@article {pmid42346783,
year = {2026},
author = {Gomes-Bispo, A and Cardoso, C and Afonso, C and Lourenço, HM and Pedro, S and Moniz, P and Bandarra, NM},
title = {Marine Lipids and Alzheimer's Disease: Biochemistry, Bioaccessibility/Bioavailability, Metabolism, and Health Effects.},
journal = {Marine drugs},
volume = {24},
number = {6},
pages = {},
pmid = {42346783},
issn = {1660-3397},
support = {MAR-016.9.1-FEAMPA-00008//Mar 2030/ ; 101060712//European Commission/ ; PRR - FF 483//Government of Portugal/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Lipids/chemistry/pharmacology/pharmacokinetics/therapeutic use ; *Aquatic Organisms/chemistry ; Biological Availability ; Lipid Metabolism ; },
abstract = {Due to its high prevalence and significant impact on modern society, Alzheimer's disease (AD) is one of the most important neurodegenerative disorders. It is more common among individuals over the age of 65, and its incidence has increased sharply as a result of rising life expectancy. Several factors have made it challenging to identify an effective treatment for AD. One major difficulty lies in its complexity, as the mechanisms involved in its progression are not yet fully understood. Nevertheless, the role of diet and lipids has been highlighted by numerous studies, underscoring their potential influence on this pathology. Due to the intricacy of its biochemical and metabolic interactions, this subject continues to be of particular interest, highlighting the need for further research. In this sense, this comprehensive and updated review aimed to elucidate these aspects, especially regarding marine-derived lipids, whose bioactive potential may become an irreplaceable tool in the management of AD, whether in terms of its treatment or prevention.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
Animals
*Lipids/chemistry/pharmacology/pharmacokinetics/therapeutic use
*Aquatic Organisms/chemistry
Biological Availability
Lipid Metabolism

@article {pmid42347121,
year = {2026},
author = {Xiao, D and Duvvuri, A and Makrigiannis, LV and Fuller, C},
title = {The Neuroprotective Role of Exercise in Alzheimer's Disease: An Integrative Review of Animal and Human Studies.},
journal = {Neurology international},
volume = {18},
number = {6},
pages = {},
doi = {10.3390/neurolint18060113},
pmid = {42347121},
issn = {2035-8385},
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is characterized by progressive cognitive decline along with hallmark brain pathologies including amyloid-beta accumulation, hyperphosphorylated tau, neuroinflammation and neuronal mitochondrial dysfunction. As current pharmaceutical treatments only provide modest symptomatic improvement, there is an urgent need for effective non-pharmaceutical treatment options for the prevention or slowing down of this disease. This review synthesizes results from randomized controlled trials, observational studies, and animal model research on the ability of exercise to influence cognitive functions, brain structural changes, inflammatory processes, and neuroplasticity-related pathways. Exercise has demonstrated the capacity to enhance neurotrophic signaling, improve the regulation of mitochondria, improve cerebrovascular function and reduce pro-inflammatory cytokine levels in preclinical and mild cognitive impairment (MCI) subjects. Additionally, aerobic and resistance training has been shown to enhance physical performance and functional capacity. Furthermore, mind-body, dual-task and multimodal types of interventions may also provide additional cognitive and psychological benefits. Although the overall cognitive effect of exercise in individuals with established AD is generally small, it has been demonstrated that exercise can contribute to maintaining brain health through multiple interconnected metabolic, vascular and molecular pathways, thereby preserving cognitive reserve and slowing disease progression, particularly when initiated during early to midlife prior to the onset of AD symptoms. Therefore, future research will require establishing stage-specific exercise recommendations based on modality type, intensity and duration to achieve optimal clinical outcomes.},
}

@article {pmid42348056,
year = {2026},
author = {Zhang, C and Long, W and Ni, J and Chen, Z and Wu, X and Li, M and Du, F and Zhao, Y and Shen, J and Cho, CH and He, X and Xiao, Z},
title = {The Biological Basis, Mechanisms of Action, and Optimization Strategies of Exosomes Derived from Mesenchymal Stem Cells for the Treatment of Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42348056},
issn = {1559-1182},
mesh = {*Exosomes/metabolism/transplantation ; Humans ; *Alzheimer Disease/therapy/metabolism/pathology ; Animals ; *Mesenchymal Stem Cells/metabolism ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder whose pathological process involves multiple mechanisms, including Aβ deposition, tau protein abnormalities, neuroinflammation, synaptic damage, and neuronal loss. Current therapeutic approaches remain ineffective in halting disease progression; therefore, the development of multi-targeted, low-immunogenicity therapeutic strategies with efficient brain delivery is of great significance. Mesenchymal stem cell-derived exosomes (MSC-derived exosomes) inherit the immunomodulatory, neuroprotective, and tissue-repairing properties of MSCs, and possess good biocompatibility and the potential to cross the blood-brain barrier. Studies have shown that MSC-derived exosomes exert therapeutic effects by modulating neuroinflammation, promoting neurogenesis and synaptic plasticity, reducing Aβ deposition and tau pathology, and regulating multiple AD-related signaling pathways. At the same time, the molecular composition and functions of MSC-derived exosomes derived from different tissues exhibit heterogeneity, and their therapeutic efficacy is influenced by factors such as the source cells, culture conditions, preparation processes, and administration methods. In recent years, strategies such as engineered surface modification, functional molecule loading, three-dimensional culture, microenvironment pretreatment, large-scale production, as well as intranasal administration and biomaterial delivery systems have provided new directions for enhancing the brain-targeting ability, stability, yield, and therapeutic efficacy of MSC-derived exosomes. This review summarizes the biological basis of MSC-derived exosomes, their mechanisms of action in AD treatment, and optimization strategies, providing a reference for their further development and translational application as a cell-free therapeutic approach for AD.},
}

*Exosomes/metabolism/transplantation
Humans
*Alzheimer Disease/therapy/metabolism/pathology
Animals
*Mesenchymal Stem Cells/metabolism

@article {pmid42348083,
year = {2026},
author = {Yildirim, C and Cevik, S and Bal, R and Kaplan, DS and Yilmaz, SG and Ulusal, H and Bekerecioglu, S},
title = {Vitexin Protects Against Scopolamine-Induced Cognitive Impairment by Preserving Synaptic Integrity and Modulating Nrf2/HO-1 and NF-κB Signaling Pathways.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42348083},
issn = {1559-1182},
mesh = {Animals ; *Apigenin/pharmacology/therapeutic use ; Male ; *NF-kappa B/metabolism ; *Signal Transduction/drug effects ; *NF-E2-Related Factor 2/metabolism ; *Synapses/drug effects/metabolism/pathology ; Rats, Wistar ; *Cognitive Dysfunction/chemically induced/drug therapy/prevention & control/metabolism ; Scopolamine ; Oxidative Stress/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Heme Oxygenase-1/metabolism ; Rats ; Maze Learning/drug effects ; *Heme Oxygenase (Decyclizing)/metabolism ; Hippocampus/drug effects/metabolism/pathology ; },
abstract = {Alzheimer's disease is characterized by progressive cognitive decline driven by oxidative stress, neuroinflammation, and synaptic dysfunction. This study investigated the neuroprotective effects of vitexin in a scopolamine (Sco)-induced rat model of cognitive impairment. Forty-two male Wistar rats were randomly assigned to six groups (n = 7 per group): saline, Sco (2 mg/kg/day, i.p.), Sco + vitexin (30 mg/kg/day, oral), Sco + donepezil (1.5 mg/kg/day, i.p.), vitexin alone, and donepezil alone. All treatments were administered for 14 consecutive days. Behavioral assessments using the morris water maze and elevated plus maze revealed that Sco significantly impaired spatial learning and memory while increasing anxiety-like behaviors. Vitexin treatment markedly improved these deficits, with efficacy comparable to donepezil. Biochemically, Sco elevated acetylcholinesterase activity, lipid peroxidation, and oxidative/nitrosative stress markers (TOS, OSI, MDA, Peroxynitrite, NO, and NOS) while decreasing total antioxidant status (TAS). Vitexin reversed these changes. Western blot and immunofluorescence analyses demonstrated that Sco reduced hippocampal BDNF, GDNF, PSD95, and synaptophysin levels and increased GFAP, IL-6, TNF-α, NF-κB p65, and COX-2 expression. Vitexin restored neurotrophic and synaptic proteins, suppressed astrocyte activation and inflammatory signaling, and activated the Nrf2/HO-1 pathway. These findings were further supported by qRT-PCR analysis of BDNF, GDNF, GPX4, and NF-κB. In conclusion, vitexin exerts significant neuroprotective and synaptoprotective effects against Sco-induced cognitive impairment by simultaneously restoring redox balance, suppressing neuroinflammation, and preserving synaptic integrity. These results position vitexin as a promising therapeutic candidate for neurodegenerative disorders, including Alzheimer's disease.},
}

Animals
*Apigenin/pharmacology/therapeutic use
Male
*NF-kappa B/metabolism
*Signal Transduction/drug effects
*NF-E2-Related Factor 2/metabolism
*Synapses/drug effects/metabolism/pathology
Rats, Wistar
*Cognitive Dysfunction/chemically induced/drug therapy/prevention & control/metabolism
Scopolamine
Oxidative Stress/drug effects
*Neuroprotective Agents/pharmacology/therapeutic use
*Heme Oxygenase-1/metabolism
Rats
Maze Learning/drug effects
*Heme Oxygenase (Decyclizing)/metabolism
Hippocampus/drug effects/metabolism/pathology

@article {pmid42348482,
year = {2026},
author = {Xue, D and Peng, J and Yue, L and Qi, W},
title = {Understanding Discrepancies and Predictors of Self- versus Proxy-Rated Quality of Life in Chinese Community-Dwelling Older Adults with Mild Dementia: A Cross-Sectional Study.},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1-19},
doi = {10.1159/000553237},
pmid = {42348482},
issn = {1421-9824},
abstract = {BACKGROUND: Accurate evaluation of quality of life (QoL) is essential for optimal dementia management, yet notable discrepancies exist between patient self-rated and proxy-rated QoL. This study aimed to analyse the discrepancies and agreement between self-rated and proxy-rated QoL and identify their independent predictors among community-dwelling persons with mild dementia (PwMD).

METHODS: This cross-sectional study included 129 PwMD and their primary caregivers. Assessments included sociodemographic information, the QoL-Alzheimer's Disease scale, Mini-Mental State Examination, Geriatric Depression Scale, Activities of Daily Living, Functional Activities Questionnaire and Neuropsychiatric Inventory Questionnaire. Differences and agreement were analyzed using Wilcoxon tests, Spearman correlations, and intraclass correlation coefficients (ICC). Independent predictors were identified through multiple linear regression.

RESULTS: Patients rated their QoL significantly higher than their caregivers did, with poor-to-fair agreement at the total, dimensional and item levels (ICC = 0.11-0.50). Higher depressive symptoms (β = -0.354, p = 0.001), lower severity of elation (β = 0.214, p = 0.013), and greater disinhibition (β = -0.174, p = 0.041) independently predicted poorer self-rated QoL. By contrast, greater neuropsychiatric symptom severity (β = -0.283, p < 0.001), poorer Activities of Daily Living function (β = -0.230, p = 0.006), and polypharmacy (β = -0.208, p = 0.009) predicted lower proxy-rated QoL.

CONCLUSION: Self- and proxy-rated QoL reflect distinct evaluative perspectives in PwMD. Self-reports are influenced by emotional and psychological states, whereas proxy ratings are shaped by observable symptoms, functional dependency and treatment burden. These findings suggest the need to integrate both assessment perspectives in clinical practice.},
}

@article {pmid42349060,
year = {2026},
author = {Changchien, TC and Zul, DD and Cheng, KD and Mathurin, TV and Dagbue, AC and Fang, YY and Liang, CS and Yeh, WC and Hsu, TW},
title = {Lithium versus valproate in bipolar disorder: Associations with dementia, mortality, suicide attempt, and end-stage renal disease in adults aged 45 years and older - a propensity score-matched retrospective cohort study.},
journal = {Psychiatry research},
volume = {364},
number = {},
pages = {117284},
doi = {10.1016/j.psychres.2026.117284},
pmid = {42349060},
issn = {1872-7123},
abstract = {BACKGROUND/OBJECTIVE: Patients with bipolar disorder (BD) are at increased risk of dementia. However, few studies have directly compared subsequent dementia risk between BD patients treated with lithium and valproate, the two first-line mood stabilizers.

METHODS: This retrospective cohort study used the TriNetX collaborative network, which aggregates de-identified electronic health records across the United States. Adults aged≧45 years with BD who initiated lithium or valproate for the first time between 2000 and 2025 were included. 1:1 propensity score matching was applied. The primary outcome was all-cause dementia, and secondary outcomes were Alzheimer's disease, vascular dementia, unspecified dementia (ICD10 code: F03), mortality, suicide attempt, and ESRD.

RESULTS: After applying exclusion criteria and matching, 3056 patients remained in each group. Lithium use was associated with a lower risk of all-cause dementia than valproate use (207 [7.1%] vs 311 [10.8%]; Relative risk [RR], 0.658; 95% confidence interval [CI], 0.556-0.778; Hazard ratio [HR], 0.689; 95% CI, 0.578-0.822; both P<.001). Lithium use was also associated with lower risks of unspecified dementia (HR, 0.677; 95% CI, 0.530-0.865; P=.002) and suicide attempt (HR, 0.594; 95% CI, 0.399-0.885; P=.010). Although the relative risk of Alzheimer disease was lower in the lithium group, the adjusted hazard ratio did not reach statistical but marginal significance. No significant between-group differences were observed for vascular dementia, mortality, or ESRD.

LIMITATIONS: Residual confounding may persist due to the observational design, and dementia diagnoses relied on clinical coding within electronic health records.

CONCLUSIONS: In this large, compliance-verified cohort, lithium treatment was associated with lower risks of dementia compared to valproate, without excess ESRD or mortality risk. These findings support lithium as a preferred long-term mood stabilizer for preserving cognitive outcomes in older adults with bipolar disorder, though observational data preclude causality inferences.},
}

@article {pmid42349617,
year = {2026},
author = {Li, Q and Liu, X and Xing, R and Qi, F and Li, X and Wang, K and Chen, L},
title = {5-Methoxyseselin inhibits neuronal ferroptosis and β-amyloid production in female APP/PS1 transgenic mice.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118188},
doi = {10.1016/j.bcp.2026.118188},
pmid = {42349617},
issn = {1873-2968},
abstract = {Nrf2 signaling dysregulation drives progressive cognitive decline in Alzheimer's disease (AD), as the brain's endogenous defenses fail to neutralize oxidative stress and ferroptotic neuronal attrition. Here, we report that 5-Methoxyseselin (5-Met), a natural coumarin derivative, is a nuclear factor erythroid 2-related factor 2 (Nrf2) inducer that facilitates glutathione peroxidase 4 (GPX4)-mediated lipid-repair machinery. Mechanistically, 5-Met may bind to Kelch-like ECH-associated protein 1 (Keap1), thereby disrupting the Keap1-Nrf2 inhibitory interaction and promoting Nrf2 stabilization. This leads to upregulated GPX4 expression and subsequent suppression of neuronal ferroptosis in APP/PS1 mice. Consistently, 5-Met treatment effectively protected N2a cells from ferroptotic challenges induced by ferric ammonium citrate (FAC), erastin, or RSL3 via upregulating GPX4 expression. Furthermore, 5-Met modulated β-amyloid (Aβ) homeostasis by inhibiting β-amyloid precursor protein-cleaving enzyme 1 (BACE1)-mediated Aβ production and enhancing low-density lipoprotein receptor-related protein 1 (LRP1)-mediated Aβ efflux. In addition, 5-Met treatment improved cognitive performance in APP/PS1 mice. Collectively, these findings identify 5-Met as a multi-target neuroprotective agent that restores Aβ homeostasis and inhibits neuronal ferroptosis, suggesting it may be a therapeutic compound for AD.},
}

@article {pmid42349816,
year = {2026},
author = {Abdel-Aal, RA and Abdelnabi, S and Badary, DM and Hussein, AMR},
title = {Effect of Metformin on Anti-Alzheimer Activity of Rivastigmine in Aluminum Chloride-Induced Alzheimer's Disease in Rats: A Behavioral, Biochemical, Immunohistopathological Evidence of Crosstalk between Amyloid, Tau, Autophagy, and Apoptosis.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179087},
doi = {10.1016/j.ejphar.2026.179087},
pmid = {42349816},
issn = {1879-0712},
abstract = {AIM: This study investigates how the anti-Alzheimer's effectiveness of rivastigmine (RIVA) is affected by the antidiabetic drug metformin (MET).

METHOD: ology: Male rats were randomly divided into a control group, an Alzheimer's disease (AD) group receiving aluminum chloride (AlCl3), a RIVA-treated group, a MET-treated group, and a RIVA+MET combination group. Cognitive performance was assessed using passive avoidance (PA), the radial arm maze (RAM), the Morris water maze (MWM), and novel object recognition (NOR) tests. Hippocampal microtubule-associated protein tau (MAPT), beta-site APP cleaving enzyme 1 (BACE1), acetylcholinesterase (AChE), and autophagy marker Sequestosome 1 (SQSTM1/p62) were measured, while amyloid-beta (Aβ) and caspase-3 expression were analyzed immunohistochemically. Histopathology and electron microscopy were used to assess neuronal integrity.

RESULTS: MET, RIVA, and their combined treatment mitigated the neurodegenerative alterations induced by AlCl3. The combination of MET+RIVA failed to yield significant differences in behavioral performance [PA, RAM, MWM, and NORT], MAPT levels, and AChE activity compared with the treatment with RIVA monotherapy. However, the combination therapy showed significant reductions in hippocampal BACE1, Aβ deposition, and SQSTM1/p62 levels, indicating enhanced suppression of amyloidogenic processing and improved autophagy. Although differences between MET+RIVA combination and RIVA monotherapy were not statistically significant for these markers, the combination markedly reduced caspase-3 immunoreactivity compared with the diseased group, indicating greater attenuation of apoptosis.

CONCLUSION: These results highlight the crosstalk among the amyloid, tau, autophagy, and apoptotic pathways in AD and suggest that the MET+RIVA combination showed promising molecular improvements but no clear behavioral superiority, indicating the need for further optimization.},
}

@article {pmid42351553,
year = {2026},
author = {Hong, B and Tao, T and Li, Y and Gu, Z and Zhang, H and Chen, J and Yue, L},
title = {Prediction of Antipsychotic Drug Doses for BPSD in Alzheimer's Disease Using Deep Learning Techniques.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {12},
pages = {},
doi = {10.3390/diagnostics16121894},
pmid = {42351553},
issn = {2075-4418},
support = {STI2030-Major Projects-2022ZD0213100//National Natural Science Foundation of China/ ; STI2030-Major Projects-2022ZD029000//National Natural Science Foundation of China/ ; NA//the integrated innovation team project of Shanghai Mental Health Center/ ; JCYJ-SHFY-2022-014//Shanghai Pilot Program for Basic Research-Chinese Academy of Science, Shanghai Branch/ ; 20Y11906800//Shanghai Science and Technology Committee/ ; No.KCXFZ20211020163408012//Shenzhen Science and Technology Program/ ; NA//the Program of High-Level Medical Talents, National Health Commission of China/ ; 2023-TX-018//the Programe of Chen Frontier Lab for AI and Mental Health (TCCI) - Shanghai Mental Health Center (SMHC)/ ; SHDC12025118//Shanghai Shen-Kang Hospital Development Center/ ; SHDC22025303//Shanghai Shen-Kang Hospital Development Center/ ; NA//the Integrated Innovation Team Project of Shanghai Mental Health Center/ ; NA//The Scientific Research Program of FuRong Laboratory/ ; 19MC1911100//Shanghai Clinical Research Center for Mental Health/ ; 13dz2260500//Shanghai Key Laboratory of Psychotic Disorders/ ; },
abstract = {Background/Objectives: Antipsychotic dosing for behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease remains empirical and variable. This study develops a deep learning model to predict individualized antipsychotic doses from structural MRI. Methods: A transfer learning approach with a cascaded ResNet (Cas-ResNet) was used. The model was first pre-trained on a large healthy aging dataset (CBMFM, n = 646) for brain age prediction, then fine-tuned on a BPSD dataset (SMHC, n = 86) to predict the defined daily dose (DDD) of antipsychotics. Model interpretability was performed using Grad CAM to identify predictive brain regions. Results: The proposed model achieved a mean absolute error of 0.19 and a Pearson correlation of 0.66 between predicted and actual doses, outperforming baseline 3DCNN, VGG, and DenseNet. Key contributing regions included the left inferior temporal gyrus, right parahippocampal gyrus, right putamen, left middle temporal gyrus, and left caudate. Conclusions: This proof-of-concept study demonstrates that deep learning can predict personalized antipsychotic doses from structural MRI, offering an objective tool to standardize BPSD pharmacotherapy and reduce empirical prescribing. The identified brain regions provide neurobiological insights into treatment response.},
}

@article {pmid42351734,
year = {2026},
author = {Dragomir, AF and Barbu, AC and Stoleru, S and Zugravu, A and Dumitrescu, MC and Bazar, G and Ghita, CIV and Fratea, S and Stoleru, CM and Coman, OA and Fulga, I},
title = {Comparative Effects of Donepezil and Tacrine on Recall-Related Exploratory Behavior in a Subacute Lipopolysaccharide-Induced Neuroinflammatory Model of Cognitive Impairment.},
journal = {Biomedicines},
volume = {14},
number = {6},
pages = {},
doi = {10.3390/biomedicines14061306},
pmid = {42351734},
issn = {2227-9059},
abstract = {Background/Objectives: Neuroinflammation is increasingly recognized as an important contributor to Alzheimer-like cognitive impairment. Lipopolysaccharide (LPS) is commonly used in experimental models to trigger systemic immune activation and behavioral alterations associated with neuroinflammation. This study aimed to validate a subacute LPS-induced model of recall-phase impairment and to compare the effects of donepezil and tacrine on recall-related exploratory behavior in rats. Methods: Male Wistar rats were tested in a two-trial Y-maze paradigm consisting of an acquisition trial followed by a recall trial 24 h later. In the validation experiment, rats received saline or LPS 1 mg/kg intraperitoneally for four consecutive days. In the intervention experiment, rats received saline, LPS, or LPS combined with donepezil 1 or 3 mg/kg or tacrine 3 or 5 mg/kg. The primary recall-phase outcome was the unknown/known arm time ratio (U/K time ratio). Additional outcomes included arm times, arm entries, U/K entry ratios, discrimination indices, and mean time per entry. Results: Repeated LPS administration significantly reduced the U/K time ratio, decreased time- and entry-based discrimination indices, reduced time spent in the unknown arm, and decreased unknown-arm entries, without significantly altering acquisition-phase behavior, total entries, or mean time per entry. In the intervention experiment, donepezil 1 mg/kg and tacrine 5 mg/kg significantly increased the U/K time ratio compared with LPS. Discrimination indices and entry-based measures further supported a treatment-related shift toward novelty-directed exploration, while total arm entries and mean time per entry were not significantly changed. Conclusions: Subacute LPS administration produced a measurable recall-phase exploratory impairment in the Y-maze. Donepezil and tacrine attenuated several components of this impairment, with partially distinct dose-related behavioral profiles.},
}

@article {pmid42351738,
year = {2026},
author = {Sarwar, T and Rehman, AA and Arif, H and Alwanian, WM and Alharbi, HOA and Rahmani, AH},
title = {Biophysical and Computational Insights into Alpha-1 Antitrypsin Aggregation and Its Inhibition by Natural Polyphenols.},
journal = {Biomedicines},
volume = {14},
number = {6},
pages = {},
doi = {10.3390/biomedicines14061310},
pmid = {42351738},
issn = {2227-9059},
abstract = {Background/Objectives: Protein misfolding and amyloid fibril formation underlie several degenerative diseases, including Alzheimer's disease and Parkinson's disease. Alpha-1 antitrypsin (A1AT), a serpin protein, is particularly prone to misfolding, with polymerization and aggregation implicated in alpha-1 antitrypsin deficiency and associated hepatic and pulmonary disorders. In this study, we examined the structural changes in A1AT induced by the fluorinated alcohol, trifluoroethanol (TFE), and assessed the inhibitory effects of two natural polyphenols, amentoflavone (AMF) and theaflavin (TF), on aggregation and fibril formation. Methods: A library of selected phytocompounds was virtually screened against the crystal structure of A1AT (PDB 3NE4) using AutoDock Vina to elucidate their binding affinity towards it. Based on binding affinities, two compounds, AMF and TF, were selected for further studies. Protein aggregation was induced with TFE, and the protective effects of AMF and TF were evaluated using protease inhibitory activity, intrinsic fluorescence, turbidity, Rayleigh scattering, ANS fluorescence, and ThT fluorescence assays. Furthermore, 100 ns molecular dynamics simulation and MM-PBSA calculations were performed to assess the stability and binding interactions of the A1AT-ligand complexes. Results: Pre-treatment of A1AT with AMF or TF significantly inhibited TFE-induced aggregation in a dose-dependent manner, with AMF being consistently more effective. ThT fluorescence analysis revealed a ~60-65% decrease in aggregate formation upon treatment with polyphenols, with IC50 values estimated at ~40 µM for AMF and ~50 µM for TF, both of which are statistically significant. Molecular docking and 100 ns molecular dynamics simulation also revealed stable A1AT-polyphenol interactions, with AMF exhibiting greater binding affinity and greater attenuation of solvent-induced conformational perturbation. Conclusions: Collectively, our findings show that TFE causes A1AT misfolding via a molten globule-like intermediate, resulting in fibril formation at 30-40% TFE, and natural polyphenols AMF and TF inhibited aggregation in a concentration-dependent manner. These observations suggest the potential of AMF and TF as lead scaffolds for anti-aggregation strategies, as modulators of amyloidogenic processes.},
}

@article {pmid42352265,
year = {2026},
author = {Tian, M and Feng, R and Gong, C and Ben, X and Ma, Z and Yi, X and Guo, Q},
title = {Intranasal Adipose-Derived MSC Extracellular Vesicles Confer Sustained Cognitive Improvement and Suppress Alzheimer's Pathology in APP/PS1 Mice.},
journal = {Biomolecules},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/biom16060798},
pmid = {42352265},
issn = {2218-273X},
support = {ZDYF2024SHFZ137//Department of Science and Technology of Hainan Province/ ; 823QN246//Department of Science and Technology of Hainan Province/ ; 82301632//National Natural Science Foundation of China/ ; QCQTXM202213//Department of Science and Technology of Hainan Province/ ; },
mesh = {Animals ; *Alzheimer Disease/therapy/pathology/metabolism/genetics ; *Extracellular Vesicles/metabolism/transplantation ; Administration, Intranasal ; Mice ; Female ; Mice, Transgenic ; *Mesenchymal Stem Cells/metabolism/cytology ; Amyloid beta-Protein Precursor/genetics/metabolism ; Amyloid beta-Peptides/metabolism ; Presenilin-1/genetics/metabolism ; Cognition ; Disease Models, Animal ; *Adipose Tissue/cytology ; Hippocampus/metabolism/pathology ; Humans ; Cognitive Enhancement ; },
abstract = {Alzheimer's disease (AD) lacks effective disease-modifying therapies, and extracellular vesicles (EVs) derived from adipose-derived mesenchymal stromal cells (ADMSCs) have emerged as promising therapeutic candidates. In this study, we investigated the brain biodistribution and dose-dependent effects of intranasally administered ADMSC-EVs in female APP/PS1 mice, with age-matched wild-type mice and vehicle-treated transgenic mice serving as controls. EV biodistribution was assessed using PKH26 labeling, cognitive performance was evaluated using the Morris water maze, Y-maze, and novel object recognition tests, and hippocampal amyloid pathology and plasma AD-related biomarkers were analyzed. Intranasally delivered ADMSC-EVs rapidly reached multiple brain regions, including the hippocampus, improved learning and memory performance, and reduced hippocampal amyloid-β 1-42 (Aβ42) deposition and plaque burden. These effects followed a nonlinear dose-response pattern, with reduced efficacy at low doses and no additional benefits at high doses. Notably, partial behavioral and pathological benefits persisted after treatment cessation. Together, these findings show that intranasal ADMSC-EVs exert therapeutic effects in APP/PS1 mice and support the importance of dose optimization and post-treatment durability in the development of EV-based interventions for AD.},
}

Animals
*Alzheimer Disease/therapy/pathology/metabolism/genetics
*Extracellular Vesicles/metabolism/transplantation
Administration, Intranasal
Mice
Female
Mice, Transgenic
*Mesenchymal Stem Cells/metabolism/cytology
Amyloid beta-Protein Precursor/genetics/metabolism
Amyloid beta-Peptides/metabolism
Presenilin-1/genetics/metabolism
Cognition
Disease Models, Animal
*Adipose Tissue/cytology
Hippocampus/metabolism/pathology
Humans
Cognitive Enhancement

