration research, emphasizing its critical potential as a novel therapeutic target for AD and other neurodegenerative conditions.},
}

@article {pmid42769580,
year = {2026},
author = {Li, M and Wang, Q and Li, J and Liu, Y and Chen, L and Liu, P and Guo, J},
title = {Spatial omics of neuroinflammation: insights across brain diseases.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1923995},
pmid = {42769580},
issn = {1664-3224},
mesh = {Humans ; Multiomics ; *Neuroinflammatory Diseases/metabolism/pathology/etiology ; Animals ; *Brain Diseases/metabolism/pathology ; Spatial Transcriptomics ; Proteomics/methods ; *Brain/metabolism/pathology ; Metabolomics/methods ; Microglia/metabolism ; },
abstract = {Neuroinflammation is a common pathological feature of diverse brain diseases, but inflammatory activity is rarely distributed uniformly across diseased tissue. Instead, microglia, astrocytes, infiltrating immune cells and inflammatory mediators are often organized around specific pathological structures, including amyloid plaques, demyelinated lesion rims, ischemic borders, necrotic tumor regions and perivascular white matter compartments. Although bulk and dissociation-based single-cell approaches have defined many inflammatory cell states, they cannot determine where these states reside, how they relate to local pathology, or whether inferred cell-cell interactions occur within plausible spatial neighborhoods. Spatial omics addresses this limitation by preserving molecular information within intact tissue architecture. In this review, we summarize major spatial transcriptomic, proteomic, metabolomic and same-section multi-omic technologies, with emphasis on the types of neuroinflammatory questions each platform can answer. We then examine how spatial omics has reshaped the understanding of neuroinflammation across Alzheimer's disease and tauopathies, multiple sclerosis, ischemic stroke, glioma, infection-related neuroinflammation and aging. Across these settings, spatial studies have revealed plaque-associated glial niches, lipid- and iron-enriched lesion rims, core-penumbra inflammatory zonation, and hypoxic or perivascular immune microenvironments. These findings suggest that neuroinflammation should be understood not only as a set of molecular or cellular states, but also as a spatially organized tissue process shaped by local pathology, cellular adjacency and microenvironmental gradients and spatial compartments. Finally, we discuss the limitations of current spatial maps, including resolution, human tissue constraints and insufficient functional validation, and outline future directions toward integrated, temporal and clinically translatable spatial atlases.},
}

Humans
Multiomics
*Neuroinflammatory Diseases/metabolism/pathology/etiology
Animals
*Brain Diseases/metabolism/pathology
Spatial Transcriptomics
Proteomics/methods
*Brain/metabolism/pathology
Metabolomics/methods
Microglia/metabolism

@article {pmid42769715,
year = {2026},
author = {Arriola-Pacheco, F and Pinzón-Té, AL and Serrano-Piña, R and Carrillo-Ávila, BA and Díaz-Zúñiga, J and Melgar-Rodríguez, S and Martínez-Aguilar, VM},
title = {Periodontitis and Alzheimer's disease, common pathways in down syndrome.},
journal = {Frontiers in dental medicine},
volume = {7},
number = {},
pages = {1930049},
pmid = {42769715},
issn = {2673-4915},
abstract = {Down Syndrome (DS) involves widespread systemic issues, including a near-universal development of early-onset Alzheimer's Disease, driven by factors beyond Amyloid Precursor Protein (APP) over-expression, such as chronic neuroinflammation and endosomal dysfunction. High prevalence of periodontitis in this population acts as a significant source of peripheral inflammation that may accelerate this cognitive decline, necessitating further study into the bidirectional, pro-inflammatory links between systemic health and neurodegeneration in DS. This review analyzes the common pathophysiological pathways linking periodontitis and AD development within the DS population, evaluating how oral dysbiosis acts as a systemic driver of neurodegeneration. We synthesized current molecular, microbiological, and clinical evidence evaluating the bidirectional relationships between trisomy 21-induced immune dysfunction, severe periodontitis, and accelerated cognitive decline. Individuals with DS exhibit a heightened susceptibility to aggressive, early-onset periodontitis starting as early as age six. This chronic oral dysbiosis facilitates microbial translocation, allowing periodontal pathogens (e.g., Porphyromonas gingivalis) and their virulence factors to cross the blood-brain barrier via circulatory or trigeminal routes. In the central nervous system, these pathogens encounter microglial populations already genetically primed by trisomy 21. This induces an exacerbated M1 microglial phenotype response, triggering sustained neuroinflammation, defensive over-deposition of Amyloid-β (Aβ) plaques, and upregulation of GSK-3β, which accelerates Tau protein hyperphosphorylation. While bidirectional links are strongly indicated, current literature lacks robust longitudinal studies connecting periodontal, microbiological, and cognitive data to establish definitive causality. Early clinical intervention and management of gum disease present a critical therapeutic window to delay the onset and slow the progression of AD in this vulnerable population.},
}

@article {pmid42769797,
year = {2026},
author = {Patel, MM and Nguyen, MD and Pistone, ES and Chowdhury, A and Phan, MH and El Ayadi, A and Song, J and Erickson, M},
title = {Out of the Fire, Into the Fog: Association Between Early Mechanical Ventilation and Delirium in Hospitalized Burn Patients.},
journal = {Cureus},
volume = {18},
number = {8},
pages = {e114981},
pmid = {42769797},
issn = {2168-8184},
abstract = {Introduction Delirium is a common and clinically significant complication among hospitalized burn patients, associated with increased morbidity, mortality, and healthcare utilization. While multiple factors contribute to delirium risk, mechanical ventilation has been associated with delirium, although this relationship may reflect underlying illness severity and ICU-level treatment exposure. However, large-scale, multicenter administrative analyses comparing coded outcomes between mechanically ventilated and non-ventilated burn patients remain limited. Methods A retrospective cohort study was conducted using the TriNetX (TriNetX, LLC, Cambridge, Massachusetts, United States) database to identify adult hospitalized burn patients with International Classification of Diseases (ICD)-coded burns involving ≥20% total body surface area. Patients were stratified into two cohorts based on receipt of mechanical ventilation within five days of the index burn event. Exclusion criteria included age <18 years and diagnoses of dementia, Alzheimer's disease, substance use disorders, or other conditions associated with baseline cognitive impairment. Cohorts were propensity score matched for age, sex, race, ethnicity, ICD-coded burn extent history, hypertension, diabetes, ischemic heart disease, sepsis, inhalation injury, and respiratory disorders. Outcomes assessed within 30 days included administratively documented delirium, disorientation, mortality, anxiety disorders, depressive disorders, and acute stress-related disorders. Results There were 1,541 patients in each cohort after matching. Ventilated patients had higher rates of administratively documented delirium (risk ratio (RR): 2.16, 95% CI: 1.51-3.09, p<0.0001), mortality (RR: 5.06, 95% CI: 4.23-6.05, p<0.0001), anxiety disorders (RR: 1.88, 95% CI: 1.58-2.21, p<0.0001), disorientation (RR: 3.39, 95% CI: 2.27-5.06, p<0.0001), and acute stress-related disorders (RR: 1.77, 95% CI: 1.40-2.22, p<0.0001). Depressive disorders were not significantly different between cohorts (RR: 1.42, 95% CI: 0.85-2.39, p=0.19). Discussion Early mechanical ventilation was associated with higher rates of administratively documented delirium, mortality, anxiety disorders, disorientation, and acute stress-related disorders among adult hospitalized burn patients. However, these findings likely reflect both ICU-level treatment exposure and substantial residual confounding by underlying illness severity. Early mechanical ventilation may identify a high-risk subgroup that warrants structured neurocognitive monitoring, psychological screening, sedation-conscious care, and post-extubation support. Given the observational design and reliance on administrative coding, these findings should be interpreted as hypothesis-generating.},
}

@article {pmid42769842,
year = {2026},
author = {Hou, C and Gao, Y and Wang, H},
title = {Exercise timing as a potential temporal regulator of neurolymphatic physiology in neurodegenerative proteinopathies: a mechanistic framework.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1879617},
pmid = {42769842},
issn = {1662-4548},
abstract = {Although physical activity is consistently associated with lower risks of cognitive decline, dementia, and Parkinson's disease, most exercise research in neurodegeneration still defines exposure by dose-based variables such as duration, intensity, frequency, step count, and cardiorespiratory fitness. This framework is useful for public-health guidance but biologically incomplete for progressive proteinopathies, in which the temporal accumulation and dissemination of misfolded proteins are central to disease evolution. In this review, we propose a temporal intervention framework in which exercise timing is treated as a mechanistic variable that may influence neurodegenerative biology through glymphatic-meningeal lymphatic clearance, vascular pulsatility, circadian alignment, and sleep architecture. We focus on Alzheimer's disease and Parkinson's disease because tau and α-synuclein propagation are disease-relevant processes that may be most amenable to intervention during preclinical or prodromal stages. Morning exercise may act primarily through circadian entrainment, afternoon exercise through vascular-metabolic stimulation, appropriately timed evening or low-intensity activity through sleep-related pathways, and sedentary fragmentation through effects on daytime cerebrovascular dynamics and rest-activity rhythm stability. Although the glymphatic-meningeal lymphatic axis provides a plausible link between timed exercise and extracellular protein handling, current human evidence remains indirect and relies heavily on imaging surrogate markers. Future matched-dose trials should integrate accelerometry, sleep physiology, circadian measures, vascular assessments, neurolymphatic imaging, and disease-specific protein biomarkers, including tau PET, plasma p-tau217, and α-synuclein seed amplification assays. Timed exercise should therefore be viewed as a testable biological perturbation that may clarify whether movement timing influences protein propagation in early neurodegenerative disease, not as a proven disease-modifying treatment.},
}

@article {pmid42770059,
year = {2026},
author = {Miller, DA and Price, HB and Wang, W and Wax, A},
title = {OCT-guided angle-resolved low-coherence interferometry for microstructural analysis of the human retina.},
journal = {Biomedical optics express},
volume = {17},
number = {9},
pages = {4870-4883},
pmid = {42770059},
issn = {2156-7085},
abstract = {Angle-resolved low-coherence interferometry (a/LCI) is an optical technique for extracting depth-resolved angular scattering profiles from biological tissues. Analysis of these angular scattering profiles can be used to compute the two-point spatial correlation function, which enables quantification of tissue structural heterogeneity at sub-cellular length scales. Building on previous work that combined a/LCI and optical coherence tomography (OCT) to detect biomarkers of Alzheimer's disease (AD) in ex vivo murine models, this study seeks to translate the platform for noninvasive scattering analysis of the human retina. The resulting system combines OCT image guidance, enabled by our high-performance, low-cost OCT platform, with parafoveal angular scattering measurements in each retinal quadrant, using 2D a/LCI. Measurements from 11 healthy participants were used to characterize retinal microstructure at length scales ranging from 4.8 μm to 9.5 μm. Our results revealed consistent variations in the structural correlations across retinal layers and quadrants, establishing baseline healthy measurements for future studies. This dual-modality approach offers a promising framework for improving diagnostic sensitivity in a variety of retinal and neurological disorders.},
}

@article {pmid42770090,
year = {2026},
author = {Zhuang, F and Wen, Z and Davatzikos, C and Shen, L},
title = {Expert-Driven Survival Machines: Improving Stratification and Interpretability in Multiple Clinical Cohorts.},
journal = {ACM-BCB ... ... : the ... ACM Conference on Bioinformatics, Computational Biology and Biomedicine. ACM Conference on Bioinformatics, Computational Biology and Biomedicine},
volume = {2026},
number = {},
pages = {29},
pmid = {42770090},
abstract = {Survival prediction plays a central role for healthcare providers and clinical researchers. Accurate risk stratification enables early intervention and improved patient management. Most existing deep survival models learn one common feature representation for all patients, which may hide important differences between patient subgroups. In contrast, a Mixture-of-Experts (MoE) framework allows different parts of the model to focus on different patient patterns, leading to more individualized representations. Therefore, in this work, we propose a mixture-of-experts enhanced adaptive deep clustering survival framework (AdaCSM) for modeling such heterogeneous survival patterns. We introduce a routing-based expert mechanism that enables conditional specialization within a parametric survival modeling framework. The proposed architecture allocates patients to specialized risk predictors dynamically while preserving the patient survival and subtype clustering objectives. We compare our method with state-of-the-art survival and deep clustering models on multiple real-world longitudinal clinical cohorts spanning diverse disease domains. The proposed method demonstrates improved predictive performance and leads to interpretable results in survival analysis.},
}

@article {pmid42770357,
year = {2026},
author = {Sahu, K and Sahu, R and Mishra, M and Chhabra, N and Tiwari, S and Kaur, K and Rathore, H and Lodhi, R and Sulakhiya, K},
title = {Designing Multi-functional Antioxidants for Neurodegenerative Disorders.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575494157260901095536},
pmid = {42770357},
issn = {1875-5607},
abstract = {Neurodegenerative disorders (NDs), including Alzheimer's disease, Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD) and Multiple Sclerosis (MS), pose a major global health threat due to complex pathology, increased prevalence, and lack of effective therapies. Numerous findings have indicated that oxidative stress (OS) is a central and unifying pathological mechanism driving neuronal dysfunction and degeneration across these disorders. Excessive reactive oxygen species (ROS) and nitrogen species (RNS) generation, coupled with impaired endogenous antioxidant defenses, leads to lipid peroxidation, protein misfolding, nucleic acid damage, mitochondrial dysfunction, neuroinflammation, metal dyshomeostasis, and disruption of the blood-brain barrier (BBB). These interconnected processes form self-perpetuating pathogenic cycles that accelerate synaptic failure and neuronal loss. This review is a compilation of thoroughly searched literature from the last 20 years (2006-2026) on OS-mediated neurodegeneration and emerging antioxidant-based therapeutic strategies for neurodegenerative disorders, sourced from PubMed, Scopus, ScienceDirect, Google Scholar, and Web of Science. Relevant articles were selected using specific keywords "Neurodegenerative Disorders", Neurodegenerative disorders and antioxidants", "Alzheimer's Disease and Oxidative Stress", "Parkinson's Disease and Oxidative Stress", "Alzheimer's Disease and Multi-functional Antioxidants", "Parkinson's Disease and Multifunctional Antioxidants", "Neurodegenerative Disorders and Antioxidant therapies". Despite strong mechanistic support, conventional antioxidant-based therapies have demonstrated limited clinical success, largely due to poor bioavailability, inadequate BBB penetration, and failure to address the multifactorial nature of neurodegeneration. Consequently, there is a paradigm shift toward the development of multi-functional antioxidants capable of simultaneously targeting multiple redoxdriven pathways. Such agents are designed to combine free-radical scavenging, metal chelation, mitochondrial protection, modulation of redox-sensitive signaling pathways, and regulation of neuroinflammatory responses within a single therapeutic framework. By restoring redox homeostasis while preserving physiological redox signaling, multi-functional antioxidants offer a rational and promising disease-modifying strategy. This review critically examines OS-mediated mechanisms underlying major NDs and emphasizes the therapeutic potential of designed multi-functional antioxidants as next-generation neuroprotective agents.},
}

@article {pmid42770359,
year = {2026},
author = {Kumari, N and Dwivedi, S and Yadav, S and Kosey, S},
title = {Ferroptosis in Neurodegenerative Diseases: Iron Dysregulation, GPX4/FSP1 Signaling, and Emerging Neuroprotective Strategies.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026502165260904054005},
pmid = {42770359},
issn = {1875-5739},
abstract = {INTRODUCTION: Neurodegenerative Diseases (NDDs), including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease (HD), and Multiple Sclerosis (MS), are increasingly associated with ferroptosis, a regulated irondependent form of cell death characterised by the excessive accumulation of lipid peroxides.

