@article {pmid41699413,
year = {2026},
author = {Shaldam, MA and Carradori, S and Balaha, M and Guglielmi, P and Diomede, F and D'Agostino, I and Tawfik, HO},
title = {Patents involving monoamine oxidase (MAO): a comprehensive update (2022-2025) on its inhibitors and applications.},
journal = {Expert opinion on therapeutic patents},
volume = {},
number = {},
pages = {},
doi = {10.1080/13543776.2026.2633345},
pmid = {41699413},
issn = {1744-7674},
abstract = {INTRODUCTION: Monoamine oxidases (MAOs) A and B are key enzymes for the oxidative deamination of monoamine neurotransmitters, including dopamine, serotonin, norepinephrine, and tyramine. Selective MAO-B inhibitors are clinically employed as adjuvant therapies for neurodegenerative disorders, whereas selective MAO-A inhibitors are mainly considered third-line options in the treatment of depression. However, due to their function in regulating synaptic activity and exogenous monoamine metabolism, research in this field is continually expanding.

AREAS COVERED: This review summarizes patents on MAO inhibitors between 2022 and 2025. For the most investigated chemotypes (14 synthetic cores along with compounds from natural sources), biological activities were analyzed. The compounds are divided into two main categories, naturally occurring molecules and newly synthesized derivatives, with a total of 114 compounds discussed. To provide a more comprehensive perspective on the therapeutic potential of these inhibitors, additional treatment alternatives are also outlined.

EXPERT OPINION: Recently patented MAO inhibitors show notable properties, including significant isoform selectivity and therapeutic potential toward other diseases, such as fibromyalgia, CDKL5-deficient disorder, neuropathic pain, and Alzheimer's disease.},
}

@article {pmid41699353,
year = {2026},
author = {Casciati, A and Colantoni, E and Camera, F and Fratini, E and Casula, EP and Mencarelli, L and Di Lorenzo, F and Bonnì, S and Koch, G and Tanno, B and Merla, C},
title = {Deregulation of Synaptic Plasticity-Related MicroRNAs After Repetitive Transcranial Magnetic Stimulation in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {442},
pmid = {41699353},
issn = {1559-1182},
support = {Regione Lazio POR FESR Lazio 2014-2020 n. A0375-2020-36546//Regione Lazio/ ; },
abstract = {Repetitive transcranial magnetic stimulation (rTMS) is an emerging non-invasive therapeutic approach to slow down cognitive and functional decline in Alzheimer's disease (AD), potentially through plasticity-related mechanisms. MicroRNAs (miRNAs) play a crucial role in synaptic plasticity, and their deregulation contributes to AD-related cognitive impairment. In the present study, we first used a dosimetric model to translate rTMS field applied in AD patients to an in vitro system, identifying miRNAs as potential biomarkers responsive to rTMS. We found that rTMS induced in vitro deregulation of miR-26b, miR-125b, miR-181c, and miR-146a. Then, we investigated the effects of rTMS over precuneus during a 3-week, randomized, sham-controlled trial in AD patients. In patient serum, miR-26b, miR-30b, and miR-125b were significantly modulated in AD patients compared to healthy controls, though no significant modulation emerged between sham and rTMS groups before or after stimulation. Subsequently, the correlation analyses, which incorporated patients' cognitive scores, revealed that reduced miR-25 levels were significantly associated with cognitive improvement. However, no significant differences emerged between Real- and sham-rTMS correlation coefficients, likely due to the limited sample size, indicating that miR-25 may represent a general prognostic marker rather than a treatment-specific indicator. Furthermore, the ability of this miRNA to discriminate responders from non-responders, shown by ROC analysis, highlights its potential as a promising predictor of rTMS treatment efficacy to be validated in a larger patient cohort. Altogether, our findings suggest, for the first time, that rTMS may modulate specific miRNAs in AD patients, with miR-25 representing a pivotal key target for future validation studies.},
}