@article {pmid42352894,
year = {2026},
author = {Janpaijit, S and Verma, K and Widoyanti, AAE and Tencomnao, T and Prasansuklab, A},
title = {Exploring Mechanistic Targets of Areca catechu Against Neurodegenerative Diseases Through an Integrated Network Pharmacology, Molecular Docking, and Experimental Approaches.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125169},
pmid = {42352894},
issn = {1422-0067},
support = {Fundamental Fund//Thailand Science Research and Innovation Fund, Chulalongkorn University/ ; },
mesh = {Molecular Docking Simulation ; Animals ; Network Pharmacology/methods ; *Areca/chemistry ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/chemistry ; Humans ; Caenorhabditis elegans/drug effects ; *Plant Extracts/pharmacology/chemistry ; Mice ; Microglia/drug effects/metabolism ; Alzheimer Disease/drug therapy/metabolism ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most prevalent neurodegenerative disorders, while the therapeutic efficacy of current drugs for both diseases remains limited, with unfavourable side effects. The fruit of Areca catechu L. (AC) is recognised as a popular chewing item across China and Southeast Asia and has been used for centuries as a traditional remedy, ranging from relieving digestive issues to depression. The neuroprotective role of AC has been underscored in previous studies; however, its mechanisms of action remain unclear. The present study aimed to investigate anti-neurodegenerative mechanisms of AC for the treatment of AD and PD. An integrated approach combining untargeted metabolite profiling, network pharmacology, bioinformatics analysis, and molecular docking was utilised. Experimental validation was performed using in vitro cell-based and in vivo models. The study revealed TNF-α, IL-1β, IL-6, CASP3, MAPK3, and AKT1 as top-ranked hub targets by which AC exerts its action on AD and PD. Enrichment analyses of these genes identified significant biological and functional pathways involved in neuroinflammation, apoptosis, and AD. Experimental validation showed that AC extracts significantly downregulated hub gene expressions in the neuroinflammatory BV-2 microglia cell model and prolonged the survival of the transgenic Caenorhabditis elegans AD model. Docking analysis suggested lucidine B, oxolucidine B, solanocapsine, evodiamine, and liquiritigenin are the principal phytocompounds underlying the neuroprotective properties of AC. The findings revealed the pharmacological mechanisms of AC and highlighted its potential value as an effective, multitargeting natural agent to address challenges in AD and PD therapies.},
}

Molecular Docking Simulation
Animals
Network Pharmacology/methods
*Areca/chemistry
*Neurodegenerative Diseases/drug therapy/metabolism
*Neuroprotective Agents/pharmacology/chemistry
Humans
Caenorhabditis elegans/drug effects
*Plant Extracts/pharmacology/chemistry
Mice
Microglia/drug effects/metabolism
Alzheimer Disease/drug therapy/metabolism

@article {pmid42352925,
year = {2026},
author = {Czubowicz, K and Motyl, JA and Wencel, A and Strosznajder, RP},
title = {The Role of Sphingosine-1-Phosphate Signaling in Cerebral Ischemia/Reperfusion Injury and Alzheimer's Disease Pathology.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125200},
pmid = {42352925},
issn = {1422-0067},
support = {the statutory budget of MMRI PAS, under theme No. 7//Mossakowski Medical Research Institute, Polish Academy of Sciences/ ; },
abstract = {Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive sphingolipid that regulates key cellular processes, like proliferation, apoptosis, inflammation, and vascular homeostasis. S1P acts as a signaling molecule both inside and outside cells by interacting with five G-protein-coupled S1P receptors (S1PR1-S1PR5). Accumulating evidence indicates that dysregulation of S1P signaling is implicated in the pathophysiology of cerebral ischemia/reperfusion (I/R) injury and Alzheimer's disease (AD). In I/R injury, S1P signaling regulates vascular permeability, immune cell infiltration, and neuronal survival and death. In AD, alterations in S1P metabolism are associated with β-amyloid deposition, tau hyperphosphorylation, synaptic dysfunction, and sustained neuroinflammation. S1P receptor (S1PR) modulators represent promising therapeutic agents in both preclinical and clinical studies. Fingolimod was the first oral disease-modifying therapy approved for the treatment of multiple sclerosis and, at the same time, the first S1PR modulator introduced into clinical practice. New selective S1PR-targeting agents, including siponimod and ozanimod (S1PR1 and S1PR5), as well as the S1PR1-selective agent ponesimod, have also been approved for clinical use. In addition to their immunomodulatory properties, S1PR modulators have direct effects in the central nervous system, facilitating the maintenance of blood-brain barrier integrity, reducing microglial activation, and enhancing neuronal survival pathways. Building on this knowledge, we discuss the role of S1P signaling, highlighting recent advances in S1PR modulators as promising therapeutic agents for cerebral I/R injury and AD.},
}

@article {pmid42353002,
year = {2026},
author = {Kanubaddi, KR and Yaung, CL and Harn, HJ and Chiou, TW and Hsu, SX and Wijaya, I and Lin, SZ and Wuli, W},
title = {Astragalus and Cordyceps Derivatives in the Treatment of Aging-Related Chronic Diseases and Neurodegenerative Disorders.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125273},
pmid = {42353002},
issn = {1422-0067},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Cordyceps/chemistry ; Animals ; *Aging/drug effects ; Chronic Disease/drug therapy ; *Astragalus Plant/chemistry ; *Drugs, Chinese Herbal/therapeutic use/chemistry ; },
abstract = {Aging is associated with a rising burden of chronic metabolic, cardiovascular, musculoskeletal, and neurodegenerative diseases that share interconnected pathological mechanisms, including oxidative stress, chronic inflammation, mitochondrial dysfunction, metabolic imbalance, and immune dysregulation. Because these disorders arise from complex and overlapping biological disturbances, conventional single-target therapies often provide only limited benefit. In this context, traditional Chinese herbal medicines, characterized by multi-component and multi-target actions, are being re-evaluated using modern pharmacological and systems biology approaches. Among these, Astragalus membranaceus and Cordyceps species have attracted attention as representative tonic medicines with long-standing traditional use and growing biomedical relevance. Their principal bioactive constituents, including polysaccharides, saponins, flavonoids, sterols, and nucleoside derivatives such as cordycepin, exert pleiotropic effects on inflammatory signaling, redox homeostasis, mitochondrial function, metabolic regulation, and immune responses. This review summarizes current evidence on bioactive derivatives from Astragalus and Cordyceps in aging-related chronic and neurodegenerative disorders, including diabetes, cardiovascular dysfunction, osteoarthritis, cancer, Alzheimer's disease, and Parkinson's disease. It focuses on mechanistic findings from cellular and animal studies and critically discusses key translational challenges, such as compositional variability, poor bioavailability, lack of standardized preparation, limited clinical validation, and safety concerns related to toxicity and herb-drug interactions.},
}

Humans
*Neurodegenerative Diseases/drug therapy/metabolism
*Cordyceps/chemistry
Animals
*Aging/drug effects
Chronic Disease/drug therapy
*Astragalus Plant/chemistry
*Drugs, Chinese Herbal/therapeutic use/chemistry

@article {pmid42353032,
year = {2026},
author = {Shahabian, L and Kynigopoulos, D and Papacharalambous, R and Ioannou, E and Dionysiou, S and Christou, S and Picolos, M and Pipis, M and Panayiotou, E},
title = {Semaglutide Selectively Improves Metabolic and Cognitive Function in 5xFAD Mice.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125311},
pmid = {42353032},
issn = {1422-0067},
mesh = {Animals ; Semaglutide ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; Male ; *Cognition/drug effects ; Female ; Disease Models, Animal ; *Glucagon-Like Peptides/pharmacology ; Mice, Transgenic ; Diet, High-Fat/adverse effects ; Amyloid beta-Peptides/metabolism ; Adiponectin/metabolism ; Glucagon-Like Peptide-1 Receptor/metabolism ; Hippocampus/metabolism/drug effects ; Body Weight/drug effects ; },
abstract = {Alzheimer's disease (AD) and metabolic syndrome often occur together, sharing characteristics such as insulin resistance, dyslipidemia, and chronic inflammation. Metabolic dysfunction frequently precedes cognitive decline, indicating that early intervention might alter the disease's progression. We investigated whether the GLP-1 receptor agonist semaglutide (SMGL) influences metabolic impairment and AD pathology in an AD mouse model. Male and female 5xFAD and wild-type (WT) mice on regular (RD) or high-fat diets (HFD) were administered SMGL for 13 weeks. SMGL-treated groups exhibited significant, context-dependent effects. In metabolically challenged 5xFAD HFD mice, treatment led to reduced body weight, improved glucose tolerance, normalized cholesterol levels, and a restored balance of adiponectin and leptin. These improvements were associated with reduced Aβ40 and Aβ42 levels, restored GLP-1 receptor expression, increased synaptophysin and βIII-tubulin levels, and enhanced spatial memory. SMGL also decreased Iba1 and CD68 immunoreactivity in the hippocampus and cortex, reduced macrophage infiltration, and lowered CD36 expression in visceral adipose tissue (VAT), indicating coordinated anti-inflammatory effects. WT RD mice showed minimal metabolic responses and a modest decline in Y-maze performance, suggesting that excessive GLP-1 receptor activation may disrupt neuronal homeostasis when metabolic status is normal. SMGL acts as a context-specific metabolic and neuroprotective agent, offering the greatest benefits under conditions of metabolic dysfunction. These findings in a preclinical model suggest that targeting early metabolic disturbances provides a testable hypothesis for attenuating AD-related neurodegeneration, though further translational studies are required.},
}

Animals
Semaglutide
*Alzheimer Disease/drug therapy/metabolism
Mice
Male
*Cognition/drug effects
Female
Disease Models, Animal
*Glucagon-Like Peptides/pharmacology
Mice, Transgenic
Diet, High-Fat/adverse effects
Amyloid beta-Peptides/metabolism
Adiponectin/metabolism
Glucagon-Like Peptide-1 Receptor/metabolism
Hippocampus/metabolism/drug effects
Body Weight/drug effects

@article {pmid42353174,
year = {2026},
author = {Lee, S and Yoo, YJ and Kim, G and Kim, E and Yun, S and Kim, J and Ryu, H and Chung, W},
title = {Kilovoltage Energy Significantly Enhances the Therapeutic Efficacy of Low-Dose Radiation in a 3xTg-AD Mouse Model of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125458},
pmid = {42353174},
issn = {1422-0067},
support = {RS-2023-00253427//Ministry of Science and ICT/ ; RS-2022-NR070632, RS-2026-255417//Ministry of Science and ICT/ ; RS-2024-00467661//Ministry of SMEs and Startups/ ; RS-2024-00441564//Ministry of SMEs and Startups/ ; RS-2025-02317308//Ministry of Science and ICT/ ; BT250232//Seoul R&BD Program/ ; KHU-20251295//Kyung Hee University in 2025/ ; },
mesh = {Animals ; *Alzheimer Disease/radiotherapy/metabolism/pathology ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Brain/metabolism/radiation effects/pathology ; Male ; },
abstract = {Low-dose radiation (LDR) has emerged as a promising therapeutic modality for Alzheimer's Disease (AD). Although different irradiation protocols have been explored, the optimal parameters for maximizing therapeutic efficacy remain unclear. Radiation energy has been shown to influence radiobiological responses, with more pronounced effects at lower energy ranges. We therefore investigated whether kilovoltage LDR (KLDR) provides superior therapeutic efficacy compared with megavoltage LDR (MLDR) in a murine model of AD(3xTg-AD). To this end, we directly compared the efficacy of MLDR and KLDR in AD model mice to identify an optimal irradiation strategy for LDR treatment with potential relevance to clinical translation in AD. X-rays with 110-kV or 6-MV energy were applied to the brain of AD model mice at an early-stage of disease progression (26-28 weeks age; 0.6 Gy × 5 fractions for 2.5 weeks). After LDR treatment, cognitive function was assessed in AD model mice using passive avoidance (PA) test and novel object recognition (NOR) test. In addition, different molecular markers associated with inflammation, amyloid-beta (Aβ) plaques, tau burden, and neuronal and synaptic degeneration were analyzed in the brain of AD model mice. KLDR (110 kV) significantly inhibited cognitive decline in AD model mice, as demonstrated by both the PA and NOR tests. In addition, KLDR significantly reduced hippocampal levels of GFAP, Iba-1, and pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), while increasing anti-inflammatory cytokines (TGF-α, TGF-β, and IL-10), and was associated with marked reductions in Aβ and tau levels. Furthermore, the expression levels of Aβ40 and Aβ42 were quantified by ELISA following KLDR and MLDR treatment, revealing a statistically significant reduction in the KLDR group. The degeneration of neurons and synapses was significantly suppressed also at the kilovoltage energy level. Conversely, MLDR (6 MV) exerted minimal effects and did not produce statistically significant improvements. Taken together, our findings demonstrate that radiation energy level is a key determinant of LDR therapeutic efficacy in AD model mice, with KLDR showing significantly greater effectiveness in improving AD-related pathological features than MLDR. Therefore, KLDR may be recommended as a novel radiation protocol for AD treatment.},
}

Animals
*Alzheimer Disease/radiotherapy/metabolism/pathology
Disease Models, Animal
Mice
Mice, Transgenic
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Brain/metabolism/radiation effects/pathology
Male

@article {pmid42353197,
year = {2026},
author = {Honjo, A and Yako, H and Kasai, M and Chiba, M and Satsuka, A and Kato, T and Yagi, M and Nishi, A and Miyamoto, Y and Yamauchi, J},
title = {Hesperetin Rescues Amyloid Beta-Induced Defects in Neurite Outgrowth Under In Vitro Mild Cognitive Impairment-like Cellular Conditions.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125481},
pmid = {42353197},
issn = {1422-0067},
mesh = {*Amyloid beta-Peptides/metabolism/toxicity ; Animals ; *Hesperidin/pharmacology ; *Neuronal Outgrowth/drug effects ; *Cognitive Dysfunction/metabolism/drug therapy/pathology ; *Peptide Fragments ; Mice ; Neurons/drug effects/metabolism ; *Neurites/drug effects/metabolism ; Cell Differentiation/drug effects ; Cell Line ; },
abstract = {Accumulation of aggregated amyloid beta (Aβ) species is a defining pathological hallmark of Alzheimer's disease and is associated with extensive neuronal structural abnormalities. Mild cognitive impairment (MCI), a transitional stage between normal aging and the onset of dementia, is thought to represent an early phase of this pathological continuum. Studies at the cellular level suggest that the conditions impair the maintenance of established neuronal processes/networks and restrict their capacity for elongation or re-elongation. They may also attenuate the activation and process extension of quiescent neural progenitor or stem-like cells. These early cellular changes precede overt neurodegeneration in neural tissue and are likely to contribute to cognitive decline. They highlight the importance of in vitro models for identifying molecular targets involved in recovery from disease. In this study, we investigated the effects of aggregated Aβ (25-35) on neuronal process elongation and associated intracellular events in the N1E-115 cell line, a widely used model of neuronal differentiation. Addition of aggregated Aβ to cultured N1E-115 cells attenuated process elongation in a concentration-dependent manner. This morphological impairment was accompanied by decreased expression of neuronal differentiation markers. In contrast, at the half-maximal inhibitory concentration for process elongation, long-term cultured cells did not exhibit apparent process retraction or degenerative morphology. This mild but progressive impairment, without extensive cell death, is consistent with the cellular features of early-stage conditions rather than advanced Alzheimer's pathologies. Similar results were observed in primary cortical neurons. Aβ also decreased the level of GTP-bound Ras and phosphorylation of the downstream mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). Furthermore, treatment with hesperetin, a bioactive flavonoid compound, recovered the Aβ-induced inhibition of neuronal process elongation. Hesperetin also restored Ras and MAPK/ERK states, suggesting that its effects are associated, at least in part, with modulation of signaling through Ras and MAPK/ERK. Our findings suggest that hesperetin may serve as a useful molecular probe for modulating early cellular responses associated with Alzheimer's disease-related pathology. This in vitro model might serve as a useful platform for investigating the molecular target candidates involved in recovery from nervous system disorders.},
}

*Amyloid beta-Peptides/metabolism/toxicity
Animals
*Hesperidin/pharmacology
*Neuronal Outgrowth/drug effects
*Cognitive Dysfunction/metabolism/drug therapy/pathology
*Peptide Fragments
Mice
Neurons/drug effects/metabolism
*Neurites/drug effects/metabolism
Cell Differentiation/drug effects
Cell Line

@article {pmid42353204,
year = {2026},
author = {Olajide, AT and Aunsorn, S and Kehinde, SA and Kaewmanee, T and Chusri, S},
title = {From Tradition to Translation: A Critical Appraisal of Bacopa monnieri for Neuroprotection from Preclinical and Clinical Perspectives and Challenges in Utilization.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125488},
pmid = {42353204},
issn = {1422-0067},
support = {67A307000040//National Science, Research, and Innovation Fund (NSRF) and Mae Fah Luang University (Fundamental Fund Grant)/ ; },
mesh = {*Bacopa/chemistry ; Humans ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology/chemistry ; *Alzheimer Disease/drug therapy ; *Plant Extracts/therapeutic use/pharmacology/chemistry ; *Neuroprotection/drug effects ; Cognitive Enhancement ; },
abstract = {Dementia, and more specifically Alzheimer's disease (AD), is a progressive neurodegenerative disorder that has become a growing health menace in the world with an escalation in incidence as well as enormous social and economic consequences. Existing pharmacological treatment including cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists are not very effective in reducing the symptoms and fail to prevent the disease process. The non-pharmacological treatment interventions such as diet, exercise and cognitive training have supportive effects and cannot be used as standalone treatments. Therapeutic gap has resulted in increased interest in complementary and alternative therapies, especially that of pleiotropic action of herbal medicines. Bacopa monnieri (BM) is an Ayurvedic herb that has historically been used to treat memory enhancement and now has both preclinical and clinical evidence supporting its ability to modulate neurotransmission, reduce oxidative stress and suppress neuroinflammation. However, such difficulties as low bioavailability, instability of the environmental factors, and variations in formulations restrict its clinical applicability. New technologies with a lot of potential such as microencapsulation technology can provide the solution to this problem by increasing stability, solubility, and targeted delivery of compounds that will increase treatment efficacy. This narrative review is a synthesis of the existing information on the pathogenesis of dementia, therapeutic approaches, and the effectiveness of BM as a complementary intervention. It points out links between traditional medicine and modern neuroscience, strengths and limitations of on-going evidence, gaps that need further research, such as long-term clinical trials, standardized formulations, and discovery of the role of BM in the gut-brain axis. BM is a prime example of how herbal medicines can be used as a complement to conventional treatment and play a role in multi-modal approaches aimed at reducing the cognitive impairment associated with dementia.},
}

*Bacopa/chemistry
Humans
Animals
*Neuroprotective Agents/therapeutic use/pharmacology/chemistry
*Alzheimer Disease/drug therapy
*Plant Extracts/therapeutic use/pharmacology/chemistry
*Neuroprotection/drug effects
Cognitive Enhancement

@article {pmid42353279,
year = {2026},
author = {Jorda, A and Alvarez-Gamez, K and Vergani, S and Paba, I and Perez, M and Aldasoro, M and Vila, JM and Valles, SL},
title = {Insulin Regulates AKT/GSK-3β Signalling, Tau Phosphorylation, and Redox Homeostasis in SH-SY5Y Neuroblastoma Cells.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125565},
pmid = {42353279},
issn = {1422-0067},
support = {CIAICO/2023/143//Generalitat Valenciana/ ; },
mesh = {Humans ; *Glycogen Synthase Kinase 3 beta/metabolism ; *tau Proteins/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Insulin/pharmacology/metabolism ; Phosphorylation/drug effects ; *Signal Transduction/drug effects ; Cell Line, Tumor ; *Neuroblastoma/metabolism/pathology ; Oxidative Stress/drug effects ; Oxidation-Reduction/drug effects ; Homeostasis/drug effects ; Apoptosis/drug effects ; Cell Survival/drug effects ; NF-E2-Related Factor 2/metabolism ; },
abstract = {Insulin (Ins) regulates multiple intracellular signalling pathways involved in cell survival, oxidative stress responses, and tau phosphorylation. Dysregulation of these pathways has been implicated in neurodegenerative disorders, including Alzheimer's disease (AD). The present study evaluated the effects of insulin on protein kinase B/glycogen synthase kinase-3 beta (AKT/GSK-3β) signalling, tau phosphorylation, and oxidative stress-related markers in SH-SY5Y neuroblastoma cells. Cell metabolic activity was assessed using the (diphenyltetrazolium bromide) MTT assay, while cell number and viability were evaluated by Trypan Blue exclusion, necrosis by lactate dehydrogenase (LDH) release, and apoptosis by Caspase-3 activity. Western blot analysis was performed to evaluate the expression of phosphorylated AKT (p-AKT), phosphorylated GSK-3β (p-GSK-3β Ser9), phosphorylated TAU (pTAU), nuclear factor erythroid 2-related factor 2 (NRF2), manganese superoxide dismutase (Mn-SOD), and copper/zinc superoxide dismutase (Cu/Zn-SOD). Lipid peroxidation was determined by measuring malondialdehyde (MDA) levels using a colorimetric/fluorometric assay. Insulin treatment increased MTT reduction (31.25%) and cell metabolic activity (119.15%) while reducing LDH release (19.2%) and Caspase-3 activity (31.26%). In addition, insulin significantly increased p-AKT (34.2%) and p-GSK-3β (Ser9) (19.9%) levels. A reduction in pTAU levels (53.39%) was also observed following insulin treatment. Furthermore, insulin increased NRF2 expression (18.77%), Cu/Zn-SOD (37.29%), and Mn-SOD (50.16%) and reduced MDA levels (13.95%). These findings indicate that insulin modulates signalling pathways associated with tau phosphorylation and cellular redox regulation in SH-SY5Y cells. Insulin treatment was associated with increased AKT and GSK-3β phosphorylation, reduced tau phosphorylation, and changes in oxidative stress-related markers in SH-SY5Y neuroblastoma cells. These findings support a role for insulin in the modulation of molecular pathways implicated in cellular stress responses and tau regulation. Further studies using differentiated neuronal models and disease-relevant conditions are required to determine the relevance of these observations to neurodegenerative disorders.},
}

Humans
*Glycogen Synthase Kinase 3 beta/metabolism
*tau Proteins/metabolism
*Proto-Oncogene Proteins c-akt/metabolism
*Insulin/pharmacology/metabolism
Phosphorylation/drug effects
*Signal Transduction/drug effects
Cell Line, Tumor
*Neuroblastoma/metabolism/pathology
Oxidative Stress/drug effects
Oxidation-Reduction/drug effects
Homeostasis/drug effects
Apoptosis/drug effects
Cell Survival/drug effects
NF-E2-Related Factor 2/metabolism

@article {pmid42353615,
year = {2026},
author = {ALNasser, MN and Carter, WG},
title = {Phytochemicals as NMDA Receptor Inhibitors and Their Potential for Treating Excitotoxicity-Related Neurotoxicity: A Systematic Review.},
journal = {Current issues in molecular biology},
volume = {48},
number = {6},
pages = {},
doi = {10.3390/cimb48060611},
pmid = {42353615},
issn = {1467-3045},
support = {KFU260924//King Faisal University/ ; },
abstract = {Excitotoxicity caused by excessive activation of glutamate receptors, particularly N-methyl-D-aspartate receptors (NMDARs), significantly contributes to neuronal damage in neurodegenerative diseases (NDDs), such as Alzheimer's, Parkinson's, and Huntington's diseases. This systematic review aimed to evaluate the effects of plant extracts and phytochemicals on NMDAR-mediated excitotoxicity and to summarize their proposed neuroprotective mechanisms. The review protocol was registered in PROSPERO (CRD42024528160). A systematic search of Medline, Embase, Web of Science Core Collection, and PubMed identified 323 records, with an additional 7 records identified through manual searching that specifically considered in vitro and in vivo inhibitors of NMDAR excitotoxicity using plant extracts and isolated phytochemicals. Twenty-seven studies demonstrated that plant extracts and phytochemicals attenuate excitotoxicity through multiple mechanisms, including inhibition of NMDAR-induced currents, reduction of intracellular calcium influx, modulation of NMDAR expression, attenuation of oxidative stress, and mitochondrial dysfunction. However, the evidence base was largely dominated by in vitro and ex vivo studies, with limited in vivo validation, restricting translational relevance. Risk-of-bias assessment using an adapted version of the Office of Health Assessment and Translation (OHAT) Risk of Bias Tool indicated that 4 studies had a low overall risk of bias, 12 had low to moderate risk, and 11 were at moderate risk, with key limitations related to inadequate reporting of blinding, randomization, and allocation concealment. In contrast, exposure characterization, outcome assessment, and confounding control were generally strong across studies. Although the findings support the mechanistic neuroprotective potential of certain plant extracts and phytochemicals against NMDAR-mediated excitotoxicity, further well-designed in vivo and clinical studies are required to establish their therapeutic relevance for the treatment of neurodegenerative diseases.},
}

@article {pmid42353761,
year = {2026},
author = {Xu, J and Ashebir, YA and Shao, Y},
title = {Molecular Basis of Synergistic Causal Effect of Dual GLP-1R and GIPR Agonists for Risk Reduction in Diabetic Retinopathy, Alzheimer Disease, and Coronary Artery Disease in Diabetic Patients.},
journal = {Genes},
volume = {17},
number = {6},
pages = {},
doi = {10.3390/genes17060602},
pmid = {42353761},
issn = {2073-4425},
support = {U01OH012486/CC/CDC HHS/United States ; P30AG066512/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Coronary Artery Disease/genetics/drug therapy/prevention & control ; *Alzheimer Disease/genetics/drug therapy/prevention & control ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Diabetic Retinopathy/genetics/drug therapy/prevention & control ; *Diabetes Mellitus, Type 2/drug therapy/genetics/complications ; *Receptors, Gastrointestinal Hormone/agonists/genetics ; Glucagon-Like Peptide-1 Receptor/genetics ; Glycated Hemoglobin/metabolism ; Male ; Hypoglycemic Agents/therapeutic use/pharmacology ; Female ; },
abstract = {Background: The dual agonism of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) becomes a groundbreaking treatment for type 2 diabetes (T2D) that achieves robust glycemic control and maintains body weight. It also induces potential risk reduction in diabetic retinopathy (DR), Alzheimer disease (AD), and heart diseases including coronary artery disease (CAD) in treated T2D patients. To date, the molecular basis underpinning the remarkable causal treatment effects and synergy of the dual agonism of GLP-1R and GIPR on risk reduction in T2D, CAD, DR and AD has not been systematically investigated. Methods: To elucidate the treatment effects and potential synergy of dual GLP-1R/GIPR agonism on risk reduction in T2D, CAD, DR and AD while minimizing the impact of confounders, we used a robust cis-Mendelian randomization (cis-MR) with a principal component-based generalized method of moments (PC-GMM) where blood-based glycated hemoglobin (HbA1c), high- and low-density lipoprotein cholesterol (HDL-c, LDL-c), and BMI were used as mediating biomarkers. Results: Our cis-MR analyses confirmed a synergistic causal protective effect of dual GLP-1R/GIPR agonism on T2D via HbA1c reduction [OR = 0.17; 95% CI = (0.11, 0.26); p = 3.68 × 10[-17]] which is more significant than either GLP-1R agonism or GIPR agonism alone. Similarly, the causal protective effect of dual GLP-1R/GIPR agonism via HbA1c reduction was also significant for DR [OR = 0.20; 95% CI = (0.11, 0.36); p = 9.22 × 10[-8]]. Further, our multivariate cis-MR (or cis-MVMR) analyses revealed that after adjusting for HbA1c, a synergistic protective effect on DR via a reduction in LDL-c is significant in dual GLP-1R/GIPR agonism [OR = 0.57; 95% CI = (0.29, 0.94)], while the protective effect on DR of LDL-c reduction is non-significant in either GLP-1R agonism or GIPR agonism alone. Also, after adjusting for HbA1c, the multivariate cis-MR results showed significant protective effects on AD via a reduction in LDL-c in GLP-1R/GIPR agonism [OR = 0.44; 95% CI = (0.25, 0.81)]. Importantly, the multivariate cis-MR results also revealed that dual GLP-1R/GIPR agonism has significant protective effects on CAD via both a reduction in BMI [OR = 0.46; 95% CI = (0.28, 0.75)] and an improvement in HDL [OR = 0.59; 95% CI = (0.39, 0.90)]. This is in support of the hypothesis that dual GLP-1R/GIPR agonism has a synergistic protective effect on CAD that is stronger than that of GLP-1R agonism alone, which yielded a non-significant causal effect for both HDL and BMI, and GIPR agonism alone also yielded a non-significant causal effect for HDL when adjusted for BMI. Conclusions: These novel findings have significant implications for repurposing dual incretin agonism in terms of diabetic drugs to serve as a unifying, precision prevention strategy against CAD, DR and AD as leading drivers of mortality and morbidity in diabetic patients.},
}

Humans
*Coronary Artery Disease/genetics/drug therapy/prevention & control
*Alzheimer Disease/genetics/drug therapy/prevention & control
*Glucagon-Like Peptide-1 Receptor Agonists
*Diabetic Retinopathy/genetics/drug therapy/prevention & control
*Diabetes Mellitus, Type 2/drug therapy/genetics/complications
*Receptors, Gastrointestinal Hormone/agonists/genetics
Glucagon-Like Peptide-1 Receptor/genetics
Glycated Hemoglobin/metabolism
Male
Hypoglycemic Agents/therapeutic use/pharmacology
Female