METHODS: This review examines the molecular underpinnings of ferroptosis, focusing on dysregulation in iron homeostasis, increased vulnerability of polyunsaturated fatty acids in neuronal membranes, and impairment of antioxidant defence systems, particularly the Glutathione-GPX4 and FSP1-CoQ10-NADPH pathways. Relevant literature was critically analysed to explore mechanistic insights and therapeutic implications.

RESULTS: Pathological hallmarks such as amyloid-β, tau, and α-synuclein were found to disrupt iron metabolism, thereby exacerbating oxidative stress and mitochondrial dysfunction across various NDDs. These alterations significantly contribute to neuronal damage and disease progression through ferroptosis-related mechanisms.

DISCUSSION: Emerging therapeutic strategies, including radical-trapping antioxidants, iron chelators, and nanotechnology-based delivery systems, show potential in targeting ferroptosis. However, challenges in clinical translation persist. Artificial intelligence and personalised medicine approaches may address these issues by enabling patient stratification, biomarker discovery, and optimisation of therapeutic interventions.

CONCLUSION: Ferroptosis represents a promising therapeutic target for mitigating oxidative and metal-induced neurotoxicity in neurodegenerative disorders. Future research integrating multiomics profiling, longitudinal clinical data, and advanced computational modelling is essential to validate the efficacy of ferroptosis-targeted interventions and facilitate their successful translation into precision neurotherapeutics.},
}

@article {pmid42770363,
year = {2026},
author = {Chi, L and Xu, F and Dai, X and Li, Z and Li, J and Li, Z},
title = {Immunity and Inflammation in Alzheimer's Disease: A Narrative Review on Mechanisms and Therapeutic Prospects.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050493089260903062914},
pmid = {42770363},
issn = {1875-5828},
abstract = {Alzheimer's Disease (AD) is an age-related neurodegenerative disorder of the Central Nervous System (CNS), characterized by amyloid-β (Aβ) deposition and Neurofibrillary Tangles (NFTs) caused by the hyperphosphorylation of tau protein. Neuroinflammation is an increasingly recognized feature of AD, playing a critical role in disrupting the immune microenvironment within the brain parenchyma. High levels of various inflammatory mediators have been documented in both AD patients and experimental AD models. Similarly, multiple immune cells have been found to accumulate in the brain parenchyma, the meninges, and the choroid plexus. Therefore, antiinflammatory therapies, including Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), and immune regulatory strategies hold promise as potential novel approaches for the prevention and treatment of AD. Currently, a variety of anti-inflammatory agents and immunotherapies have demonstrated efficacy in AD animal models, and several clinical trials of immunotherapeutic interventions have been completed or are underway. This review systematically summarizes the core pathophysiological mechanisms by which inflammatory and immune dysfunctions contribute to AD pathogenesis and explores potential therapeutic interventions targeting these mechanisms, thereby providing theoretical insights for clinical translational research on AD treatment.},
}

@article {pmid42770364,
year = {2026},
author = {Pluta, R and Ułamek-Kozioł, M},
title = {Vitamin C versus Alzheimer's Disease. Commentary on the Effect of Ascorbic Acid on the Transgenic Drosophila Expressing Human Aβ-42 in the Neurons.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050513704260903053055},
pmid = {42770364},
issn = {1875-5828},
abstract = {A recent article by Siddique et al. published in Current Alzheimer's Research suggests that vitamin C may have a neuroprotective effect in Alzheimer's disease, which inspired us to write this commentary. In this commentary, we focus on the effects of vitamin C treatment on amyloid in a transgenic Drosophila melanogaster model of Alzheimer's disease. It should be noted that some of the information presented in this article raises more questions than it answers. The article does not provide a clear answer to the question posed in the title. We note that the authors demonstrated, to a very limited extent, the ameliorative effects of vitamin C on oxidative stress, cholinergic function, improved behavior, and prolonged lifespan, yet their enthusiasm for the therapeutic potential of vitamin C in Alzheimer's disease has not faded. In conclusion, the work contains controversial and speculative statements; therefore, drawing far-reaching conclusions and applying vitamin C to Alzheimer's disease are not justified by the available evidence.},
}

@article {pmid42770365,
year = {2026},
author = {Mehra, A and Sharma, R and Mittal, A},
title = {Cholinesterase Inhibitors in Alzheimer's Disease: Medicinal Chemistry, Mechanistic Insights, and Emerging Multitarget Strategies.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273435274260907101735},
pmid = {42770365},
issn = {1996-3181},
abstract = {Alzheimer's disease (AD) is the leading neurodegenerative disorder in the world. Although several decades of research have focused on its multifactorial pathogenesis, treating it remains a great challenge. The approved treatment options include cholinesterase inhibitors (ChEIs), which are the most common symptomatic treatment choice. These drugs act by inhibiting acetylcholinesterase (AChE) and, in some cases, butyrylcholinesterase (BuChE), preventing the breakdown of acetylcholine and increasing cholinergic neurotransmission in the brain. This review provides a broad consideration of ChEIs, focusing on their bioactivity, biochemical action, clinical significance, and SAR trends. It provides a comparative analysis of all the major chemical classes of ChEIs, namely the carbamates and organophosphates, as well as multiple heterocyclic scaffolds, with particular assessment of BBB permeability, metabolic stability, and toxicity attributes. Recent advances in medicinal chemistry have led to a shift in interest toward multi-target-directed ligands (MTDLs) that are designed not only to inhibit ChEs but also to exert antioxidant, anti-inflammatory, anti-amyloid, and metalchelating activity. These can target multiple pathogenic mechanisms to achieve a better therapeutic effect and neuroprotection. This review is based on a robust literature search conducted between 2020 and 2025. The progress, limitations, and prospects of ChEIs in the treatment of AD are critically assessed in this work. It also underscores the need for rational drug design to develop multitargetdirected drugs that may have disease-modifying effects, to overcome the limitations of existing symptomatic cholinesterase-inhibitor monotherapy.},
}

@article {pmid42770369,
year = {2026},
author = {Yan, W and Zhang, SH and Yan, WJ and Tian, SY and Zi, Y and Liu, GJ and Xue, T and He, XH and Qi, ZX and Zhuang, QX},
title = {Role of the Dorsal Striatum in Cognitive Functions and Related Disorders with Cognitive Impairment.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X484443260903062736},
pmid = {42770369},
issn = {1875-6190},
abstract = {The dorsal striatum, recognized as a primary input nucleus of the basal ganglia, has traditionally been viewed as a crucial center for motor control. However, emerging evidence over the past five decades has sparked a paradigm shift, underscoring its vital role in a wide array of higher-order cognitive functions such as procedural learning, habit formation, working memory, executive function, and inhibitory control. This expanded understanding is grounded in the dorsal striatum's intricate architecture, which includes GABAergic Medium Spiny Neurons (MSNs) that form both the direct and indirect pathways, a diverse array of interneurons, and a compartmental organization characterized by striosomes and matrix. Furthermore, the dorsal striatum plays a pivotal role within the cortico-basal ganglia-thalamo-cortical loops and is influenced by the midbrain dopaminergic system. Dysfunction of the dorsal striatum, marked by neurotransmitter imbalances-such as dopaminergic depletion in Parkinson's Disease (PD) and cholinergic deficits in Alzheimer's Disease (AD)-along with synaptic plasticity impairments and the aggregation of pathological proteins (e.g., α-synuclein in PD and amyloid-β/tau in AD), is closely associated with cognitive decline in major neurodegenerative disorders. This review aims to provide a systematic overview of the structural and functional foundations of the dorsal striatum in cognitive regulation. It delineates the pathological mechanisms that contribute to cognitive impairments observed in PD and AD and addresses current challenges as well as future research directions. The goal is to establish a comprehensive framework that positions the dorsal striatum as a shared therapeutic target for cognitive dysfunction across various diseases, thereby offering valuable insights for the development of early diagnostic biomarkers and innovative intervention strategies.},
}

@article {pmid42770380,
year = {2026},
author = {Pan, K and Zhu, K and E, Y and He, Y and Ding, S},
title = {ApoE4 as a Therapeutic Target in Epilepsy: From Pathogenic Mechanisms to Precision Medicine.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {9},
pages = {e71167},
doi = {10.1002/cns.71167},
pmid = {42770380},
issn = {1755-5949},
support = {LJHSQY26H090003//Natural Science Foundation of Zhejiang Province/ ; 2026-3-127//the Major (Key) Science and Technology Project of Jinhua City/ ; },
mesh = {Humans ; *Epilepsy/genetics/metabolism/drug therapy ; *Apolipoprotein E4/genetics/metabolism ; Animals ; *Precision Medicine/methods/trends ; Blood-Brain Barrier/metabolism ; Neuroinflammatory Diseases/metabolism ; Anticonvulsants/administration & dosage ; },
abstract = {BACKGROUND: Epilepsy is a heterogeneous central nervous system disorder characterized by recurrent seizures and is frequently accompanied by cognitive and neuropsychiatric comorbidities. Although apolipoprotein E4 (ApoE4) is well established as a genetic risk factor in Alzheimer's disease, its role as a modifier of epilepsy susceptibility, progression, and therapeutic response remains incompletely understood.

OBJECTIVE: This review aims to summarize current evidence regarding the molecular mechanisms, clinical implications, and therapeutic potential of ApoE4 in epilepsy, with emphasis on its relevance to precision medicine.

METHODS: A narrative review was conducted by synthesizing preclinical and clinical studies investigating the relationship between ApoE4 and epilepsy, including mechanisms related to neuroinflammation, synaptic dysfunction, lipid metabolism, blood-brain barrier (BBB) integrity, clinical phenotypes, and targeted therapeutic strategies.

RESULTS: ApoE4 contributes to epileptogenesis through multiple interconnected pathways. It promotes neuroinflammatory responses by activating microglia and inflammatory signaling, disrupts synaptic plasticity through N-methyl-D-aspartate receptor dysfunction and excitation-inhibition imbalance, impairs lipid and energy metabolism leading to neuronal hyperexcitability, and compromises BBB integrity. Clinically, ApoE4 carriers show increased seizure susceptibility, accelerated cognitive decline, hippocampal atrophy, and variable responsiveness to antiseizure medications. Emerging therapeutic approaches include ApoE4 structural correction, modulation of metabolic and inflammatory pathways, and gene-based interventions.},
}

Humans
*Epilepsy/genetics/metabolism/drug therapy
*Apolipoprotein E4/genetics/metabolism
Animals
*Precision Medicine/methods/trends
Blood-Brain Barrier/metabolism
Neuroinflammatory Diseases/metabolism
Anticonvulsants/administration & dosage

@article {pmid42770444,
year = {2026},
author = {Duan, X and Li, Y and Zhao, R and Jiang, X and Xia, C and Xie, F},
title = {Cell Therapy Targeting Pathological Networks in Neurodegenerative Diseases: Mechanisms and Translation from Stem Cells to Extracellular Vesicles.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026476083260903180127},
pmid = {42770444},
issn = {1875-5739},
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, are characterized by interacting pathological processes such as protein aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation, and impaired proteostasis. This narrative review examines how embryonic/ induced pluripotent stem cells, neural stem cells, mesenchymal stem/stromal cells, immune cells, and extracellular vesicles may intervene across these pathological networks. A targeted PubMed search and reference-list screening through 5 July 2026 identified relevant mechanistic, preclinical, clinical, manufacturing, and regulatory evidence. The reviewed strategies act through cell replacement, paracrine support, immunomodulation, metabolic stabilization, and pathological- protein clearance. Evidence maturity differs substantially by disease and product: pluripotent stem cell-derived dopaminergic progenitors have entered early clinical evaluation in Parkinson's disease, whereas most mesenchymal stem/stromal cell studies remain small and exploratory, and immune-cell and extracellular-vesicle approaches are predominantly preclinical or early translational. Major barriers include product heterogeneity, mechanism-linked potency testing, longterm safety, delivery and dose optimization, disease-stage selection, clinically meaningful endpoints, and regulatory comparability. Future development should emphasize standardized manufacturing, biomarker-guided trial design, transparent reporting of negative findings, and rational combinations with pharmacological or gene-based therapies. Cell-based interventions remain promising, but durable clinical benefit has not yet been established.},
}

@article {pmid42770452,
year = {2026},
author = {Maleksabet, H and Movahed, MA and Zarghi, A},
title = {Integrative Perspectives on COX-2 Signaling and Selective Inhibitors in Central Nervous System Disorders: A Narrative Review.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673496586260831110156},
pmid = {42770452},
issn = {1875-533X},
abstract = {INTRODUCTION: Central nervous system disorders include various neurodegenerative and psychiatric conditions characterized by progressive neuronal damage, synaptic dysfunction, and chronic neuroinflammation, affecting millions worldwide. This group includes Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), schizophrenia, Multiple Sclerosis (MS), Major Depressive Disorder (MDD), and epilepsy, among others. Recent studies have emphasized the significant role of Cyclooxygenase-2 (COX-2), an inducible enzyme in the arachidonic acid pathway, in maintaining neuroinflammatory cascades that worsen these conditions.

METHODS: For this review, we gathered and carefully analyzed published literature related to COX-2 signaling in CNS disorders. We reviewed preclinical studies, animal models, and clinical trials to understand how COX-2 contributes to disease mechanisms and whether selective inhibitors show real therapeutic promise.

RESULTS: Inflammatory cytokines or excitotoxic insults upregulate COX-2 and promote the formation of prostaglandins, including PGE2. These mediators subsequently trigger the activation of microglia and astrocytes, cytokine release, oxidative stress, disruption of the blood-brain barrier, and neuronal apoptosis. Despite variations in disease-specific features, the mechanisms dependent on COX-2 are generally consistent across these disorders.

DISCUSSION: The consistent involvement of COX-2-driven neuroinflammation across multiple CNS disorders suggests it could be a promising therapeutic target. However, failures in some clinical trials highlight the complexity of translating preclinical findings into patient care. This may be due to the stage-dependent expression of COX-2, the multifunctional roles of the enzyme in normal brain function, and the cardiovascular risks associated with long-term COX-2 inhibition. These factors must be carefully considered in future research and drug development.