@article {pmid41698644,
year = {2026},
author = {Xu, Z and Li, X and Wang, S and Lyu, J and Zhu, S and Chen, S and Li, Y and Zhang, Y and Wang, F and Duan, R},
title = {Diminazene attenuates astrocytic oxidative stress and neuronal ferroptosis via miR-10b-3p/NOX4 axis in Alzheimer's Disease Model.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110880},
doi = {10.1016/j.neuropharm.2026.110880},
pmid = {41698644},
issn = {1873-7064},
abstract = {PURPOSE: Diminazene (DIZE), an agonist of the Ang-(1-7) system, has been proven to suppress astrocytic neuroinflammatory responses in Alzheimer's disease (AD). NADPH oxidase 4 (NOX4) is abundantly expressed in astrocytes and critically mediates oxidative stress damage and ferroptosis. However, the mode of DIZE in AD-related NOX4 overactivation and ferroptosis remains to be revealed.

METHODS: Male APP/PS1 mice received DIZE and the ferroptosis inhibitor Liproxstatin-1 (LIP) treatment. Behavioral tests, Nissl staining, Western blotting, ELISA and immunofluorescence were performed to evaluate the effects of DIZE on neuronal loss, synaptic damage, inflammation and iron accumulation. Astrocytes from APP/PS1 mice were underwent high-throughput miRNA sequencing to identity the most differentially expressed miRNAs after DIZE administration. Subsequently, the role of this miRNA in DIZE's anti-ferroptosis impact within primary astrocytes was explored.

RESULTS: DIZE markedly reduced iron accumulation while lowering oxidative stress and inflammation in APP/PS1 mice. Simultaneously, DIZE significantly mitigated cognitive deficits and synaptic injury in APP/PS1 mice. DIZE suppressed the expression level of NOX4 and upregulated miR-10b-3p. Importantly, miR-10b-3p levels were notably elevated in astrocytes of APP/PS1 mice administered DIZE, targeting the NOX4 protein. Inhibition of miR-10b-3p expression significantly reversed the therapeutic effect of DIZE.

CONCLUSION: These findings indicate that DIZE suppresses astrocytic oxidative stress and neuronal ferroptosis via miR-10b-3p/NOX4 axis in AD model.},
}

@article {pmid41698287,
year = {2026},
author = {Bengs, B and Swerdlow, RH and Burns, J and Slawson, C and , and McCoy, M and Sardiu, ME},
title = {Digital siblings unveil distinct molecular and clinical subtypes in Alzheimer's disease via omics-driven profiling.},
journal = {Journal of the neurological sciences},
volume = {482},
number = {},
pages = {125812},
doi = {10.1016/j.jns.2026.125812},
pmid = {41698287},
issn = {1878-5883},
abstract = {Alzheimer's Disease (AD) is a multifactorial neurodegenerative disorder marked by extensive biological and clinical heterogeneity, complicating prognosis and personalized treatment strategies. Because of this, data-driven methods that characterize patient similarity and subgroup-specific molecular signatures are essential for advancing precision medicine in AD. We applied manifold learning techniques to fuse proteomic, demographic, and clinical data from 438 AD patients, enabling the identification of "digital siblings"-patients with closely related molecular and clinical profiles within a learned latent space. This framework enabled robust clustering and stratification of patient subgroups, revealing distinct pathway enrichments associated with clinical traits such as age, alcohol use, and comorbidities. Moreover, structural and network analyses of key protein interactions within these subgroups provided insights into the molecular mechanisms potentially driving disease heterogeneity. While this approach primarily clustered patients based on comprehensive molecular patterns, it lays critical groundwork for developing predictive models that incorporate longitudinal progression and intervention outcomes. Overall, our results underscore the potential of "digital sibling"-based stratification to refine patient subgroup characterization and serve as a foundation for future dynamic modeling in AD.},
}

@article {pmid41697669,
year = {2026},
author = {Coughlan, GT and Ourry, V and Townsend, D and Klinger, H and Brown, JA and Cuppels, M and Betthauser, T and Langhough, R and Cody, K and Seto, M and Birkenbihl, C and Li, A and Farrell, M and Thibault, E and Kivisäkk Webb, P and Arnold, S and Rissman, RA and Properzi, M and Schultz, A and Johnson, K and Langford, O and Donohue, MC and Villeneuve, S and Johnson, SC and Yang, HS and Manson, JE and Sperling, R and Buckley, RF and , },
title = {Sex Differences in P-Tau217, Tau Aggregation, and Cognitive Decline.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2025.5670},
pmid = {41697669},
issn = {2168-6157},
abstract = {IMPORTANCE: Among individuals with high levels of amyloid-β (Aβ), women exhibit higher insoluble tau burden and accumulation than age-matched men. It remains unclear whether this sex difference is influenced by soluble phosphorylated tau (p-tau), a biomarker that changes early in Alzheimer disease.