@article {pmid42356271,
year = {2026},
author = {Sarti, G and Tognozzi, G and Magni, G and Lana, D and Rossi, F and Traini, C and Vannucchi, MG},
title = {The Multiple Functions of Amyloid Beta in the Gut Epithelium and the Role of the Microbiota: A Study in the APP/PS1 Animal Model Subjected to Chronic Synbiotic Treatment.},
journal = {Nutrients},
volume = {18},
number = {12},
pages = {},
doi = {10.3390/nu18121883},
pmid = {42356271},
issn = {2072-6643},
support = {PRIN2022SC_VANNUCCHI//Ministero dell'università e della ricerca/ ; VANMBANCAITALIA23//Bank of Italy/ ; 58513_CHIARA TRAINIRICATEN24//University of Florence/ ; },
mesh = {Animals ; *Synbiotics/administration & dosage ; *Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; *Intestinal Mucosa/metabolism/microbiology ; *Alzheimer Disease/microbiology/metabolism ; Mice, Transgenic ; *Gastrointestinal Microbiome/physiology ; Intestinal Barrier Function ; Colon/metabolism/microbiology ; Amyloid beta-Protein Precursor/genetics/metabolism ; Mice ; Presenilin-1/genetics ; Ileum/metabolism/microbiology ; Tight Junctions/metabolism ; Male ; },
abstract = {Background:/ Over the past decade, increasing evidence has shifted attention from the brain to the gut microbiota (MB) as a source and site of systemic dissemination of amyloid-β (Aβ), an APP derivative responsible for plaque formation in the brains of Alzheimer's disease (AD) patients. Furthermore, AD patients and APP/PS1 mice, a transgenic model of AD, exhibit dysbiosis. Objectives: Using APP/PS1 mice treated from 2 to 8 months of age, we studied ileal and colonic epithelial integrity, intestinal barrier (IB) integrity assessed through tight junction (TJ) protein expression, local immune system, the presence/increase in Aβ expression in enterocytes, and the protective effects of synbiotic treatment. Methods: The tissue was stained with Periodic Acid-Schiff and Alcian Blue to evaluate epithelial morphology and mucus production, and immunohistochemistry was performed to assess TJs, immune markers, and Aβ expression. Results: Our results demonstrate that colonic and ileal epithelium of 8-month-old APP/PS1 mice displays IB impairment in term of alterations of goblet cells staining and TJ protein expression and signs of immune involvement. The ileum was more severely affected, showing a reduced epithelial surface area, decreased lysozyme production, and fewer tuft cells. Long-term synbiotic treatment largely prevented APP/PS1 mouse changes and caused a significant increase in Aβ expression in all treated mice. Conclusions: These findings support the belief in early intestinal involvement in AD and highlight the potential of the microbiota as a target for early intervention aimed at modifying the progression to neurodegeneration. Increased epithelial Aβ labeling after treatment raises the possibility of intestinal management of Aβ, which requires further validation.},
}

Animals
*Synbiotics/administration & dosage
*Amyloid beta-Peptides/metabolism
Disease Models, Animal
*Intestinal Mucosa/metabolism/microbiology
*Alzheimer Disease/microbiology/metabolism
Mice, Transgenic
*Gastrointestinal Microbiome/physiology
Intestinal Barrier Function
Colon/metabolism/microbiology
Amyloid beta-Protein Precursor/genetics/metabolism
Mice
Presenilin-1/genetics
Ileum/metabolism/microbiology
Tight Junctions/metabolism
Male

@article {pmid42357346,
year = {2026},
author = {Costanzi, E and Fontana, L and Giroldo, F and Coco, S},
title = {Advancing MSC-EV Therapies: Harnessing Preconditioning and Mito-EVs to Tackle Neuroinflammation and Neurodegeneration.},
journal = {Pharmaceutics},
volume = {18},
number = {6},
pages = {},
doi = {10.3390/pharmaceutics18060730},
pmid = {42357346},
issn = {1999-4923},
support = {P2022LR49L//Ministry of Universities and Research/ ; 202229X8HW//Ministry of Universities and Research/ ; },
abstract = {Neuroinflammation plays a central role in the onset and progression of neurodegenerative disorders. Several disease-modifying therapies have been developed to target neuroinflammatory pathways in specific disorders. However, their ability to stop disease progression or restore neuronal and mitochondrial homeostasis remains limited. This is still a major unmet clinical need. In this context, mesenchymal stromal cell (MSC)-derived Extracellular Vesicles (EVs) have emerged as a promising cell-free therapeutic strategy due to their ability to modulate immune responses and promote neuroprotection through the delivery of bioactive cargo. Recent evidence has identified a distinct subset of EVs, known as mitochondrial EVs (mito-EVs), which carry mitochondrial DNA, proteins, and functional components. These vesicles may uniquely influence cellular bioenergetics, redox balance, and neuroinflammatory signaling, offering additional therapeutic potential compared to conventional MSC-EVs. This review summarizes the role of MSC-derived EVs in neuroinflammatory disorders, with a particular focus on mito-EVs. It also discusses preconditioning strategies to enhance EV efficacy, including hypoxic, inflammatory, pharmacological priming and genetic engineering approaches. Finally, we critically evaluate current preclinical evidence regarding the treatment of major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis, as well as Traumatic Injury, highlighting the key challenges for clinical translation.},
}

@article {pmid42357417,
year = {2026},
author = {Sharma, N and An, SSA},
title = {Multitarget Actions of Pentacyclic Triterpenic Acids in Alzheimer's Disease: Mechanistic Insights.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {12},
pages = {},
doi = {10.3390/molecules31122018},
pmid = {42357417},
issn = {1420-3049},
support = {RS-2021-NR060117//Ministry of Education/ ; RS-2025-02292973//Ministry of Oceans and Fisheries/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Neuroprotective Agents/therapeutic use/pharmacology/chemistry ; *Pentacyclic Triterpenes/therapeutic use/pharmacology/chemistry ; Animals ; Amyloid beta-Peptides/metabolism ; Phytochemicals/chemistry/pharmacology/therapeutic use ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder with features of amyloid-beta (Aβ) accumulations, tau hyperphosphorylation, oxidative stress, neuroinflammation, and synaptic losses. Despite extensive therapeutic investigations for many decades, the clinical treatment options remained largely symptomatic, while anti-amyloid antibody therapies were expensive and had limited accessibility. A subclass of triterpenoids generated from plants, pentacyclic triterpenic acids (PTAs), exhibited a variety of pharmacological properties. The neuroprotective effects of some important PTAs in AD models were reviewed in this study. These phytochemicals displayed a multimodal neuroprotection by lowering amyloid and tau, improving mitochondrial function, inhibiting inflammation, and improving synaptic plasticity and cognition. However, the neuroprotective mechanisms of several PTAs remained poorly characterized. In addition, most evidence were preclinical, while poor bioavailability and the limited clinical validation hindered the therapeutic translation. Studies were needed to evaluate these phytochemicals in AD, improve their pharmacokinetics, and enhance brain delivery. Their diverse bioactivities and encouraging preclinical findings suggest these compounds may serve as promising lead candidates for future drug development in neurodegenerative diseases.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Neuroprotective Agents/therapeutic use/pharmacology/chemistry
*Pentacyclic Triterpenes/therapeutic use/pharmacology/chemistry
Animals
Amyloid beta-Peptides/metabolism
Phytochemicals/chemistry/pharmacology/therapeutic use
tau Proteins/metabolism

@article {pmid42358353,
year = {2026},
author = {Nowar, R and Velma, GR and Fu, J and Kidwai, A and Bauc, G and Ackerman-Berrier, M and Thatcher, GRJ and Brady, ST and Ben Aissa, M},
title = {Inhibition of pathogenic tau signaling via blocking of the phosphatase-activating domain by novel small molecules.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1829420},
pmid = {42358353},
issn = {1663-9812},
abstract = {INTRODUCTION: Tau pathology is a major feature of Alzheimer's disease (AD) and multiple other adult-onset neurodegenerative diseases. Aberrant exposure of an N-terminal phosphatase-activating domain (PAD) is characteristic of pathological tau, representing a toxic gain of function. Exposure of the PAD in pathological tau leads to dysregulation of protein phosphatase 1/glycogen synthase kinase 3 (PP1/ GSK3β) signaling, inhibition of fast axonal transport, synaptic dysfunction, and altered transcription, along with other pathological consequences. Previous studies showed that TNT1, an antibody against the PAD, blocked toxicity of pathogenic forms of tau.

METHODS: In this article, we describe a high-throughput screen for small molecules that block TNT1 binding to the PAD in an AlphaLISA screen and bind specifically to the PAD in surface plasmon resonance assays. Candidate PAD ligands (PADis) were identified, and initial biochemical and biophysical optimization produced PADis with increased affinity and selectivity. Three candidate PADis were evaluated in neuronal (rat E18 embryonic cortical neurons) and non-neuronal cells (HEK293T human embryonic kidney cells) using a nano-bioluminescence resonance energy transfer (nanoBRET) assay to assess PP1 binding and cell toxicity.

RESULTS AND DISCUSSION: All three compounds prevented PP1 binding to PAD and neurite degeneration due to pathological tau in primary cultured cortical neurons. The final candidates had an IC50 value between 10 and 20 nM in neurons with low cytotoxicity, CC50 > 75 μM in primary cultured neurons, and 40-100 μM in non-neuronal cells. PADi treatment of primary cultured neurons transfected with pathogenic tau restored axonal growth and prevented neurodegeneration. These studies establish a novel approach to therapeutics for Alzheimer's disease and tauopathies.},
}

@article {pmid42358562,
year = {2026},
author = {Cribb, L and Moreno-Betancur, M and Sarant, J and Wolfe, R and Pase, MP and Rance, G and Mielke, MM and Murray, AM and Owen, A and Woods, RL and Zhou, Z and Wu, Z and Sheets, KM and Chong, TT and Shah, RC and Ryan, J},
title = {The effect of treating hearing loss with hearing aids on plasma biomarkers of Alzheimer's disease and related dementias.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70397},
pmid = {42358562},
issn = {2352-8729},
abstract = {BACKGROUND: Though evidence indicates that treating hearing loss with hearing aids (HAs) could reduce dementia risk, the effects on biomarkers of Alzheimer's disease and related dementias (ADRD) remain unknown.

METHODS: Observational data from Aspirin in Reducing Events in the Elderly (ASPREE) study participants without dementia and with hearing problems were used. We emulated two target trials to estimate the effect of (1) new HA prescription and (2) the frequency of HA use on plasma ADRD biomarkers after 7 years using targeted maximum likelihood estimation, with multiple imputation for missing data.

RESULTS: There was a median of 2842 individuals (mean 75 years, 48% female) across imputed datasets, and 735 new HA prescriptions. Estimated treatment effects were close to null for phosphorylated tau181, neurofilament light chain, glial fibrillary acidic protein, and amyloid beta 42/40. There was little evidence of effect modification (e.g., by apolipoprotein E ε4 genotype).

DISCUSSION: In older people with hearing loss, HA prescription and frequency of use had minimal association with levels of ADRD biomarkers.},
}

@article {pmid42358604,
year = {2026},
author = {Hindle, A and Chen, Y and Yin, X and Manczak, M and Decourt, B and Neugebauer, V},
title = {Transsynaptic complex dysfunction in the hippocampus of Alzheimer's disease patients.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1837327},
pmid = {42358604},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) involves not only amyloid-β and tau pathology but synaptic dysfunction and impaired autophagy, though the underlying mechanisms and their relationship to AD progression are not well understood. Transsynaptic complexes involving presynaptic neurexins (Nrxn1/2/3), secreted cerebellins (Cbln1/2/3/4), and postsynaptic glutamate delta receptors (GluD1/2) play critical roles in organizing synapses and synaptic plasticity. Studies in pain models have reported that treatment with recombinant Cbln1 rescues AMPA glutamate receptor imbalance, promotes autophagy, and inhibits hyperexcitability and pain behaviors. Here we tested the novel hypothesis that dysregulation of Cbln-GluD-based transsynaptic complexes may occur in the brain of AD patients, providing insights into disease progression and potential avenues for therapeutic development.

METHODS: We analyzed human hippocampal tissues from the TTUHSC Garrison Brain Bank and the NIH NeuroBioBank for expression of transsynaptic complex components in addition to autophagy and neuroplasticity pathways. Their expression in hippocampus was compared between control samples of Braak stages 0/1 and AD samples showing either mild (Braak stage 2) or severe (Braak stages 5/6) neurofibrillary tangle pathology. Co-immunoprecipitation was used to examine protein-protein interactions.

RESULTS: We found significantly decreased protein levels of Cbln1 and GluD2 in AD hippocampus. In the autophagy pathway, PIST and beclin-1 were decreased in AD hippocampus. Co-immunoprecipitation revealed interactions between GluD1 and PIST and between PIST and beclin-1, suggesting possible regulatory interactions between transsynaptic complex elements and autophagy in human hippocampus. We further observed decreased BDNF, consistent with diminished neuroplasticity. Finally, cofilin phosphorylation was decreased in AD, suggesting disruption of trafficking and formation of cofilin-actin rods.

DISCUSSION: These results suggest that the homeostasis of signaling molecules important for synaptic integrity is disrupted in the human hippocampus at both early- and late-stage AD. The loss of transsynaptic complex expression is accompanied by the downregulation of autophagy and neuroplasticity markers that are known to be linked to AD pathology.},
}

@article {pmid42359179,
year = {2026},
author = {Saito, T and Fukaya, H and Omodaka, S and Yazawa, Y},
title = {An Elderly Patient With Status Epilepticus Caused by a Dural Arteriovenous Fistula.},
journal = {Cureus},
volume = {18},
number = {5},
pages = {e109568},
pmid = {42359179},
issn = {2168-8184},
abstract = {Dural arteriovenous fistulas (DAVFs) are a rare cause of epilepsy. Therefore, they can be misdiagnosed or overlooked. We report a case of an 84-year-old female with Alzheimer's disease who developed status epilepticus as the initial manifestation of the left transverse sinus DAVF. On admission, symptomatic epilepsy secondary to Alzheimer's disease was suspected, and medical therapy was started; however, clinical improvement was limited. Magnetic resonance imaging and magnetic resonance angiography findings provided clues for the diagnosis of the left transverse sinus DAVF. Endovascular treatment led to improvement in behavioral symptoms and electroencephalography findings with no seizure recurrence. One month later, she returned to her baseline condition. This case highlights the importance of including DAVF in the differential diagnosis of seizures in older adults and of recognizing that invasive endovascular therapy may offer a curative option.},
}

@article {pmid42360038,
year = {2026},
author = {Bouges, S and Alagoz, E and Gutierrez-Meza, D and Noell, D and Hollnagel, F and Oby, A and Flowers-Benton, S and Fischer, B and Gooding, DC and Anthony, RL and Carter, FP and Ennis, GE and Van Hulle, C and Zuelsdorff, M and Lambrou, NH and James, TT and Umucu, E and Carlsson, CM and Asthana, S and Gleason, CE and Passmore, SR},
title = {Engendering trustworthiness in the community: Strategies for researchers.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261458800},
doi = {10.1177/13872877261458800},
pmid = {42360038},
issn = {1875-8908},
abstract = {BackgroundDespite significant advances in Alzheimer's disease treatment, underrepresentation of ethnoracialized groups in clinical trials limit the generalizability of study findings. Though mistrust in health care research is a known barrier to clinical trial participation, methods are needed to quantitate this multidimensional subjective term. This study investigated how Black participants view trustworthiness.ObjectiveTo provide an overview of participants' views of a trustworthy study design and investigator.MethodsThis qualitative study utilized focus group discussions with Black participants 45 years and older. Transcripts were coded by three researchers by means of content analysis. After central categories were identified using concept mapping, we constructed a conceptual model of trust to reflect participants' views of trustworthiness.ResultsParticipants self-identified as Black, were a mean age of 62, and predominantly female (80%). Focus group analysis revealed that a trustworthy study design and its impact as well as a trustworthy investigator were central categories of trustworthiness. Comprehensive study outlines, detailed information on the disease being studied, and sharing of study results improved participants' willingness to be involved in studies. Participants also value researchers who are scientifically and culturally competent, knowledgeable, attentive and who engage in education and sharing comprehensive resources on diseases impacting vulnerable populations.ConclusionsThese findings suggest that trustworthy features of the study design and researcher characteristics can provide a foothold to build trust with a population whose mistrust of research is well-documented. Further research on trustworthiness is necessary to develop tools to create a framework for building a trustworthy research environment.},
}

@article {pmid40982093,
year = {2025},
author = {Hassanzadeh, G and Ashouri, S and Kargar, R and Shamosi, A and Mahakizadeh, S},
title = {Effectiveness of Insulin-Induced umbilical cord stem cells on Seladin-1/APP/GFAP expression in rat hippocampal CA1/CA3 regions following chronic hypoxia.},
journal = {Journal of molecular histology},
volume = {56},
number = {5},
pages = {321},
pmid = {40982093},
issn = {1567-2387},
support = {94-02-30-28381//Tehran University of Medical Sciences/ ; 94-02-30-28381//Tehran University of Medical Sciences/ ; },
abstract = {Dementia, a syndrome characterized by cognitive impairment, significantly impacts the global elderly population. Given their paracrine properties, mesenchymal stem cells (MSCs) represent a promising avenue for developing novel treatments for neurodegenerative disorders. Chronic hypoxia models Alzheimer’s disease-like pathology by triggering neuroinflammation and altering key biomarkers. This study evaluated the therapeutic potential of MSCs, insulin-induced MSCs, and insulin in a rat model of Alzheimer’s disease (AD). Forty-eight rats were allocated into eight experimental groups: normoxic control, sham-surgery control, and six hypoxic intervention groups (exposed to 8% O2). Intraventricular administration of MSCs or insulin-induced MSCs, intranasal administration of insulin, or both insulin and MSCs were used in the intervention groups. Hypoxic exposure significantly elevated pro-inflammatory cytokines (IL-1β, TNF-α) and increased expression of glial fibrillary acidic protein (GFAP) and amyloid precursor protein (APP), while decreasing levels of the neuroprotective factor Seladin-1. Administration of MSCs or Ins-MSCs effectively mitigated these hypoxia-induced alterations. Specifically, treatment with MSCs or Insulin induced-MSCs restored Seladin-1, GFAP, and APP expression levels to those observed in normoxic controls. Furthermore, these treatments attenuated the hypoxia-associated increase in Nissl body pathology within the hippocampal pyramidal cell layer. The most pronounced therapeutic benefits were observed following combined intranasal insulin and intraventricular MSC administration. Consequently, the combinatorial approach of MSCs and insulin warrants further investigation as a potential therapeutic strategy for Alzheimer’s disease. Combining intranasal insulin with insulin-induced MSCs may offer a strategy to target multiple AD pathology pathways.},
}

@article {pmid41758465,
year = {2026},
author = {Gönüllü, S and Aydın, Ş and Çelik, H and Çelik, O and Küçükler, S and Topal, A and Akay, R and Yıldız, MO and Alım, B and Özdemir, S},
title = {Therapeutic Effects of miR-21-5p-Enriched Milk Extracellular Vesicles on Alzheimer's Disease-Associated Neurotoxicity in Vitro.},
journal = {Cell biochemistry and biophysics},
volume = {84},
number = {2},
pages = {2609-2625},
pmid = {41758465},
issn = {1559-0283},
abstract = {Progressive neuronal degeneration linked to oxidative stress, mitochondrial malfunction, and persistent neuroinflammation are the hallmarks of Alzheimer’s disease (AD). The current study investigated the neuroprotective potential of miR-21-5p–loaded milk-derived small extracellular vesicles (sEV_miR-21-5p) against amyloid beta (Aβ)–induced toxicity in SH-SY5Y neuroblastoma cells. Milk-derived sEVs were isolated and characterized following the MISEV 2018 guidelines, and miR-21-5p was actively loaded into the vesicles. Aβ-induced oxidative stress was effectively reduced by treatment with sEV_miR-21-5p, as evidenced by decreased levels of ROS, MDA, LDH, and GPX1, along with restored SOD activity. Furthermore, sEV_miR-21-5p mitigated mitochondrial dysfunction, indicated by increased TFAM expression and decreased Cyt-c, PINK1, and DNM1L levels. The treatment also downregulated inflammation-associated signaling molecules (TNF-α and ICAM1) while enhancing BDNF expression, suggesting modulation of neuronal stress–response and survival pathways. In addition, miR-21-5p delivery normalized neuronal cytoskeletal and stress-related protein (NfL), preserved synaptic protein expression (CPLX2 and SMOC1), and significantly reduced tau hyperphosphorylation and Aβ accumulation. These findings demonstrate that milk-derived sEVs serve as efficient, biocompatible carriers for miR-21-5p, enabling targeted delivery and functional recovery in neuronal cells. Taken together, this study underscores the therapeutic potential of sEV_miR-21-5p as a biocompatible and scalable platform for targeted intervention in AD.},
}

@article {pmid41915110,
year = {2026},
author = {Asl, AD and Naeimzadeh, F and Yonjali, RM and Mohammadpour, A and Khankandi, PG and Afkhami, A and Mahmoodpoor, A and Sanaie, S and Naseri, A},
title = {Selenium and probiotics co-supplementation: A scoping review of clinical evidence.},
journal = {Inflammopharmacology},
volume = {34},
number = {5},
pages = {3625-3635},
pmid = {41915110},
issn = {1568-5608},
support = {74645//Student Research Committee, Tabriz University of Medical Sciences/ ; },
abstract = {BACKGROUND: Selenium and probiotics have been individually recognized for their antioxidant, anti-inflammatory, and immune-modulating properties. However, the potential synergistic effects of their co-supplementation in human health remain minimally investigated. This scoping review aimed to summarize the current evidence on the impact of co-supplementation with selenium and probiotics. METHODS: A comprehensive literature search was conducted across PubMed, Scopus, Embase, and Web of Science databases to identify clinical trials investigating the effects of selenium and probiotics co-supplementation. Eligible studies included randomized controlled trials (RCTs) and non-randomized clinical trials assessing clinical, metabolic, inflammatory, oxidative stress, and immune-related outcomes. RESULTS: Ten clinical studies met the inclusion criteria, including populations with polycystic ovary syndrome, Alzheimer’s disease, schizophrenia, leukemia, gestational diabetes, elderly nursing home residents, and ICU patients with stage I–II bedsores. Co-supplementation was associated with changes in glycemic indices (fasting plasma glucose, insulin, HOMA-IR, QUICKI), selected lipid parameters (triglycerides, total cholesterol, LDL cholesterol), oxidative stress markers (total antioxidant capacity, glutathione, malondialdehyde), and inflammatory markers, particularly high-sensitivity C-reactive protein. Studies also reported improvements in mental health scores, cognitive function (MMSE), and immune-related markers including adhesion molecules. Gene expression changes, including TNF-α and PPAR-γ, were reported in limited studies. Overall, co-supplementation was well tolerated, with no serious adverse events reported. CONCLUSIONS: Selenium and probiotics co-supplementation may provide beneficial effects on metabolic regulation, oxidative stress, and inflammation-related conditions. However, heterogeneity in study design, probiotics’ strains, selenium dosage, and treatment duration limits firm conclusions. Larger, well-designed randomized controlled trials with long-term follow-up are needed.},
}

@article {pmid41981348,
year = {2026},
author = {Abdellatif, AI and Elsharab, A and Moubarak, ES and Alsaadany, KR and Ayad, YW},
title = {Focused and unfocused transcranial ultrasound stimulation in Alzheimer's disease: a systematic review and meta-analysis of randomized controlled trials.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {5},
pages = {},
pmid = {41981348},
issn = {1590-3478},
abstract = {BACKGROUND: Transcranial ultrasound stimulation (TUS) is a non-invasive method that allows deep brain structures to be targeted, and it may benefit individuals with Alzheimer'sdisease (AD). We conducted a systematic review and meta-analysis to assess the effect of TUS on global cognitive function in mild-to-moderate AD, comparing focused transcranial pulse stimulation (TPS) with unfocused low-intensity pulsed ultrasound (LIPUS). METHODS: We searched PubMed, Scopus, Cochrane, and Web of Science for randomized controlled trials (RCTs) comparing TUS with sham stimulation. The primary outcome was the change in global cognitive function. Secondary outcomes included functional status,depressive symptoms, and safety. RESULTS: Three RCTs (N=84) were included. Pooled analysis showed that TUS did not significantly improve global cognition compared with sham (SMD=0.31, p=0.54). However,subgroup analysis showed a significant difference between modalities (p=0.047):unfocused LIPUS had a larger effect size (SMD=0.73) than focused TPS (SMD=0.17).Notably, significant cognitive improvement was observed in patients <70 years. Active treatment showed higher disease stabilization rates ("responders"), reduced depressive symptoms (specifically TPS, p=0.008), and improved cerebral perfusion without amyloid-related imaging abnormalities (ARIA). CONCLUSION: While pooled analyses did not show a global cognitive benefit, the results favoured unfocused LIPUS over focused TPS; TUS had an excellent safety profile and higher disease stabilization rates; the potential benefits in younger populations and the biological effects suggest that TUS is a promising adjunct that should be further optimized for stimulation. REGISTRATION: This review was registered on PROSPERO (CRD420251276660).},
}

@article {pmid42018225,
year = {2026},
author = {Liu, L and Zhu, B},
title = {Advancements in the Study of Missense Mutations in ABCA7 in Alzheimer's Disease.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {2},
pages = {},
pmid = {42018225},
issn = {1559-1166},
abstract = {Alzheimer’s disease (AD) is a neurodegenerative disorder affecting millions of people worldwide. In recent years, genetic factors, particularly missense mutations in susceptibility genes, have been proven to play a key role in the pathogenesis of AD. The ABCA7, a regulator of lipid metabolism and amyloid-beta clearance, has missense mutations that impact phospholipid transport and phagocytic functions, thus contributing to the development of AD. Genome-wide association studies (GWAS) and whole-genome sequencing have identified various missense mutations in ABCA7, such as G1527A and R880Q, with risk ratios up to 1.15 times. Furthermore, differences in the distribution of these mutations across different ethnic groups have been widely reported. Future research should focus on the prevalence and functional effects of these mutations in different populations and their specific effects on ABCA7 protein function. A deeper understanding of these mutations could provide new scientific bases for the early diagnosis and treatment of AD. In summary, the missense mutations in ABCA7 provide important insights into the genetic susceptibility of AD and represent potential candidate targets for the development of personalized treatment strategies.},
}

@article {pmid42339068,
year = {2026},
author = {La Joie, R and Blazhenets, G and Maiti, P and Chiotis, K and Eloyan, A and Kirby, K and Hammers, D and Koeppe, RA and Ackley, SF and Robison, J and Soleimani-Meigooni, DN and Carrillo, MC and Dickerson, BC and Apostolova, LG and Rabinovici, GD and , },
title = {Identification of patients receiving amyloid-targeting therapies in observational studies using amyloid PET trajectories: Insights from LEADS.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70408},
pmid = {42339068},
issn = {2352-8729},
abstract = {INTRODUCTION: As amyloid-targeting therapies (ATTs) enter clinical care, observational cohorts must accurately ascertain ATT exposure. We developed an approach to flag mis/undocumented ATT in the Longitudinal Early-Onset Alzheimer's Disease Study using longitudinal amyloid positron emission tomography (PET).

METHODS: We analyzed 742 [[18]F]florbetaben PET from 270 participants with early-onset Alzheimer's disease. Using PET acquired before US Food and Drug Administration (FDA) approval of ATTs, we quantified Centiloid (CL) variability between two consecutive scans (PET "segments") to determine unusual CL decline thresholds that were then applied to post-FDA approval segments.

RESULTS: Pre-FDA approval segments increased by a median of 4.1 CL/year (whole cerebellum reference) and 3.6 CL/year (composite reference); unusual CL decline thresholds, defined as mean - 2 standard deviations of the pre-approval distributions were -15.8 and -9.4 CL/year, respectively. When applied to segments acquired post-FDA approval, extreme declines were observed in 59% to 78% of treated (n = 54) versus 4% to 8% of untreated segments (n = 344).

DISCUSSION: Longitudinal amyloid PET analyses can help identify ATT exposure in observational studies.},
}

@article {pmid42339400,
year = {2026},
author = {Williams, T and Jang, SR and Lanctôt, KL and Kang, A and Bloudek, L and Wang, G},
title = {Simulation of long-term lecanemab treatment effect on Alzheimer's disease progression.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {2},
pages = {e70274},
pmid = {42339400},
issn = {2352-8737},
abstract = {INTRODUCTION: Anti-amyloid therapies such as lecanemab have demonstrated statistically significant slowing of decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) in patients with early Alzheimer's disease (AD) in pivotal trials. Converting treatment differences on CDR-SB into time saved from disease progression may help convey clinical relevance for patients and caregivers more effectively.

METHODS: Disease progression models were developed using Alzheimer's Disease Neuroimaging Initiative and National Alzheimer's Coordinating Center data. A 37% treatment-related time delay, derived from the Clarity AD trial, was applied to estimate long-term efficacy of lecanemab.