CONCLUSION: COX-2 plays a central role in driving neuroinflammation and disease progression in AD, PD, ALS, schizophrenia, MS, MDD, and epilepsy. Selective COX-2 inhibitors show promising neuroprotective potential, especially in early stages or in combination therapies, but inconsistent efficacy and cardiovascular risks necessitate safer next- generation inhibitors.},
}

@article {pmid42770464,
year = {2026},
author = {Xing, R and Sun, W and Zhou, J and Chen, T and Chen, L and Peng, P and Xu, G},
title = {Quantitative analysis of intersecting pentagon drawings for interpretable cognitive impairment screening.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261489816},
doi = {10.1177/13872877261489816},
pmid = {42770464},
issn = {1875-8908},
abstract = {BackgroundThe intersecting pentagon drawing task in the Mini-Mental State Examination (MMSE), also referred to as the Pentagon Drawing Test (PDT), is a brief cognitive screening tool in Alzheimer's disease (AD) and other cognitive disorders. However, conventional manual scoring is coarse and may overlook clinically meaningful variation in drawing performance.ObjectiveTo evaluate whether quantitative PDT features can support interpretable screening for cognitive impairment.MethodsWe analyzed participants who completed the MMSE, Montreal Cognitive Assessment (MoCA), and PDT. Cognitive impairment was defined using education-adjusted MMSE and MoCA cutoffs. Eight quantitative drawing features characterized geometric integrity, spatial organization, and graphomotor characteristics. These features, together with demographic variables, were evaluated for prediction of a modified MMSE-derived cognitive score and classification of cognitive status using cross-validation.ResultsA total of 3478 participants were included, including 2463 with cognitive impairment and 1015 cognitively normal individuals. All eight quantitative drawing features were significantly lower in the cognitive impairment group. Shape regularity, vertices, alignment and intersection area proportion showed the strongest positive correlations with modified MMSE scores. The model achieved an R[2] of 0.42 for score prediction and showed a positive correlation between predicted and observed scores (Spearman ρ = 0.64). For cognitive impairment classification, the model achieved a ROC-AUC of 0.832, sensitivity of 82.5%, specificity of 67.4%, PPV of 86.0%, NPV of 61.4%, and F1-score of 0.842.ConclusionsQuantitative features of PDT showed interpretable associations with cognitive screening outcomes. This approach may support scalable and objective cognitive screening and serve as a complement to clinical assessment.},
}

@article {pmid42770466,
year = {2026},
author = {Uchiyama, M and Sato, T and Mamiya, Y and Takato, T and Matsui, T and Imamura, T},
title = {Functional hearing difficulty in Alzheimer's disease: Selective links to verbal fluency and behavioral and psychological symptoms of dementia severity.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261489803},
doi = {10.1177/13872877261489803},
pmid = {42770466},
issn = {1875-8908},
abstract = {BackgroundHearing loss is a well-established risk factor for dementia. However, the clinical relevance of everyday listening difficulties after the diagnosis of Alzheimer's disease (AD) remains insufficiently understood, particularly in relation to cognition and behavioral and psychological symptoms of dementia (BPSD). Functional hearing difficulty refers to perceived difficulties in everyday listening situations that are not fully captured by standard audiometric thresholds.ObjectiveTo examine the associations between caregiver-rated functional hearing difficulty, cognitive measures commonly used in clinical practice, and overall BPSD severity in patients with AD.MethodsThis single-center cross-sectional study included 101 patients with clinically diagnosed AD attending a memory clinic. Functional hearing difficulty was assessed using a caregiver-based structured interview. Associations with widely used cognitive measures and BPSD severity, operationalized as the Neuropsychiatric Inventory five-domain total score, were examined using regression models adjusted for relevant covariates.ResultsGreater functional hearing difficulty was selectively associated with poorer verbal fluency, whereas no significant associations were observed with other cognitive measures. Functional hearing difficulty was also associated with greater BPSD severity. Exploratory analyses showed a pattern statistically consistent with an indirect association via verbal fluency.ConclusionsCaregiver-rated functional hearing difficulty was selectively linked to verbal fluency and BPSD severity in patients with AD. These findings suggest that functional hearing difficulty may capture communication-related cognitive processes relevant to everyday functioning beyond global disease severity, although longitudinal studies are needed to clarify temporal relationships.},
}

@article {pmid42770505,
year = {2026},
author = {Luo, Y and Chen, L and Yin, S and Zhang, L and Chen, B and Wen, H},
title = {Auditory brainstem response deficits precede and are associated with subsequent auditory cortical amyloid burden in male APP/PS1 mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261487603},
doi = {10.1177/13872877261487603},
pmid = {42770505},
issn = {1875-8908},
abstract = {BackgroundAuditory dysfunction is considered one of the early manifestations of Alzheimer's disease (AD). However, its evolutionary characteristics with the progression of AD have not been fully studied, and the temporal relationship between this sensory impairment and the typical pathology of the disease is unclear.ObjectiveTo investigate whether auditory dysfunction precedes auditory cortical amyloid-β (Aβ) deposition during AD progression.MethodsThis study longitudinally assessed the threshold and amplitude of auditory brainstem response (ABR) in male APP/PS1 mice and male wild-type littermate mice at different ages, and quantitatively analyzed Aβ plaques in the auditory cortex of APP/PS1 mice using immunofluorescence. Further evaluation was conducted on the correlation between early ABR indicators and subsequent Aβ burden. A multivariate logistic regression model was constructed based on ABR features to distinguish APP/PS1 mice from wild-type controls in the pre-plaque stage.ResultsAPP/PS1 mice exhibited progressive hearing impairment, with auditory impairment emerging at 8-12 weeks of age and detectable Aβ deposition appearing at 20 weeks of age. Early ABR abnormalities were significantly correlated with subsequent Aβ burden. Furthermore, a multivariable logistic regression model based on ABR threshold and the amplitudes of waves I, III, and IV showed good discriminatory performance for distinguishing APP/PS1 mice from wild-type controls during the pre-plaque stage.ConclusionsABR abnormalities occur before detectable cortical plaque deposition in APP/PS1 mice and are associated with subsequent auditory cortical Aβ burden. These findings suggest that ABR-based features may serve as candidate non-invasive functional indicators for assessing early pathological progression of AD.},
}

@article {pmid42770506,
year = {2026},
author = {Tan, LF and Chong, YF and Ng, AS and Liew, TM and Yap, PL},
title = {Alzheimer's disease: from breakthroughs to real-world impact.},
journal = {Singapore medical journal},
volume = {67},
number = {9},
pages = {535-536},
pmid = {42770506},
issn = {2737-5935},
}

@article {pmid42761825,
year = {2026},
author = {Dunton, KL and Monchal, H and Achorn, BE and Mandé-Niedergang, B and Roucard, C and Roche, Y and Evrard, A and Menniti, FS},
title = {Human P301L tau expression in mice alters neuronal excitability independent of neurodegeneration.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1814637},
pmid = {42761825},
issn = {1662-4548},
abstract = {Variation in the microtubule-binding protein tau is causally implicated in numerous neurodegenerative diseases, including Alzheimer's disease. However, the mechanisms by which such variation results in disease are not well understood. The JNPL3(P301L) mouse model mimics the effects of the P301L mutation on human tau associated with frontotemporal dementia. As previously reported, phospho-tau aggregates immunolabeled with AT8 increase with age in a rostral progression from the brainstem; however, there is relatively limited forebrain pathology by the time these animals die prematurely at approximately 1 year of age. In this study, we investigated the functional effects of P301L tau expression on electrophysiological signatures as a function of age in mice expressing P301L tau from 3 to 10 months. The P301L mice had a distinct electrophysiological phenotype of increased power in higher EEG frequency bands detected with a depth electrode in the hippocampus and, to a lesser extent, with dural surface electrodes over the frontal and parietal cortices. Significantly, this electrophysiological phenotype was present at the first recording at 3 months of age and did not differ over monthly recordings up to 9 months of age, after which point animals became moribund and were euthanized. P301L mice at 10 months of age also showed electrical synchronization to a 40 Hz tone (ASSR) that was not observed in WT mice and an increase in inter-trial coherence compared with WT mice. We confirmed that AT8, as well as markers of neuroinflammation, increased progressively with age from the hindbrain to the forebrain, as previously reported. Together, these data suggest an increase in neuronal excitability in P301L mice compared with WT, but that this phenotype is not correlated with the age-dependent accumulation of AT8-labeled tau aggregates and the accompanying neuroinflammation. We hypothesize that the expression of P301L mutant tau disrupted the physiological functions of tau, resulting in the functional electrophysiological phenotype. Whether this functional effect drives neurodegeneration or is a separable phenomenon has implications for understanding the mechanisms underlying the role of tau variation in neurodegenerative conditions.},
}

@article {pmid42761867,
year = {2026},
author = {El Sayed, T and Patel, A and Xu, K and Salaiza, JA and Azhakath Valappil, H and Majumdar, S and Sutton, BP and Mirica, LM},
title = {Design of bifunctional pyridinophane ligands as Mn[2+] MRI agents for diagnostic imaging of Alzheimer's disease.},
journal = {Inorganic chemistry frontiers},
volume = {},
number = {},
pages = {},
pmid = {42761867},
issn = {2052-1553},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose prevalence is rising with the aging of the global population. Among the proposed pathological hallmarks, the beta-amyloid (Aβ) peptide aggregates and soluble Aβ oligomers are established biomarkers and remain valuable diagnostic targets. While positron emission tomography (PET) imaging agents dominate AD diagnostic imaging, there are no FDA-approved MRI agents for AD. Herein, we report five bifunctional chelators built on the 2,11-diaza[3.3](2,6)pyridinophane framework, and which were evaluated as chelators for Mn[2+]-based MRI contrast agents. Based on in vitro studies, including thermodynamic stability and kinetic inertness measurements, T 1 relaxivity and [17]O transverse relaxivity measurements to extract hydration numbers and water-exchange parameters, we obtained a clear structure-activity correlation for the corresponding bifunctional chelators: anionic picolinate and acetate arms increase thermodynamic stability and kinetic inertness, while the benzothiazolyl-phenol arm accelerates water exchange. Importantly, a high hydration number alone is insufficient, as a rapid water exchange is also needed for an appreciable contrast. Moreover, we show both the bifunctional chelators and their Mn[2+] complexes exhibit appreciable affinity for Aβ aggregates, both in vitro and in 5xFAD mouse brain sections. [Mn(TE-8)], the most kinetically inert complex with favorable relaxivity, log D, and Aβ affinity, was advanced to in vivo MRI studies. Unlike MnCl2, which accumulates non-specifically, [Mn(TE-8)] cleared through renal and hepatobiliary routes and produced measurable brain contrast enhancement. Together, these results establish the diazapyridinophane scaffold as a viable first-generation platform for blood-brain barrier (BBB)-permeable Mn[2+] MRI contrast agents.},
}

@article {pmid42762164,
year = {2026},
author = {Thorpe, RJ and Esiaka, D and Surawkar, S and Nwakasi, C and Kim, B},
title = {Correlates of Subjective Cognitive Impairment Among Community Dwelling Older Non-Hispanic Black and Non-Hispanic White Men.},
journal = {Journal of aging and health},
volume = {},
number = {},
pages = {8982643261490956},
doi = {10.1177/08982643261490956},
pmid = {42762164},
issn = {1552-6887},
abstract = {BackgroundSubjective cognitive impairment (SCI) predicts Alzheimer's disease and related dementias (ADRD). Identifying SCI correlates may identify cognitive risk earlier in the ADRD continuum. We examined SCI correlates among older non-Hispanic Black (NHB) and non-Hispanic White (NHW) men.MethodCross-sectional data were from 669 men in the 2012 National Health and Aging Trends Study. Logistic regression was used to identify SCI correlates, accounting for complex sampling and attrition.ResultHigher education (OR = 0.33, 95% CI: 0.13-0.87) and former smoking (OR = 0.38, 95% CI: 0.16-0.91) were associated with lower SCI odds. Sleep difficulties (OR = 2.81, 95% CI: 1.22-6.47), multimorbidity (OR = 2.16, 95% CI: 1.09-4.29), and ADL disability (OR = 4.19, 95% CI: 2.03-8.61) were associated with higher odds.DiscussionEducation, smoking status, sleep, multimorbidity, and functional status may be important SCI correlates among older NHB and NHW men. Addressing modifiable correlates may support cognitive health earlier in the ADRD continuum.},
}

@article {pmid42762305,
year = {2026},
author = {Onwu, DO and Oria, RS and Adekunle, YA and Adams, MD and Ani, ON and Adele, H and Tyohemba, TS and Osioma, E and Popoola, BM and Bakare, OS and Okon, VE and Maxwell, CC},
title = {Integration of network pharmacology, structure-based pharmacophore modeling, DFT, molecular docking, and molecular dynamics simulations to identify multi-target small molecule inhibitors against Alzheimer's disease.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42762305},
issn = {1432-1912},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with cognitive impairment, synaptic malfunction, oxidative stress, cholinergic deficits, and a lack of effective disease-modifying therapeutics. In this study, we integrated in silico approaches with network pharmacology to identify novel multi-target ligands against three key AD-associated proteins: acetylcholinesterase (AChE), protein kinase B (AKT1), and monoamine oxidase B (MAO-B). Structure-based e-pharmacophore modeling and virtual screening were conducted using Pharmit, a large compound library from the ZINC and COCONUT databases, followed by stringent ADMET filtering to obtain drug-like candidates. Network pharmacology analysis identified AKT1 as the best hub gene between predicted hit compounds and AD-associated gene-enriched pathways, such as PI3K-Akt, FoxO, calcium, and cAMP signaling pathways. Four hits (1-4) were screened for binding affinity evaluation using molecular docking, followed by MM-GBSA, and molecular dynamics (MD) simulations. Hit1 (N-(2-(1H-indol-3-yl)ethyl)-7-hydroxy-5,6-dimethoxy-[1,2,4]triazolo[4,3-a]quinazoline-3-carboxamide) (ZINC000033435965) demonstrated the strongest binding affinities across all complexes, with docking scores of - 11.4, - 11.8, and - 12.1 kcal/mol for hAChE, AKT1, and MAO-B, respectively. MD simulations over 100 ns for Hit1 revealed stable interaction as described by RMSD, RMSF, Rg, SASA, and HB profiles. E-pharmacophore and validation demonstrated strong predictive performance across the complexes, especially for AKT1 and MAO-B with high enrichment factors and ROC-AUC values (0.95 and 0.94). Additionally, DFT analysis of Hit1 revealed a favorable electronic stability energy (- 1479.283992 Eh). ADMET profiling predicted favorable oral bioavailability, BBB permeability, drug-likeness, and low predicted toxicity. The findings of this study suggest that Hit1 could be a promising multi-target molecule capable of modulating cholinergic transmission, neuronal survival pathways, and oxidative stress in AD. Experimental validation, including in vitro enzymatic assays and in vivo evaluations, is essential to further establish the therapeutic potential of Hit1.},
}

@article {pmid42762360,
year = {2026},
author = {Carroll, JA and Soukup, J and Groveman, BR and Orrú, CD and Race, B and Haigh, CL},
title = {Life at the interface: Byron Caughey's search for prion disease inhibitors through chemistry, structure, and cell physiology.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42762360},
issn = {1432-0533},
mesh = {Humans ; *Prion Diseases/drug therapy/history ; Animals ; *Prions/metabolism ; History, 20th Century ; *Drug Discovery/history ; History, 21st Century ; },
abstract = {The search for effective therapeutics that can bring hope to patients and families affected by rare prion diseases is ongoing. Self-propagating, misfolded proteins underlie a broad range of neurodegenerative disorders that include prion diseases as well as more common conditions such as Parkinson's and Alzheimer's disease. Byron Caughey was a pioneer in the field of prion therapeutic discovery. His seminal contributions in drug development included elucidating disease biochemistry, understanding the need to target conformational changes, and developing cell-free conversion assays to monitor protein misfolding in real time. These advances laid the foundation for therapeutic strategies aimed at preventing, slowing or reversing the conversion of native protein into a pathogenic, seed-competent conformer and/or its assembly into amyloid fibrils. Within the Caughey laboratory, small molecule inhibitors targeting the misfolded prion, the process of conversion and aggregation, or stimulating disassembly were studied intensively. More recent approaches targeted the relocation, removal or downregulation of the normal protein substrate. These efforts in combination with high-resolution structural characterization of the infectious prions now offer new opportunities for intelligent drug design. Equally important to drug discovery have been advances in the development of sensitive and reliable methods to detect the agent and its clearance, which is necessary to validate that putative treatments are efficacious. Herein, we highlight 4 decades of Byron Caughey's contributions and dedication to the search for anti-prion therapeutics.},
}