OBJECTIVE: To investigate whether sex and aggregated Aβ synergistically predict plasma phosphorylated tau 217 (p-tau217) levels and whether levels of p-tau217 predict cross-sectional and longitudinal tau aggregation in a sex-specific manner (as measured by positron emission tomography [PET]).

This longitudinal study analyzed data between September 7, 2024, and October 29, 2025, from 1 clinical trial cohort and 4 observational study cohorts including men and women without cognitive impairment who had undergone multiple assessments via tau PET (18F-flortaucipir or 18F-MK-6240) and plasma p-tau217 assay at baseline. Cognitive performance was measured with the Preclinical Alzheimer Cognitive Composite. Data on cognitive performance were available from 3 of the 5 cohorts for a mean of 4.6 years (SD, 3.1 years). Across the 5 cohorts, the mean follow-up for tau PET was 3.6 years (SD, 1.7 years).

EXPOSURES: Self-reported sex (male or female), tau PET, and p-tau217 assay.

MAIN OUTCOMES AND MEASURES: The primary analyses used linear and mixed-effects models to assess baseline and longitudinal sex × p-tau217 interactions for 9 tau PET regions. The secondary analyses assessed sex × p-tau217 interactions for cognitive change using the Preclinical Alzheimer Cognitive Composite.

RESULTS: Across the 5 cohorts, there were a total of 1292 participants (63.6% women; mean age, 70.6 [SD, 6.4] years) with tau PET assessments. Compared with men, women had significantly higher baseline p-tau217 levels at higher aggregated Aβ Centiloid levels (β, -0.21 [95% CI, -0.37 to -0.05], P = .009; highest interaction was found in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration [A4/LEARN] cohort). The sex × p-tau217 interactions at baseline were significant for 1 tau PET region in the Harvard Aging Brain Study (HABS) cohort, for 2 tau PET regions in the A4/LEARN cohort, for 6 tau PET regions in the Wisconsin Registry of Alzheimer's Prevention (WRAP) cohort, and for 4 tau PET regions in the Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) cohort. Longitudinal interactions were significant for 4 tau PET regions in the A4/LEARN cohort, for 5 tau PET regions in both the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort and the WRAP cohort, and for 2 PET regions in both the HABS cohort and the PREVENT-AD cohort. Compared with men, women displayed greater tau deposition and accumulation at higher p-tau217 levels. Use of a secondary model showed women with higher p-tau217 levels also exhibited faster rates of cognitive decline relative to men in the both the WRAP cohort and the ADNI cohort.

CONCLUSION AND RELEVANCE: These findings add to growing evidence that women have a differential tau response to Aβ that may emerge at the point of p-tau secretion. These findings have implications for the therapeutics and diagnostics of preclinical Alzheimer disease.},
}

@article {pmid41697185,
year = {2026},
author = {Cottrell, S and Yoon, S and Wei, X and Dickson, A and Wei, GW},
title = {Computational Drug Repurposing for Alzheimer's Disease via Sheaf Theoretic Population-Scale Analysis of snRNA-Seq Data.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c02862},
pmid = {41697185},
issn = {1520-4804},
abstract = {Single-cell and single-nucleus RNA sequencing are used to reveal heterogeneity in cells, showing a growing potential for precision and personalized medicine. Nevertheless, sustainable drug discovery must be based on a population-level understanding of molecular mechanisms, which calls for a population-scale analysis of this data. This work introduces a sequential target-drug selection model for drug repurposing against Alzheimer's Disease (AD) targets inferred from snRNA-seq data of AD progression- involving hundreds of thousands of nuclei from multipatient and multiregional studies. We utilize Persistent Sheaf Laplacians (PSL) to facilitate a Protein-Protein Interaction (PPI) analysis inferred from disease related differential gene expression (DEG). We then use an ensemble of machine learning models to predict repurpose-able compounds. We screen the efficacy of different small compounds and further examine their central nervous system relevant ADMET properties, resulting in a list of potential molecular targets as well as pharmaceutical lead candidates for AD treatment.},
}