RESULTS: Natural progression models estimated 11.5 to 13.7 years from mild cognitive impairment due to AD to severe AD. When starting treatment at CDR-SB 3.2, lecanemab delayed progression to severe AD by 2.5 to 3.7 years when assuming patients remained on treatment and 2.0 to 3.0 years when accounting for treatment discontinuation. Results were consistent across different datasets.

DISCUSSION: Projections suggest lecanemab substantially delays clinical progression of AD, preserving patients' time in earlier stages of AD.},
}

@article {pmid42339401,
year = {2026},
author = {Burke, J and Weerman, A and Hanson, M and Zhang, Q and Monfared, AAT and Mattke, S},
title = {Travel barriers to amyloid-targeting infusion access among older adults.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {2},
pages = {e70282},
pmid = {42339401},
issn = {2352-8737},
abstract = {INTRODUCTION: Amyloid-targeting treatments (ATT) for Alzheimer's disease require regular infusions and caregiver accompaniment for approximately 80% of patients. Travel time to infusion sites and caregiver availability can therefore impede access to care, especially in rural and lower income populations.

METHODS: We conducted a survey in a nationally representative Internet panel with more than 2300 adults aged ≥65 years to estimate willingness to travel for bi-weekly infusion treatment, and access to an accompanying caregiver. Addresses of respondents and infusion sites were geocoded and driving times to the nearest infusion centers were calculated using Google Maps road network data. To estimate potential access gains under subcutaneous (SC) delivery, we estimated access by relaxing the travel and accompaniment requirements in a scenario analysis.

RESULTS: Median willingness-to-travel time was 97.5 minutes (interquartile range [IQR]: 67.5-187.5 minutes) one way for bi-weekly infusions over a 5-year period. Approximately 90% of respondents were willing to travel the required time to reach an infusion site. However, 18% indicated that it would be unlikely that they could identify someone to accompany them. When caregiver accompaniment was incorporated as a constraint, 75% met both the travel and caregiver criteria. In regression analysis, respondents with annual incomes above $60,000 and those residing in metropolitan areas were 9 and 19 percentage points more likely, respectively, to meet travel and caregiver criteria. In a scenario analysis, SC delivery increased overall access by up to 33%, in relative terms, with larger proportional gains for low income and rural respondents.

DISCUSSION: A meaningful number of individuals in a nationally representative sample live farther from their nearest site than they would be willing to travel, and obstacles to access worsen if individuals need a caregiver to accompany them, as is common among early-stage AD patients. Treatments that do not require infusion delivery could improve equitable access to care.},
}

@article {pmid42339433,
year = {2024},
author = {Jellinger, KA},
title = {Mild cognitive impairment in Parkinson's disease: current view.},
journal = {Frontiers in cognition},
volume = {3},
number = {},
pages = {1369538},
pmid = {42339433},
issn = {2813-4532},
abstract = {Parkinson's disease (PD), the most common motor movement disorder and second most common neurodegenerative disorder after Alzheimer's disease (AD), is often preceded by a period of mild cognitive impairment (MCI), which is associated with impairment of a variety of cognitive domains including executive function, attention, visuospatial abilities and memory. MCI, a risk factor for developing dementia, affects around 30% of de novo PD patients and can increase to 75% after more than 10 years. While 30-40% remain in the MCI state, up to 60% will convert to dementia. Characteristic findings are slowing of EEG rhythms, frontotemporal hypoperfusion, decreased functional connectivity in the default mode and attentional networks, prefrontal and basal-ganglia-cortical circuits, which often manifests prior to clinical symptoms and overt brain atrophy. The heterogeneity of cognitive phenotypes suggests that a common neurodegenerative process affects multiple functional neuronal networks and neuromodulatory systems that may be superimposed by Lewy body and Alzheimer's-related or other co-pathologies. Sparse neuropathological data for PD-MCI revealed a heterogenous picture with various morphological changes similar to MCI in other diseases. This review highlights the essential epidemiological, clinical, neuroimaging and morphological changes in PD-MCI, available biomarkers, and discusses the heterogenous pathobiological mechanisms involved in its development. In view of its complex pathogenesis, well-designed longitudinal clinico-pathological studies are warranted to clarify the alterations leading to MCI in PD, which may be supported by fluid and neuroimaging biomarkers as a basis for early diagnosis and future adequate treatment modalities of this debilitating disorder.},
}

@article {pmid42340126,
year = {2026},
author = {Thunell, J and Tysinger, B and Baumgart, M and Carrillo, M and Crimmins, E and Goldman, D and Heun-Johnson, H and Jacobson, M and Joyce, G and Leaf, D and Neumann, LTV and Zissimopoulos, J},
title = {The cost of dementia in the United States in 2026.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71480},
pmid = {42340126},
issn = {1552-5279},
support = {U01AG086827/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; United States ; *Dementia/economics/epidemiology ; *Cost of Illness ; Aged ; *Health Care Costs/statistics & numerical data ; Quality of Life ; Female ; Middle Aged ; Male ; Caregivers/economics ; Health Expenditures/statistics & numerical data ; },
abstract = {INTRODUCTION: Comprehensive cost measurement is essential for an effective policy response to societal dementia costs.

METHODS: Using dynamic microsimulation, the Health and Retirement Study, and other national data, we quantified the 2026 cost of dementia in the United States.

RESULTS: In 2026, 5.7 million (95% confidence interval [CI] [5.6, 6.0]) US adults aged 51 and older are living with dementia, supported by 5.2 million (95% CI [4.9, 5.5]) care partners. Total costs are $818 billion (B, 95% CI [759, 866]), driven by quality-of-life losses for persons with dementia ($320B, 95% CI [269, 363]) and care partners ($15B 95% CI [6, 25]). Unpaid care ($237B, 95% CI [220, 253]), earnings losses ($23B), and out-of-pocket costs combined with quality-of-life losses account for 80% of costs and are borne by families. Governments cover 70% of healthcare costs ($222B, 95% CI [209, 237]).

DISCUSSION: The costs of dementia fall on families, highlighting limited policy and work supports. Treatment innovation may increase medical costs but reduce caregiver burden and improve quality of life.

HIGHLIGHTS: The costs of dementia in the United States in 2026 are $818 billion. Quality-of-life losses are the largest driver of dementia's total burden. Individuals and families bear over three times the cost versus health systems. Methods enable analysis of treatment, care, and policy innovations on future costs.},
}

Humans
United States
*Dementia/economics/epidemiology
*Cost of Illness
Aged
*Health Care Costs/statistics & numerical data
Quality of Life
Female
Middle Aged
Male
Caregivers/economics
Health Expenditures/statistics & numerical data

@article {pmid42340306,
year = {2026},
author = {Brookman, R and Christensen, J and Maurice, OR and Aghaei, M and Cass, A and Monzaviyan, S and Shatnawi, E and Carter, M and Tran, J and McIlwain, N and Garrido, S and Siette, J and Strutt, P and Harris, CB},
title = {Measures used to evaluate psychosocial interventions in dementia care: A narrative review and synthesis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261459125},
doi = {10.1177/13872877261459125},
pmid = {42340306},
issn = {1875-8908},
abstract = {Psychosocial interventions are widely used in dementia care, yet standardized outcome measurement remains highly variable, and recent frameworks emphasize outcomes prioritized by people living with dementia and their care partners. This narrative, measurement-focused review does not appraise or synthesize treatment effects. Instead, it aims to map outcome measures to the International Consortium for Health Outcomes Measurement (ICHOM) dementia set plus an additional carer-wellbeing domain, to organize them into a taxonomy of wellbeing domains that highlights patterns and gaps in measurement practice. Eligible studies included participants with Alzheimer's disease and related dementias, evaluated a psychosocial intervention, and reported standardized pre- and post-intervention outcome measures at short and/or long-term follow-up. A total of 136 studies met inclusion criteria. Interventions encompassed arts and creative therapies, cognitive and reminiscence approaches, education and psychosocial support, physical and movement-based therapies, sensory and relaxation therapies, environmental and daily living support, and animal/robot-assisted programs. Outcome measures clustered on neuropsychiatric symptoms (205 instances) and cognitive functioning (146 instances), with fewer measures of social functioning (22 instances) and health-related quality of life (13 instances). Measurement approaches were highly variable (43 distinct neuropsychiatric measures, 47 cognitive measures, 14 social functioning measures). Outcomes were predominantly assessed using short-term measures, with some long-term follow-up, and few observational in-the-moment measures capturing engagement, enjoyment, reciprocity or mastery. This review presents a taxonomy of outcome measures that highlights the mismatch between current evaluation practices and person-centered psychosocial priorities in dementia care, and guides more purposeful measure selection.},
}

@article {pmid42341593,
year = {2026},
author = {Wik, E and Dahlén, AD and Julku, U and Xiong, M and Michno, W and Syvänen, S and Sehlin, D},
title = {Brain interstitial fluid pharmacokinetics and therapeutic effect of a BBB penetrating amyloid beta antibody measured by microdialysis.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {4},
pages = {e00949},
doi = {10.1016/j.neurot.2026.e00949},
pmid = {42341593},
issn = {1878-7479},
abstract = {The disease-modifying antibody lecanemab for treating Alzheimer's disease (AD) was initially designed to target amyloid-beta (Aβ) protofibrils, i.e. soluble aggregates of Aβ, but it has also been successful in clearing insoluble amyloid plaques in clinical studies. Therefore, this study aimed to investigate how a brain penetrating, bispecific murine variant of lecanemab (RmAb158-scFv8D3) distributes in the brain and interacts with different pools of aggregated Aβ in APP transgenic mice. The alpha-synuclein targeting antibody RmAbSynO2-scFv8D3 was used as control. Further, by performing in vivo high cut-off microdialysis in freely moving animals, brain interstitial fluid (ISF) was continuously collected across 24 h to assess concentrations of free antibody in the brain. Post mortem distribution of the antibodies was analyzed by sequential extraction of brain tissue. RmAb158-scFv8D3 showed rapid ISF clearance as well as a redistribution from brain extracts containing small, soluble Aβ species toward brain extracts containing insoluble, plaque-associated Aβ with time. A treatment effect was detected already at 12 h post injection, whereby the RmAb158-scFv8D3-treated animals showed lower concentrations of the smallest, most soluble Aβ aggregates. Collectively, these findings suggest that within the first 24 h after a single injection of the bispecific RmAb158-scFv8D3 antibody we can capture the antibody's initial brain distribution and interactions with both soluble Aβ aggregates and insoluble, plaque-associated Aβ. These interactions mediate a swift reduction of soluble Aβ, while clearance of insoluble Aβ requires longer treatment time.},
}

@article {pmid42343047,
year = {2026},
author = {Jiang, Z and Zhang, J and Zhang, X and Xie, C and Chen, X and Ma, G and Lu, X and Ai, Y and Jia, T},
title = {Targeting NOX4 with Quercetagetin-PLGA nanomaterials: a novel therapeutic strategy for Alzheimer's disease.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42343047},
issn = {1432-1912},
abstract = {This study aims to address NOX4 (NADPH oxidase 4)-driven oxidative injury in Alzheimer's disease (AD) and the poor bioavailability of the natural flavonoid Quercetagetin, we developed an α7 nicotinic acetylcholine receptor (α7-nAChR)-targeted, Quercetagetin-loaded PLGA nanocarrier (PLGA@Quercetagetin@α7-nAChR) for receptor-mediated delivery, NOX4 suppression, and neuroprotection. Using the GSE97760 dataset, bioinformatic screening combined with LASSO regression was performed to identify candidate targets. Single-cell RNA sequencing (scRNA-seq) with pseudotime analysis was applied to delineate cell type-resolved and trajectory-associated expression patterns. Nanoparticles were fabricated by a double-emulsion method and characterized for physicochemical properties. In an Aβ-induced HT-22 neuronal injury model, genetic perturbation, western blotting, and flow cytometry were used to validate the pathogenic role of NOX4 and to evaluate the pharmacological efficacy of the nanoplatform. NOX4 emerged as the key gene, showing enriched expression in oligodendrocytes and endothelial cells and an increase along the inferred disease-associated trajectory. In vitro, Aβ stimulation upregulated NOX4, whereas NOX4 knockdown or Quercetagetin treatment alleviated Aβ-induced cytotoxicity and apoptosis. The nanoparticles exhibited an average diameter and sustained drug release over 72 h. α7-nAChR targeting enhanced neuronal uptake by ~ fivefold, markedly reduced NOX4 mRNA levels, and decreased the apoptotic rate from 18.3% to 5.0%. Notably, encapsulation also mitigated the hepatorenal toxicity observed with high-dose free Quercetagetin. These in vitro findings suggest NOX4 as a potential target in AD, and the PLGA@Quercetagetin@α7-nAChR nanoplatform shows improved cellular uptake and reduced short-term toxicity compared to free drug. However, claims regarding brain targeting and translational potential are limited by the absence of in vivo validation, non-targeted controls, drug exposure normalization, and key formulation parameters (e.g., encapsulation efficiency). Future in vivo studies are required to substantiate this targeted strategy for AD.},
}

@article {pmid42343519,
year = {2026},
author = {Zhou, B and Zhu, C and Chen, X and Li, J and Gao, D and Wu, A and Tao, L and Yuan, X and Yang, G and Chen, X and Xie, M and Cheng, L and Wang, X},
title = {[Mechanism of moxibustion at the governor vessel for regulating autophagy against Alzheimer's disease via lncRNA-RP4-mediated Wnt/β-catenin pathway].},
journal = {Zhongguo zhen jiu = Chinese acupuncture & moxibustion},
volume = {46},
number = {6},
pages = {929-947},
doi = {10.13703/j.0255-2930.20250309-k0001},
pmid = {42343519},
issn = {0255-2930},
mesh = {Animals ; *Alzheimer Disease/therapy/genetics/metabolism/physiopathology ; *RNA, Long Noncoding/genetics/metabolism ; *Moxibustion ; *Autophagy ; Mice ; Humans ; *Wnt Signaling Pathway ; Male ; Mice, Inbred C57BL ; *beta Catenin/metabolism/genetics ; Mice, Transgenic ; MicroRNAs/genetics/metabolism ; Acupuncture Points ; Membrane Proteins/genetics/metabolism ; },
abstract = {OBJECTIVE: To observe the effect of moxibustion at the governor vessel on lncRNA-RP4/miR-939-5p and Bnip3 in APP/PS1 double transgenic mice mediated by Wnt/β-catenin pathway, and to explore the mechanism of moxibustion in the treatment of Alzheimer's disease (AD).

METHODS: Sixty 6-month-old APP/PS1 mice were randomly divided into a model group, a rapamycin group, a moxibustion+ 3-methyladenine (3-MA) group and a moxibustion group, with 15 mice in each group. Fifteen C57BL/6J mice of the same age were used as the control group. The rapamycin group was given intraperitoneal injection of rapamycin (2 mg/kg). The moxibustion group was given moxibustion at "Baihui" (GV20),suspended moxibustion at "Fengfu" (GV16) and "Dazhui" (GV14) for 20 min. The moxibustion+3-MA group was injected with 1.5 mg/kg 3-MA on the basis of the moxibustion group. After 6 consecutive treatments, rest for 1 d, and lasted 2 weeks.HEK293T cells were cultured in vitro and transfected with miR-939-5p and its empty plasmid, and transfected with lncRNA-RP4 and Bnip3 wild-type and mutant. HT22 cells cultured in vitro were randomly divided into a control group and a model (Aβ 1-42) group. The lncRNA-RP4 overexpression group, the lncRNA-RP4 knockdown group, the miR-939-5p mimic group, the miR-939-5p inhibitor group, the Bnip3 overexpression group, the Bnip3 knockdown group and the corresponding empty plasmid group were set up, and transfection was performed on the basis of the model group. Morris water maze test was used to detect the learning and memory ability of mice. HE staining was used to observe the morphology of hippocampus in each group. The structure of nerve cells, the number and structure of autophagic vacuoles and autophagic lysosomes in hippocampal CA1 region of mice in each group were observed by transmission electron microscopy. The expression of Aβ 1-42 protein in hippocampus was detected by immunohistochemistry. The expression of mTOR, TFEB, P62, Wnt3 a, β-catenin, GSK-3β, lncRNA-RP4, miR-939-5 p and Bnip3 mRNA in hippocampus of mice in each group was detected by real-time fluorescence quantitative PCR. Western blot was used to detect the expression of mTOR, TFEB, P62, LC3 B-Ⅰ,LC3 B-Ⅱ, CTSB, Lamp1, V-ATPase, Wnt3a, β-catenin, GSK-3β and Bnip3 protein in hippocampus of mice in each group.Dual luciferase assay was used to verify the targeting relationships among lncRNA-RP4, miRNA-939-5p and Bnip3 in HEK293T cells. The concentration of Aβ 1-42 in HT22 cells of each group was detected by ELISA. The expression of lncRNA-RP4, miR-939-5p, Bnip3, Wnt3a, β-catenin and GSK-3β mRNA in HT22 cells of each group was detected by real-time fluorescence quantitative PCR. The expression of Bnip3, Wnt3a, β- catenin and GSK-3β protein in HT22 cells of each group was detected by Western blot.

RESULTS: Compared with the model group, the escape latency of the rapamycin group and the moxibustion group was shortened (P<0.05), and the number of crossing the platform was increased (P<0.05).The number of hippocampal neurons was large, and a small amount of cell necrosis was observed. The cells were arranged in an orderly manner with clear boundaries. Some neurons were deformed, atrophied and irregular, and autophagic vacuoles increased. The expression of A β 1-42 protein, mTOR, P62, GSK-3β mRNA and protein, and miR-939-5p mRNA in hippocampus was decreased (P<0.05), while the expression of TFEB, Wnt3a, β-catenin, Bnip3 mRNA and protein, LC3B-Ⅰ, LC3B-Ⅱ, CTSB, Lamp1, V-ATPase protein, and lncRNA-RP4 mRNA was increased (P<0.05). Compared with the rapamycin and moxibustion groups, the escape latency of the moxibustion+3-MA group was prolonged (P<0.05), and the number of crossing the platform was decreased (P<0.05). The number of hippocampal neurons decreased slightly, the cell necrosis was more, the cell arrangement was irregular, the boundary was blurred, and a small amount of autophagic vacuoles and more deformed neurons were occasionally seen. The expression of A β 1-42 protein, mTOR, P62, GSK-3β mRNA and protein, and miR-939-5p mRNA in hippocampus increased (P<0.05), while the expression of TFEB, Wnt3a, β-catenin,Bnip3 mRNA and protein, LC3B-Ⅰ, LC3B-Ⅱ, CTSB, Lamp1, V-ATPase protein, and lncRNA-RP4 mRNA decreased (P<0.05). Dual luciferase assay confirmed that there was a targeting relationship among lncRNA-RP4, miR-939-5p and Bnip3.After the intervention of lncRNA-RP4 in vitro, compared with the model group, the expression of Aβ 1-42 protein,miR-939-5p mRNA, GSK-3 β mRNA and protein in the lncRNA-RP4 overexpression group was decreased (P<0.05), and the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a, β-catenin mRNA and protein was increased (P<0.05). The expression of Aβ 1-42 protein, miR-939-5p mRNA, GSK-3 β mRNA and protein in lncRNA-RP4 knockdown group was increased (P<0.05), while the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a and β-catenin mRNA and protein was decreased (P<0.05). Compared with the lncRNA-RP4 overexpression group, the expression of Aβ 1-42 protein, miR-939-5p mRNA, GSK-3 β mRNA and protein in the lncRNA-RP4 knockdown group was increased (P<0.05), and the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a, β-catenin mRNA and protein was decreased (P<0.05). After intervention with miR-939-5p, compared with the model group, the expression of Aβ 1-42 protein, miR-939-5p mRNA, GSK-3 β mRNA and protein in the miR-939-5p mimic group was increased (P<0.05), and the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a,β-catenin mRNA and protein was decreased (P<0.05). The expression of A β 1-42 protein, miR-939-5p mRNA, GSK-3 β mRNA and protein in miR-939-5p inhibitor group was decreased (P<0.05), while the expression of lncRNA-RP4 mRNA,Bnip3, Wnt3a and β-catenin mRNA and protein was increased (P<0.05). Compared with the miR-939-5p mimic group, the expression of Aβ 1-42 protein, miR-939-5p mRNA, GSK-3β mRNA and protein in the miR-939-5p inhibitor group was decreased (P<0.05), and the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a, β-catenin mRNA and protein was increased (P<0.05). After Bnip3 intervention, compared with the model group, the expression of Aβ 1-42 protein,miR-939-5p mRNA, GSK-3 β mRNA and protein in the Bnip3 overexpression group was decreased (P<0.05), while the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a and β-catenin mRNA and protein was increased (P<0.05). The expression of A β 1-42 protein, miR-939-5p mRNA, GSK-3 β mRNA and protein in the Bnip3 knockdown group was increased (P<0.05), while the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a and β-catenin mRNA and protein was decreased (P<0.05). Compared with the Bnip3 overexpression group, the expression of Aβ 1-42 protein, miR-939-5p mRNA,GSK-3β mRNA and protein in Bnip3 knockdown group was increased (P<0.05), and the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a, β-catenin mRNA and protein was decreased (P<0.05).

CONCLUSION: Moxibustion at the governor vessel ameliorates AD cognitive deficits by activating the lncRNA-RP4/miR-939-5p/Bnip3 axis, enhancing Wnt/β-catenin pathway, restoring autophagosome-lysosome activity, promoting autophagy, accelerating A β 1-42 clearance, and improve cognitive dysfunction of AD. This study elucidates a novel epigenetic mechanism underlying moxibustion's therapeutic efficacy in AD.},
}

Animals
*Alzheimer Disease/therapy/genetics/metabolism/physiopathology
*RNA, Long Noncoding/genetics/metabolism
*Moxibustion
*Autophagy
Mice
Humans
*Wnt Signaling Pathway
Male
Mice, Inbred C57BL
*beta Catenin/metabolism/genetics
Mice, Transgenic
MicroRNAs/genetics/metabolism
Acupuncture Points
Membrane Proteins/genetics/metabolism

@article {pmid42343674,
year = {2026},
author = {Feng, ZP and Xiao, J and Yu, CC and Zhang, X and Yu, ZX and Pan, YK and Yang, S and Shen, F},
title = {[Mechanism of electroacupuncture at "Neiguan" (PC6) and "Jianshi" (PC5) in ameliorating blood-brain barrier damage in APP/PS1 mice based on the nucleus tractus solitarius-locus coeruleus neural circuit].},
journal = {Zhen ci yan jiu = Acupuncture research},
volume = {51},
number = {6},
pages = {677-687},
doi = {10.13702/j.1000-0607.20250903},
pmid = {42343674},
issn = {1000-0607},
mesh = {Animals ; *Electroacupuncture ; *Locus Coeruleus/metabolism ; *Blood-Brain Barrier/metabolism ; Male ; Mice ; *Solitary Nucleus/metabolism ; Mice, Inbred C57BL ; *Alzheimer Disease/therapy/metabolism/genetics/physiopathology ; *Acupuncture Points ; Humans ; Disease Models, Animal ; },
abstract = {OBJECTIVES: To observe the role of tyrosine hydroxylase (TH)-positive neurons in the nucleus tractus solitarius (NTS) and locus coeruleus (LC) in electroacupuncture (EA)-mediated improvement of blood-brain barrier (BBB) damage in APP/PS1 mice, so as to explore the mechanism of the NTS[TH]-LC neural circuit underlying the effect of EA on prevention and treatment of Alzheimer's disease (AD).

METHODS: (1) Eight 4-month-old male C57BL/6 mice served as the control group, and 16 age-matched male APP/PS1 mice were randomly divided into the model and EA groups (n=8). The EA group received EA stimulation at "Neiguan" (PC6) and "Jianshi" (PC5) once every other day for 4 weeks. After intervention, Morris water maze and novel object recognition tests were used to evaluate learning and memory abilities. Western blot was performed to detect the expression levels of hippocampal tight junction proteins, including Occludin, Claudin-5, and zonula occludens-1 (ZO-1). Immunofluorescence was used to assess the co-localization of TH/c-Fos in NTS and LC, as well as TH/norepinephrine (NE) co-localization in LC. (2) Five TH-cre mice received retrograde tracing virus injection into LC to observe whether TH-positive neurons in NTS project to LC. (3) Twenty-one 7-month-old APP/PS1 mice were injected with chemogenetic activation virus (AAV2/9-hSyn-DIO-hM3D-mCherry-WPRE-hGH-pA) or empty virus (AAV2/9-Ef1α - DIO-mCherry-WPRE-hGH-pA) into the NTS, and AAVretro-TH-CRE-WPRE-hGH-pA virus into the LC. After 21 d of virus expression, 6 mice injected with empty virus were taken as mCherry+CNO+EA group;3 mice from the activation virus group were randomly selected for brain slice patch-clamp to verify virus functionality. The remaining mice were randomly divided into 2 groups (n=6):hM3D+CNO+EA, and hM3D+saline+EA groups. EA was applied to PC6 and PC5 once daily for 15 d. After intervention, learning and memory abilities were evaluated by Morris water maze and novel object recognition tests. BBB permeability was detected by Evans blue (EB) staining. Immunofluorescence was used to measure TH/c-Fos and TH/NE co-localization in the LC.

RESULTS: (1) Compared with the control group, the model group showed significantly impaired learning and memory abilities (P<0.01), decreased expressions of hippocampal Occludin, Claudin-5, and ZO-1 (P<0.01), and increased TH/c-Fos co-localization (c-Fos expression in TH-positive neurons) in NTS and LC, as well as TH/NE co-localization in LC (P<0.01). Compared with the model group, the EA group exhibited improved learning and memory abilities (P<0.05, P<0.01), increased expressions of hippocampal tight junction proteins (P<0.01), and reduced TH/c-Fos and TH/NE co-localization (P<0.01, P<0.05). (2) Retrograde tracing confirmed that TH-positive neurons in NTS project to LC. (3) Compared with the mCherry+CNO+EA group and hM3D+saline+EA group, the hM3D+CNO+EA group showed significantly impaired learning and memory (P<0.01), increased EB content in brain tissue, and elevated TH/c-Fos and TH/NE co-localization in the LC (P<0.01).

CONCLUSIONS: EA at PC6 and PC5 can ameliorate BBB damage and learning/memory deficits in AD mice, and its mechanism may be related to inhibiting the activation of the NTS[TH]-LC neural circuit.},
}

Animals
*Electroacupuncture
*Locus Coeruleus/metabolism
*Blood-Brain Barrier/metabolism
Male
Mice
*Solitary Nucleus/metabolism
Mice, Inbred C57BL
*Alzheimer Disease/therapy/metabolism/genetics/physiopathology
*Acupuncture Points
Humans
Disease Models, Animal

@article {pmid42346109,
year = {2026},
author = {Huang, H and Xu, K and Lardellia, M},
title = {Ketone-Dependent Restoration of Autophagy and Mitochondrial Quality Control Through VPS35 in a Drosophila Model of C99-Induced Neurodegeneration.},
journal = {Cells},
volume = {15},
number = {12},
pages = {},
pmid = {42346109},
issn = {2073-4409},
mesh = {Animals ; *Mitochondria/metabolism/drug effects/ultrastructure ; *Autophagy/drug effects ; *Vesicular Transport Proteins/metabolism ; Disease Models, Animal ; *Ketones/pharmacology/metabolism ; Humans ; Neurons/metabolism/drug effects ; *Amyloid beta-Protein Precursor/metabolism ; Drosophila melanogaster/metabolism ; *Drosophila Proteins/metabolism ; Alzheimer Disease/metabolism ; },
abstract = {BACKGROUND: Early endolysosomal and autophagic defects are among the earliest cellular alterations observed in Alzheimer's disease (AD). However, the molecular mechanisms linking amyloid precursor protein (APP) metabolism to vesicle trafficking dysfunction remain incompletely understood. The APP-derived fragment C99 has emerged as a potential upstream mediator of intracellular toxicity, but its impact on organelle homeostasis and its modulation by metabolic interventions remain unclear.

METHODS: To investigate these mechanisms, we expressed human C99 in Drosophila neurons and examined intracellular pathology using ultrastructural analysis, fluorescent reporters of autophagy and mitochondrial turnover, and proteomic interactome mapping. The effects of the ketone body β-hydroxybutyrate (BHB) were evaluated to assess the impact of metabolic intervention.

RESULTS: Neuronal C99 expression induced pronounced vesicular abnormalities, impaired autophagic turnover, and disrupted mitochondrial quality control. Transmission electron microscopy revealed extensive accumulation of enlarged vesicular compartments, accompanied by reduced mitochondrial turnover and accumulation of aged mitochondria. BHB treatment restored autophagic cargo clearance, improved mitochondrial turnover, and normalized vesicular ultrastructure. These protective effects required neuronal ketone transport, indicating a neuron-intrinsic metabolic mechanism. Proteomic analysis of the C99-associated interactome revealed that ketone treatment remodels networks enriched for vesicle trafficking and proteostasis pathways. Network prioritization identified the retromer component VPS35 as a candidate regulatory hub. Functional analyses demonstrated that depletion of VPS35 abolished the BHB-dependent restoration of autophagy, mitochondrial turnover, and vesicle morphology.