Humans
*Prion Diseases/drug therapy/history
Animals
*Prions/metabolism
History, 20th Century
*Drug Discovery/history
History, 21st Century

@article {pmid42762395,
year = {2026},
author = {Katsumata, Y and Morganti, JM and Liao, A and Zhou, W and Zhong, Y and Fister, S and Saito, K and Qiao, Q and Artiushin, S and Wei, A and Jian, G and Nichols, CG and Lee, TL and Niedowicz, DM and Shahidehpour, RK and Norris, CM and Rogers, CB and Fardo, DW and Cao, J and Nelson, PT},
title = {ABCC9/SUR2 has a Complex Expression Pattern in Human Brain Gliovascular Unit Cells, Including Astrocytes.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {4},
pages = {},
pmid = {42762395},
issn = {1559-1166},
support = {grants P30 AG072946, R01 NS118584, RF1 AG082339, P01 AG078116, and R01 AG076932//NIH/ ; },
mesh = {Humans ; *Astrocytes/metabolism ; Animals ; *Sulfonylurea Receptors/genetics/metabolism ; *Brain/metabolism/cytology/blood supply ; Mice ; Pericytes/metabolism ; },
abstract = {The ABCC9 gene and its cognate protein SUR2 play important roles in neurovascular coupling and are implicated in hippocampal sclerosis of aging (HS-Aging). However, prior studies have not focused on human brain SUR2 expression or SUR2 in glial cells. Here we analyzed cell type-specific ABCC9/SUR2 expression patterns, and correlation with known genetic risk variants, using multiple data sets and a novel antiserum. Existing single-nucleus RNA sequencing data sets and new spatial transcriptomics data indicated that SUR2 transcripts were expressed primarily in human brain pericytes, astrocytes, smooth muscle cells, and endothelial cells. Evaluation of Sur2 expression in a sample of mice brains showed similar results except Sur2 was not detected in the mice astrocytes. In a SUR2-enriched subcluster of human astrocytes, the pattern of transcript expression suggested responsiveness to thyroid hormone signaling: SUR2-correlated gene products were enriched for thyroid hormone-sensitive transcripts and SLCO1C1, the astrocyte thyroid hormone importer, was the transcript with the strongest correlation with SUR2 expression. Cells in the SUR2 + astrocyte cluster tended to have been derived from individuals lacking severe Alzheimer's disease pathology. An ABCC9 single nucleotide variant (rs1914361, also a HS-Aging risk allele) was associated with increased SUR2 expression in astrocytes, but not other cell types. SUR2 mRNA splicing differed between cell types; astrocytes preferentially expressed the SUR2B variant. A novel SUR2 antiserum immunolabeled blood vessel walls and some astrocyte-morphology cells in human brain. Overall, human brain SUR2 expression was enriched among different cell types of the gliovascular unit. A SUR2-enriched, possibly-homeostatic astrocyte subcluster suggested connections to thyroid hormone signaling.},
}

Humans
*Astrocytes/metabolism
Animals
*Sulfonylurea Receptors/genetics/metabolism
*Brain/metabolism/cytology/blood supply
Mice
Pericytes/metabolism

@article {pmid42762549,
year = {2026},
author = {Zhijian, C and Haizhi, Z and Yihong, H and Weiyang, X and Jingjing, Z and Qiuyan, C and Tianxiu, Z},
title = {Diagnostic value of intravoxel incoherent motion imaging of deep gray matter nuclei in Alzheimer's disease.},
journal = {European journal of radiology},
volume = {205},
number = {},
pages = {113244},
doi = {10.1016/j.ejrad.2026.113244},
pmid = {42762549},
issn = {1872-7727},
abstract = {OBJECTIVE: To evaluate clinical diagnostic value of intravoxel incoherent motion (IVIM) imaging in Alzheimer's disease (AD).

METHODS: Sixty-six subjects from Ningde City Hospital were classified into AD (n = 23), mild cognitive impairment (MCI) (n = 28), and normal control (NC) (n = 15) groups. Standardized apparent diffusion coefficient (ADCst) and IVIM parameters, including true diffusion coefficient (D), perfusion fraction (f), and pseudo-diffusion coefficient (D*), were measured in the caudate nucleus, thalamus, putamen, globus pallidus, and amygdala using 3.0 T magnetic resonance imaging. Mini-mental state examination (MMSE) scores were recorded, and Pearson correlation and receiver operating characteristic analyses were performed.

RESULTS: IVIM-f in the right thalamus was significantly reduced in the AD group compared with the NC and MCI groups (p < 0.05), and IVIM-f in the bilateral amygdala was lower in AD than in NC (p < 0.01). IVIM-D* in the right caudate nucleus was significantly decreased in AD relative to both NC and MCI groups (p < 0.001), whereas IVIM-D in the left putamen was increased in AD compared with NC (p < 0.001). No significant intergroup difference was observed for ADCst (p > 0.05). Correlation analysis showed that MMSE scores were positively associated with IVIM-f in the right thalamus (r = 0.5471, p < 0.001), IVIM-D* in the right caudate nucleus (r = 0.6587, p < 0.001), and IVIM-f in the right amygdala (r = 0.6129, p < 0.0001), and negatively associated with IVIM-D in the left putamen (r =  - 0.5078, p < 0.001). ROC analysis showed that IVIM-f yielded higher AUC values than ADCst for distinguishing AD from non-AD participants (AUC = 0.7644 vs. 0.6643), NC from MCI participants (AUC = 0.8548 vs. 0.6571), and MCI from AD participants (AUC = 0.7205 vs. 0.6211); however, this comparison should be interpreted cautiously because ADCst did not show significant intergroup differences.

CONCLUSION: IVIM-derived parameters are closely associated with cognitive impairment severity and provide improved differentiation among AD, MCI, and normal controls, supporting their potential clinical utility for early diagnosis and disease assessment.},
}

@article {pmid42763018,
year = {2026},
author = {Patergnani, S and Trentini, A and Rosta, V and Guindani, P and Greatti, A and Pedrini, D and Meneguzzo, G and Rigon, L and Filippini, N and Giusto, E and Zuliani, G and Pinton, P and Cervellati, C},
title = {Dysfunctional mitophagy in Alzheimer's disease: evidence from peripheral Optineurin.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2026.09.013},
pmid = {42763018},
issn = {1873-4596},
abstract = {Mitophagy and mitochondrial quality-control pathways are impaired in Alzheimer's disease (AD), but the relevance of peripheral mitophagy markers and their regulation during sustained amyloid-β (Aβ) stress remain unclear. We investigated whether serum optineurin, a mitophagy receptor, is altered in mild cognitive impairment (MCI) and AD, and explored mitophagy dynamics in an in vitro model of Aβ1-42-induced mitochondrial stress. To achieve this aim, serum optineurin was measured in 458 older individuals, including controls and patients with AD, mild cognitive impairment (MCI), and mixed Alzheimer's disease/ vascular dementia (MIXED). Complementary in vitro experiments were performed in SH-SY5Y neuroblastoma cells exposed to Aβ1-42 over time, to evaluate mitochondrial function, oxidative stress, lipid peroxidation, lactate release, Parkin/optineurin recruitment, mitophagy, mitochondrial quality-control markers, apoptosis, and cell viability. Serum optineurin was markedly lower in MCI and AD groups than in controls (p < 0.001 for both) and was also reduced in MIXED (p < 0.001). Serum 4-HNE was increased in MCI and AD, consistent with systemic oxidative stress. In vitro, Aβ1-42 induced an early increase in mitophagy and optineurin expression, followed by a later decline associated with impaired mitochondrial quality-control markers, apoptotic activation, and reduced cell viability. In conclusion, optineurin emerges as a candidate peripheral biomarker associated with AD and MCI. In vitro, Aβ1-42 exposure was associated with an early increase in mitophagy-related responses followed by progressive mitochondrial dysfunction, oxidative stress, apoptotic activation, and reduced cell viability. These findings support the relevance of optineurin within mitochondrial quality-control pathways under AD-related stress.},
}

@article {pmid42763022,
year = {2026},
author = {Zhang, B and Wang, Z and Zhao, X and Zhu, J and Zhang, Y and Wang, Y and Yang, J and Cheng, J and Yang, X and Zhu, F and Shen, W and Lu, W},
title = {D-Cycloserine ameliorates innate fear deficits in young adult male APP/PS1 mice: Involvement of GluN2B-containing NMDA receptor.},
journal = {Pharmacology, biochemistry, and behavior},
volume = {},
number = {},
pages = {174272},
doi = {10.1016/j.pbb.2026.174272},
pmid = {42763022},
issn = {1873-5177},
abstract = {Neuropsychiatric symptoms can emerge early in Alzheimer's disease (AD), but whether innate fear is altered prior to amyloid plaque deposition remains unclear. This study aimed to examine innate fear responses in young adult male APP/PS1 mice and to evaluate whether D-cycloserine (DCS) rescues such deficits via GluN2B-containing NMDA receptors. Male APP/PS1 mice (2-3 months old) exhibited impaired innate fear responses in the looming disk test, while their motor function and contextual fear memory remained intact. Hippocampal Grin2b expression was reduced in the APP/PS1 mice. DCS restored normal fear responses, an effect blocked by GluN2B antagonists but unaffected by GluN2A inhibition. Our results demonstrate that innate fear deficits emerge early in male APP/PS1 mice and are rescued by DCS through activation of hippocampal GluN2B-containing NMDA receptor, highlighting a potential target for early AD-related neuropsychiatric symptoms.},
}

@article {pmid42763072,
year = {2026},
author = {Shehu, K and Onimisi, OB and Bunza, HA and Umar, SM and Oyem, JC and Adewumi, TA},
title = {Prenatal origins of neurodegeneration: The role of maternal immune activation in Alzheimer's and Parkinson's pathobiology.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {116029},
doi = {10.1016/j.expneurol.2026.116029},
pmid = {42763072},
issn = {1090-2430},
abstract = {Recent evidence suggests that prenatal environmental factors, particularly maternal infection or maternal immune activation (MIA), may influence the progression of brain aging and lifetime risk for neurodegenerative disorders. The hypothesis is that even a short-lived inflammatory event during pregnancy may leave a lasting imprint on the developing brain and immune system of the fetus, such that aging or subsequent insults may later unmask neurodegenerative disorders. Support for this hypothesis comes largely from animal studies, where gestational inflammation has been shown to potentiate the onset of Alzheimer's and Parkinson's diseases (AD/PD), by increasing amyloid/tau pathology, reducing synaptic connections, and damaging nigrostriatal dopaminergic neurons. We review convergent mechanisms, including microglial priming, chronic cytokine excess, oxidative stress, epigenetic marks and proteostatic deficits, through which maternal immune activation may embed a latent "hit" that synergizes with aging to precipitate AD or PD. Furthermore, we appraise experimental models and available human data linking MIA to AD versus PD, noting shared and distinct pathways. Despite growing preclinical evidence, translation to human cohorts remains limited by heterogeneity in MIA exposure timing and outcome measures. An understanding of MIA's impact on neurodegeneration could suggest preventive strategies and interventions for early diagnosis and treatment.},
}

@article {pmid42763160,
year = {2026},
author = {Chen, CH and She, BC and Chen, YL and Wang, CC and Wu, SM},
title = {Magnetic-assisted catalytic hairpin assembly fluorescent aptasensor for highly sensitive detection of amyloid-beta oligomers as Alzheimer's disease biomarker.},
journal = {Analytica chimica acta},
volume = {1422},
number = {},
pages = {346100},
doi = {10.1016/j.aca.2026.346100},
pmid = {42763160},
issn = {1873-4324},
mesh = {*Amyloid beta-Peptides/analysis/blood ; *Aptamers, Nucleotide/chemistry ; *Alzheimer Disease/diagnosis/blood ; Humans ; *Biosensing Techniques/methods ; Biomarkers/blood/analysis ; Limit of Detection ; *Fluorescent Dyes/chemistry ; Catalysis ; Spectrometry, Fluorescence ; Magnetic Phenomena ; },
abstract = {BACKGROUND: The abnormal accumulation of amyloid-beta peptides is a key contributor to Alzheimer's disease. Of these peptides, soluble amyloid-beta oligomers (AβOs) have emerged as potent neurotoxins and early pathological biomarkers. Although AβOs are highly specific biomarkers, their low physiological abundance, structural heterogeneity and matrix interference associated present considerable challenges for conventional diagnostic approaches. Herein, we report a novel fluorescent aptasensor platform for the ultrasensitive detection of AβOs. The platform integrates magnetic preconcentration with a signal amplification strategy based on catalytic hairpin assembly (CHA).

RESULTS: To achieve simultaneous selective recognition of AβOs and efficient CHA initiation, magnetic beads were functionalized with rationally designed double-stranded DNA complexes, which were formed through the hybridization of an AβO-specific aptamer and a CHA-initiator fragment. Upon the specific binding of AβOs, the AβO-specific aptamer competitively dissociates from the magnetic beads, thereby unmasking the surface-tethered initiator to trigger the CHA circuit. The circularly generated CHA products serve as a self-amplifying signal indicator, whereas the magnetic beads enhance target-capturing capacity and facilitate the removal of complex matrix interferences prior to amplification. Experimental results revealed that the proposed system exhibited a broad linear detection range from 10 pg mL[-1] to 10 ng mL[-1] with a detection limit of 4.1 pg mL[-1] (r = 0.9821). Furthermore, to demonstrate its applicability, plasma samples from healthy individuals were analyzed. The results indicated that the AβO level ranged from 87 to 290 pg mL[-1].