@article {pmid41697144,
year = {2026},
author = {Lee, WT and Wang, JT and Tsai, MH and Fang, YW},
title = {GLP-1 receptor agonists reduce dementia and Alzheimer disease risk in diabetic Patients with CKD.},
journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association},
volume = {},
number = {},
pages = {},
doi = {10.1093/ndt/gfag032},
pmid = {41697144},
issn = {1460-2385},
abstract = {BACKGROUND: Patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) are at increased risk of developing dementia and Alzheimer's disease due to vascular dysfunction, insulin resistance, and chronic inflammation. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown neuroprotective properties; however, their impact on dementia risk in diabetic patients with CKD remains uncertain. This study evaluated the association between GLP-1RAs use and dementia risk in patients with CKD stage 3 or later, compared to dipeptidyl peptidase-4 inhibitors (DPP4is).

METHODS: This retrospective cohort study analyzed data from the TriNetX global research network, comprising electronic medical records from 67 healthcare organizations in the US Collaborative Network. We identified patients with CKD stage 3 or later and T2DM who were newly prescribed GLP-1RAs or DPP4is between January 1, 2015, and December 31, 2020. Patients with prior GLP-1RAs or DPP4is use, a dementia diagnosis within 12 months before the index date, or recent hospitalization were excluded. The primary outcome was the incidence of dementia, Alzheimer's disease, vascular dementia, frontotemporal dementia, Parkinson's disease, extrapyramidal and movement disorders, and dementia with Lewy bodies, assessed over a follow-up period ranging from 90 days to 5 years. Statistical analyses included Kaplan-Meier survival curves and Cox proportional hazards models.

RESULTS: GLP-1RAs use was associated with a significantly lower risk of dementia (HR: 0.80, 95% CI: 0.71-0.91, p = 0.001) and Alzheimer's disease (HR: 0.76, 95% CI: 0.59-0.98, p = 0.033) compared to DPP4is use. However, no significant differences were observed in vascular dementia, frontotemporal dementia, Parkinson's disease, extrapyramidal and movement disorders, or dementia with Lewy bodies.

CONCLUSIONS: GLP-1RAs therapy may reduce the risk of dementia and Alzheimer's disease in patients with CKD stage 3 or later, offering potential neuroprotective benefits beyond glycemic control. Research is needed to confirm these findings and optimize treatment strategies for this vulnerable population.},
}

@article {pmid41696896,
year = {2026},
author = {Jubair, H},
title = {Glial cells in dementia: From cellular dysfunction to therapeutic frontiers.},
journal = {Cell transplantation},
volume = {35},
number = {},
pages = {9636897251414216},
doi = {10.1177/09636897251414216},
pmid = {41696896},
issn = {1555-3892},
mesh = {Humans ; *Neuroglia/metabolism/pathology ; *Dementia/pathology/therapy/metabolism ; Animals ; },
abstract = {Neurodegenerative dementias, including Alzheimer's disease and vascular dementia, have long been viewed through a neuron-centric lens. However, growing evidence highlights the indispensable and multifaceted roles of glial cells, astrocytes, microglia, and oligodendrocytes in both the onset and progression of these disorders. While prior reviews have cataloged glial dysfunction in isolation, this review offers a novel, integrative framework that maps the interconnected roles of glial subtypes across molecular, cellular, and circuit-level pathology in dementia. We critically synthesize recent advances in single-cell RNA sequencing, spatial transcriptomics, and glial imaging to redefine glial heterogeneity and function in disease states. Special emphasis is placed on the dynamic cross talk between glial populations and the feedback loops that govern their dual roles in neuroprotection and neurodegeneration. Furthermore, we examine emerging therapeutic strategies targeting glial-specific pathways, including NF-κB, JAK/STAT, CSF1R, and TREM2 signaling, as well as remyelinating agents and stem cell-based interventions. By integrating glial biology with therapeutic innovation, this review positions glial cells not as supporting actors but as central regulators and potential gatekeepers of dementia pathogenesis and treatment.},
}