CONCLUSIONS: Ketone treatment restores mitochondrial quality control and autophagic homeostasis through a VPS35-dependent mechanism in C99-induced neurodegeneration. These findings provide mechanistic insight into how metabolic interventions may restore intracellular homeostasis in Alzheimer's disease.},
}

Animals
*Mitochondria/metabolism/drug effects/ultrastructure
*Autophagy/drug effects
*Vesicular Transport Proteins/metabolism
Disease Models, Animal
*Ketones/pharmacology/metabolism
Humans
Neurons/metabolism/drug effects
*Amyloid beta-Protein Precursor/metabolism
Drosophila melanogaster/metabolism
*Drosophila Proteins/metabolism
Alzheimer Disease/metabolism

@article {pmid42333278,
year = {2026},
author = {Ravella, B and Theli, A and Gadde, EC and Ravipati, H},
title = {Jejunal Diverticulitis With Contained Perforation and Abscess Successfully Managed With Conservative Therapy: A Case Report and Review of the Literature.},
journal = {Cureus},
volume = {18},
number = {6},
pages = {e111181},
pmid = {42333278},
issn = {2168-8184},
abstract = {Jejunal diverticulosis is a rare condition that predominantly affects elderly individuals and is often asymptomatic. However, complications such as diverticulitis, perforation, and abscess formation can result in significant morbidity. Perforated jejunal diverticulitis has traditionally been managed surgically, although increasing evidence supports conservative treatment in selected patients. We report a case of a 74-year-old female with hypothyroidism, hyperlipidemia, and Alzheimer's dementia who presented with acute bilateral lower abdominal pain and nausea. Laboratory evaluation demonstrated leukocytosis, elevated inflammatory markers, and lactic acidosis. CT of the abdomen and pelvis revealed jejunal diverticulitis with focal perforation and an adjacent 2.4 × 3.6 cm gas-containing abscess. Given her hemodynamic stability and absence of generalized peritonitis, she was managed nonoperatively with bowel rest, IV fluids, ceftriaxone, and metronidazole. The patient improved clinically with normalization of inflammatory markers and was discharged on oral antibiotics. Follow-up imaging demonstrated complete resolution of the abscess and eventual resolution of inflammatory changes without surgical intervention. This case contributes to the growing body of evidence supporting conservative management of contained perforated jejunal diverticulitis and highlights the importance of careful patient selection and longitudinal radiographic follow-up.},
}

@article {pmid42333463,
year = {2026},
author = {Lee, N and Youn, K and Moon, M and Lee, DS and Kim, DH and Ho, CT and Jun, M},
title = {Fucoxanthin enhances AMPK/mTOR-dependent autophagic flux and attenuates ferroptosis in Alzheimer's disease models.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6fo01264g},
pmid = {42333463},
issn = {2042-650X},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, impaired proteostatic clearance, and oxidative damage, all of which contribute to neuronal dysfunction and disease progression. Fucoxanthin (FX), a marine-derived carotenoid abundant in brown algae, has shown antioxidant and neuroprotective potential. However, its role in autophagy-lysosome dysfunction and ferroptosis-associated oxidative injury under amyloidogenic conditions remains unclear. In this study, the effects of FX were investigated in APP Swedish mutant-expressing Neuro2a (SweAPP N2a) cells treated with 0.1-5 μM FX and in 5XFAD transgenic mice orally administered FX at 200 mg kg[-1]. FX treatment increased LC3-II expression and reduced p62 accumulation in SweAPP N2a cells, indicating enhanced autophagic degradation. FX also increased the expression of the lysosomal markers LAMP1 and cathepsin D (CTSD), suggesting enhanced lysosome-associated degradative capacity. These responses were accompanied by AMPK activation and suppression of mTOR signaling, together with increased autophagic flux as confirmed by bafilomycin A1-based analysis. Moreover, FX significantly reduced intracellular ROS levels and lipid peroxidation marker 4-hydroxynonenal (4-HNE), while modulating ferroptosis-associated proteins, including GPX4 and FTH1. Consistent with the cellular findings, FX administration in 5XFAD mice modulated autophagy-lysosome-related and ferroptosis-associated proteins in the brain and significantly reduced ThS-positive amyloid plaque burden. Collectively, these findings demonstrate that FX enhances autophagy-lysosome-associated proteostatic regulation through AMPK/mTOR signaling and attenuates ferroptosis-linked oxidative injury under amyloidogenic conditions. These results provide mechanistic evidence supporting the role of FX as a marine-derived bioactive compound for modulating AD-related pathological processes.},
}

@article {pmid42333562,
year = {2026},
author = {Srivastava, V and Chakraborty, S and Srivastava, R},
title = {Toll-Like Receptor-Mediated Neuroinflammation and Its Role in Neurocognitive Functions.},
journal = {Current reviews in clinical and experimental pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/0127724328415188260605204430},
pmid = {42333562},
issn = {2772-4336},
abstract = {Toll-like receptors (TLRs) are a family of pattern recognition receptors that recognise both pathogen-associated and damage-associated molecular patterns. While their expression was initially believed to be restricted to immune cells, accumulating evidence now demonstrates their presence across multiple neural cell types. Due to their significant involvement in neuroinflammatory and neurodegenerative processes, TLRs have garnered growing attention for their potential contributions to neurocognitive disorders, including Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and other forms of dementia. Potential treatment targets for lowering neuroinflammation and slowing the evolution of neurocognitive diseases include TLR signalling pathways, namely the MYD88-dependent and TRIF-dependent cascades. To initiate signalling, Toll-like receptors (TLRs) recruit specific adaptor molecules that activate the transcription factors NF-κB and IRFs, which regulate the induction of innate immune responses. Over the past decade, a combination of genetic, biochemical, structural, cellular, and bioinformatics approaches has been utilised to elucidate the detailed molecular mechanisms underlying TLR signalling. These studies have clarified how TLRs interact with cytosolic innate immune sensors to orchestrate effective immunological reactions. The function of different TLRs expressed in various brain immune cells and their contribution to the pathophysiology of neuroinflammation are described. This paper discusses the involvement of TLRs in autoimmune and neuroinflammatory circumstances like multiple sclerosis (MS), bacterial meningitis, viral encephalitis, stroke, Alzheimer's disease, and Parkinson's disease. It is intended for TLR biologists and immunologists studying neuroinflammation, as well as neuroscientists delving into central nervous system processes mediated by TLRs.},
}

@article {pmid42333570,
year = {2026},
author = {Abubakar, MD and Gupta, J and Daksh, R and Chavan, PR and Alom, S and Mondal, A and Azizuddin, S and Pal, B and Murti, K and Kumar, D and Kumar, N},
title = {Neurodegenerative Disease Molecular Therapeutics based on Structural Activity Connections of Microglia Activation and Priming: A Comprehensive Review.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266405995260414053514},
pmid = {42333570},
issn = {1873-4294},
abstract = {INTRODUCTION: In neurodegenerative diseases (NDDs) such as Alzheimer's (AD) and Parkinson's (PD), neuroinflammation plays a crucial role in the development and advancement of these disorders by contributing to the buildup of defective protein folding. Native immune response cells, known as microglial cells, enhance neuroinflammation by altering their shape and producing cytokines that promote inflammation. Inflammation in NDDs causes synapse pathology and dysfunction, although microglia-synapse relationships are unclear. Microglial structural activity alters physiology and architecture, causing functional changes and degeneration. Neurodegeneration and protein accumulation trigger microglial priming, which activates and regenerates microglia, resulting in heightened inflammatory responses. The biological activities and structural activation of microglia are studied to improve NDD therapy.

METHODS: An exhaustive search was conducted using the internet databases of PubMed, ScienceDirect, Google Scholar, DOAJ, and Wiley to identify any papers that discussed microglial activation, priming of this process, and molecular intervention in NDDs. First, molecular, preclinical, and clinical data were carefully reviewed for extraneous or redundant references, then narratively merged to offer a conceptual overlay.

RESULTS: This review examines the role of microglial cells in NDDs, highlighting potential interventions such as peptide- and RNA-based therapies, NF-κB, TLR4, JAK inhibitors, antibodies, and biologics.

DISCUSSION: The results suggest that stimulating microglial cells and enhancing neuron connections may improve treatment outcomes. The review indicates that translational research should be conducted to connect molecular pathways with clinically effective medicines.

CONCLUSION: Targeting microglia- and astrocyte-driven molecular markers could help resolve neuroinflammation and facilitate reliable therapeutic interventions in the progression of NDDs.},
}

@article {pmid42334062,
year = {2026},
author = {Corriveau-Lecavalier, N and Falgàs, N and Putcha, D and Graff-Radford, J and Yong, KXX and Boon, BDC and Mohanty, R and Westman, E and Groot, C and Jones, DT and Grinberg, LT and Rabinovici, GD and Whitwell, JL and Apostolova, LG and Murray, ME and Hammers, DB and Schindler, SE and Atonsdottir, I and Rhodus, EK and Schott, JM and Illán-Gala, I and Chukwuanugo, O and Guerra, JJL and Peters, R and Abner, EL and Abdelnour, C and Lladó, A and La Joie, R and de Souza, LC and Rezaii, N and Shir, D and Pijenburg, YAL and Carrillo, MC and Dickerson, BC and Aisen, P and Ossenkoppele, R and Raman, R},
title = {Improving the clinical trial landscape for patients with atypical variants of Alzheimer's disease: a call to action.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71521},
pmid = {42334062},
issn = {1552-5279},
support = {JR22/00014//Instituto de Salud Carlos III/ ; R01-AG50603/GF/NIH HHS/United States ; R01-AG075802/GF/NIH HHS/United States ; P30 AG 062677/GF/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/therapy/diagnosis ; *Clinical Trials as Topic ; Disease Progression ; },
abstract = {Patients with atypical variants of Alzheimer's disease (AD) often present at a younger age with predominantly non-amnestic impairments and a more aggressive disease course. Historically, individuals with atypical presentations have not been included in large-scale clinical trials, which typically focus on late-onset, sporadic amnestic-predominant AD. Consequently, treatment options and research efforts specific to atypical AD remain limited. The emergence of amyloid-targeting therapies that slow disease progression underscores these challenges, as evidence supporting their efficacy in early-onset amnestic and non-amnestic AD variants is scarce. This perspective article argues that atypical AD represents an excellent disease model for clinical trials and proposes strategies to address critical gaps in clinical trial design for this population. Key considerations include optimizing participant selection approaches, establishing syndrome-specific or surrogate biological and clinical endpoints, and fostering advocacy to enhance early and accurate diagnosis, equitable representation, and outcomes for these populations.},
}

Humans
*Alzheimer Disease/therapy/diagnosis
*Clinical Trials as Topic
Disease Progression

@article {pmid42334485,
year = {2026},
author = {Coleman, JS and Capstick, RA and Chang, S and Rios, DJ and Bubser, M and Thompson Gray, AD and Zagol-Ikapitte, I and Krishnan, S and Cho, HP and Rodriguez, AL and Niswender, CM and Boutaud, O and Garcia, GP and Elder, GA and Engers, DW and Jones, CK and Lindsley, CW},
title = {Discovery of VU6066098: A Selective and CNS-Penetrant mGlu2 NAM with Robust Antidepressant-, Antipsychotic-, and Procognitive-like Activity in Rodents.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00324},
pmid = {42334485},
issn = {1948-7193},
abstract = {Herein, we report the discovery and development of an optimized mGlu2 Negative Allosteric Modulator (NAM) in vivo tool compound, VU6066098, based on a novel, structurally distinct chemotype. VU6066098 is a potent, selective, and CNS-penetrant mGlu2 NAM with excellent rat PK (CLp = 23.9 mL/min/kg, t1/2 = 2.2 h, %F = 100, Kp = 1.28, Kp,uu = 0.25), making it ideal to explore the therapeutic potential of selective mGlu2 inhibition in preclinical rat models. In a rat forced swim test, VU6066098 displayed an oral minimum effective dose (MED) of 1 mg/kg and was equi-efficacious to ketamine. In amphetamine-induced hyperlocomotion, VU6066098 displayed an oral minimum effective dose (MED) of 30 mg/kg. While in the preclinical cognitive tasks of rat novel object recognition and acquisition of contextual fear conditioning, VU6066098 produced robust dose-dependent effects at oral minimum effective doses (MED) of 3 mg/kg and 0.3 mg/kg, respectively. In a blast-related traumatic brain injury (TBI) model, administration of VU6066098 at a dose of 10 mg/kg IP was effective acutely, and the effect on NOR memory was sustained up to 30 days postdose. Thus, mGlu2 NAMs show therapeutic potential for the treatment of a broad range of affective and cognitive symptoms associated with Major Depressive Disorder, Alzheimer's disease, TBI, and acute psychosis; moreover, these data strongly support further optimization of mGlu2 NAMs for future clinical development.},
}

@article {pmid42336161,
year = {2026},
author = {Zhang, Y and Zhang, X and Huang, J and Sun, Z},
title = {Lamivudine ameliorates neuropathology in 5×FAD mice via coordinated inhibition of the cGAS-STING pathway with enhancement of mitophagy.},
journal = {Brain research bulletin},
volume = {243},
number = {},
pages = {112014},
doi = {10.1016/j.brainresbull.2026.112014},
pmid = {42336161},
issn = {1873-2747},
abstract = {Alzheimer's disease is a neurodegenerative disorder for which there is currently no effective treatment available. Epidemiological and clinical evidence suggests that lamivudine, a nucleoside reverse transcriptase inhibitor, is associated with a reduced risk of Alzheimer's disease and shows potential in alleviating neuroinflammation. This study therefore aims to employ AD mouse models to further investigate the molecular mechanisms by which lamivudine ameliorates AD-related phenotypes. In this study, we showed that lamivudine administration inhibited cGAS-STING activation and attenuated mitochondrial damage in the 5 ×FAD mouse model, as supported by improved mitochondrial morphology and enhanced mitophagy. These changes were associated with improved spatial memory, alongside reduced neuronal apoptosis and synaptic loss. Our findings underscore the neuroprotective potential of lamivudine in AD via coordinated preservation of mitochondrial integrity and suppression of innate immune signaling, suggesting its promise for clinical translation in neurodegenerative disorders.},
}

@article {pmid42336952,
year = {2026},
author = {Arabhalvaei, V and Rajaei, SN and Alinaghi, MM and Talebi, M and Dashti, F and Abachi, SF and Khodayar, Z and Jafroodi, AR and Jamalaldin, M and Mehboodi, M and Maleki, MH and Rahimi, A and Baziyar, P},
title = {Investigation of the effects of sodium butyrate on SH-SY5Y neurons treated with amyloid beta42 and lipopolysaccharide: A computational and experimental study.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-59446-2},
pmid = {42336952},
issn = {2045-2322},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid beta42 (Aβ42) aggregation, neuroinflammation, and synaptic dysfunction. This study combines computational and experimental approaches to investigate the neuroprotective effects of sodium butyrate (NaB). Differentiated SH-SY5Y neurons were exposed to lipopolysaccharide (LPS) and Aβ1-42 to model AD-like conditions, and the potential protective effects of NaB were evaluated. MD simulations indicated that NaB may be associated with destabilization of organized Aβ42 fibrils. Alterations in RMSD, Rg, and SASA values indicated structural instability of Aβ42 fibrils in the presence of NaB. Treatment with NaB (10 and 50 µM) significantly improved cell viability compared to the LPS + Aβ group (p < 0.001) and attenuated apoptosis, as evidenced by reduced expression of Bax, Caspase-3, and FOXO3a (p < 0.0001), alongside upregulation of the anti-apoptotic marker Bcl-2 (p < 0.01). Moreover, NaB markedly increased the expression of neuroprotective and antioxidant genes, including BDNF, Nrf2, SIRT1, and CREB (p < 0.001), thereby restoring pathways involved in neuronal survival, oxidative stress defense, and synaptic plasticity. Collectively, these effects mitigated LPS + Aβ-induced cytotoxicity, suggesting that NaB exerts its neuroprotective action through epigenetic regulation of stress-response and plasticity networks. Our findings provide robust evidence supporting sodium butyrate as a promising therapeutic candidate for preventing or slowing AD-related neuronal degeneration and highlight its potential translational relevance for future in vivo and clinical investigations.},
}

@article {pmid42337598,
year = {2026},
author = {Labrador-Espinosa, MA and Franzmeier, N and Karagianni, S and Moscoso, A and Schöll, M},
title = {Clinico-biological trajectories stratified by combined tau biomarkers in preclinical Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42337598},
issn = {1758-9193},
mesh = {Humans ; Female ; *tau Proteins/blood/metabolism ; *Alzheimer Disease/diagnostic imaging/blood/metabolism/drug therapy/pathology ; Positron-Emission Tomography ; Aged ; Biomarkers/blood ; Male ; Amyloid beta-Peptides/metabolism ; Brain/diagnostic imaging/metabolism/pathology ; Magnetic Resonance Imaging ; Disease Progression ; Antibodies, Monoclonal, Humanized/therapeutic use ; Cognitive Dysfunction/diagnostic imaging ; Longitudinal Studies ; },
abstract = {BACKGROUND: Tau pathology biomarkers provide prognostic indicators of neurodegeneration and cognitive decline in Alzheimer's disease (AD), making them crucial to early patient stratification for disease-modifying interventions. Plasma p-tau217 indexes early tau pathophysiology, whereas FDA/EMA-approved [[18]F]flortaucipir PET (tau-PET) visual assessments indicate advanced neurofibrillary tangle pathology. Here, we identified concordant and discordant profiles based on combined plasma p-tau217 status and tau-PET visual assessments in cognitively unimpaired amyloid-β (Aβ)-positive older adults and investigated whether these profiles delineate distinct longitudinal trajectories of Aβ and tau accumulation, neurodegeneration, and cognitive decline.

METHODS: We included 330 cognitively unimpaired Aβ-PET-positive participants (72.2 ± 4.8 years; 58% female; 48% randomized to receive solanezumab) from the A4 Study, who underwent plasma p-tau217 and tau-PET at baseline. Plasma positivity (T1 +) followed A4 core criteria as previously reported (≥ 0.28 U/mL), while tau-PET positivity (T2 +) was determined by three expert visual readers with strong inter-rater agreement (κ = 0.954). Participants were stratified as T1[- / +]T2[- / +] at baseline and were followed for 5.0 ± 1.7 years. Baseline and longitudinal differences in regional Aβ- and tau-PET SUVR, MRI-measured gray-matter (GM) volume, and cognitive performance were examined using ANCOVA and mixed-effects models. All models accounted for treatment, with additional sensitivity analyses excluding treated participants.

RESULTS: At baseline, 57% were negative-concordant (T1 - T2 - : n = 187), 24% were discordant (T1 + T2 - : n = 53; T1 - T2 + : n = 27), and 19% were positive-concordant (T1 + T2 + : n = 63). T1 + T2 + profile constituted the highest-risk state, showing the greatest baseline cortical Aβ burden, the strongest neocortical tau progression (fronto-temporo-parietal pattern; p(FDR) < 0.05), marked baseline atrophy with accelerated longitudinal GM loss in overlapping regions, and the fastest cognitive decline (PACC: d = -1.84, p < 0.001). Consistently, T1 + T2 + exhibited the highest hazard of progression to more advanced clinico-biological stages over follow-up (HRClinical = 3.03, HRBiological = 9.98; p < 0.001). Discordant profiles showed comparatively limited progression, suggesting earlier or low-tau states. Results were essentially unchanged after excluding treated participants.

CONCLUSIONS: Integrating plasma p-tau217 with tau-PET visual assessment reveals clinically meaningful tau-biomarker heterogeneity in preclinical AD. Our findings highlight the value of combining these biomarkers to refine early risk prediction and support prioritization strategies for prevention trials. The frequency of discordance also motivates refining tau-PET visual assessments beyond binary classification (e.g., ordinal/semi-quantitative staging) to better capture subtle early tau signal.},
}

Humans
Female
*tau Proteins/blood/metabolism
*Alzheimer Disease/diagnostic imaging/blood/metabolism/drug therapy/pathology
Positron-Emission Tomography
Aged
Biomarkers/blood
Male
Amyloid beta-Peptides/metabolism
Brain/diagnostic imaging/metabolism/pathology
Magnetic Resonance Imaging
Disease Progression
Antibodies, Monoclonal, Humanized/therapeutic use
Cognitive Dysfunction/diagnostic imaging
Longitudinal Studies

@article {pmid42337797,
year = {2026},
author = {Soni, H and Sutherland, GT and Hofer, MJ},
title = {The complement system in Alzheimer's disease: evaluating biomarker potential in a complex neuroimmune context.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03927-8},
pmid = {42337797},
issn = {1742-2094},
abstract = {Neuroinflammatory processes are increasingly recognised as important modulators of Alzheimer's disease (AD) progression, driving interest in immune-related biomarkers beyond classical pathological measures. Among these, the complement system has attracted attention because of its interactions with amyloid-β (Aβ) and tau pathology, genetic associations with AD risk, and evidence of activation within affected brain regions. However, these biological observations do not directly translate into straightforward biomarker signals. Complement activity is highly dynamic, spans multiple activation and regulatory states, and may reflect both central and peripheral immune processes. This complexity limits interpretation when complement markers are assessed in isolation, as age, systemic inflammation, vascular comorbidity, and blood-brain barrier integrity can influence measured levels. Current evidence does not support complement-derived biomarkers as stand-alone diagnostic classifiers comparable to established amyloid, tau, and neurodegeneration (AT(N)) measures. Their independent or additive value within multimodal biomarker frameworks remains unclear, partly because of cohort heterogeneity, incomplete assay harmonisation, uncertain tissue-source attribution, and limited longitudinal validation. This review critically evaluates complement-derived measures as biologically informative markers of neuroimmune activity in AD, distinguishing biological plausibility from analytical and clinical utility. We argue that their most defensible current role is within multimodal biomarker frameworks, where they may provide context-specific information on inflammatory state rather than function as independent diagnostic, staging, or treatment-monitoring tools. Progress toward clinical application will require rigorous standardisation, mechanistic clarification, and validation across large, longitudinal, and diverse cohorts.},
}

@article {pmid42337854,
year = {2026},
author = {Lee, S and Choi, BJ and Park, MH and Park, S and Kim, J and Jin, HK and Shim, H and Jeon, JW and Bae, JS},
title = {A novel antibody against CD300c ameliorates cognitive deficits and reduces pathology in the late-stage of APP/PS1 mouse model.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261458360},
doi = {10.1177/13872877261458360},
pmid = {42337854},
issn = {1875-8908},
abstract = {BackgroundA major pathological hallmark of Alzheimer's disease (AD), the most common cause of dementia, is the accumulation of amyloid-β (Aβ) plaques. However, currently approved therapeutic agents fail to fundamentally halt disease progression and have limitations in terms of efficacy, sustainability, and safety. CD300c is an immunoregulatory molecule that modulates monocyte differentiation and activates macrophages. We recently developed a fully human anti-CD300c antibody, CB201, demonstrating its therapeutic potential in early and late 5xFAD mice.ObjectiveThis study investigated the efficacy of CB201 in late-stage AD using the APP/PS1 transgenic mouse model. We analyzed the effects of administering CB201 on changes in memory and cognitive function and Aβ and tau protein accumulation in the brain.MethodsTo assess long- and short-term memory improvements, behavioral tests were conducted using the Morris water maze and fear conditioning. Immunostaining was performed to quantify changes in Aβ and tau accumulation.ResultsCB201-treated late-stage AD mice demonstrated improved cognitive performance and memory, comparable to wild-type controls. Histopathological analysis further revealed that CB201 treatment reduced Aβ and tau accumulation.ConclusionsCB201 exerts significant therapeutic effects on functional impairments and pathological alterations in late-stage AD. These results confirm CB201 as a potential immunotherapeutic for the treatment of AD.},
}

@article {pmid42337953,
year = {2026},
author = {Chang, A and Kim, M and Glittenberg, M and Qu, W and Li, D and Li, L},
title = {HDL-mimetic peptide treatment reverses APOE4-induced transcriptomic and lipidomic alterations in the brain of humanized APOE mice.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71568},
doi = {10.1002/alz.71568},
pmid = {42337953},
issn = {1552-5279},
support = {AG058081/NH/NIH HHS/United States ; AG056976/NH/NIH HHS/United States ; AG059654/NH/NIH HHS/United States ; AG081426/NH/NIH HHS/United States ; AG077772/NH/NIH HHS/United States ; T32AG029796//NIH training grant/ ; //College of Pharmacy, University of Minnesota/ ; },
mesh = {Animals ; *Brain/metabolism/drug effects ; Mice ; *Apolipoprotein E4/genetics/metabolism ; *Lipid Metabolism/drug effects ; Lipidomics ; Mice, Transgenic ; Humans ; *Transcriptome/drug effects ; *Lipoproteins, HDL/pharmacology ; Alzheimer Disease/genetics/metabolism ; *Peptides/pharmacology ; Apolipoproteins E/genetics ; Disease Models, Animal ; Apolipoprotein A-I ; },
abstract = {INTRODUCTION: The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE4 has reduced lipidation capacity and impaired lipid transport, disrupting neuronal maintenance. The high-density lipoprotein (HDL)-mimetic peptide 4F offers a potential therapeutic strategy.

METHODS: To investigate how APOE4 alters brain gene expression and lipid metabolism and to evaluate the therapeutic potential of 4F, we performed dual-omics analysis in APOE4/4 and APOE3/3 mice treated intraperitoneally with D-enantiomer of 4F (D4F) or vehicle for 12 weeks from 10 to 13 months of age.

RESULTS: APOE4/4 mice showed widespread transcriptomic and lipidomic alterations, including downregulation of lipid metabolism and synaptic pathways, increased ceramides, sphingomyelins, and cholesteryl esters, with decreased diglycerides and triglycerides. D4F treatment shifted relevant gene expression and lipid profiles toward APOE3/3 levels.

DISCUSSION: These findings reveal molecular mechanisms underlying APOE4-driven dysregulation and support the therapeutic potential of HDL-mimetic peptides to mitigate APOE4-associated alterations in AD.},
}

Animals
*Brain/metabolism/drug effects
Mice
*Apolipoprotein E4/genetics/metabolism
*Lipid Metabolism/drug effects
Lipidomics
Mice, Transgenic
Humans
*Transcriptome/drug effects
*Lipoproteins, HDL/pharmacology
Alzheimer Disease/genetics/metabolism
*Peptides/pharmacology
Apolipoproteins E/genetics
Disease Models, Animal
Apolipoprotein A-I

@article {pmid42338509,
year = {2026},
author = {Malvankar, SR and Wolfe, MS},
title = {The γ-secretase complex: from discovery to a therapeutic target.},
journal = {RSC chemical biology},
volume = {},
number = {},
pages = {},
pmid = {42338509},
issn = {2633-0679},
abstract = {γ-Secretase is an intricate intramembrane aspartyl protease that cleaves within the transmembrane domain of ∼150 substrates and is considered the 'proteasome of the membrane'. This enzyme consists of four different subunits, with presenilin being the catalytic subunit. This review provides a brief overview of γ-secretase as a proteolytic enzyme, from its biochemistry and biology to its roles in disease and potential as a therapeutic target. A detailed discussion on the discovery and structure of γ-secretase is followed by a survey of its substrates, including the most studied amyloid precursor protein and the Notch1 receptor, and a description of substrate processing and sequence specificity. The role of γ-secretase in human biology and pathology is also detailed, with a particular focus on Alzheimer's disease (AD), in which the pathogenicity of the γ-secretase product amyloid-β peptide is still a matter of controversy. Lastly, the potential of γ-secretase inhibitors and modulators for the treatment of AD and other diseases is considered.},
}

@article {pmid42338648,
year = {2026},
author = {Riaz, R and Fatima, M and Ramzan, S and Rathi, D and Fatima, F and Farooq, M and Shaukat, A and Khaliq, N and Akilimali, A},
title = {FDA Approval of Donanemab-azbt: A New Dawn in Alzheimer's Disease Treatment.},
journal = {Health science reports},
volume = {9},
number = {6},
pages = {e72688},
pmid = {42338648},
issn = {2398-8835},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition marked by the accumulation of beta-amyloid plaques and neurofibrillary tangles, leading to neuronal death and cognitive decline. Acetylcholinesterase inhibitors (AChEIs) such as donepezil, galantamine, and rivastigmine are commonly used to enhance cognitive function by increasing acetylcholine levels, but they can cause side effects like nausea, bradycardia, and headaches. NMDA receptor antagonists, like memantine, reduce glutamatergic activity and are used to manage symptoms, yet are also associated with adverse effects including dizziness and agitation. Recently, monoclonal antibodies such as aducanumab have been developed to target amyloid-beta aggregates, though they are associated with amyloid-related imaging abnormalities (ARIA).

AIMS: This article aims to summarize current pharmacological approaches to AD and to highlight the emerging role of Donanemab-azbt, an FDA-approved monoclonal antibody for early symptomatic AD, in reducing amyloid plaques and slowing cognitive decline.

METHODS: This overview synthesizes data from clinical trials and therapeutic experience with acetylcholinesterase inhibitors, NMDA receptor antagonists, and monoclonal antibodies, with a particular focus on Donanemab-azbt, its mechanism of targeting amyloid-beta aggregates, and its efficacy and safety profile in early symptomatic AD.