SIGNIFICANCE AND NOVELTY: These findings demonstrate the potential of integrating aptamer-mediated magnetic capture with CHA-driven signal amplification for ultrasensitive AβO detection. The spatial separation of AβO-aptamer binding and CHA amplification through magnetic beads effectively minimizes matrix interference while permitting large sample volumes. This strategy has the potential to serve as sensitive tool for early Alzheimer's disease diagnosis.},
}

*Amyloid beta-Peptides/analysis/blood
*Aptamers, Nucleotide/chemistry
*Alzheimer Disease/diagnosis/blood
Humans
*Biosensing Techniques/methods
Biomarkers/blood/analysis
Limit of Detection
*Fluorescent Dyes/chemistry
Catalysis
Spectrometry, Fluorescence
Magnetic Phenomena

@article {pmid42763350,
year = {2026},
author = {Duan, X and Chen, Z and Tong, X and Li, X and Liu, Z and Yang, Y and Liu, X and Liu, W},
title = {Irisin-BDNF axis mediates muscle-brain communication: a complete molecular cascade and potential bidirectional feedback from peripheral activation to central protection.},
journal = {Biogerontology},
volume = {27},
number = {5},
pages = {},
pmid = {42763350},
issn = {1573-6768},
support = {Grant No. 2026JJ90271//Natural Science Foundation of Hunan Province/ ; },
mesh = {Humans ; *Brain-Derived Neurotrophic Factor/metabolism ; *Fibronectins/metabolism ; Animals ; *Brain/metabolism ; *Muscle, Skeletal/metabolism ; *Alzheimer Disease/metabolism ; Myokines ; Signal Transduction ; Feedback, Physiological ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by cognitive decline, with core pathological mechanisms including β-amyloid (Aβ) deposition, tau protein hyperphosphorylation, neuroinflammation, and impaired synaptic plasticity. Although exercise has neuroprotective effects, the molecular mechanisms by which it mediates peripheral-central communication remain unclear. The concept of the 'muscle-brain dialogue' offers a new perspective on this process. irisin, secreted by skeletal muscle in response to exercise, forms a molecular link between peripheral exercise and central neuroprotection by specifically regulating brain-derived neurotrophic factor (BDNF). This review summarizes the molecular cascade mechanisms of the irisin-BDNF axis in mediating the muscle-brain dialogue: Irisin is synthesized via the peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)/fibronectin domain-containing protein 5 (FNDC5) pathway. Current evidence suggests that peripheral irisin may communicate with the central nervous system through mechanisms related to the blood-brain barrier, including potential αVβ5 integrin-mediated interactions, thereby participating in the regulation of BDNF. As a core effector molecule, BDNF improves cognitive decline in AD by enhancing neuroplasticity, reducing Aβ deposition, inhibiting tau hyperphosphorylation, and alleviating neuroinflammation. However, oxidative stress and mitochondrial dysfunction associated with AD pathology negatively regulate this axis, creating a vicious cycle. Therefore, this paper explores potential intervention strategies and the prospects for future translational research, including upstream exercise interventions, midstream barrier-crossing enhancing peptides, and downstream small-molecule TrkB agonists. Targeting this axis provides a new theoretical foundation and translational direction for the early prevention and treatment of AD, as well as for drug development.},
}

Humans
*Brain-Derived Neurotrophic Factor/metabolism
*Fibronectins/metabolism
Animals
*Brain/metabolism
*Muscle, Skeletal/metabolism
*Alzheimer Disease/metabolism
Myokines
Signal Transduction
Feedback, Physiological

@article {pmid42763575,
year = {2026},
author = {Jahanbin, K and , },
title = {Glial and Vascular Plasma Biomarkers Across the Alzheimer's Disease Continuum: An ADNI-Based Longitudinal Study.},
journal = {FASEB bioAdvances},
volume = {8},
number = {9},
pages = {e70155},
pmid = {42763575},
issn = {2573-9832},
abstract = {Alzheimer's disease (AD) is increasingly recognized as a multicellular disorder involving neurovascular unit dysfunction. Investigating glial and vascular biomarkers together may provide a more integrated view of AD biology. This study characterized baseline distributions, interrelationships, and longitudinal trajectories of plasma glial (GFAP, sTREM2) and vascular/endothelial (VEGF, sICAM-1, sVCAM-1) biomarkers across the AD continuum. Using Alzheimer's Disease Neuroimaging Initiative (ADNI) data, this retrospective longitudinal cohort study included a covariate-complete clinical cohort of 2650 participants classified as cognitively unimpaired (CU), mild cognitive impairment (MCI), or AD dementia. Biomarker-specific analytic samples were determined by assay availability and complete-case requirements. Associations were evaluated using covariate-adjusted linear regression and linear mixed-effects models with participant random intercepts, adjusted for baseline age, sex, education, and APOE ε4 status. Vascular models were additionally refitted with body mass index, systolic blood pressure, antihypertensive and antidiabetic medication use, smoking history, and estimated glomerular filtration rate. Baseline GFAP showed a robust stepwise elevation from CU to MCI to AD (56.3% higher in AD than CU, q = 1.7 × 10[-14]; area under the curve 0.82), whereas sTREM2 distributions overlapped across groups. VEGF and sVCAM-1 were higher in AD than CU (14.1%, q = 0.014; 14.7%, q = 0.002), with areas under the curve of 0.61 and 0.63 and more than 80% distribution overlap. GFAP increased by 4.50% per year in CU participants and sTREM2 by 2.99% per year, with no significant diagnosis-by-time interactions for either. Over a 12-month interval, sICAM-1 declined in CU participants, and this decline was attenuated in MCI and AD, while sVCAM-1 increased in CU participants and showed negative diagnosis-by-time interactions. The vascular longitudinal findings were unchanged by adjustment for cardiometabolic and renal covariates, by time-varying diagnosis, and by separating stable MCI from MCI-to-AD converters. Correlations among vascular markers were consistent and well estimated, whereas glial-vascular correlations were based on 64 to 94 overlapping participants and were not significant. Glial and vascular plasma biomarkers did not progress synchronously across the AD continuum. GFAP showed the strongest and most discriminating diagnosis-associated elevation. Vascular markers showed statistically robust but small group-level differences with no individual-level discriminative utility, and their divergent 12-month trajectories require replication over longer follow-up before they can be interpreted as stage-dependent regulation.},
}

@article {pmid42763636,
year = {2026},
author = {Sarangal, M and Sarangal, C and Vora, J and Soni, K},
title = {Auvelity (Dextromethorphan-Bupropion) for Agitation and Aggression in Alzheimer's Disease Dementia: Mechanism, Efficacy, Safety, and Clinical Considerations.},
journal = {Psychopharmacology bulletin},
volume = {56},
number = {4 Suppl 1},
pages = {82-87},
pmid = {42763636},
issn = {2472-2448},
mesh = {Humans ; *Dextromethorphan/therapeutic use/adverse effects/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/psychology/complications ; Drug Combinations ; *Psychomotor Agitation/drug therapy/etiology ; *Aggression/drug effects ; *Bupropion/therapeutic use/adverse effects/pharmacology/administration & dosage ; Cytochrome P-450 CYP2D6 Inhibitors/therapeutic use/adverse effects/pharmacology ; },
abstract = {BACKGROUND: Agitation and aggression in Alzheimer's disease (AD) are highly distressing behavioral symptoms traditionally managed with off-label atypical antipsychotics, despite boxed warnings for increased mortality in elderly patients. The emergence of Auvelity (dextromethorphan-bupropion) provides a critical, non-antipsychotic therapeutic alternative.

MECHANISM: This combination utilizes bupropion as a CYP2D6 inhibitor to achieve therapeutic central nervous system concentrations of dextromethorphan. Dextromethorphan acts as an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist, bypassing dopaminergic blockade to promote synaptic plasticity via glutamatergic and monoaminergic modulation.

EFFICACY: Key clinical trials (ADVANCE-1 and ACCORD) demonstrate that dextromethorphan-bupropion produces rapid, statistically significant reductions in Cohen-Mansfield Agitation Inventory (CMAI) scores. Furthermore, it offers robust long-term maintenance, demonstrating a 3.6-fold lower risk of agitation relapse compared to placebo.

SAFETY: The combination therapy was generally well-tolerated in trials, successfully avoiding the sedation, cognitive blunting, and heightened fall risks characteristic of antipsychotics. Clinicians must, however, monitor for blood pressure changes and potential CYP2D6 drug-drug interactions.

CONCLUSION: Dextromethorphan-bupropion represents a highly efficacious, safer paradigm shift in the pharmacological management of AD-associated agitation, offering targeted symptom relief while minimizing the severe risks associated with standard antipsychotic use.},
}

Humans
*Dextromethorphan/therapeutic use/adverse effects/pharmacology/administration & dosage
*Alzheimer Disease/drug therapy/psychology/complications
Drug Combinations
*Psychomotor Agitation/drug therapy/etiology
*Aggression/drug effects
*Bupropion/therapeutic use/adverse effects/pharmacology/administration & dosage
Cytochrome P-450 CYP2D6 Inhibitors/therapeutic use/adverse effects/pharmacology

@article {pmid42763949,
year = {2026},
author = {Higashi, K and Sasaki, T and Takahashi, H and Kawai, Y and Hennig, S and Shimizu, K and Nakai, M and Takahashi, K and Nakamura, Y},
title = {Population pharmacokinetic analysis and exposure-response analysis of brexpiprazole in Japanese patients with agitation in Alzheimer's dementia.},
journal = {Drug metabolism and pharmacokinetics},
volume = {71},
number = {},
pages = {101549},
doi = {10.1016/j.dmpk.2026.101549},
pmid = {42763949},
issn = {1880-0920},
abstract = {The efficacy and safety of brexpiprazole in patients with agitation in Alzheimer's dementia (AAD) were demonstrated in Japanese study with 1 and 2 mg/day doses. The purpose of this study was to investigate need for dose adjustment in Japanese patients with AAD using population pharmacokinetics (PopPK) and exposure-response (ER) analysis, given that this population was older and renally impaired. First, using PopPK analysis, applicability of the previous PopPK model for Japanese healthy volunteers and patients with schizophrenia, established in a previous study, was confirmed to predict brexpiprazole concentrations in Japanese patients with AAD. Then, using exposure data from the PopPK model, ER analysis demonstrated that ER relationship was adequately described by sigmoid Emax model, although some parameters (EC50 and Hill) had RSEs >60%. Covariate analysis using PopPK model indicated that older age and/or reduced renal function were associated with increased exposure. However, these changes were considered to remain within the plateau region of ER relationship, suggesting limited clinical impact on efficacy. Therefore, brexpiprazole dose adjustment according to patient characteristics was not considered necessary in Japanese patients with AAD. Given the limited data and residual model instability in ER analysis, further investigation may be warranted to confirm the findings.},
}

@article {pmid42763962,
year = {2026},
author = {Ye, J and Yin, S and Lin, Y and Yang, S and Ma, L and Wang, Y and Gao, K and Wang, Y and Yang, X and Yang, Z and Wang, N and Liu, H and Xu, S and Cui, W and Zhang, B},
title = {Substituted methyl acridone-carboxylate derivatives as CD1/CD2 dual-targeting HDAC6 inhibitors to ameliorate the pathological phenotype of Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {320},
number = {},
pages = {119350},
doi = {10.1016/j.ejmech.2026.119350},
pmid = {42763962},
issn = {1768-3254},
abstract = {Histone deacetylase 6 (HDAC6) has emerged as a promising target for Alzheimer' disease (AD). Although most reported HDAC6 inhibitors were designed to target CD2 catalytic domain, recent studies highlighted the functional importance of CD1 domain for the regulation of AD-related substrates. In this study, a series of substituted methyl acridone-carboxylate derivatives bearing a methyl ester moiety were discovered as CD1/CD2 dual-targeting HDAC6 inhibitors. The leading compound 6c could direct bind to HDAC6, and selectively inhibits HDAC6 with a high affinity in vitro. Molecular docking analysis revealed that 6c forms non-chelating coordination interactions with the zinc ions in both CD1 and CD2 domains of HDAC6. 6c inhibited Aβ oligomer-induced microtubule depolymerization and microglial phagocytic impairments in vitro. Furthermore, 6c effectively prevented HDAC6-driven α-tubulin and Hsp90 deacylation, as well as cognitive impairments in Aβ1-42 oligomer-treated mice. Combined with the acceptable physicochemical properties and promising biosafety of 6c, this study suggested that substituted methyl acridone-carboxylate derivatives, as CD1/CD2 dual-targeting HDAC6 inhibitors, might be developed as a novel lead drug for the treatment of AD.},
}

@article {pmid42763975,
year = {2026},
author = {Thattil, HJ and M N, A},
title = {Global transfer learning pipeline for protein disease association in Alzheimer's disease.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 1},
pages = {109408},
doi = {10.1016/j.compbiolchem.2026.109408},
pmid = {42763975},
issn = {1476-928X},
abstract = {Researchers have prioritized the study of protein-disease associations to decode triggers of clinical pathology and isolate high-value targets for drug development. Comprehensive modeling of genetic network dynamics is equally vital for advancing our functional understanding of these disorders. In this study, we applied a hierarchical, transfer-learning framework to address the challenge of protein-disease association prediction, specifically targeting scenarios with limited labeled data for specific diseases. We used Alzheimer's disease as a case study to demonstrate the efficacy of our proposed Global Transfer Learning Pipeline model. We combined the embeddings generated from protein-protein interactions along with protein-cluster association and protein sequences to train the proposed model. We addressed the scarcity of reliable negatives by employing PU learning strategies with deep fusion architecture to ensure robustness of the model. The ordinal regression was integrated to the learning pipeline to learn granular confidence levels for protein-disease associations which was later fed into the stacked meta model. The model also uses techniques of hyperparameter optimization to enhance the prediction performance. Our model achieved a weighted F1 score of 96% with average AUC 0.852 and AUPRC 0.967 which outperforms the individual gradient boosting, tree models and deep neural network models. These results demonstrate the effectiveness of the proposed model in predicting protein-disease associations for Alzheimer's disease.},
}

@article {pmid42763978,
year = {2026},
author = {Lisazo, C and Casamitjana, A and Oliver, A and Lladó, X and , and , },
title = {Learning age-conditioned brain atlases via free-prototype modeling for brain age prediction.},
journal = {Artificial intelligence in medicine},
volume = {182},
number = {},
pages = {103534},
doi = {10.1016/j.artmed.2026.103534},
pmid = {42763978},
issn = {1873-2860},
abstract = {Brain age (BA) estimation from structural MRI is a promising biomarker for the early detection, monitoring, and risk stratification of neurodegenerative disorders, yet most existing approaches rely on black-box deep learning models that limit clinical interpretability. Prototype-based learning offers a promising alternative by grounding predictions in reference representations, but current methods depend on selecting prototypes from real training samples, introducing subject-specific variability and requiring curated datasets. In this work, we propose a free-prototype framework that directly learns age-conditioned prototypes in latent space instead of anchoring them to individual training samples. These prototypes are decoded into age-conditioned brain atlases that provide clinically interpretable visual references of anatomical aging. Extensive experiments across multiple large-scale neuroimaging cohorts demonstrate that the proposed approach achieves BA predictive performance comparable to state-of-the-art convolutional models in-domain while improving robustness under distribution shift in external datasets. Moreover, our results show that deviations from age-matched prototypes capture clinically relevant information beyond the conventional BA gap, enabling improved discrimination between healthy controls and Alzheimer's disease patients. Hence, beyond the limited notion of accelerated aging as a biomarker of disease, our findings support the use of residual information as complementary evidence to improve diagnostic frameworks in clinical settings. Finally, structural analyses confirm that the learned atlases follow smoother and more biologically consistent aging trajectories than prototype representations based on real-image selection. These findings demonstrate that structuring the latent space around learned prototypes enables accurate and robust BA estimation while providing clinically interpretable normative references for understanding deviations from healthy brain aging.},
}