Humans
*Neuroglia/metabolism/pathology
*Dementia/pathology/therapy/metabolism
Animals

@article {pmid41696300,
year = {2026},
author = {Bajaj, S and Mahesh, R},
title = {Galantamine-Escitalopram Combination Therapy in Alzheimer's Comorbid Depression Model in Mice: Role of BDNF/KYN Pathways, Neuroinflammation, and Oxidative Stress.},
journal = {ACS omega},
volume = {11},
number = {5},
pages = {7396-7414},
pmid = {41696300},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia, accounting for more than two-thirds of cases in older adults. AD is associated with neuropsychiatric symptoms such as depression, anxiety, and sleep disturbances. The coexistence of AD with depression, in particular, poses serious challenges and often results in suboptimal outcomes with conventional therapies. The present study therefore aimed to investigate the therapeutic potential of escitalopram (ESC; SSRI) in combination with galantamine (GAL; AChE inhibitor) on key pathological pathways, including the neurotrophic system, hypothalamic-pituitary-adrenal (HPA) axis, kynurenine pathway, inflammation, and oxidative stress, in an animal model of AD comorbid with depression. Swiss albino mice were subjected to chronic mild stress (CMS) for 21 days and received intrahippocampal administration of amyloid-β peptide to mimic AD-depression comorbidity. Subsequently, ESC (10 mg/kg) combined with GAL (5 mg/kg) was administered orally for 20 days alongside the CMS protocol, followed by behavioral, biochemical, and histopathological assessments. The combined GAL + ESC treatment significantly alleviated depressive symptoms and improved working and spatial memory in CMS and amyloid-β-exposed mice. Furthermore, the therapy normalized hippocampal levels of BDNF, proinflammatory cytokines (IL-6, TNF-α), kynurenine metabolites (3-HK, QUIN), and oxidative stress markers toward those observed in the sham group. Histopathological analysis further confirmed the preservation of hippocampal integrity with combined therapy. Overall, the findings highlight the potential of ESC as an adjunct to GAL in ameliorating depressive symptoms and cognitive deficits, underscoring its promise for further clinical evaluation in the management of AD comorbid with depression.},
}

@article {pmid41696149,
year = {2026},
author = {Fang, W and Zhao, J and Li, L and Wang, Y and Xu, ZP and Zhang, L},
title = {An anti-inflammatory neuroenhancer mitigates amyloid-β pathology to improve Alzheimer's disease therapy.},
journal = {Materials today. Bio},
volume = {37},
number = {},
pages = {102874},
pmid = {41696149},
issn = {2590-0064},
abstract = {β-amyloid (Aβ) inhibition significantly attenuates the early-stage Alzheimer's disease (AD) progression, but the improvement in cognitive function remains limited by neuroinflammation. Here, we developed a bioinspired neuroenhancer that concurrently targets both Aβ aggregation and neuroinflammation. Rutin and small interfering RNA targeting beta-site amyloid precursor protein cleaving enzyme 1 (siBACE1) were co-loaded into the calcium phosphate core, which was further coated with lipid bilayers and Angiopep-2/rabies virus glycoprotein 29 peptides to form the multifunctional neuroenhancer (RB@LCP-AR). RB@LCP-AR not only releases siBACE1 to silence BACE1 expression and block Aβ production from the cleavage of amyloid precursor protein, but also releases Rutin to suppress the Aβ aggregation. Moreover, the released Rutin of RB@LCP-AR directly alleviates Aβ-induced mitochondria dysfunction and intracellular ROS production in neuronal cells. Notably, the targeting of RB@LCP-AR to neurons and the inhibition of Aβ reduce the microgliosis and astrogliosis, further alleviating neuroinflammation and synapse loss. Consequently, AD mice receiving RB@LCP-AR treatment efficiently recovered their memory and cognition. Our study thus provides a coordinated targeting of Aβ and neuroinflammation inhibition, holding considerable potential to promote the recovery of memory and cognition in AD.},
}