RESULTS: Donanemab-azbt has demonstrated efficacy in clinical trials, significantly reducing amyloid plaque burden and slowing cognitive decline in patients with early symptomatic AD. However, its use may result in ARIA and other adverse effects, necessitating careful clinical and radiological monitoring during treatment.

CONCLUSION: Despite the risks of ARIA and other adverse events, Donanemab-azbt represents a promising addition to AD therapy, offering the potential for improved outcomes in patients with early symptomatic disease and expanding the therapeutic options beyond traditional symptomatic treatments.},
}

@article {pmid42338764,
year = {2026},
author = {Li, N and Peng, X and Xiong, W and Yang, C and Wang, W},
title = {Neuroprotective effects of Ershiwuwei Shanhu pills on APP/PS1 mice through antioxidant enhancement, anti-apoptosis, and MAPK pathway regulation.},
journal = {Translational neuroscience},
volume = {17},
number = {1},
pages = {20250396},
pmid = {42338764},
issn = {2081-3856},
abstract = {OBJECTIVES: Alzheimer's disease (AD) involves cognitive impairment, neuronal degeneration, oxidative imbalance, and abnormal MAPK signaling. This study investigated the protective effects of Ershiwuwei Shanhu Pills (ESP) on cognition, oxidative stress, neuronal apoptosis, and MAPK pathway regulation in APP/PS1 mice.

METHODS: Sixty mice were used, including 50 APP/PS1 transgenic mice randomly assigned to five groups: untreated AD model, donepezil (0.5 mg/kg), and low- (100 mg/kg), medium- (200 mg/kg), or high-dose (400 mg/kg) ESP. Ten wild-type C57BL/6J mice served as normal controls. All treatments were administered orally for 60 days. Cognitive performance was assessed by the Morris water maze. Hippocampal pathology and apoptosis were evaluated by histology and TUNEL staining, while oxidative stress markers, AD-related proteins, and MAPK phosphorylation were measured via ELISA and Western blot.

RESULTS: ESP treatment improved learning and memory performance, reduced hippocampal neuronal damage, and decreased neuronal apoptosis. Antioxidant enzyme activities (SOD, CAT, GSH, GSH-PX) increased, whereas MDA and GSSG levels decreased. Circulating Aβ1-40, Aβ1-42, TAU181, and γ-secretase levels were reduced. ESP also downregulated phosphorylation of JNK, ERK, and p38. The medium-dose group showed therapeutic effects comparable to donepezil.

CONCLUSIONS: ESP exerts neuroprotective effects in APP/PS1 mice by alleviating oxidative stress, inhibiting neuronal apoptosis, and modulating MAPK signaling. These findings suggest ESP as a promising multi-target therapeutic strategy for AD.},
}

@article {pmid42036434,
year = {2026},
author = {Mohammadi, F and Koohi, MK and Adeli, S and Hassan, J and Amini, A and Azadbakht, AR and Zayerzadeh, E and Babaei, JF},
title = {Effects of co-administered melatonin and methylphenidate on cognitive impairment and histopathological alterations in an AlCl3-induced neurotoxicity model of alzheimer's disease in BALB/C mice.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42036434},
issn = {2045-2322},
abstract = {UNLABELLED: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuropathological hallmarks such as amyloid plaques and neurofibrillary tangles. Environmental factors, including aluminum chloride (AlCl3) exposure, have been implicated in neurotoxicity and AD pathogenesis. This study evaluated the combined therapeutic effects of methylphenidate (MPH) and melatonin in a mice model of AlCl3-induced neurotoxicity. Male BALB/c mice were administered AlCl3 (300 mg/kg, orally) for 15 days, followed by treatment with melatonin (10 mg/kg), MPH (10 mg/kg), or their combination for 7 days. Behavioral tests, including the Morris water maze, open field, and Y-maze, were used to assess cognitive function. Hippocampal tissues were analyzed for oxidative stress markers (SOD, MDA), inflammatory cytokines (TNF-α, IL-10), apoptosis-related proteins (Bax, Bcl-2), and histological changes. The combination treatment significantly improved memory and learning, enhanced antioxidant capacity, reduced lipid peroxidation, and suppressed neuroinflammation and apoptosis. Histological examinations revealed increased neuronal density and CA1 hippocampal volume. These findings demonstrate that co-treatment with melatonin and MPH mitigates key pathological features of AD, suggesting a promising combinatorial strategy for targeting oxidative stress, neuroinflammation, and apoptosis in Alzheimer’s disease.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-43776-2.},
}

@article {pmid42327192,
year = {2026},
author = {Fulghum, K and Hayir, A and Ankeriasniemi, R and Shaddy-Gouvion, C and Vang, CM and Salathe, SF and Queathem, ED and Hughey, CC and Haeri, M and Thyfault, JP and Puchalska, P and Crawford, PA},
title = {Diet-Dependent Cognitive Benefits of Exogenous Ketone Body Precursor, (R,S)-1,3,-Butanediol, in a Mouse Model of Tauopathy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.03.729999},
pmid = {42327192},
issn = {2692-8205},
abstract = {Alzheimer's disease and related tauopathies are escalating public health threats, particularly in the context of obesity and metabolic dysfunction, which accelerate cerebral glucose hypometabolism, tau pathology, neurodegeneration, and cognitive decline. Ketogenic therapies reconfigure systemic fuel metabolism, with emerging evidence for neuroprotection. (R,S)-1,3-butanediol (BD) raises circulating D- and L-β-hydroxybutyrate (βOHB) concentrations. To evaluate whether BD improves cognitive function across dietary contexts, male and female tau-transgenic mice and littermate controls received 10% BD in drinking water for 20 or 30 weeks starting at 6 weeks of age. BD rapidly induced ketosis (1.5-3.0 mM βOHB) in chow-fed mice, with L-βOHB contributing to ∼75% of the circulating βOHB pool. Despite minimal effects of BD on body weight and glucose homeostasis, and no effect on histopathological tau signal, 20-week BD treatment improved memory to control levels in chow-fed female tauopathy mice. Isotope-tracing untargeted metabolomics revealed that BD-treatment differentially affected glucose-derived [13] C-enrichment of metabolites in brains of male and female mice. BD-induced cognitive benefits in tau-transgenic mice were abrogated when mice were maintained on BD for 30 weeks on standard chow or when mice were administered BD over 20 weeks while maintained on a high-fat, Western diet, Notably, BD-induced ketosis was blunted in mice consuming Western diet. Moreover, intermittent ketogenic diet-induced ketosis failed to improve cognition in Western diet-fed tauopathy mice. These results suggest BD-induced ketosis extends cognitive benefits in a manner dependent on biological sex and nutritional metabolic status. Taken together, these data contextualize the roles of βOHB as modulators of cognitive resilience in tauopathy.},
}

@article {pmid42328129,
year = {2026},
author = {Yang, Z and Chen, Y and Li, S and Lei, X and Wu, X and Wang, Y and Deng, S},
title = {Overcoming Biological Barriers: A Comprehensive Review of Advanced Melatonin Delivery Systems for Therapeutic Applications.},
journal = {International journal of medical sciences},
volume = {23},
number = {7},
pages = {2462-2485},
pmid = {42328129},
issn = {1449-1907},
mesh = {*Melatonin/administration & dosage/pharmacokinetics/chemistry/therapeutic use ; Humans ; *Drug Delivery Systems/methods ; Animals ; Neurodegenerative Diseases/drug therapy ; Blood-Brain Barrier/drug effects/metabolism ; Drug Carriers/chemistry ; Neoplasms/drug therapy ; Antioxidants/administration & dosage/pharmacokinetics ; Nanoparticles/chemistry ; },
abstract = {Melatonin is a pleiotropic hormone with well-documented antioxidant, anti-inflammatory, neuroprotective, and immunomodulatory properties, making it a promising candidate for the treatment of diverse diseases including neurodegenerative disorders, cardiovascular diseases, cancer, and sleep disturbances. However, its clinical translation has been hampered by several biopharmaceutical limitations, including poor aqueous solubility, extensive hepatic first-pass metabolism, rapid systemic clearance, and low oral bioavailability. Additionally, physiological barriers such as the blood-brain barrier, stratum corneum, and mucosal epithelia restrict its accumulation at target sites. In recent years, nanotechnology-based drug delivery systems have emerged as powerful tools to overcome these challenges. This review provides a comprehensive overview of advanced melatonin nanocarriers with a focus on their design principles, formulation strategies, and therapeutic applications. A central theme of this review is the integration of carrier design with biological barrier circumvention and administration routes-elucidating how specific nanocarrier platforms address the shortcomings of conventional immediate- and prolonged-release melatonin formulations through spatial and temporal control over drug distribution. We summarize recent preclinical progress in melatonin nanocarriers for a wide range of disease models, including Alzheimer's disease, Parkinson's disease, myocardial infarction, retinal degeneration and glaucoma, depression, and various cancers, with emphasis on the relationship between administration routes and therapeutic outcomes. Finally, critical challenges in clinical translation are addressed, including large-scale manufacturing, long-term toxicity evaluation, regulatory considerations, and the development of chronotherapy-compatible delivery systems. By integrating insights from materials science, pharmaceutics, and nanomedicine, this review aims to provide a rational framework for the future design and clinical application of melatonin-based nanotherapeutics.},
}

*Melatonin/administration & dosage/pharmacokinetics/chemistry/therapeutic use
Humans
*Drug Delivery Systems/methods
Animals
Neurodegenerative Diseases/drug therapy
Blood-Brain Barrier/drug effects/metabolism
Drug Carriers/chemistry
Neoplasms/drug therapy
Antioxidants/administration & dosage/pharmacokinetics
Nanoparticles/chemistry

@article {pmid42328310,
year = {2026},
author = {Hosseinpoor-Dashatani, S and Ebrahimi, N},
title = {Global trends in Alzheimer's disease randomized controlled trials: a bibliometric analysis.},
journal = {Dementia & neuropsychologia},
volume = {20},
number = {},
pages = {e20250423},
pmid = {42328310},
issn = {1980-5764},
abstract = {UNLABELLED: Alzheimer's disease (AD) is the most common form of dementia worldwide, creating substantial clinical and socioeconomic burdens. Randomized controlled trials (RCTs) provide the highest level of evidence to evaluate interventions, yet global publication trends and thematic evolution have not been systematically analyzed.

OBJECTIVE: As far as we are aware, there has been no bibliometric analysis that has thoroughly assessed RCTs in AD, despite their pivotal influence on the development of treatment and prevention strategies. Therefore, in this study, we conducted a bibliometric mapping analysis of global RCTs on AD.

METHODS: A bibliometric analysis of human RCTs on AD from September 2010 to September 2025 was conducted using PubMed and Web of Science. VOSviewer was employed for keyword co-occurrence, co-authorship mapping, and co-citation analyses to identify research themes, collaborations, and temporal trends.

RESULTS: A total of 4,482 RCTs were identified, revealing five main themes: pharmacological interventions, lifestyle and prevention strategies, pathophysiological mechanisms, cognitive and behavioral interventions, and clinical trial methodology. After 2015, focus shifted from traditional pharmacology to multidomain, prevention-oriented, and precision-driven approaches. Emerging topics included digital health, gut microbiome, and machine learning. Collaboration networks highlighted the dominance of the US and Europe, with rapid growth in Asia and emerging regions.

CONCLUSION: Findings indicate a paradigm shift in AD RCTs toward integrative, technology-enabled designs, emphasizing both pharmacological and non-pharmacological strategies. These trends can guide future global research priorities and intervention development.},
}

@article {pmid42328628,
year = {2026},
author = {Castro E Silva, JH and Marangon, D and Boccazzi, M and Raffaele, S and Cignitti, N and Bavetta, M and Arisi, I and Fumagalli, M and Abbracchio, MP and Lecca, D},
title = {The GPR17 agonist galinex restores oligodendrocyte maturation under inflammatory conditions.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1838997},
pmid = {42328628},
issn = {1663-9812},
abstract = {INTRODUCTION: Chronic neuroinflammation disrupts oligodendrocyte differentiation and limits effective remyelination across multiple neurological disorders. Among the molecular regulators integrating inflammatory cues with oligodendrocyte maturation, G protein-coupled receptor 17 (GPR17) has emerged as a critical checkpoint. Physiologically, GPR17 expression is low in early oligodendrocyte precursor cells (OPCs), peaks in immature oligodendrocytes, and is subsequently downregulated to allow terminal maturation. Under neuroinflammatory conditions, GPR17 expression persists, suggesting a possible role in impaired oligodendrocyte maturation and defective myelination. Here, we tested whether receptor modulation by the selective GPR17 agonist Galinex (GAL) can support oligodendrocyte maturation under inflammatory conditions.

METHODS: Differentiating oligodendroglial cultures were exposed to a pro-inflammatory cytokine cocktail composed of TNFα, IL-1β, and IFNγ. We first identified a subtoxic inflammatory condition, defined as cytokine exposure that did not cause overt loss of cell viability, and assessed oligodendrocyte maturation, myelin-associated marker expression, GPR17 expression, and transcriptional remodelling. Publicly available transcriptomic signatures from neuroinflammatory mouse models and human Alzheimer's disease and multiple sclerosis brains were used for cross-comparison. The effect of GAL was then evaluated by molecular, morphological, and functional readouts, including a synthetic nanofiber myelination assay.

RESULTS: Subtoxic cytokine exposure consistently impaired oligodendrocyte morphological maturation, reduced the expression of myelin-associated markers, and was accompanied by increased GPR17 expression. Transcriptomic analysis revealed coordinated remodelling of pathways related to protein synthesis and proteostasis, mitochondrial metabolism, lipid homeostasis, and inflammatory/immunogenic-like responses, together with senescence- and DNA damage-associated features. Cross-comparison with disease-associated transcriptomic signatures showed significant overlap with neuroinflammatory modules, supporting the relevance of the inflammatory pathways engaged in our model. GAL treatment partially restored terminal maturation-associated features and oligodendrocyte morphology. Moreover, in the nanofiber assay, GAL significantly increased the length of MBP-positive segments compared with CTK-treated cells, suggesting improved wrapping/myelination-like capacity after inflammatory challenge.

DISCUSSION: Together, this study establishes a controlled in vitro model linking inflammatory cytokine exposure, disease-associated transcriptional alterations, and impaired oligodendrocyte differentiation. Our findings indicate that pharmacological modulation of GPR17 can promote oligodendrocyte maturation and wrapping features under non-permissive inflammatory conditions. This strategy should be considered as an oligodendroglial-directed approach that may complement anti-inflammatory or immunomodulatory interventions.},
}

@article {pmid42329240,
year = {2026},
author = {Xu, Z and Ding, J and Su, X and Wang, G and Xie, K and Zhao, Y and Xiong, C and McDade, E and Schneider, LS and Liu, L},
title = {Subgroup identification via Interaction Tree and Mixed Model for Repeated Measures with application to Alzheimer's disease.},
journal = {Biometrics},
volume = {82},
number = {2},
pages = {},
pmid = {42329240},
issn = {1541-0420},
support = {UL1 TR002345/GF/NIH HHS/United States ; R21 AG084054/GF/NIH HHS/United States ; 5928//Washington University CTFRP/ ; },
mesh = {*Alzheimer Disease/drug therapy/therapy ; Humans ; Computer Simulation ; *Models, Statistical ; *Precision Medicine/methods ; Treatment Effect Heterogeneity ; Longitudinal Studies ; Algorithms ; },
abstract = {In precision medicine, subgroup identification is crucial for designing personalized treatments. This research focuses on subgroup identification in longitudinal clinical trials by integrating the Interaction Tree (ITree) with the Mixed Model for Repeated Measures (MMRM). Our ITree-MMRM approach retains the flexibility of tree-based methods in capturing nonlinear treatment interactions for heterogeneous treatment effects, while adhering to Food and Drug Administration guidelines for assessing treatment effects at the conclusion of longitudinal studies using MMRM. Additionally, we explore various options for tuning parameters and employ bootstrap methods to prune trees, reducing the risk of overoptimism. We demonstrate that our method outperforms existing subgroup identification techniques in simulations. The ITree-MMRM model is applied to an Alzheimer's disease clinical trial to identify subgroups with long-term treatment responses.},
}

*Alzheimer Disease/drug therapy/therapy
Humans
Computer Simulation
*Models, Statistical
*Precision Medicine/methods
Treatment Effect Heterogeneity
Longitudinal Studies
Algorithms

@article {pmid42329254,
year = {2026},
author = {Paliwal, S and Bhardwaj, JS and Taliyan, R},
title = {Exploring the Neuroprotective Potential of 5-Azacytidine on the Streptozotocin-Induced Rat Model of Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00234},
pmid = {42329254},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) associated with insulin resistance represents a major challenge in sporadic neurodegeneration, where impaired neuronal survival and synaptic plasticity are compounded by aberrant DNA methylation. Epigenetic silencing of Wnt pathway genes under insulin-resistant conditions exacerbates β-amyloid accumulation, tau hyperphosphorylation, and oxidative stress. The present study aimed to establish insulin-resistant AD models and evaluate the mechanistic potential of DNA methyltransferase (DNMT) inhibition, with a specific focus on canonical Wnt/β-catenin restoration. An in vitro AD model was generated by exposing SHSY-5Y cells to streptozotocin (STZ, 400 μM), resulting in elevated DNMT1, Aβ1-42, and sFRP1 levels, alongside reduced β-catenin and survivin expression. Treatment with the DNMT1 inhibitor 5-azacytidine (5-AZA), employed here as a mechanistic probe rather than a therapeutic candidate, reversed these changes, restoring Wnt signaling and attenuating amyloid burden. In vivo, intracerebroventricular administration of STZ (3 mg/kg) in rats induced an insulin-resistant AD-like pathology characterized by cognitive decline, increased pTau and acetylcholinesterase activity, and reduced neuroprotective markers. 5-AZA treatment improved memory and behavior, decreased pTau and AChE levels, and enhanced ADAM10, TREM2, BDNF, and antioxidant activity. Histological analysis further revealed preservation of neuronal layers and structural integrity. Collectively, these findings demonstrate that DNMT inhibition, exemplified by 5-AZA as a mechanistic tool, can mitigate STZ-induced molecular and behavioral alterations by relieving hypermethylation-mediated repression and supporting partial reactivation of canonical Wnt/β-catenin signaling. While 5-AZA itself is not a viable therapeutic option, the results highlight DNMT inhibition as a promising disease-modifying strategy in insulin resistance-associated AD.},
}

@article {pmid42330346,
year = {2026},
author = {Nie, C and Yang, R and Wang, X and Jia, P and Zhang, X and Dai, Y and Bai, X and Duan, S and Li, Y and Zheng, P and Tian, X and Jiang, L and Wang, C},
title = {Lilrb4a Suppression Reprograms Microglia to Mitigate APOE4-Associated Amyloid Plaques and Cerebral Amyloid Angiopathy in Association With a PPAR-Linked Pro-Clearance State.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e24167},
doi = {10.1002/advs.202524167},
pmid = {42330346},
issn = {2198-3844},
support = {82271470//National Natural Science Foundation of China/ ; LG-GG-202401-ADA010100//Lingang Laboratory AD Special Project/ ; 2023NSCQ-MSX3605//Natural Science Foundation of Chongqing Municipal Bureau of Science and Technology/ ; //National Science Fund for Excellent Young Scholars/ ; KZD-JI202400406//Scientific and Technological Research Program of Chongqing Municipal Education Commission/ ; STI2030-Major Projects 2021ZD0202400//Key Technologies Research and Development Program/ ; },
abstract = {The mouse gene Lilrb4a, an ortholog of human leukocyte immunoglobulin-like receptor B4 (LILRB4), is markedly upregulated in microglia in Alzheimer's disease models and has been implicated in Apolipoprotein E (APOE)-related signaling. However, its contribution to amyloid pathology under an APOE4 background remains unclear. Here, 5xFAD mice carrying human APOE4 were used to assess the impact of Lilrb4a reduction by genetic deletion or antisense oligonucleotide treatment. Both approaches significantly reduced cortical amyloid plaque burden and APOE4-associated cerebral amyloid angiopathy without altering amyloid-β (Aβ) production. Bulk RNA sequencing identified enrichment of peroxisome proliferator-activated receptor (PPAR)-related and broader metabolic pathways in Lilrb4a-deficient mice. Consistently, biochemical analyses showed reduced p-SHP-2, NF-κB-p65, and p-STAT1, increased p-STAT3, and induction of anti-inflammatory and clearance-associated effectors, including Arg-1, TGF-β, and Cyp2e1. In primary microglia, pharmacological interrogation supported a functional contribution of PPAR-γ signaling to the enhanced Aβ uptake and degradation associated with Lilrb4a suppression, whereas PPAR-γ agonism recapitulated key pro-clearance phenotypes in vitro and attenuated amyloid pathology in vivo. Together, these data support Lilrb4a as an APOE4-associated microglial checkpoint candidate linked to impaired amyloid clearance and identify a PPAR-linked pro-clearance program as a potential downstream component of this response.},
}

@article {pmid42330959,
year = {2026},
author = {Du, Y and Sun, C and Wu, L and Wu, Z and Tong, Y and Tian, H and Mao, Y and Shi, X and Ding, H and Xie, W and Yao, W and Chen, S and Gao, X},
title = {Oral GLP-1 receptor agonist promotes astrocyte-neuron lactate and lipid transfer with neuroprotective effects.},
journal = {Cell metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cmet.2026.05.014},
pmid = {42330959},
issn = {1932-7420},
abstract = {Glucagon-like peptide-1 receptor (GLP-1R) activation is widely assumed to regulate the metabolic disorder in Alzheimer's disease (AD). However, direct evidence for this hypothesis is lacking, and currently, there is no oral GLP-1R agonist with effective blood-brain barrier-penetrating ability. Here, we show that a candidate peptide, OHP2, an oral GLP-1R agonist with blood-brain barrier permeability, exhibits promising therapeutic potential for AD. OHP2 primarily activates GLP-1R on astrocytes, leading to increased aerobic glycolysis and driving lactate release. Astrocyte-derived lactate is taken up by neurons and elevates histone H3 lysine 9 lactylation (H3K9la), which in turn facilitates lipid transport from neurons back to astrocytes. This astrocyte-neuron metabolic coupling sustains continuous aerobic glycolysis and offers a potential treatment strategy for AD. The H3K9la derived from OHP2 links glucose and lipid metabolic cycle and facilitates metabolic coupling between astrocytes and neurons, which leads to remission of metabolic disturbances in AD. Thus, our study provides a new candidate molecule for drug research in treating AD and illustrates that intracerebral GLP-1R activation, which facilitates astrocyte-neuron metabolic coupling, may be a potential approach for the treatment of AD.},
}

@article {pmid42332435,
year = {2026},
author = {He, W and Zhang, K and Jia, X and Lv, Y and Cheng, T and Han, L and Xia, Y and Zhang, X and Zhai, W and Yang, F and Wang, S and Jin, L},
title = {Design, Biological Characterization, and Discovery of the Brain-Penetrant NLRP3 Inhibitor Based on a [1,2,4]Triazolo[1,5-a]pyrimidine Scaffold for the Treatment of Central Nervous System Diseases.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.6c00839},
pmid = {42332435},
issn = {1520-4804},
abstract = {NLRP3 inflammasome is a critical cytosolic multiprotein complex central to the innate immune response. Upon activation, NLRP3 oligomerizes and recruits the adapter protein ASC; this scaffold recruits and activates pro-caspase-1. Active caspase-1 catalyzes the proteolytic maturation and secretion of the potent pro-inflammatory cytokines IL-1β and IL-18, and induces a programmed cell death called pyroptosis. Dysregulated or chronic NLRP3 inflammasome activation is a major driver of pathogenesis in a wide spectrum of peripheral inflammatory diseases, including gout, pericarditis, atherosclerosis, nonalcoholic steatohepatitis, and NLRP3 gain-of-function autoinflammatory disorders known as CAPS, as well as neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Herein we described the discovery of NLRP3 inhibitors based on the [1,2,4]triazolo[1,5-a]pyrimidine scaffold. Represented by compound 25, this scaffold exhibited exceptional potency, favorable physicochemical properties, and desirable pharmacokinetic profiles, including good brain penetration. Compound 25 showed potential as a candidate for the treatment of Parkinson's disease.},
}

@article {pmid42332767,
year = {2026},
author = {Ye, J and Deng, Y and Zhang, B and Li, C and Guo, X and Yue, R and Wan, H and Hao, Y and Xiao, S},
title = {HDAC7 acts as an astrocytic mediator of Aβ pathology that directly engages IKK to drive astrocyte neurotoxicity and neurodegeneration in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02121-5},
pmid = {42332767},
issn = {1758-9193},
support = {82101493//National Natural Science Foundation of China/ ; 82474227//National Natural Science Foundation of China/ ; 2025A1515012551//Basic and Applied Basic Research Foundation of Guangdong Province/ ; JCYJ20240813141825034//Shenzhen science and technology research and development funds/ ; 20231121103959001//Shenzhen Science and Technology Innovation Commission/ ; 2023SHIBS0003//Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions/ ; },
abstract = {BACKGROUND: Astrocytes undergo reactive transformations in response to pathological stimuli and play a critical role in neuronal loss associated with Alzheimer's disease (AD). However, the intrinsic mechanisms through which astrocytes detect amyloid-β (Aβ) pathology and develop neurotoxic properties remain inadequately understood. The dysregulation of class IIa Histone deacetylases (HDACs) has been implicated in astrocyte dysfunction under pathological conditions. This study aims to elucidate the role of HDAC7 as an astrocytic mediator of Aβ that drives the formation of neurotoxic reactive astrocytes, and to propose HDAC7 as a potential therapeutic target for mitigating neuronal loss and cognitive deficits in AD.

METHODS: We examined HDAC7 expression in APP/PS1 mice of varying ages using RT-qPCR, Western blotting, and immunostaining analysis. Astrocyte-specific HDAC7 overexpression and knockdown were achieved through adeno-associated virus (AAV) delivery (GfaABC1D promoter) in wild-type (WT) and APP/PS1 mice, followed by behavioral tests, immunostaining, RT-qPCR, and RNA-seq. Mechanistic studies were conducted using primary astrocytes derived from WT and Hdac7[flx/flx] mice, employing co-immunoprecipitation, Western blotting, and neuron viability assays. Pharmacological inhibition of HDAC7 in APP/PS1 mice was performed via intraperitoneal injection of TMP195, and the effects on neurotoxic reactive astrocytes, neuronal and synaptic loss, and behavioral performance were measured.

RESULTS: HDAC7 was selectively upregulated in plaque-adjacent astrocytes in APP/PS1 mice. Overexpression of HDAC7 specifically in astrocytes was sufficient to induce a neurotoxic transcriptional profile, neuronal loss, and cognitive deficits in both WT and young APP/PS1 mice. Mechanistically, upon Aβ stimulation, the upregulated HDAC7 directly interacted with and deacetylated IKKα and IKKβ, resulting in the activation of IKK, translocation of NF-κB to the nucleus, and subsequent expression of neurotoxic genes. This neurotoxic conversion was dependent on IKK activity, as IKK inhibition nullified the effects in astrocytes overexpressing HDAC7. Conversely, astrocytic HDAC7 knockdown or treatment with TMP195 attenuated IKK-NF-κB signaling, reduced the presence of neurotoxic reactive astrocytes, and rescued neurodegeneration and cognitive deficits in APP/PS1 mice.

CONCLUSIONS: HDAC7 acts as an intrinsic effector within astrocytes, responding to Aβ pathology and converting astrocytes into a neurotoxic state through direct interaction with IKK. Targeting HDAC7 presents a promising strategy for astrocyte-directed therapeutic interventions in Alzheimer's disease.},
}

@article {pmid42332768,
year = {2026},
author = {Lee, CY and Hsu, CW and Tseng, PT and Fang, YY and Stubbs, B and Thompson, T and Carvalho, AF and Lin, YH and Kao, YC and Yang, FC and Hsu, TW and Liang, CS},
title = {Real-world effectiveness of monoclonal antibody lecanemab versus acetylcholinesterase inhibitors in Alzheimer's disease: a target trial emulation.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02095-4},
pmid = {42332768},
issn = {1758-9193},
abstract = {BACKGROUND: Acetylcholinesterase inhibitors (AChEIs) provide symptomatic relief in Alzheimer's disease (AD), whereas lecanemab may modify disease progression; however, real-world evidence on its safety and clinical impact remains limited. Therefore, this study aimed to compare the safety and effectiveness of initiating lecanemab versus AChEIs in patients with mild cognitive impairment (MCI) or AD.

METHODS: Using the TriNetX US electronic health record network, we conducted a retrospective cohort study including individuals diagnosed with MCI or AD between July 2023 and September 2025. A target trial emulation with 1:1 propensity score matching and Cox models estimated comparative risks.