@article {pmid42764010,
year = {2026},
author = {Shao, F and Hu, J and Traylor, A and Lei, H and Zhang, P and Akarapipad, P and Park, JS and Hsieh, K and Wang, TH},
title = {CRISPR-AMPED: A CRISPR/Cas-based immunoassay with attomolar sensitivity enabled by magnetic proximity extension and detection.},
journal = {Biosensors & bioelectronics},
volume = {315},
number = {},
pages = {119227},
doi = {10.1016/j.bios.2026.119227},
pmid = {42764010},
issn = {1873-4235},
abstract = {Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas-associated systems have emerged as powerful tools for next-generation molecular diagnostics, particularly for nucleic acid detection. However, ultrasensitive protein detection is equally critical across diverse applications in biology and medicine, especially for diagnosing and prognosing diseases such as cancer, traumatic brain injury (TBI), Alzheimer's disease, and cardiovascular diseases. Despite recent efforts to adapt CRISPR/Cas systems for protein detection, these methods have typically achieved sensitivity in the femtomolar to picomolar range, underscoring the need for enhanced detection capabilities. Here, we developed CRISPR-AMPED, a CRISPR/Cas-based immunoassay enhanced by magnetic proximity extension and detection. This approach combines proximity extension assay (PEA) with magnetic beads to convert protein targets into DNA barcodes while enabling effective washing to reduce background noise. The resulting DNA barcodes are detected through recombinase polymerase amplification (RPA) coupled with CRISPR/Cas12a, eliminating thermocycling and providing simultaneous target and signal amplification. CRISPR-AMPED achieves attomolar-level sensitivity, surpassing ELISA by over three orders of magnitude and outperforming existing immunoassays and CRISPR/Cas-based protein detection systems. As an initial demonstration of clinical utility, we applied CRISPR-AMPED to detect the inflammatory biomarker interleukin-8 (IL-8) in serum samples from patients with TBI and healthy controls. Further integration with a smartphone-based detection device demonstrates its potential for portable testing, while the digital format extends the dynamic range and enhances quantitation precision. Together, these results establish CRISPR-AMPED as a sensitive protein detection approach using IL-8 as an initial model target and provide a framework for future adaptation to additional protein biomarkers.},
}

@article {pmid42764037,
year = {2026},
author = {Pereira, CS and Abid, H and Adair, C and Domalewski, RJ and Jabr, L and Nichols, MR},
title = {Aggregated amyloid-β(1-42) is internalized more efficiently than monomers by HEK293T cells.},
journal = {Biochimica et biophysica acta. Proteins and proteomics},
volume = {},
number = {},
pages = {141178},
doi = {10.1016/j.bbapap.2026.141178},
pmid = {42764037},
issn = {1878-1454},
abstract = {An early and continual event in Alzheimer's disease (AD) is upregulation of the immune response concomitant with accumulation of aggregated amyloid-β peptide (Aβ). The mechanisms by which Aβ can trigger an immune response involve stimulation of cell surface receptors and intracellular pathways, as well as internalization of Aβ into the cell cytosol. The HEK293T cell line has been a valuable model system for exploring a variety of biological processes, including internalization of protein aggregates such as Aβ. There have been some questions regarding the role of Aβ conformation in the HEK293T internalization process. The current study investigated the influence of Aβ42 conformation on HEK293T internalization using ELISA, confocal microscopy and flow cytometry. Analysis of HEK293T cell lysates by ELISA after exposure to Aβ42 conformational species indicated that protofibrillar and fibrillar Aβ42 were internalized to a much greater extent compared to purified Aβ42 monomers. The same trend was observed in HEK293T whole cells by confocal fluorescence imaging. HEK293T cell internalization occurred by 4 h for aggregated Aβ42 at concentrations in the low micromolar range. Fluorescent labeling of Aβ42 did not impact cell internalization and facilitated the use of flow cytometry as a third strategy to show significantly greater internalization of Aβ42 protofibrils compared to monomers, further confirming the Aβ42 conformational influence on HEK293T cell internalization. HEK293T cell models are valuable tools for mechanistic investigations of human disease and characteristically generate detailed information about cellular processes or pathways. These include Aβ cellular internalization and intracellular Aβ, which are key aspects of AD pathogenesis.},
}

@article {pmid42764107,
year = {2026},
author = {Desale, SH and Doshi, PP and Khutale, AA and Suresh, S},
title = {Unlocking the Blood-Brain Barrier: Can Low-Intensity Focused Ultrasound Enable Effective Delivery of Anti-Amyloid and Anti-Tau Antibodies in Alzheimer's Disease?.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103379},
doi = {10.1016/j.arr.2026.103379},
pmid = {42764107},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) remains a major unmet medical challenge despite decades of progress in medicines that target tau and amyloid-β (Aβ) pathology. The clinical benefit of monoclonal antibodies (mAbs) against Aβ is limited, with current data showing only slight slowing of cognitive decline despite encouraging biomarker responses and recent regulatory approval of these drugs. Moreover, their wider clinical use is restricted by dose-dependent toxicities such as amyloid-related imaging abnormalities (ARIA), and by the need for continuous long-term assessment of efficacy and safety in AD patients. The poor penetration of the blood-brain barrier (BBB) by large biologics is a significant but often overlooked factor contributing to this discrepancy. Low-intensity focused ultrasound (LIFU) has emerged as a non-invasive technique for transient localized modification of BBB permeability when paired with intravenously administered microbubbles. This evaluation examines LIFU as a means of delivering anti-tau and anti-amyloid antibodies to AD patients. By integrating data from early-phase clinical research with biological insights, we investigate whether altering the BBB can overcome the pharmacokinetic (PK) limitations of existing immunotherapies. LIFU has biological effects that are critical to the pathophysiology of AD in addition to aiding the mobility of macromolecules, such as enhanced lymphatic clearance and focused neuroimmune activation, which could help treatments based on antibodies. Clinical research to date shows that, in properly chosen AD cohorts, LIFU-mediated BBB opening is practical, reversible, and generally safe; however, there is still a lack of conclusive evidence connecting BBB modulation to elevated intraparenchymal antibody levels or long-term cognitive enhancement. We propose that LIFU should currently be regarded as a promising investigational adjunct to immunotherapy rather than an established therapeutic modality for AD. Biomarker-driven evidence of enhanced cerebral medication distribution and therapeutic effects determines its translational significance; BBB alteration could become a standard Alzheimer's therapeutic strategy if LIFU is successful.},
}

@article {pmid42764149,
year = {2026},
author = {Omori, W and Kajitani, N and Okada-Tsuchioka, M and Takebayashi, M},
title = {Cerebrospinal Fluid p75 Neurotrophin Receptor Ectodomain Levels Across Clinically Diagnosed Alzheimer's Disease, Late-Life Depression, and Healthy Aging: A Preliminary Cross-Sectional Study.},
journal = {Neuropsychopharmacology reports},
volume = {46},
number = {3},
pages = {e70171},
pmid = {42764149},
issn = {2574-173X},
support = {23K14818//JSPS KAKENHI/ ; 18H02756//JSPS KAKENHI/ ; 18K07620//JSPS KAKENHI/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; Female ; Male ; Cross-Sectional Studies ; Aged ; *Healthy Aging/cerebrospinal fluid ; *Receptors, Nerve Growth Factor ; *Depression/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Aged, 80 and over ; *Nerve Tissue Proteins/cerebrospinal fluid ; Receptor, Nerve Growth Factor ; },
abstract = {OBJECTIVE: The p75 neurotrophin receptor ectodomain (p75NTR-ECD) has been implicated in amyloid-β-related neurotoxicity, but cerebrospinal fluid (CSF) levels in late-life depression (LLD) remain uncertain. We compared clinically diagnosed Alzheimer's disease (AD), LLD, and healthy controls (HC) and reassessed exploratory symptom and cognitive associations.

METHODS: CSF p75NTR-ECD was measured in 50 participants (HC, n = 19; LLD, n = 19; AD, n = 12). The primary linear model adjusted for age, sex, and body mass index. Exploratory symptom and cognitive models additionally adjusted for diagnostic group; six p values underwent Benjamini-Hochberg false discovery rate (FDR) correction. Plate and below-calibrator sensitivity analyses were performed.

RESULTS: CSF p75NTR-ECD was higher in HC than in AD (B = 131.2 pg/mL, 95% CI 42.8-219.6, p = 0.005) and higher in LLD than in AD (B = 154.6 pg/mL, 95% CI 68.9-240.3, p < 0.001); HC and LLD did not differ. No symptom or cognitive association remained significant after diagnostic-group adjustment and FDR correction (all q ≥ 0.117). Plate adjustment did not materially change the primary contrasts. Excluding three concentrations below the lowest calibrator preserved the LLD-AD contrast but attenuated the HC-AD contrast.

CONCLUSIONS: CSF p75NTR-ECD showed preliminary differences across clinically defined groups. Because the sample was small, the recruitment site was perfectly confounded with AD versus non-AD status, and diagnoses were not uniformly biomarker-confirmed, the findings do not establish causality, clinical diagnostic utility, or added value beyond established AD biomarkers and require independent multisite replication.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/diagnosis
Female
Male
Cross-Sectional Studies
Aged
*Healthy Aging/cerebrospinal fluid
*Receptors, Nerve Growth Factor
*Depression/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
Aged, 80 and over
*Nerve Tissue Proteins/cerebrospinal fluid
Receptor, Nerve Growth Factor

@article {pmid42764315,
year = {2026},
author = {Shao, Y and Zhang, RF and Wang, Z and Gan, J and Jiang, XJ and Yang, L},
title = {From Dysbiosis to Blood-Brain Barrier Disruption: The Metabolite-Mediated Gut-Brain Axis in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42764315},
issn = {1559-1182},
mesh = {Humans ; *Blood-Brain Barrier/metabolism/pathology ; Animals ; *Alzheimer Disease/metabolism/pathology/microbiology ; *Dysbiosis/metabolism ; *Gastrointestinal Microbiome/physiology ; *Brain-Gut Axis/physiology ; *Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is not merely a central nervous system disorder; rather, it is a systemic condition profoundly influenced by the peripheral internal environment. Recent research has revealed that imbalances in the gut microbiota (GM) and metabolite disturbances contribute to AD onset and progression. Clinical and animal studies have indicated that AD patients commonly exhibit reduced GM diversity, decreased populations of short-chain fatty acid (SCFA)-producing and indole-producing bacteria, disrupted bile acid (BA) profiles, and elevated levels of trimethylamine N-oxide (TMAO) and kynurenine pathway (KP) activity. These alterations not only reflect gut dysbiosis, but also impair blood-brain barrier (BBB) integrity and amplify neuroinflammation by modulating tight junction proteins and inflammatory signaling through their effects on receptors and transporters such as G protein-coupled receptors(GPR41/43), aryl hydrocarbon receptor(AhR), Farnesoid X receptor(FXR)/ Takeda G protein-coupled receptor 5(TGR5), L-type amino acid transporter 1(LAT1), and Major Facilitator Superfamily Domain containing 2A(MFSD2A). From an integrative perspective, these changes -including short-Chain Fatty Acids (SCFAs) deficiency, elevated TMAO and toxic BA levels, overactivation of the KP, and Lipopolysaccharides (LPS) leakage-often act synergistically, collectively forming key pathological nodes in the "metabolic network-BBB-AD" axis. GM-targeted strategies such as dietary interventions, probiotics and fecal microbiota transplantation (FMT) have demonstrated potential in improving metabolite profiles and BBB homeostasis. Future research should utilize induced pluripotent stem cell-derived organoids and multi-omics integration approaches to elucidate the spatiotemporal dynamics of metabolites within the gut-brain axis (GBA), thereby laying the foundation for precise microbiome-based interventions in AD.},
}

Humans
*Blood-Brain Barrier/metabolism/pathology
Animals
*Alzheimer Disease/metabolism/pathology/microbiology
*Dysbiosis/metabolism
*Gastrointestinal Microbiome/physiology
*Brain-Gut Axis/physiology
*Brain/metabolism

@article {pmid42764330,
year = {2026},
author = {Marimuthu, A and Singh, MT and Balasubramanian, S and Krishnamurthy, PT},
title = {Targeting the BACE1-GSK-3β Signaling Axis in Alzheimer's Disease: From Molecular Crosstalk to Nanotechnology-Based Translational Strategies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42764330},
issn = {1559-1182},
mesh = {Humans ; *Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors ; *Alzheimer Disease/metabolism/drug therapy ; *Glycogen Synthase Kinase 3 beta/metabolism ; *Aspartic Acid Endopeptidases/metabolism/antagonists & inhibitors ; Animals ; *Signal Transduction/physiology/drug effects ; *Nanotechnology/methods ; *Translational Research, Biomedical/methods ; *Glycogen Synthase Kinase 3/metabolism ; },
abstract = {Recent evidence demonstrates that the interplay of amyloidogenesis and tauopathy plays a significant role in exacerbating neurodegeneration in Alzheimer's disease. This interplay of molecular pathways aids in the formation and accumulation of amyloid beta and neurofibrillary tangles extracellularly and intracellularly, respectively. These interconnected pathways highlight the need for the simultaneous inhibition of BACE1 and GSK-3β for the mitigation of disease progression. There are several drugs developed against BACE1 and GSK-3β separately, but they have limited therapeutic efficacy and failed in clinical trials. The failure is due to systemic toxicity and off-target side effects, limited blood-brain barrier permeation, and lower therapeutic benefits. Advances in brain-targeted drug delivery approaches aim to provide site-specific drug delivery, co-delivery of dual drugs, and enhanced stability. Nanoformulations such as lipid-based nanoparticles, polymeric nanoparticles, and hybrid nanoformulations with surface functionalization demonstrate better results in pre-clinical studies. Various research studies have established that targeting amyloidogenesis and tau hyperphosphorylation pathways is a promising therapeutic approach for attenuating neurodegeneration, with the integration of nanotechnology. This review article provides insights into the interplay of BACE1 and GSK-3β molecular signaling pathways, examines the limitations of conventional therapies, and highlights the potential of dual-targeting nanoformulations, while emphasizing the challenges of clinical translation and effective therapeutic strategies to overcome these and treat AD.},
}

Humans
*Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors
*Alzheimer Disease/metabolism/drug therapy
*Glycogen Synthase Kinase 3 beta/metabolism
*Aspartic Acid Endopeptidases/metabolism/antagonists & inhibitors
Animals
*Signal Transduction/physiology/drug effects
*Nanotechnology/methods
*Translational Research, Biomedical/methods
*Glycogen Synthase Kinase 3/metabolism

@article {pmid42764440,
year = {2026},
author = {Ye, Z and Zhang, Q and Zhang, B and Teng, B and Wang, S and Chen, J and Li, B and Jin, H and Zheng, Z and Yang, Z and Hu, X and Zhao, X and Huang, S and Weng, Y and Yang, D},
title = {Baseline cerebrospinal fluid complement balance is associated with longitudinal memory decline in relation to plasma p‑tau181 levels in mild cognitive impairment.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71836},
doi = {10.1002/alz.71836},
pmid = {42764440},
issn = {1552-5279},
support = {82302081//National Natural Science Foundation of China/ ; LQ24H090003//Zhejiang Provincial Natural Science Foundation of China/ ; },
mesh = {Humans ; *Cognitive Dysfunction/cerebrospinal fluid/blood ; *tau Proteins/blood/cerebrospinal fluid ; Female ; Male ; Aged ; *Memory Disorders/cerebrospinal fluid/blood ; Longitudinal Studies ; Biomarkers/cerebrospinal fluid/blood ; Phosphorylation ; Neuropsychological Tests ; Cross-Sectional Studies ; *Complement C3/cerebrospinal fluid ; Alzheimer Disease/cerebrospinal fluid ; Aged, 80 and over ; },
abstract = {INTRODUCTION: The role of complement in Alzheimer's disease (AD) remains unclear, particularly regarding tau pathology and memory decline.