RESULTS: Lecanemab was associated with a fivefold higher incidence of neuroimaging abnormalities than AChEIs, while 1-year treatment persistence was similar (53.4% vs 52.5%). After matching, 589 patients were included in each cohort. Compared with AChEIs, lecanemab was associated with significantly lower risks of behavioral and psychological symptoms of dementia (BPSD) (HR, 0.52; 95% CI, 0.36-0.77) and emergency visits (HR, 0.66; 95% CI, 0.51-0.85), but a higher risk of hospitalization (HR, 1.31; 95% CI, 1.03-1.67). Lecanemab was also associated with lower use of antipsychotics (HR, 0.47; 95% CI, 0.32-0.70), antidepressants (HR, 0.60; 95% CI, 0.43-0.85), melatonin/orexin antagonists (HR, 0.61; 95% CI, 0.42-0.88), antibiotics (HR, 0.61; 95% CI, 0.44-0.86), and antifungals (HR, 0.57; 95% CI, 0.37-0.88), whereas steroid use was higher among lecanemab users (HR, 2.19; 95% CI, 1.55-3.10).

CONCLUSIONS: Compared with an AChEI-based conventional care strategy, lecanemab initiation was associated with comparable treatment persistence and lower observed risks of BPSD, emergency visit as well as reduced use of psychotropic and infection-related medications in exploratory analyses. However, the higher incidence of neuroimaging abnormalities associated with lecanemab, along with increased risks of hospitalization and corticosteroid use, likely reflects proactive clinical monitoring and management of amyloid-related imaging abnormalities (ARIA). While residual confounding cannot be excluded and results warrant cautious interpretation, these exploratory findings warrant further validation in biomarker-confirmed cohorts and head-to-head randomized trials.},
}

@article {pmid42332917,
year = {2026},
author = {Lee, YS and Roh, S and Moon, H and Steele, JS and Yoon, DP and Warne, DK},
title = {If a Family Member Develops Alzheimer's Disease: Gender Differences in Help-Seeking Intentions Among American Indians.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648261459708},
doi = {10.1177/07334648261459708},
pmid = {42332917},
issn = {1552-4523},
abstract = {This study examined psychosocial factors associated with help-seeking intentions if and when a family member developed Alzheimer's disease (AD) among American Indian populations, focusing on gender differences. Guided by Andersen's behavioral model of health service use, predisposing, enabling, and need factors were considered as potential sources for AD help-seeking intentions. Multivariate regression analyses were conducted on a sample of 226 American Indian adults residing in South Dakota. Subjective norms and family support were positively associated with help-seeking intentions for both men and women. Gender differences emerged. American Indian women were more likely than men to intend to seek help for a family member with AD if the need arose, while self-confidence in completing medical forms was positively associated with help-seeking intentions among American Indian men only. Identifying common and gender-specific AD intervention strategies can promote timely help-seeking and improve treatment outcomes in American Indian communities.},
}

@article {pmid42320781,
year = {2026},
author = {Bashaw, AG and Roman-Ortiz, C and Gao, SX and Schier, LA and Borner, T and Kanoski, SE},
title = {Glucagon-like peptide-1 signaling in learning and memory: evidence, mechanisms, and therapeutic implications.},
journal = {Biological psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biopsych.2026.06.006},
pmid = {42320781},
issn = {1873-2402},
abstract = {Glucagon-like peptide-1 (GLP-1) is primarily known for its role in glucose homeostasis and food intake control, and GLP-1 analogs (either as monotherapy or dual agonists) are commonly used for Type 2 Diabetes and obesity treatment in humans. Beyond these functions, the receptor for GLP-1 (GLP-1R) is widely expressed throughout the brain, including in the hippocampus and interconnected regions that contribute to learning and memory processes. Here we review emerging evidence supporting a role for GLP-1 signaling in promoting learning and memory function, particularly in dementia and other conditions that present hippocampal dysfunction. Evidence is synthesized from preclinical rodent models revealing that GLP-1 analog treatment improves deficits in memory function and hippocampal neuronal signaling processes in various models of dementia, aging, and metabolic disruption. While findings from human clinical trials and meta-analyses also show promise for GLP-1 analog-based treatment for memory disorders, results thus far are mixed, with many studies underpowered and/or lacking comprehensive memory evaluation. We describe several distinct yet non-mutually exclusive neurobiological mechanisms via which GLP-1R signaling can enhance memory, including blood-brain barrier penetration and direct action on hippocampal GLP-1Rs, improved peripheral and central insulin sensitivity, vagus nerve GLP-1R activation, and peripheral metabolic and inflammatory improvements. We conclude by emphasizing important considerations for future clinical trials for GLP-1 analogs in the treatment of Alzheimer's and other memory disorders, including focusing on metabolically vulnerable individuals, stratifying results by cardiovascular and metabolic status, and leveraging existing GLP-1 analogs and drug delivery approaches towards maximizing bioavailability and brain penetrance.},
}

@article {pmid42321014,
year = {2026},
author = {Kehmeier, MN and Famiano, A and Cullen, AE and Leonhardt, T and Ferguson, SJ and Snyder, M and McCurdy, CE and Tyrrell, DJ and Alkayed, NJ and Walker, AE},
title = {APOE4 negates the effects of ovarian hormones on cerebrovascular endothelial and mitochondrial function.},
journal = {The Journal of physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/JP290852},
pmid = {42321014},
issn = {1469-7793},
support = {//John L. Luvaas Family Fund/ ; 23PRE1023169//AHA/ ; //Endocrine Technologies Core/ ; R01AG064106//HHS, National Institutes of Health/ ; P51OD011092//HHS, National Institutes of Health/ ; S10OD026701//HHS, National Institutes of Health/ ; },
abstract = {The APOEε4 allele and oestrogen deficiency independently predispose females to an increased risk of vascular and metabolic impairments, but their cerebrovascular effects are less understood. The purpose of this study was to determine the interaction between APOE genotype and oestrogen on cerebrovascular endothelial and mitochondrial function. We studied young female homozygous APOEε3 and APOEε4 mice (n = 19-20/group; ∼6 months old) that were fed a high-fat diet and were ovariectomized (OVX), OVX and supplemented with 17β-oestradiol, or left intact. In APOEε3 mice, OVX was associated with impaired posterior cerebral artery endothelium-dependent dilatation, which was rescued by 17β-oestradiol. However, in APOEε4 mice, there was no effect of OVX or 17β-oestradiol on cerebral artery endothelial function. Carotid artery passive stiffness was greater with OVX and lower with 17β-oestradiol treatment in APOEε3 mice, but there was no impact of OVX or 17β-oestradiol in the APOEε4 mice. In cerebral arteries and arterioles, 17β-oestradiol led to higher mitochondrial complex I respiration in APOEε3 but not APOEε4 mice. These functional differences were concomitant with group differences in mitochondrial DNA copy number, antioxidant enzymes and pro-inflammatory factors. Overall these results indicate that the APOE genotype modulates the impact of OVX and oestradiol on the cerebral vasculature. We found that 17β-oestradiol enhances cerebrovascular endothelial and mitochondrial function in OVX APOEε3 mice but not in APOEε4 mice. This suggests that 17β-oestradiol supplementation may have more cerebrovascular benefits for APOEε4 non-carriers. KEY POINTS: Females have twice the risk of Alzheimer's disease than males, and the APOEε4 genetic variant has a greater risk for Alzheimer's disease than the APOEε3 variant. The risk for Alzheimer's disease increases after menopause in females, suggesting that the loss of female sex hormones may play a role. There are highly inconsistent results among past studies examining the interaction between APOE genotype and oestrogens on brain outcomes, and their impact on the vasculature has not been studied. We aimed to determine the impact of APOEε4 genotype on the cerebrovascular response to ovariectomy and oestradiol. We found that oestradiol improved cerebral artery endothelial function and mitochondrial respiration in ovariectomized APOEε3 mice following ovariectomy. In contrast APOEε4 mice were resistant to the beneficial effects of ovarian hormones on cerebrovascular and mitochondrial function. This research suggests that APOE genotype may be a consideration when weighing the risks and benefits of prescribing hormone replacement therapy to postmenopausal females.},
}

@article {pmid42321855,
year = {2026},
author = {Gheibi, FS and Hosseini, L and Kalejahi, P and Dastgiri, S and Shafiee-Kandjani, AR and Noorazar, SG},
title = {Therapeutic potential of AdipoRon in cognitive, depressive, and anxiety disorders: a systematic review and meta-analysis.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-026-01323-0},
pmid = {42321855},
issn = {1756-6606},
abstract = {Rising cases of cognitive disorders, depression, and anxiety underscore the need for new treatments, given the limited effectiveness and side effects of current options. AdipoRon targets adiponectin receptors and shows promise for protecting the brain, reducing inflammation, and supporting metabolism. This review examines preclinical data to determine whether AdipoRon consistently improves mood and cognitive function and to identify the underlying neurobiological pathways. We conducted a comprehensive literature search using PubMed, Embase, Web of Science, and Scopus, with no time limit, up to August 30, 2025. The quality of the selected studies was evaluated using the Collaborative Approach to Meta-Analysis and Review of Animal Studies (CAMARADES) checklists and the SYRCLE risk of bias tool. The studies found that AdipoRon treatment significantly reduced immobility in the forced swim test and had a significant anxiolytic effect in the open field test, especially in chronic unpredictable mild stress models. It also improved recognition memory in the novel object recognition test in models of Alzheimer's and Parkinson's diseases. Additionally, AdipoRon increased the expression of synaptic proteins, such as synaptophysin and PSD-95, in rodent models of these diseases. It also modulated the production of inflammatory cytokines. This review establishes AdipoRon's capacity to resolve depressive, anxious, and cognitive deficits in rodent models. Because the meta-analyses were based on a limited number of studies and substantial heterogeneity was observed across studies, the findings should be interpreted with caution. However, further well-designed preclinical and clinical investigations are essential to confirm these findings.},
}

@article {pmid42322185,
year = {2026},
author = {Lozupone, M and Dibello, V and Sardone, R and Zupo, R and Castellana, F and Bortone, I and Lampignano, L and Di Matteo, M and Moramarco, G and Dellegrazie, F and Daniele, A and Solfrizzi, V and Panza, F},
title = {Evaluating emerging amyloid-β centric drugs for the treatment of Alzheimer's disease.},
journal = {Expert opinion on emerging drugs},
volume = {},
number = {},
pages = {},
doi = {10.1080/14728214.2026.2693701},
pmid = {42322185},
issn = {1744-7623},
abstract = {INTRODUCTION: The amyloid cascade hypothesis provided a compelling rationale for Alzheimer's disease (AD) drug development, but many amyloid-β (Aβ)-targeted agents failed to show benefit. The present review article evaluated emerging Aβ-directed therapies, focusing on mechanisms, clinical efficacy, safety, and regulatory progress.

AREAS COVERED: The recent approvals of lecanemab and donanemab offered the first convincing evidence that reducing Aβ burden can modestly slow cognitive decline in early AD. Beyond these first-generation monoclonal antibodies, the pipeline includes next-generation antibodies with enhanced brain penetration (trontinemab), therapies designed also for presymptomatic intervention (remternetug tested for secondary prevention), and novel approaches targeting galectin-3 to disrupt Aβ aggregation and neuroinflammation. Active immunotherapies like UB-311 and small molecules such as ALZ-801, avoiding amyloid-related imaging abnormalities (ARIA), broaden the therapeutic horizon with potentially safer and more accessible options, but with no proven efficacy.

EXPERT OPINION: Clinical benefits for Aβ-centric therapies are modest, ARIA pose ongoing safety concerns, and high costs coupled with intensive monitoring limit accessibility. Regulators have begun to restrict approval to genetically defined subgroups according to apolipoprotein E genotype, underscoring the need for precision medicine. Therefore, while Aβ-centric therapies are incremental, they represent essential steps toward combination and precision strategies in the treatment of AD.},
}

@article {pmid42322653,
year = {2026},
author = {Cui, S and Jiang, Q and Chen, S},
title = {Locus coeruleus-norepinephrine system dysfunction: A new concept in cognitive aging and neurodegenerative diseases.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00910},
pmid = {42322653},
issn = {1673-5374},
abstract = {The role of the locus coeruleus in aging and neurodegenerative diseases has recently attracted attention. There is growing evidence of changes in the locus coeruleus-norepinephrine system in aging and neurodegenerative diseases, including increased tau accumulation, an inverted U-shaped pattern in the neuromelanin signal, and altered functional connectivity. This review summarizes the research applications and advancements in the study of cognitive aging and dysfunction of the locus coeruleus-norepinephrine system in neurodegenerative diseases. Recent evidence has suggested pathologic protein accumulation, locus coeruleus degeneration, reduced neuromelanin signal, and altered functional connectivity in neurodegenerative diseases in both human and animal models. Notably, the specific regions affected and the severity of these changes can vary subtly among different neurodegenerative disorders. Additionally, recent studies have shown a link between alterations in the locus coeruleus-norepinephrine system and both Alzheimer's and Parkinson's diseases. The possible mechanisms include promoting pathological protein accumulation, pro-inflammatory responses, synaptic plasticity dysfunction, oxidative stress, and blood- brain barrier dysfunction. Advanced experimental technologies have recently been applied to investigate the role of the locus coeruleus-norepinephrine system in aging, Alzheimer's disease, and Parkinson's disease. These advanced technologies, including optogenetic or chemogenetic methods and omics analysis help uncover the effects of specific locus coeruleus activation patterns and the locus coeruleus-related circuit mechanisms underlying its vulnerability during aging and neurodegenerative diseases. Thus, therapies targeting the locus coeruleus-norepinephrine system, including drugs and vagus nerve stimulation, have the potential for clinical application. Many studies have demonstrated the effects of adrenoreceptor-targeted drugs on cognitive function and Parkinson's disease, although some showed no effects. Limited data are available for norepinephrine-targeted drugs, which have demonstrated less-than-ideal results. Recent studies have demonstrated that vagus nerve stimulation can improve cognitive function in Alzheimer's disease and reduce the symptoms of Parkinson's disease, including gait function, suggesting that vagus nerve stimulation could be a new supplementary treatment for neurodegenerative diseases. Overall, the evidence reviewed suggests that the locus coeruleus-norepinephrine system is disrupted during aging and neurodegenerative diseases, and that this disruption can aggravate disease progression. Thus, the locus coeruleus-norepinephrine system is a potential therapeutic target in slowing disease progression. Future studies should focus on the locus coeruleus-norepinephrine system and use advanced experimental and neuroimaging technologies to reveal early pathological alterations and the underlying mechanisms of its vulnerability during aging and neurodegenerative diseases, along with exploring potential therapeutic approaches.},
}

@article {pmid42322910,
year = {2026},
author = {Liu, R and Wei, M and Xu, L and Qu, Z and Yu, JQ and Liu, Y and Zhang, WN and Zhang, D and Zhuang, C},
title = {A Keap1-Nrf2 protein-protein interaction inhibitor 4-95 ameliorates cognitive dysfunction by suppressing neuronal ferroptosis.},
journal = {Bioorganic chemistry},
volume = {180},
number = {},
pages = {110134},
doi = {10.1016/j.bioorg.2026.110134},
pmid = {42322910},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a severe neurodegenerative disorder. With current therapies failing to halt clinical progression, identifying novel disease-modifying therapeutics is of paramount urgency. Although ferroptosis has emerged as a crucial driver of AD pathogenesis, effective pharmacological strategies targeting this pathway remain limited. Bioinformatic analysis revealed close associations among ferroptosis, oxidative stress, the Keap1-Nrf2 pathway, and AD. Compound 4-95, a selective Keap1-Nrf2 protein-protein interaction (PPI) inhibitor, significantly alleviated Erastin and RSL-3-induced ferroptosis in SH-SY5Y and HT-22 cells. In Aβ1-42-treated cell models, 4-95 dose-dependently decreased Aβ and p-Tau expression, while increasing the anti-ferroptotic proteins GPX4 and SLC7A11. Keap1 and GPX4 knockdown verified that 4-95 inhibits ferroptosis via the Keap1-Nrf2-GPX4 axis. In vivo, 4-95 markedly improved cognitive and spatial memory deficits in Aβ1-42-induced AD mice, promoted Nrf2 nuclear translocation, upregulated the downstream antioxidant targets HO-1 and NQO1, and attenuated neuronal injury. Collectively, the study reveals a new mechanism of a Keap1-Nrf2 PPI inhibitor that mitigates AD pathogenesis by directly inhibiting ferroptosis. This novel mechanism underscores a new class of disease-modifying candidates for AD treatment, representing a new therapeutic strategy for this devastating disorder.},
}

@article {pmid42323643,
year = {2026},
author = {Bouveret, Z and Pruvost, L and Trédan, O and Le Romancer, M and Poulard, C},
title = {How post-translational modifications impact glucocorticoid receptor function in human pathologies.},
journal = {Cell communication and signaling : CCS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12964-026-03015-7},
pmid = {42323643},
issn = {1478-811X},
support = {ANR-22-CE13-0001-01//Agence Nationale de la Recherche/ ; },
abstract = {Glucocorticoid receptor (GR) is a member of the nuclear hormone receptor family, which acts as a transcription factor when bound by glucocorticoid (GC) ligands. GR is expressed in nearly all tissue types and regulates essential processes such as inflammation, immune regulation and metabolism. Given its ubiquitous role, GR has frequently been associated with a wide range of illnesses, particularly in the fields of allergy, pulmonary, dermatology, rheumatology, or ophthalmology. It was reported that GCs either contribute to their development or serve as part of their treatment, making them the most prescribed drugs worldwide. GR activity and signaling is finely regulated by a network of post-translational modifications (PTMs). Indeed, PTMs can alter GR behavior and function by modifying its localization, stability, interaction with other proteins and transcriptional activity. Aside from the well-characterized phosphorylation events, additional PTMs are implicated in GR activity and their dysregulation has been described in various diseases. This review provides an integrated overview of current knowledge on GR PTMs, highlighting both mechanistic insights and their relevance in disease. We will present how aberrant PTMs contribute to extremely prevalent diseases, such as cancer, chronic inflammatory diseases, Alzheimer's disease and other neurological diseases. Special attention will be given to the specific readers of these PTMs and to the enzymes catalyzing these modifications, as they represent promising therapeutic targets.},
}

@article {pmid42323655,
year = {2026},
author = {Monteverdi, A and Cotta Ramusino, M and Conca, F and Augello, A and Totaro, C and Grasso, PA and Castelnovo, A and Lorenzi, RM and Terzaghi, M and Farina, LM and Costa, A and Pichiecchio, A and Cappa, SF and Gandini Wheeler-Kingshott, C and Palesi, F and D'Angelo, E},
title = {Virtual brain and electroencephalography explain the variance of memory alterations in mild cognitive impairment.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02114-4},
pmid = {42323655},
issn = {1758-9193},
abstract = {BACKGROUND: Mild Cognitive Impairment (MCI) is a heterogeneous clinical condition characterized by a wide spectrum of cognitive and behavioural manifestations. Despite numerous studies, the link between neuropsychological performance and pathophysiological signatures of the disease-including Aβ and tau accumulation along with altered excitation/inhibition (E/I) balance and brain rhythms-remains elusive.

METHODS: Here Aβ/tau biomarkers were used to distinguish positive (MCI[+]- prodromal Alzheimer's disease) and negative (MCI[-]) subjects in a cohort of 30 MCI patients (18 MCI[+] and 12 MCI[-]). Virtual brain models based on high-field magnetic resonance imaging data were then developed to determine the inter-node coupling and E/I profile in resting-state networks, while node spectral information was obtained from source analysis of high-density electroencephalography (HD-EEG). Finally, virtual brains and HD-EEG parameters, creating brain digital twins of individual subjects, were correlated with cognitive performance.

RESULTS: While virtual brain simulations did not reveal E/I differences between MCI[+] and MCI[-], a positive correlation emerged between synaptic parameters of the limbic network and verbal episodic memory for both groups. EEG power spectral density revealed a lower high-frequency/low-frequency ratio in MCI[+] largely due to a reduced alpha band in the default mode, limbic, attention, frontoparietal, visual and somatomotor networks. A strong correlation emerged between multimodal parameters and memory functions, supporting that brain digital twin simulations can effectively explain the variability of neuropsychological performance in MCI patients beyond the sensitivity of individual techniques alone. In particular, the combination of HD-EEG and virtual brain parameters explained more than 90% of variance for episodic memory patients' scores, confirming the compound origin of memory performance involving network specific E/I levels and electroencephalographic activity acting in concert.

CONCLUSIONS: This multimodal and multiparametric analysis combining virtual brain modelling with HD-EEG and molecular data enhances the stratification of MCI patients and could be used to develop digital biomarkers of progression to dementia, opening new perspectives for personalized prognosis and treatment.},
}

@article {pmid42324743,
year = {2026},
author = {Sakagami, S and Yoshida, Y and Uemura, S and Kumamoto, T and Tsukamoto, R and Nishi, T and Kawano, S and Fukuoka, K and Ino, H and Hamamura, K and Ohdo, S and Matsunaga, N},
title = {Benzbromarone as a Novel Candidate for Preventing Alzheimer's Disease: Evidence From Real-World Data Screening and in Vitro Validation.},
journal = {Clinical and translational science},
volume = {19},
number = {7},
pages = {e70650},
doi = {10.1111/cts.70650},
pmid = {42324743},
issn = {1752-8062},
mesh = {Humans ; *Benzbromarone/therapeutic use/pharmacology ; *Alzheimer Disease/prevention & control/epidemiology ; *Drug Repositioning ; Female ; Male ; Japan/epidemiology ; *Uricosuric Agents/pharmacology/therapeutic use ; Aged ; Amyloid beta-Peptides/metabolism ; Aged, 80 and over ; Incidence ; Cell Line, Tumor ; },
abstract = {Drug development for Alzheimer's disease (AD) remains challenging, with only a 0.4% success rate from Phase I trials to regulatory approval. Drug repositioning leverages existing approved drugs to identify promising drug alternatives, particularly when combined with real-world data (RWD) and target trial emulation. In this study, we comprehensively screened 1,241 approved drugs using a large-scale Japanese claims database (n = 2,090,465; 2005-2023). We identified patients newly prescribed a study drug and applied an active-comparator, new-user design. We used propensity score-based inverse probability of treatment weighting (IPTW) to balance the covariates. The primary outcome was incident AD, defined using ICD-10 codes (F00 and G30). We estimated cumulative incidence using IPTW-adjusted Kaplan-Meier analysis and Cox proportional hazards models and conducted sensitivity analyses using Fine-Gray competing risk models, empirical calibration with negative control outcomes, and E-value estimation. We performed in vitro validation using Aβ-Tet-ON SH-SY5Y cells and quantified Aβ expression using western blotting. Benzbromarone, a uricosuric agent, was associated with a decreased risk of AD onset (adjusted HR: 0.54, 95% CI: 0.41-0.71, p < 0.05 post-FDR correction); this association remained robust across sensitivity analyses. In vitro, benzbromarone reduced Aβ protein expression in SH-SY5Y cells in a dose-dependent manner, even following transcriptional blockade, suggesting a posttranscriptional regulatory mechanism. In conclusion, using a combined approach of RWD-based pharmacoepidemiology and in vitro validation, we identified benzbromarone as a novel candidate potentially associated with reduced AD risk. Our findings highlight the potential of drug repositioning strategies to accelerate AD drug discovery, promoting further mechanistic and clinical investigations.},
}

Humans
*Benzbromarone/therapeutic use/pharmacology
*Alzheimer Disease/prevention & control/epidemiology
*Drug Repositioning
Female
Male
Japan/epidemiology
*Uricosuric Agents/pharmacology/therapeutic use
Aged
Amyloid beta-Peptides/metabolism
Aged, 80 and over
Incidence
Cell Line, Tumor

@article {pmid42324842,
year = {2026},
author = {Ugale, V and Sharon, N and Salunkhe, C and Salunkhe, J and Lokwani, D and Patil, K and Reddy, PN and Kulkarni, P},
title = {Naphthalene-4H-Chromene Molecular Hybrids as Dual Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease.},
journal = {Drug development research},
volume = {87},
number = {5},
pages = {e70338},
doi = {10.1002/ddr.70338},
pmid = {42324842},
issn = {1098-2299},
support = {RGSTC/File-2024/DPP-309/CR-20/332//Rajiv Gandhi Science and Technology Commission/ ; TAR/2021/000140//Department of Science and Technology (DST)-Science and Engineering Research Board (SERB)/ ; CRG/2022/004365//Department of Science and Technology (DST)-Science and Engineering Research Board (SERB)/ ; KBCNMU/RGSTC/Sanction Order/199//Kavayitri Bahinabai Chaudhari North Maharashtra University (KBCNMU)/ ; },
mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use/chemical synthesis ; Animals ; *Alzheimer Disease/drug therapy ; Mice ; *Naphthalenes/chemistry/pharmacology ; *Benzopyrans/chemistry/pharmacology ; Acetylcholinesterase/metabolism ; Butyrylcholinesterase/metabolism ; Molecular Docking Simulation ; Male ; Humans ; Scopolamine ; Cell Line ; Structure-Activity Relationship ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline associated with cholinergic dysfunction. Herein, we have designed and synthesized series of 4-(naphthalen-1-yl)-4H-chromene derivatives 4(a-n) by a one-pot three-component reaction with adequate synthetic yield and purity. Naphthalene-chromene hybrids were synthesized by formation of two C─C bonds and one C─O bond in a single synthetic step. All synthesized compounds were tested for safety and efficacy using in vitro and in vivo studies. Compounds were found devoid of cytotoxicity in BV-2 cells. Most of the synthesized compounds have shown moderate to good inhibitory activity against cholinesterase enzymes. These compounds were found to be more selective towards acetylcholinesterase (AChE) compared to butyrylcholinesterase (BuChE). Compound 4 m has shown highest inhibitory potency against AChE (AChE, IC50 = 1.08 µM; BuChE, IC50 = 82.59 µM). The prototype compound (4 m) from in-vitro screening was found to be safe in acute oral toxicity followed by histopathological analysis. Compound 4 m was evaluated for in vivo efficacy in scopolamine-induced cognitive impairment model in mice. It significantly reversed the cognitive deficit in neurobehavioral tests. Pre-treatment with 4 m have balanced key biochemical markers involved in the oxidative stress and cognitive functions. The compound 4 m alleviated neuronal tissue damage caused by scopolamine as indicated in the histological study. Molecular docking analysis also reconfirmed the binding affinity of 4 m at cholinesterase enzymes. Taken together, these findings supported the emergence of 4 m as a potential cholinesterase inhibitor for the treatment of AD.},
}

*Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use/chemical synthesis
Animals
*Alzheimer Disease/drug therapy
Mice
*Naphthalenes/chemistry/pharmacology
*Benzopyrans/chemistry/pharmacology
Acetylcholinesterase/metabolism
Butyrylcholinesterase/metabolism
Molecular Docking Simulation
Male
Humans
Scopolamine
Cell Line
Structure-Activity Relationship

@article {pmid42325226,
year = {2026},
author = {Alhowail, AH and Al Mouslem, AK and Almatrafi, MA and Aldubayan, MA},
title = {Semaglutide in cognitive dysfunction: neuroprotective potential, clinical trial limitations, and a prevention-focused framework.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1851072},
pmid = {42325226},
issn = {1663-4365},
abstract = {Metabolic dysfunction is increasingly recognized as a pivotal factor in cognitive decline and neurodegenerative diseases, such as Alzheimer's disease (AD). Glucagon-like peptide-1 receptor agonists (GLP-1RAs), notably the long-acting agonist semaglutide, exhibit significant metabolic efficacy and pronounced neuroprotective effects across a broad spectrum of preclinical models. This is corroborated by extensive epidemiological studies that consistently link GLP-1RA use with a decreased incidence of dementia. Nevertheless, promising preclinical and observational findings have not been mirrored in clinical success for the treatment of established AD. Recent negative outcomes from the pivotal phase 3 EVOKE and EVOKE+ trials, which demonstrated no clinical benefit of oral semaglutide in patients with early AD, have resulted in a notable translational paradox. This review critically examines the mechanistic, preclinical, epidemiological, and clinical evidence concerning the impact of semaglutide on cognitive function to reconcile these conflicting findings. Preclinical studies have revealed complex neuroprotective mechanisms, including suppression of neuroinflammation, restoration of metabolic function, and activation of pro-survival pathways. Conversely, clinical trials in symptomatic AD have been unsuccessful, although modest and clinically insignificant changes in cerebrospinal fluid biomarker levels have been observed. We propose the hypothesis that the current body of evidence is consistent with a prevention-focused model, wherein semaglutide's primary value may lie in modifying the upstream metabolic and inflammatory drivers of neurodegeneration, such as those prevalent in vascular and metabolic cognitive impairment, rather than reversing established amyloid-driven AD pathology. This hypothesis, however, remains speculative and requires prospective validation in appropriately designed trials. This review seeks to resolve the apparent contradictions in the literature and propose future research directions centered on appropriate patient populations and therapeutic windows.},
}