METHODS: In 123 mild cognitive impairment (MCI) participants from Alzheimer's Disease Neuroimaging Initiative (ADNI), linear mixed‑effects models and Johnson-Neyman analysis examined associations of baseline cerebrospinal fluid (CSF) C3/FH ratio with longitudinal memory decline moderated by time‑varying plasma phosphorylated tau181 (p‑tau181).

RESULTS: The three‑way interaction was significant (p = 0.023). A region of statistical significance was identified: the conditional association of C3/FH with memory decline became significant when p‑tau181 exceeded 0.76 SD, with higher C3/FH associated with slower decline at elevated p‑tau181 levels. Cross-sectionally, no significant C3/FH-memory associations were observed in any diagnostic group (all p > 0.05).

DISCUSSION: These findings indicate that complement balance is associated with memory decline in MCI in a manner dependent on plasma p‑tau181 levels, suggesting that complement may interact with AD‑related pathophysiology during the prodromal phase. The identified statistical region provides a hypothesis‑generating benchmark for future studies.},
}

Humans
*Cognitive Dysfunction/cerebrospinal fluid/blood
*tau Proteins/blood/cerebrospinal fluid
Female
Male
Aged
*Memory Disorders/cerebrospinal fluid/blood
Longitudinal Studies
Biomarkers/cerebrospinal fluid/blood
Phosphorylation
Neuropsychological Tests
Cross-Sectional Studies
*Complement C3/cerebrospinal fluid
Alzheimer Disease/cerebrospinal fluid
Aged, 80 and over

@article {pmid42764448,
year = {2026},
author = {},
title = {Correction to "Human iPSC-derived GABAergic interneuron transplantation restores circuit balance and cognitive function in an Alzheimer's disease model".},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71875},
doi = {10.1002/alz.71875},
pmid = {42764448},
issn = {1552-5279},
}

@article {pmid42764449,
year = {2026},
author = {Peng, S and Butler-Laporte, G and Johnson, SC and Engelman, CD and Lu, T},
title = {Genetic evidence suggests a protective role of immunoglobulin M in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71865},
doi = {10.1002/alz.71865},
pmid = {42764449},
issn = {1552-5279},
support = {R35GM162188/NH/NIH HHS/United States ; RF1AG054047/NH/NIH HHS/United States ; //of the National Institutes of Health/ ; P2CHD047873//the Center for Demography and Ecology/ ; P30AG017266//the Center for Demography of Health and Aging/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/immunology/blood ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; *Immunoglobulin M/genetics/blood ; Biomarkers/blood ; Immunoglobulin G/blood ; Glial Fibrillary Acidic Protein/blood ; Female ; Male ; Mendelian Randomization Analysis ; Genetic Risk Score ; Aged ; Neurofilament Proteins/blood ; Peptide Fragments/blood ; },
abstract = {INTRODUCTION: Immune dysfunction has been implicated in Alzheimer's disease (AD), but the roles of specific immunoglobulin classes remain unclear.

METHODS: We integrated human genetics and plasma biomarker analyses to evaluate immunoglobulin G (IgG), IgA, and IgM in relation to AD. Two-sample Mendelian randomization analyses were conducted with multiple sensitivity analyses. Polygenic risk scores for immunoglobulin classes were developed in the All of Us Research Program and tested in the UK Biobank for associations with AD and dementia, and in two Wisconsin-based cohorts for associations with plasma amyloid beta (Aβ)42/40, phosphorylated tau 217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP).

RESULTS: Higher genetically proxied IgM was consistently associated with lower AD risk, higher Aβ42/40, and lower p-tau217, but not with NfL or GFAP. No consistent associations were observed for IgG or IgA.

DISCUSSION: IgM-related humoral immunity may play a protective role in AD and warrants exploration for early intervention and prevention.},
}

Humans
*Alzheimer Disease/genetics/immunology/blood
Amyloid beta-Peptides/blood
tau Proteins/blood
*Immunoglobulin M/genetics/blood
Biomarkers/blood
Immunoglobulin G/blood
Glial Fibrillary Acidic Protein/blood
Female
Male
Mendelian Randomization Analysis
Genetic Risk Score
Aged
Neurofilament Proteins/blood
Peptide Fragments/blood

@article {pmid42764492,
year = {2026},
author = {},
title = {Correction to 'Exercise Snacking in Alzheimer's Disease: A Mechanistic Rationale Based on Repeated Exerkine Signaling'.},
journal = {Journal of neurochemistry},
volume = {170},
number = {9},
pages = {e70560},
doi = {10.1111/jnc.70560},
pmid = {42764492},
issn = {1471-4159},
}

@article {pmid42764574,
year = {2026},
author = {Bhise, MR and Thejomoorthy, K and Kumar, M and Patel, PKN and Mahajan, V and Naquvi, KJ and Ansari, I and Kumar, A},
title = {Advances in Novel Drug Delivery Systems for Targeting the Brain: Overcoming Barriers and Enhancing Therapeutic Efficacy.},
journal = {Current drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672018474663260907142216},
pmid = {42764574},
issn = {1875-5704},
abstract = {The blood-brain barrier (BBB) is critical in CNS pharmacotherapy; it blocks the entry of 98 per cent of small-molecule compounds and almost all macromolecules into the brain parenchyma via tight junction complexes, efflux transporter action, and enzymatic breakdown. This review focuses on the mechanistic basis of BBB resistance and analyses the current landscape of new drug delivery systems developed to overcome this barrier. We elaborate on polymeric nanocarriers, lipid-based nanocarriers, exosomes, dendrimers, and metallic nanoparticles, including surface engineering, the possibility of receptor-mediated transcytosis via transferrin, LRP1, and glucose transporter receptors, and known preclinical efficacy in glioblastoma, Alzheimer's disease, and Parkinson's disease. Non-invasive delivery through the nose is evaluated as intranasal delivery because it utilises olfactory and trigeminal receptors to circumvent systemic delivery. BBB modulation mediated by focused ultrasound is mentioned as one of the physical adjuncts to enhance CNS penetration. Clinical translation is poor, even where the preclinical data are positive. Most late-stage failures can be attributed to protein corona formation, anti-PEG immunogenicity, interpatient heterogeneity in the BBB, and manufacturing scalability. These obstacles are critically evaluated with the help of recent clinical trial evidence, where preclinical models cannot be used as predictors of human outcomes. In the future, AI-based nanocarrier design, machine-learning-driven prediction of BBB permeability, and patient-centred nanomedicine platforms will provide a viable pathway to customised CNS therapeutic approaches. Multimodal strategies integrating RMT, stimuli-responsive carriers, and CRISPRbased gene delivery may collectively overcome the translational gap that single-platform approaches have consistently failed to bridge.},
}

@article {pmid42764659,
year = {2026},
author = {Taş, NA and Taş, R and Celebioglu, HU and Taslimi, P and Kaya, S and Berisha, A},
title = {Eco-Friendly Zinc Oxide Nanoparticles from Trachystemon orientalis L.: Examination of Their Antibacterial, Anti-Alzheimer, and Antidiabetic Potentials.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673493377260828095834},
pmid = {42764659},
issn = {1875-533X},
abstract = {INTRODUCTION: This study aimed to biogenically synthesize and characterize Zinc Oxide Nanoparticles (ZnONPs) using the Trachystemon orientalis L. plant extract. It also aimed to evaluate the antibacterial potential and metabolic enzyme-inhibitory activities of these green-synthesized nanoparticles for medical and industrial applications.

METHODS: Nanoparticles were synthesized using a green chemistry approach, where the plant extract acted as a reducing agent for zinc ions. The structural and morphological properties of ZnONPs were analyzed using X-ray Diffraction (XRD), Fourier-transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), and Energy-dispersive X-ray Spectroscopy (EDX). Antibacterial efficacy was evaluated by determining the Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) against Staphylococcus aureus and Escherichia coli. Additionally, the inhibitory effects on α-glycosidase, Acetylcholinesterase (AChE), and Butyrylcholinesterase (BChE) enzymes were investigated to determine the inhibition constant (Ki) values. All experiments were conducted in triplicate, and the results are expressed as mean ± standard deviation.

RESULTS: XRD analysis confirmed the crystalline metallic structure of ZnONPs, SEM imaging revealed a predominantly rod-shaped morphology, and EDX analysis verified that the elemental composition was predominantly zinc, consistent with ZnO nanoparticle formation. FTIR spectra confirmed the successful capping of the nanoparticles by plant-derived bioactive compounds. Antibacterial assays showed significant activity, with MIC values of 125 μg/mL for S. aureus and 250 μg/mL for E. coli. Enzyme inhibition studies yielded potent results, with Ki values of 47.10 ± 3.72 μM for α-glycosidase, 3.55 ± 0.43 μM for BChE, and 15.47 ± 1.24 μM for AChE, all of which outperformed standard inhibitors such as tacrine and acarbose.

DISCUSSION: The results demonstrate that the biogenic synthesis of ZnONPs using T. orientalis is an effective and eco-friendly method for producing nanoparticles with high biological activity. The superior enzyme inhibition and antibacterial performance compared to conventional standards suggest that these nanoparticles possess unique surface properties owing to the plant-derived organic shell, enhancing their interaction with biological targets.

CONCLUSION: This study successfully synthesized rod-shaped zinc oxide nanoparticles with significant antimicrobial and enzyme-inhibitory properties. These findings highlight the potential of biogenically synthesized ZnONPs as multifunctional agents in the development of new therapeutic strategies for managing bacterial infections and metabolic disorders.},
}

@article {pmid42764670,
year = {2026},
author = {Thabtah, F and Kamalov, F and Spencer, R and Abdelhamid, N and Nami, M and , },
title = {Plasma biomarker and machine learning modeling of clinical progression in cognitively normal individuals at risk for Alzheimer's disease.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/17582024.2026.2731194},
pmid = {42764670},
issn = {1758-2032},
abstract = {AIMS: To evaluate whether plasma biomarkers can distinguish cognitively normal (CN) individuals who remain clinically stable from those who subsequently develop mild cognitive impairment (MCI) or Alzheimer's disease (AD) and to test the predictive performance of classification data‑driven models.

MATERIALS AND METHODS: Plasma biomarker follow-up data from initially CN participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed across Elecsys, Lumipulse, Precivity, and SIMOA assays. Feature selection was done using chi-square, information gain ratio, and ReliefF. K-nearest neighbors (kNN), logistic regression, support vector machine (SVM), and Extreme Gradient Boosting (XGBoost) classifiers were tested using cross-validation. Synthetic Minority Over-sampling Technique (SMOTE) was applied to alleviate class imbalance.

RESULTS: pTau217, pTau181, Aβ40, NfL, and assay-specific amyloid/tau ratios have relatively high feature importance. Class imbalance significantly reduced sensitivity in unbalanced models. Following data balancing, the best‑performing SVM model with selected Elecsys features achieved an accuracy of 71.6%, while the highest sensitivity of all models was 56%.

CONCLUSIONS: Baseline plasma biomarker data, combined with follow-up plasma biomarkers visits can help us identify patterns that are associated with subsequent clinical progression from CN to MCI/AD. However, predictive performance was moderate, and external validation in larger and more diverse cohorts is needed before clinical applications.},
}

@article {pmid42764767,
year = {2026},
author = {Wenxin, S and Youmao, Z and Wenhua, H},
title = {Basic Research on the Lymphatic System and Exploratory Research in LVA Surgery for Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050503391260907045733},
pmid = {42764767},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a common neurodegenerative disorder characterized by progressive cognitive decline. Its characteristic pathological features include Aβ plaque deposition and abnormal tau protein aggregation. Biomarker testing has improved AD diagnosis. However, current treatments are primarily symptomatic, and no effective therapies are available to slow disease progression.

MATERIALS AND METHODS: In this review, PubMed, CNKI, Wanfang Data, and the Chinese Medical Journal Full-text Database were searched using core terms including lymphatic system, Alzheimer's disease, and deep cervical lymphatic-venous anastomosis with supplementary synonyms. After deduplication and two-round screening, irrelevant, duplicate, low-quality, and non-full-text articles were excluded, and eligible literature was systematically summarized.

RESULTS: The proposal of the glymphatic system has refined the theory of cerebral fluid circulation and waste clearance. Its dysfunction is closely associated with neurodegenerative diseases such as Alzheimer's Disease (AD) and Parkinson's Disease (PD), providing a novel target for AD treatment. Deep cervical Lymphatic-Venous Anastomosis (LVA), as an emerging surgical approach with potential to alleviate AD symptoms, has been initially validated for its short-term efficacy. However, it is still in the early stage of clinical exploration, and further systematic research is required for its successful clinical translation.

DISCUSSION: The glymphatic system mediates brain fluid circulation and waste clearance, providing new insights into AD pathogenesis and treatment. Building on this understanding, deep cervical Lymphatic-Venous Anastomosis (LVA) has emerged as a promising surgical intervention to alleviate AD pathology. Nevertheless, the considerable technical demands and incompletely elucidated mechanism of LVA severely limit its clinical translation, rendering these challenges a central research priority.

CONCLUSION: Breakthroughs in the central lymphatic system have provided an important direction for exploring the pathological mechanisms of AD and developing innovative therapeutic strategies. Clarifying the theoretical basis and technical evolution of LVA surgery, as well as addressing relevant controversial issues, constitutes a key focus to advance the basic research and clinical translation of AD treatment.},
}

@article {pmid42760484,
year = {2026},
author = {Wei, X and Shao, R and Rolland, Y and Vellas, B and de Souto Barreto, P},
title = {Alzheimer's disease biomarkers in relation to non-cognitive domains within the intrinsic capacity framework: a narrative review.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42760484},
issn = {2509-2723},
abstract = {Alzheimer's disease (AD) biomarkers may be associated with decline in non-cognitive domains of intrinsic capacity (IC), but such evidence has not been synthesized. This narrative review, based on a structured PubMed search (last search: December 31, 2025), included 119 human studies examining associations of core AD biomarkers (e.g., amyloid-beta (Aβ) and tau protein) and biomarkers of non-specific processes involved in AD pathophysiology (including neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), structural magnetic resonance imaging (MRI), and fluorodeoxyglucose positron emission tomography (FDG-PET)) with composite IC scores and non-cognitive IC domains. Among included studies, 2 investigated composite IC scores, 49 depressive symptoms, 30 locomotion, 29 hearing impairment, 19 vitality, and 1 vision impairment. The very limited longitudinal evidence on composite IC scores suggests that lower IC was associated with increased p-tau181 levels and that higher baseline NfL predicted steeper IC decline, whereas plasma Aβ42/Aβ40 showed no clear association. At the IC domains' level, higher cerebral Aβ deposition was associated with poorer locomotion, especially slower gait, more consistently than other biomarker modalities. Higher levels of tau biomarkers and NfL were more often associated with lower or declining handgrip strength. Depressive symptoms represented the most investigated non-cognitive IC domain, showing consistent longitudinal associations with lower fluid Aβ42, greater cerebral amyloid deposition, and subsequent brain atrophy. Hearing impairment was linked mainly to higher tau and NfL, reduced glucose metabolism, and brain atrophy; evidence for vision impairment was almost totally absent. Overall, the pattern of associations varied by biomarker modality, IC domain, and study design, suggesting that AD-related pathology and neurodegeneration have functional correlates beyond cognition. Methodological quality, formally appraised with the Newcastle-Ottawa Scale and the JBI checklist, was acceptable for most included studies.},
}

@article {pmid42760588,
year = {2026},
author = {Abdelhamid, M and Padhi, P and Gifani, M and Beck, JS and Thomas, JP and Khadse, G and Kudela, C and Phillips, GJ and Kanthasamy, AG and Counts, SE},
title = {Bioengineered microbiotic levodopa therapy improves cognition and reduces pathology in a rat model of Alzheimer's disease.},
journal = {British journal of pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1111/bph.70670},
pmid = {42760588},
issn = {1476-5381},
support = {R01AG060731//National Institutes of Health (NIH)/ ; U01AG074960//National Institutes of Health (NIH)/ ; //Johnny Isakson Endowed Chair, Coach Mark Rich Endowment/ ; //Georgia Research Alliance Eminent Scholar funds/ ; },
abstract = {BACKGROUND AND PURPOSE: Degeneration of the pontine noradrenergic and midbrain dopaminergic systems contributes to cognitive-behavioural disturbances during the prodromal stages of Alzheimer's disease (AD). We developed a genetically engineered, programmable probiotic Escherichia coli Nissle 1917 strain (EcN[rha] L-DOPA) capable of producing L-3,4-dihydroxyphenylalanine (L-DOPA) in a sustained and titratable manner, thus offering a novel gut-brain delivery mechanism to increase brain levels of noradrenaline and dopamine during the early stages of AD.

EXPERIMENTAL APPROACH: We replicated locus coeruleus (LC) projection system degeneration in AD by administering dopamine-β-hydroxylase IgG-saporin immunotoxin into the prefrontal cortex of 6-months-old Tg344-19 AD rats. The animals then received EcN[rha] L-DOPA/benserazide or placebo by daily gavage for 6 weeks. We assessed cognitive-behavioural function prior to postmortem assessments of amyloid-β plaque load, glial cell activation and neuronal and synaptic markers. Gut colonization, along with plasma and brain L-DOPA, dopamine, noradrenaline and metabolite levels, were also measured.

KEY RESULTS: EcN[rha] L-DOPA displayed stable gut colonization and resulted in sustained therapeutic levels of L-DOPA in plasma and brain, resulting in increased cortical and hippocampal noradrenaline levels. EcN[rha] L-DOPA reduced anxiety-like behaviour improved spatial and working memory. The treatment reduced forebrain Aβ plaque and MHC-II antigen-presenting microglial load. Additionally, EcN[rha] L-DOPA increased protein levels of the dendritic spine marker PSD95.

CONCLUSIONS AND IMPLICATIONS: This translational study suggests that EcN[rha] L-DOPA modifies AD by boosting brain catecholamine production, reducing Aβ accumulation and neuroinflammation, promoting synaptic health, and enhancing cognitive function. Collectively, these results highlight EcN[rha] L-DOPA as a promising preclinical engineered gut microbiome-based therapeutic strategy for early-stage AD.},
}

@article {pmid42760755,
year = {2026},
author = {Lee, M and Wang, K and Lee, HJ},
title = {How temporal caregiving demands shape mental health among older East Asian dementia caregivers.},
journal = {Ethnicity & health},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/13557858.2026.2729317},
pmid = {42760755},
issn = {1465-3419},
abstract = {Objective: Dementia caregiving is associated with elevated psychological distress, yet limited research has examined how caregiving demands shape mental health among East Asian American caregivers, a rapidly growing but understudied population. Guided by the stress process framework, this study examined three temporal dimensions of objective caregiving demands - time intensity, frequency, and chronicity - and their associations with subjective caregiving demands and depressive symptoms among older East Asian American caregivers of individuals living with Alzheimer's disease and related dementias (AD/ADRD).Design: Survey data were collected from 82 East Asian American caregivers aged 50 years or older who were providing care to individuals with dementia in the United States. Participants were recruited through community-based organizations and ethnic community settings. Ordinary least squares regression models were estimated to examine associations among temporal caregiving demands, subjective caregiving demands, and depressive symptoms. An exploratory post hoc structural equation model was also estimated to examine indirect associations.Result: Caregivers in this sample reported substantial caregiving involvement, averaging more than 10 hours of care per day, five days per week, over a period exceeding five years. In adjusted regression models, time intensity and chronicity were not directly associated with depressive symptoms, while caregiving frequency was negatively associated with depressive symptoms. Subjective caregiving demands were strongly and positively associated with depressive symptoms. Temporal caregiving demands were positively associated with subjective caregiving demands when examined separately. An exploratory post hoc analysis suggested that chronicity was indirectly associated with depressive symptoms through subjective caregiving demands.Conclusion: Findings suggest that the mental health implications of dementia caregiving may depend less on objective time exposure alone and more on caregivers' subjective appraisal of caregiving demands. Culturally and linguistically responsive interventions should address perceived caregiving burden, improve access to formal support, and attend to the long-term caregiving experiences of East Asian American dementia caregivers.},
}

@article {pmid42761049,
year = {2026},
author = {Reus, LM and Jiang, C and Vilor-Tejedor, N and Boltz, T and Yigit, A and Gobom, J and Vos, SJB and Blennow, K and Zetterberg, H and Martinez-Lage, P and Tainta, M and Popp, J and Tsolaki, M and Vandenberghe, R and Frölich, L and Freund-Levi, Y and Dobricic, V and Braber, AD and van Harten, AC and Ophoff, RA and Holstege, H and van der Flier, WM and van der Lee, SJ and Teunissen, CE and Bertram, L and Visser, PJ and Tijms, BM},
title = {CSF proteomic quantitative trait loci mapping reveals genetic insights into Alzheimer's disease.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {40},
pmid = {42761049},
issn = {3059-4944},
abstract = {BACKGROUND: Despite the identification of numerous genetic risk variants for Alzheimer's disease (AD), mechanisms through which these variants act remain unclear. Identifying specific proteins levels affected by genetic variation can provide valuable insights into the underlying biological pathways implicated in AD.

METHODS: To gain more insight into effects of genetic variation on AD-related processes, we conducted a genome-wide protein pQTL study using untargeted TMT mass spectrometry in cerebrospinal fluid (CSF) of 2,215 proteins across 487 individuals. Replication was assessed in the independent EMIF-AD MBD cohort of 242 individuals.

RESULTS: We identified 399 independent CSF pQTL signals (P Bonferroni < 2.26 × 10⁻11) associated with 222 proteins, 69% of which were novel. Findings included gene-protein links such as RPS23P10/HSPA6 with CSF FCGR2A, BIN2 with CSF GALNT6, APOE with CSF HS3ST1, and the HLA-region with CSF HLA-DPB1 and PLXDC2. We replicated 230 of 270 gene-protein associations. A proteome-wide association study identified genetically predicted CSF protein levels to be associated with AD, including SIRPA, PLXDC2, and GALNT6. Many AD pQTLs in CSF were enriched in neuroimmune activation, suggesting a genetic basis for neuroimmune dysregulation in AD.

CONCLUSIONS: This study highlights how genetic variation shapes protein expression in the central nervous system, offering mechanistic insight into AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1186/s44477-026-00048-7.},
}

@article {pmid42761308,
year = {2026},
author = {Lee, S and Ju, IG and Lee, M and Kim, JH and Choi, Y and Baek, C and Kim, C and Moon, K and Moon, M and Kim, YJ and Oh, MS},
title = {Alismatis Rhizoma prevents AβO-induced neuronal cell death and synaptic loss in Alzheimer's disease models.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1898356},
pmid = {42761308},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's disease (AD), the most prevalent form of dementia, is a neurodegenerative disease characterized by abnormal accumulation of amyloid-β (Aβ), which leads to memory impairment, synaptic dysfunction, and neuronal loss. This study investigated whether Alismatis Rhizoma (AR) could prevent Aβ oligomer (AβO)-induced synaptic dysfunction, neuronal cell death, and consequent memory decline.

METHODS: For in vitro studies, HT22 cells and human embryonic stem cells (hESC)-derived hippocampal neurons exposed to AβO were treated with AR. For in vivo studies, we administrated AR orally at 50 and 200 mg/kg to mice intrahippocampally injected with AβO and memory function was assessed using behavioral tests. Cellular and hippocampal tissue samples were analyzed by Western blotting and immunostaining.

RESULTS: In AβO-injected mice, AR, particularly at 200 mg/kg, attenuated memory deficits, reduced hippocampal neuronal degeneration, preserved synaptic protein immunoreactivity and increased markers of hippocampal cell proliferation and immature neurons. These effects were accompanied by changes in PI3K/Akt/GSK-3β and ERK/CREB signaling, increased mature BDNF levels, and reduced cleaved caspase-3 levels. AR at 30 and 300 μg/mL protected HT22 cells and hESC-derived hippocampal neurons against AβO-induced loss of viability, while 300 μg/mL AR additionally reduced cleaved caspase-3 levels and increased inhibitory GSK-3β Ser9 phosphorylation in HT22 cells.

CONCLUSION: Collectively, AR attenuated AβO-induced neuronal and synaptic injury and the associated memory impairment in acute experimental models. These findings provide promising preclinical evidence for the neuroprotective potential of AR and support its further evaluation in chronic and progressive AD models.},
}

@article {pmid42761424,
year = {2026},
author = {Stovner, LJ and Skrindo Knudsen, AK and Lien, L and Peersen, H and Gilhus, NE},
title = {The burden of brain disorders in Norway: an analysis of data from the global burden of disease study 2023.},
journal = {The Lancet regional health. Europe},
volume = {70},
number = {},
pages = {101857},
pmid = {42761424},
issn = {2666-7762},
abstract = {BACKGROUND: The term 'Brain disorders' encompasses conditions affecting the brain and nervous system and includes neurological, mental, neurosurgical and substance use disorders. No study has previously estimated the combined burden of brain disorders in Norway.

METHODS: Data source was the Global Burden of Disease database on prevalence, incidence, Years Lived with Disability (YLDs), Years of Life Lost (YLLs), and Disability-Adjusted Life Years (DALYs), for brain disorders in Norway in 2023, with changes from 1990 to 2023.

FINDINGS: Brain disorders accounted for 26·64% of all DALYs, 30·77% of all YLDs and 22·31% of all YLLs in Norway in 2023, no uncertainty intervals (UIs) given. The highest burden in terms of DALYs was observed for Alzheimer's disease (AD) and dementias (3·82% of all DALYs, UI: 1·72-7·87), anxiety disorders (3·79%, UI: 2·77-4·97), stroke (3·43%, UI: 3·04-3·89), headache (2·5%, UI: 1·94-3·18), and depressive disorders (2·22%, UI: 1·71-2.90). Leading causes of YLDs were anxiety (7·35%, UI: 5·35-9·65), headache (4·91%, UI: 3·91-5·88), and depression (4·29%, UI: 3·47-5.42), while AD and dementias (5·47%, UI: 1·35-13·54), stroke (5·46%, UI: 4·75-5·95), and self-harm (3·51%, UI: 3·17-3·97) were important causes of YLLs. Age-standardized DALYs decreased over the 34 years for stroke, meningitis, and alcohol use disorders, whereas Parkinson's disease, anxiety, depressive, eating, and drug use disorder increased.

INTERPRETATION: Brain disorders are causing more than a quarter of all disease burden in Norway, which is of importance for prioritizing resources to health services and to research. Although there are concerning trends for some disorders, others have become considerably less burdensome since 1990, likely due to improvements in general health, prevention, and effective new treatments and rehabilitation.

FUNDING: The Gates foundation and Norwegian Institute of Public Health.},
}

@article {pmid42761463,
year = {2026},
author = {Xin, Y and Liao, Y and Cao, X and Zhu, X and Wang, J},
title = {IL-34 in neurological homeostasis and its multifaceted roles in central nervous system diseases.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1860233},
pmid = {42761463},
issn = {1664-3224},
mesh = {Humans ; Animals ; *Homeostasis ; *Central Nervous System Diseases/metabolism/immunology ; *Interleukins/metabolism/immunology ; Microglia/immunology/metabolism ; *Central Nervous System/immunology/metabolism ; Signal Transduction ; Macrophages/immunology/metabolism ; },
abstract = {Interleukin-34 (IL-34), a ligand for the macrophage colony-stimulating factor receptor (CSF1R), plays an indispensable role in the development and homeostasis maintenance of the central nervous system (CNS). This review systematically outlines the core mechanisms by which the IL-34/CSF1R signaling axis regulates the development, colonization, and functional differentiation of CNS-resident immune cells-including microglia and border-associated macrophages (BAMs). It highlights its role in critical physiological processes such as synaptic pruning, neural circuit maturation, and maintenance of blood-brain barrier integrity. Beyond its physiological functions, IL-34 modulates diverse neurological disorders-such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, ischemic stroke-with context dependent outcomes. It can confer neuroprotective effects but also drive disease progression under different conditions, providing new insights into CNS homeostasis balance and the complexity of pathological mechanisms.},
}

Humans
Animals
*Homeostasis
*Central Nervous System Diseases/metabolism/immunology
*Interleukins/metabolism/immunology
Microglia/immunology/metabolism
*Central Nervous System/immunology/metabolism
Signal Transduction
Macrophages/immunology/metabolism

@article {pmid42761489,
year = {2026},
author = {Vallés, AS and Barrantes, FJ},
title = {Common metabolic, environmental, and molecular mechanisms underlying neurodevelopmental and neurodegenerative disorders.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1860052},
pmid = {42761489},
issn = {1664-2295},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/etiology ; Animals ; *Neurodevelopmental Disorders/metabolism/etiology ; Developmental Origins of Health and Disease ; Neurodevelopment ; },
abstract = {Several neurodevelopmental disorders and neurodegenerative diseases share common pathogenic mechanisms that unfold across the lifespan, blurring the distinction between the two nosological entities. Environmental factors, particularly those shaping metabolic health during critical developmental time windows, have emerged as key modulators of long-term brain liabilities. This review critically evaluates the experimental, epidemiological, and mechanistic evidence linking early-life metabolic and environmental insults with the establishment of latent vulnerability. We propose that this status may remain clinically silent for decades until activated by aging and cumulative stressors, ultimately leading to neurodegeneration. Specifically, we analyze how early metabolic alterations disrupt mitochondrial function, redox signaling, synaptogenesis, and glial programming, particularly in microglia, thereby shaping long-term neuroinflammatory tone and dysfunctional neural circuit maturation. The review highlights the role of the α7 nicotinic acetylcholine receptor (α7nAChR) as a strategic molecular bridge onto which metabolic and inflammatory signals converge. We further discuss how early dysregulatory stressors manifest later in life as dysmetabolism, vascular impairment, and defective energy sensing, all of which accelerate neurodegenerative pathophysiological processes. This life-course perspective reframes these disorders as a continuum and highlights critical prophylactic and/or therapeutic opportunities through early nutritional, metabolic, and environmental interventions.},
}

Humans
*Neurodegenerative Diseases/metabolism/etiology
Animals
*Neurodevelopmental Disorders/metabolism/etiology
Developmental Origins of Health and Disease
Neurodevelopment