@article {pmid42325271,
year = {2026},
author = {Liang, C and Jiang, W and Chen, J and Turner, JA and Calhoun, VD and Abbott, CC and Jiang, R and Fu, Z and Wu, L and Wang, X and Qi, S and Yuan, Y},
title = {Longitudinally altered default mode network and insula multimodal brain pattern in end-stage renal disease during sustained hemodialysis treatment.},
journal = {iScience},
volume = {29},
number = {6},
pages = {116008},
pmid = {42325271},
issn = {2589-0042},
abstract = {Hemodialysis (HD) is the predominant treatment for end-stage renal disease (ESRD). Despite the efficacy of HD, the neurobiological underpinnings underlying high-risk complications remain unclear. In this study, using unsupervised fusion of functional and structural MRI, we identified a longitudinally altered default mode network (DMN)-insula pattern in ESRD receiving HD over 1-year follow-up (n = 39). This pattern was associated with cognition, and its related genes were enriched in biological processes involving DNA damage and repair, energy metabolism, and cellular activation. The baseline DMN-insula pattern demonstrated potential predictive value for follow-up cognition in ESRD. More importantly, these brain-cognition associations were validated in independent high-risk complications cohorts, including major depressive disorder (n = 60), mild cognitive impairment (n = 291), and Alzheimer's disease (n = 77) by extracting the corresponding brain features and assessing their correlations with cognition. Collectively, this study may help researchers better understand the underlying mechanisms of ESRD receiving HD from a multimodal neuroimaging and molecular perspective.},
}

@article {pmid42325273,
year = {2026},
author = {Hao, W and Yu, X and Zhou, Q and Jia, Y and Su, X and Yu, Y and Wang, Y and Wang, J and Liu, C},
title = {Different modulation patterns of theta and gamma dual-site HD-tACS on cognitive impairment.},
journal = {iScience},
volume = {29},
number = {6},
pages = {116138},
pmid = {42325273},
issn = {2589-0042},
abstract = {Alzheimer's disease (AD) is characterized by impaired local network integration and long-range connections. Theta and gamma oscillations are critical for cognitive function, so this study used dual-site fronto-temporoparietal junction (TPJ) high-density transcranial alternating current stimulation (HD-tACS) to explore its frequency-specific effects on brain networks and cognition. Thirty-six AD patients were randomized 1:1:1 to 6Hz-tACS, 40Hz-tACS and sham stimulation targeting bilateral fronto-TPJ cortex for four weeks. Cognitive functions were assessed at baseline, post-treatment and 8-week follow-up. TMS-EEG and voxel-based distance-related functional connectivity analysis evaluated network changes. Both active stimulation groups showed sustained cognitive improvements for eight weeks compared to the sham stimulation group (all p < 0.017). 40Hz-tACS also enhanced language function (p < 0.025). 6Hz-tACS increased anterior functional connections and anterior-to-posterior information flow, while 40Hz-tACS increased posterior connections and posterior-to-anterior flow, closely linked to cognitive improvements. These effects are oscillation frequency-dependent, supporting cognitive improvement in AD.},
}

@article {pmid42325435,
year = {2026},
author = {Liu, C and Zhu, Z and Lin, H and Bush, WS and Jenq, RR and Cominelli, F and Pillai, JA and Haines, JL and Zhu, X and Xu, R and Williams, SM and Cheng, F and Zhang, L},
title = {The gut-brain axis in Alzheimer's disease: early detection, microbial metabolites, mechanisms, and therapeutic opportunities.},
journal = {Frontiers in molecular biosciences},
volume = {13},
number = {},
pages = {1735332},
pmid = {42325435},
issn = {2296-889X},
abstract = {Alzheimer's disease (AD), the leading cause of dementia worldwide, imposes a growing clinical and societal burden, yet no therapies have been proven to alter its progression despite decades of intensive research. As traditional targets have yielded limited success, attention has shifted to modifiable upstream pathways, notably the gut-brain axis, a bidirectional system linking gut microbiota with CNS function. Emerging evidence indicates that microbial dysbiosis may influence key processes leading to AD, including neuroinflammation, amyloid and tau pathology, and cognitive decline. While microbiome composition is associated with AD, it remains unclear at which stage-preclinical, mild cognitive impairment (MCI), or AD dementia-these differences first arise, or how specific risk bacteria and metabolites contribute to progression. The precise roles of these microbes and metabolites in AD pathology or brain resilience also remain poorly understood, and few microbiome-targeted treatments have been validated in humans. Existing reviews often overlook host-specific factors that influence microbiome composition and confound associations with AD. To bridge these gaps, we summarize human studies published in the past 5 years. The literature suggests that gut microbial changes may precede clinical symptoms, with consistent dysbiosis observed in AD patients. We adopt a microbiome-centered perspective emphasizing bacteria-driven and metabolite-driven mechanisms, each playing distinct yet complementary roles in neural and bloodstream pathways. These pathways offer potential targets for microbiome-based prevention and treatment but require more human validation. Future studies should leverage longitudinal, multi-omics approaches and artificial intelligence (AI) tools while rigorously accounting for confounders to improve early detection and develop personalized therapies for AD.},
}

@article {pmid42325550,
year = {2026},
author = {Li, X and Chen, H and Xu, P and Guo, X and Gao, J and Yao, D and Wang, Y and Wang, T and Liu, B and Yuan, J},
title = {Exosomes: A new frontier in the treatment of neurological diseases.},
journal = {iScience},
volume = {29},
number = {7},
pages = {116331},
pmid = {42325550},
issn = {2589-0042},
abstract = {Exosomes (Exos) are an essential class of extracellular vesicles enriched with a wide range of biologically active molecules, which gives them a unique advantage in participating in intercellular signaling and communication and serving as carriers for drug delivery. Exo-based diagnostic and therapeutic strategies are currently hot topics in disease research. Owing to their naturally low immunogenicity, good biocompatibility, ability to penetrate the blood‒brain barrier (BBB), and engineered modifications, exos have significant advantages and possible applications in the treatment of nervous system diseases. Due to the serious harm of neurological diseases to human health, they have been widely studied by researchers. Exos can be administered in a variety of ways, including intranasal administration, intracranial administration, local stereotactic injection, and encapsulation in biomaterials, each of which has its own advantages and disadvantages. However, several requirements need to be met before exo-based therapies can be implemented, such as the standardization of isolation and purification techniques, an in-depth understanding of the mechanism of action, and safety assessments and regulation for clinical translation. The aim of this review is to provide a comprehensive overview of the biogenesis, molecular composition, function, and delivery modes of exos and their therapeutic roles and mechanisms in neurological diseases (e.g., multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and stroke) and to discuss the current challenges and future perspectives to support ongoing research and clinical applications.},
}

@article {pmid42327033,
year = {2026},
author = {Mostowfi, N and Foreman, R and Wang, J and Khoury, R and Albanese, A and Ma, QL and Cohn, W and Petzinger, G and Jakowec, M and Ahmed, SK and Seidler, PM},
title = {Tau Disaggregation by a CNS-Permeable Small Molecule Reduces Fibril and Oligomer Burden and Preserves Proteostasis and Behavior.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.09.731185},
pmid = {42327033},
issn = {2692-8205},
abstract = {Pathological tau aggregates drive neuronal dysfunction in Alzheimer's disease (AD) and related tauopathies, yet no approved therapy eliminates existing tau neurofibrillary tangles. Here, we report the development of a coumarin-based small-molecule series that disaggregates tau fibrils and oligomers through a stacking-driven co-assembly mechanism. Structure-activity relationships identified PT-13 as a lead compound that inhibits tau seeding by AD brain-derived matter and reduces aggregate burden measured across both fibrillar and oligomeric tau species. Mechanistic studies demonstrate that disaggregation does not generate soluble oligomeric intermediates, addressing a central question in the field. PT-13 is brain-penetrant and well tolerated in vivo. In a tauopathy mouse model, PT-13 treatment reduces tau pathology while preserving behavioral function, proteasome capacity, and synaptic integrity. These findings establish small-molecule tau disaggregation as a viable therapeutic strategy and provide a molecular framework for the design of aggregate-directed therapeutics in neurodegeneration.},
}

@article {pmid42318437,
year = {2026},
author = {Dinnerstein, E},
title = {"Doctor, if it were you, which would you choose?": Navigating personal preference questions in anti-amyloid immunotherapy selection.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70373},
pmid = {42318437},
issn = {2352-8729},
abstract = {The approval of lecanemab and donanemab represents a watershed moment in Alzheimer Disease (AD) treatment, yet clinicians face a novel challenge: guiding patients through treatment selection when head-to-head comparative data are absent. When confronted with the question "What would you do if you were me?", clinical providers must balance evidence-based medicine with the therapeutic alliance. This perspective examines the ethical, practical, and relational dimensions of responding to personal preference queries in the context of anti-amyloid immunotherapy selection, offering a framework for authentic engagement that honors both professional boundaries and patient-centered care.},
}

@article {pmid42318555,
year = {2026},
author = {Yadollahi Khales, A and Ghaedi, K and Esmaeili, F and Noorbakhshnia, M and Etemadifar, M},
title = {Plasma lncRNA signature of upregulated ATP2B1-AS1 and downregulated RPL21P28 correlates with diagnosis and cognitive severity in Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1739935},
pmid = {42318555},
issn = {1663-4365},
abstract = {BACKGROUND: The non-invasive biomarkers have considerable effects in determination and treatment of Alzheimer's disease (AD). The specificity and stability of the circulating long non-coding RNAs (lncRNAs) have made them suitable options in disease management. The aim of this study was discovering and clinically confirming a new plasma lncRNA signature and the underlying regulatory mechanisms.

METHODS: In a two-stage research, the preliminary bioinformatic screen of public transcriptomic data (GEO: GSE63060) found candidate lncRNAs. Then the level of the major candidates, ATP2B1-AS1 and RPL21P28, were validated by Real-Time qPCR in plasma of 25 AD patients and 25 healthy controls. The diagnostic performance was appraised by the Receiver Operating Characteristic (ROC) curve analysis and the presumed functions were described by a competing endogenous RNA (ceRNA) network.

RESULTS: Our study established concurrent ATP2B1-AS1 upregulation and RPL21P28 downregulation in Alzheimer's patient plasma (p < 0.001). This highly discriminatory two-lncRNA signature produced an area under the curve (AUC) of 0.81 for ATP2B1-AS1 and 0.83 for RPL21P28. Based on MMSE scores, the expressions of both lncRNAs were significantly correlated with the level of cognitive impairment. These lncRNAs were also showed a correlation to important regulation mechanisms by our ceRNA network analysis, with RPL2B1P28 linked to synaptic functional genes and ATP2B1-AS1 to neurodevelopment.

CONCLUSION: ATP2B1-AS1 and RPL21P28 plasma levels present specific AD biomarker signature. These lncRNAs show great potentials in designing a non-invasive blood test that can be used for early diagnosis and disease follow-up. It also establishes new areas for intervention therapy research.},
}

@article {pmid42319641,
year = {2026},
author = {Jetsonen, V and Välimäki, T and Selander, T and Kuvaja-Köllner, V and Martikainen, J and Koivisto, AM},
title = {Different family caregiver- and care recipient-related factors are associated with the cost of care in the early, mild, and moderate stages of Alzheimer's disease in Finland: A 5-year ALSOVA study.},
journal = {The European journal of health economics : HEPAC : health economics in prevention and care},
volume = {},
number = {},
pages = {},
pmid = {42319641},
issn = {1618-7601},
abstract = {PURPOSE: Alzheimer's disease (AD) accounts for a significant proportion of health and social care costs. We studied family caregiver (FC), care recipient (CR), and formal care provider-related factors, which are associated with the cost of care in different stages of AD in Finland.

METHODS: A 5-year follow-up was conducted with 231 individuals with AD (CRs) and their FCs as a part of the ALSOVA project. The data was collected between 2002 and 06. Significant factors associated with costs were identified using a stepwise backward elimination procedure. Neuropsychiatric symptoms were measured with the Neuropsychiatric Inventory (NPI).

RESULTS: Across all stages of AD, each additional year of CR's education was associated with a 3.4% reduction in costs (rate ratio [RR] 0.966, 95% CI 0.940-0.993). Conversely, a one-point increase on the Neuropsychiatric Inventory was associated with a 1.8% increase in costs (RR 1.018, 95% CI 1.011-1.025). CR's neuropsychiatric symptoms (RR 1.028, 95% CI 1.010-1.047) and male FC (RR 1.756, 95% CI 1.266-2.437) were associated with increased total costs in early AD, CR's comorbidities (RR 1.138, 95% CI 1.068-1.212) and FC's burden (RR 1.032, 95% CI 1.012-1.053) in mild AD and FC being a spouse (RR 1.451, 95% CI 1.105-1.905) in moderate AD. No formal care provider-related factors were associated with total costs in any stage of AD.

CONCLUSIONS: This study reveals several factors that may be manageable to control the costs of AD. Comprehensive prevention, evaluation, and treatment of a CR's neuropsychiatric symptoms and comorbidities should be executed early. Informal care can act as a substitute for formal care in early-stage AD, and supportive measures toward FCs should be considered.},
}

@article {pmid42320774,
year = {2026},
author = {Ren, L and Liu, S and Sun, X and Zhang, Y and Wang, P and Liu, L and Chen, LL},
title = {Ditan Decoction alleviates glutamate excitotoxicity in an Aβ-induced Alzheimer's disease-like model through the regulation of ERBB2/PI3K/AKT signaling pathway.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122084},
doi = {10.1016/j.jep.2026.122084},
pmid = {42320774},
issn = {1872-7573},
abstract = {Alzheimer's disease (AD), as the most prevalent form of dementia among the elders, poses a major global health challenge. Ditan Decoction (DTD), a classic prescription from traditional Chinese medicine, demonstrates potent capacity against neurological disorders. Nevertheless, the specific components of DTD and its mechanisms in treating AD remain unclear.

AIM OF THE STUDY: The study was designed to investigate the underlying substance basis and molecular mechanisms of DTD in treating Aβ1-42-induced cognitive decline in rats.

MATERIALS AND METHODS: The AD model rats established by Aβ1-42 injection were subjected to cognitive function assessment through Y-maze, Morris water maze and novel object recognition tests. Neuronal damage and dendritic spine integrity were evaluated by Nissl and Golgi staining. The constituent assignment of DTD in vitro and in vivo were accomplished by LC-MS, and potential targets for AD treatment were predicted through network pharmacology, broad-target metabolomics, molecular docking and molecular dynamics simulations. Immunofluorescence and neurotransmitter assay served to analyze neuronal activation levels and glutamate content. Protein expressions of signal pathway were detected in hippocampus and validated by serum pharmacology in HT22 cells using Western blot analysis.

RESULTS: DTD treatment significantly alleviated the cognitive dysfunction in AD model rats. LC-MS analysis identified 268 compounds in DTD, with 23 active ingredients absorbed in vivo. Integrated analyses combining network pharmacology, metabolomic profiling, molecular docking, and molecular dynamics simulations indicated that DTD may exert therapeutic effects against AD by lowering glutamate levels in hippocampus via the regulation of ERBB2/PI3K/AKT signaling pathways. DTD upregulated the expression of ERBB2 and p-AKT, reduced glutamate-induced neuronal activation levels and hippocampal glutamate content, and elevated the level of synaptic proteins PSD95, Syn1 and NR2A/B, thereby improving the structural and functional integrity of synapses. Cell tests confirmed that DTD alleviated glutamate-induced excitotoxicity and synaptic dysfunction in HT22 cells via ERBB2/PI3K/AKT pathway, which was abolished by ERBB2 inhibitor AG-825 and PI3K inhibitor LY294002.

CONCLUSIONS: This study elucidates the neuroprotective mechanism of DTD within AD model rats. DTD improves synaptic dysfunction by reducing hippocampal glutamate concentrations and counteracting glutamate-mediated excitotoxicity via the ERBB2/PI3K/AKT signaling pathway.},
}

@article {pmid42318047,
year = {2026},
author = {Wei, YT and Li, L and Xie, WT and Wang, Y and Zhao, YR and Zhang, RZ and Ma, L and Yan, XK},
title = {Altered Effective Connectivity Within the Frontoparietal Network in Alzheimer's Disease and Its Modulation by Acupuncture: A Resting-State fMRI Study.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {601136},
pmid = {42318047},
issn = {1176-6328},
abstract = {PURPOSE: Alzheimer's disease (AD) is increasingly prevalent, yet how acupuncture modulates cognitive brain networks remains unclear. We used resting-state fMRI (rs-fMRI) to examine whether acupuncture prescription regulates effective connectivity within the frontoparietal network (FPN) in AD.

PATIENTS AND METHODS: Sixty AD patients were randomized to donepezil alone (drug group) or acupuncture plus donepezil (acupuncture group) for 6 weeks (n=30/group). Seven healthy controls were scanned once. Global cognition was assessed with MoCA-B. Independent component analysis identified the FPN, and Granger causality analysis quantified directed effective connectivity before and after treatment.

RESULTS: Both interventions improved MoCA-B (P<0.05), with larger gains in the acupuncture group (P<0.05). Relative to controls, AD showed FPN disruption with compensatory reorganization. Decreased connectivity was observed from the left middle temporal gyrus (MTG) to the right inferior parietal lobule (IPL), and from the left median cingulate/paracingulate gyri (P<0.05). Increased connectivity emerged from the right IPL and left cingulate/paracingulate to the left MTG, and from the right IPL to the left medial frontal gyrus (orbital part) (P<0.05). The right IPL and left MTG were core FPN nodes. Post-treatment, the drug group showed reduced right IPL→left orbital medial frontal connectivity, whereas the acupuncture group showed reduced right IPL→left MTG connectivity (P<0.05). Between-group comparisons indicated acupuncture-specific modulation of right insula→left MTG and left precuneus→left MTG connectivity (P<0.05).

CONCLUSION: Acupuncture combined with donepezil provides superior cognitive benefits and selectively reshapes directed FPN interactions, supporting a network-level mechanism involving frontal-parietal-temporal integration.},
}

@article {pmid42311735,
year = {2026},
author = {Harikumar, N and Gupta, M and Al Janabi, T and Mand, KK},
title = {A Severe Symptomatic Case of Amyloid-Related Imaging Abnormalities After Donanemab Infusion.},
journal = {Cureus},
volume = {18},
number = {5},
pages = {e109045},
pmid = {42311735},
issn = {2168-8184},
abstract = {Amyloid-related imaging abnormalities (ARIA) are known complications of anti-amyloid monoclonal antibody therapy for Alzheimer's disease. Although many cases are asymptomatic, severe presentations can mimic stroke or toxic encephalopathy. This case highlights a rare presentation of ARIA with myoclonic movements and acute encephalopathy following donanemab infusion. We report a 75-year-old woman with Alzheimer's disease who developed acute confusion, hallucinations, and involuntary movements one day after her sixth donanemab infusion. Stroke workup was negative. MRI demonstrated findings consistent with both ARIA-E and ARIA-H. She was treated with high-dose intravenous methylprednisolone, followed by an oral prednisone taper, which resulted in gradual neurological improvement. Clinicians must maintain a high suspicion for ARIA in patients receiving anti-amyloid therapy who present with acute neurologic decline. Early MRI evaluation and prompt corticosteroid treatment may improve outcomes.},
}

@article {pmid42312520,
year = {2026},
author = {R, N and Dubey, S and Kumar, D and Walhekar, V and Tiwari, P},
title = {In Silico Prediction, Characterization, and Pre-clinical Appraisal of the Neuroprotective Effect of the Methanolic Extract of Cassytha filiformis.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026456568260601100209},
pmid = {42312520},
issn = {1875-5739},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a severe neurodegenerative disorder that progressively worsens with age. Medicinal plants have demonstrated potential for the management of AD. Cassytha filiformis, a native plant of the Indian subcontinent, has been reported to exhibit antioxidant activity, which could be beneficial in neurodegenerative disorders.

METHODS: This study evaluates the anti-neurodegenerative effect and possible mechanism of action of a methanolic extract of Cassytha filiformis (MECF). Two compounds, AC-2 and AC-4, were isolated from the extract and assessed for cognitive behavior using the Morris water maze and probe test, followed by evaluation of antioxidant, neurochemical, and anti-inflammatory parameters, as well as in silico studies.

RESULTS: Neurochemical abnormalities (acetylcholinesterase (AChE), NMDA (N-methyl-Daspartate), dopamine (DA)), neuro-inflammatory markers (TNF-α, IL-6), and antioxidant parameters (superoxide dismutase (SOD), lipid peroxidation (LPO), nitric oxide (NO)) were evaluated. Histological examination of brain cells assessed the regenerative impact of the isolated compounds. Antioxidant levels and neuroinflammation were significantly reduced (p < 0.05) in the MECF-, AC-2-, and AC-4-treated groups. Additionally, superoxide dismutase and catalase levels were significantly increased in the treated groups. Acetylcholine, NMDA, and dopamine levels showed marked improvement. Histopathological analysis revealed neuroregeneration in the test groups, and hematological evaluations supported these findings by demonstrating normalization of elevated blood profiles observed in the scopolamine-induced groups.

DISCUSSION: MECF and its isolated compounds, AC-2 and AC-4, exhibited notable antioxidant and neuro-anti-inflammatory properties, enhancing cognitive function, learning, and memory. The observed neuroprotective effects suggest a potential therapeutic role for these compounds in the management of AD.

CONCLUSION: Phenolic compounds present in AC-2 and AC-4 may be integral to the mechanism of action of MECF. Further investigations, including clinical validation, are necessary to explore the therapeutic potential of MECF, AC-2, and AC-4 in AD treatment.},
}

@article {pmid42313307,
year = {2026},
author = {Saini, K and Dhiman, P},
title = {Microglia-driven neuroinflammatory signaling in neurodegeneration: mechanisms and therapeutic opportunities.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42313307},
issn = {1573-4978},
mesh = {Humans ; *Microglia/metabolism/pathology/immunology ; *Neurodegenerative Diseases/metabolism/therapy/pathology/immunology ; Animals ; Signal Transduction ; *Neuroinflammatory Diseases/metabolism/pathology/immunology ; Blood-Brain Barrier/metabolism ; Cytokines/metabolism ; Astrocytes/metabolism ; },
abstract = {Neuroinflammation has been identified as a major component to the pathogenesis and progression of many neurodegenerative illnesses, going beyond its traditional role as a protective immune response within central nervous system (CNS). There is growing evidence that persistent activation of peripheral immune pathways, microglia and astrocytes causes progressive neurodegeneration, synaptic loss and progressive neurodegeneration. This review examines the mechanisms of microglia- driven neuroinflammatory signaling and its involvement in major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. Key neuroinflammatory mechanisms covered in depth including microglial activation, astrocyte reactivity, peripheral immune cell infiltration, cytokine dysregulation, and blood brain barrier (BBB) disruption. This review also emphasizes the role of neuroinflammation in acute neurological symptoms and mental and cognitive impairments. Glial activation markers, inflammatory cytokines, BBB proteins and kynurenine pathway metabolites are emerging as promising biomarkers for disease diagnosis and monitoring. Additionally, the potential of new mathematical and systems level computational models to describe intricate neuroimmune interactions and forecast the course of disease and treatment results is investigated. Current and emerging therapies targeting neuroinflammation include anti-inflammatory and immunomodulatory drugs, lifestyle interventions, stem cell approaches, gene-editing technologies and nanoparticle-based drug delivery systems. Despite significant progress, translating preclinical findings into effective clinical therapies remains challenging. Future developments in integrative neuroimmune modeling, biomarker-guided therapies and precision medicine may make it possible to create individualized treatments plans targeted at reducing neuroinflammation and enhancing the course of neurodegenerative illnesses.},
}

Humans
*Microglia/metabolism/pathology/immunology
*Neurodegenerative Diseases/metabolism/therapy/pathology/immunology
Animals
Signal Transduction
*Neuroinflammatory Diseases/metabolism/pathology/immunology
Blood-Brain Barrier/metabolism
Cytokines/metabolism
Astrocytes/metabolism

@article {pmid42314102,
year = {2026},
author = {Ganesh, A and Smith, EE and Mostert, J and Strijbis, EM and Schoonheim, MM and Xia, C and Nadeau, Y and Leavitt, VM and Kalia, LV and Engelborghs, S and D'Haeseleer, M and McPherson, T and Cutter, GR and Koch, MW and , },
title = {Phase 2 Futility Trials in Alzheimer Disease and Mild Cognitive Impairment: A Cohort Analysis of the ADNI Data Set.},
journal = {Neurology},
volume = {107},
number = {1},
pages = {e218227},
doi = {10.1212/WNL.0000000000218227},
pmid = {42314102},
issn = {1526-632X},
mesh = {Humans ; *Alzheimer Disease/therapy ; *Cognitive Dysfunction/therapy ; Female ; Aged ; Male ; *Clinical Trials, Phase II as Topic ; Medical Futility ; Aged, 80 and over ; Longitudinal Studies ; Cohort Studies ; },
abstract = {BACKGROUND AND OBJECTIVES: The cost and complexity of phase 2 randomized-controlled trials (RCTs) hinder further development of promising treatment candidates for Alzheimer disease (AD). The Simon Two-Stage futility trial design, originally developed for oncology, offers a streamlined approach to evaluate potential disease-modifying therapies by comparing single-arm outcomes with historical controls, but is predicated on identifying outcome measures that reliably worsen with the natural history of the disease, with minimal risk of improvement. We sought to determine the feasibility of such futility trials in AD-associated dementia and mild cognitive impairment (MCI) using a large prospective cohort.

METHODS: We analyzed longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitive decline was assessed using AD Assessment Scale-Cognitive Subscale (ADAS-Cog 11 and ADAS-Cog 13), Clinical Dementia Rating-Sum of Boxes (CDR-SB), and Mini-Mental State Examination (MMSE) at 6, 12, and 24 months using different thresholds for worsening vs improvement. Binary logistic regression models examined baseline factors associated with cognitive worsening using different thresholds of worsening for each outcome of interest to assess what additional selection criteria may be needed for futility trials in AD-associated dementia vs MCI. Sample size estimates were derived based on expected rates of decline.

RESULTS: Among 2,665 participants (mean age 73.4 years [SD: 7.5], 1,260 [47.3%] female, 424 with AD-associated dementia), the CDR-SB exhibited the largest percentage of decline in AD-associated dementia and MCI, with 60.6% of patients with AD-associated dementia showing worsening when using a threshold of ≥1.0 points at 12 months vs 6.2% showing improvement. ADAS-Cog 11 and 13 showed similar decline patterns; for example, 41.7% with AD-associated dementia worsened by ≥ 5 points at 12 months on ADAS-Cog 13, whereas 5.8% improved. MMSE exhibited lower sensitivity; 25.8% with AD-associated dementia worsened by ≥ 5 points at 12 months, whereas 2.9% improved. Shorter trials (6-12 months) with 35-62 participants seemed feasible in AD-associated dementia, whereas MCI trials seemed to require 24 months and specific entry criteria based on age, apolipoprotein E ε4 status, and baseline CDR-SB performance.

DISCUSSION: Futility trials seem feasible in AD-associated dementia, offering a faster, cost-effective alternative to traditional phase 2 RCTs. CDR-SB seems to be the optimal primary outcome. Further validation in clinical trial data sets is warranted.},
}

Humans
*Alzheimer Disease/therapy
*Cognitive Dysfunction/therapy
Female
Aged
Male
*Clinical Trials, Phase II as Topic
Medical Futility
Aged, 80 and over
Longitudinal Studies
Cohort Studies

@article {pmid42314597,
year = {2026},
author = {Li, Y and Yang, XF and Yang, SY and Wang, L and Sun, YZ and Tan, WX and Yang, Z and Zheng, YZ and Wang, J and Jin, HW and Zeng, KW and Tu, PF},
title = {Millepurpan from Astragali Radix binds condensin SMC2 to reverse microglial cell cycle arrest and metabolic reprogramming in neuroinflammation.},
journal = {Bioorganic chemistry},
volume = {180},
number = {},
pages = {110089},
doi = {10.1016/j.bioorg.2026.110089},
pmid = {42314597},
issn = {1090-2120},
abstract = {Microglia are key immune cells in the central nervous system, whose dysfunction contributes to neuroinflammation and neurological disorders. Astragali Radix (AR), the root of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao, is known for neuroprotective effects, yet its active compounds remain underexplored. This study reports the first isolation of Millepurpan (MPP) from AR extract and reveals its potent anti-inflammatory effects in BV-2 microglial cells stimulated with lipopolysaccharide (LPS). Binding assays show MPP targets the ATPase head domain of structural maintenance of chromosomes 2 (SMC2), a condensin complex subunit, inducing steric hindrance that obstructs the ATP-binding pocket. LPS suppresses SMC2 nuclear translocation, causing p21-mediated G0/G1 arrest; MPP restores nuclear SMC2 and promotes G1/S transition. Seahorse metabolic analysis indicates MPP reverses LPS-induced glycolytic reprogramming, an effect abolished by Palbociclib co-treatment, highlighting cell cycle progression's role in metabolic regulation. In vivo, MPP crosses the blood-brain barrier, reduces microglial hyperactivation, and protects neurons in LPS-treated C57BL/6 mice. Immunofluorescence confirms MPP rescues nuclear SMC2 depleted by LPS, supporting its anti-neuroinflammatory action. Reanalysis of single-cell RNA sequencing datasets indicates dysregulation of SMC2 and downstream genes in Alzheimer's disease patients, suggesting SMC2 as a potential biomarker for neuroinflammation. Together, findings reveal an SMC2-mediated pathway whereby MPP binding promotes SMC2 nuclear translocation, mitigating neuroinflammation via regulation of microglial cell cycle and metabolic homeostasis. Given cell cycle regulation's importance in cellular homeostasis, SMC2 emerges as a promising therapeutic target, and MPP as a candidate agent for neuroinflammatory disorder treatment.},
}