@article {pmid41695973,
year = {2026},
author = {Zhang, Q and Ma, L and Zhao, L and Zhu, S and Qi, H and Pan, Z and Zhou, J},
title = {Network analysis of optimal deep or machine learning strategies for classification and detection of Alzheimer's disease based on MRI scanning.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1644480},
pmid = {41695973},
issn = {1662-4548},
abstract = {BACKGROUND: Alzheimer's disease (AD) presents a significant global health challenge, with its prevalence projected to increase substantially by 2050. Despite its widespread impact, the underlying causes and mechanisms remain incompletely understood, complicating efforts toward effective diagnosis and treatment. Pathologically, AD is marked by the accumulation of senile plaques and neurofibrillary tangles, but the relationship between these factors and disease progression is complex and heterogeneous.

OBJECTIVE: The present study aimed to compare the efficacy of different deep/machine learning models based on MRI scanning.

METHODS: The study follows rigorous systematic review protocols, adhering to the Cochrane Handbook of Systematic Reviews and Interventions and the PRISMA guidelines. A comprehensive search strategy was employed across multiple databases, including PubMed, Web of Science, Cochrane, Medline, and EMBASE. Advanced statistical methods were used for data synthesis and analysis, incorporating network meta-analysis and machine learning techniques to evaluate the accuracy and efficacy of different diagnostic models.

RESULTS: The meta-analysis included 11 studies that met the predefined inclusion criteria. The studies employed various machine learning algorithms, including CNN, ResNet, and DenseNet, to classify AD and distinguish it from mild cognitive impairment (MCI) and healthy controls. The results indicate that CNN and ResNet consistently outperform other models in terms of classification accuracy. Additionally, the integration of nanotechnology and AI-driven diagnostics demonstrates significant potential in enhancing the diagnostic process.

CONCLUSION: Despite challenges such as data heterogeneity and the interpretability of AI-driven models, the study highlights the transformative potential of computational techniques and advanced imaging technologies in AD diagnosis and management. The integration of network-based analyses and machine learning approaches offers promising avenues for future research, aiming to revolutionize the understanding and approach to Alzheimer's disease.},
}

@article {pmid41695753,
year = {2026},
author = {Salvadores, N},
title = {Biomedical research in Alzheimer's disease in a Latin American developing country: challenges in the informed consent process.},
journal = {Brain communications},
volume = {8},
number = {1},
pages = {fcag011},
pmid = {41695753},
issn = {2632-1297},
abstract = {Alzheimer's disease (AD) is a significant global health issue, impacting 50 million individuals with dementia worldwide, a number projected to triple by 2050. Although research has been conducted for decades, there is no effective prevention, treatment, or early diagnostic method for AD. Research on AD in Latin America (LatAm) faces unique challenges compared to developed countries due to socioeconomic, cultural, and infrastructural factors. While the prevalence of dementia is rapidly increasing in LatAm due to demographic shifts, the region is underrepresented in research, diagnostics and care. The informed consent process, a critical aspect of research, becomes particularly complex with individuals who have cognitive impairments. It requires a balance between protecting vulnerable individuals and advancing research for their benefit. By developing and implementing best practices, ethical research can be conducted with this population, ensuring they receive appropriate care. This review provides an update on informed consent for AD research in Chile.},
}

@article {pmid41694525,
year = {2026},
author = {Jiang, X and Lv, G and Mendes, ME and Wu, J and Yuan, J and Lu, ZK},
title = {Lifetime cost-effectiveness of lecanemab for early Alzheimer's disease.},
journal = {Frontiers in public health},
volume = {14},
number = {},
pages = {1692508},
pmid = {41694525},
issn = {2296-2565},
mesh = {*Alzheimer Disease/drug therapy/economics ; Humans ; *Cost-Benefit Analysis ; *Antibodies, Monoclonal, Humanized/economics/therapeutic use ; Quality-Adjusted Life Years ; United States ; Markov Chains ; Aged ; Male ; Female ; },
abstract = {INTRODUCTION: Lecanemab is the second anti-amyloid-β monoclonal antibody to receive FDA approval for the treatment of early Alzheimer's disease (AD), following aducanumab. Unlike aducanumab, which faced restricted Medicare coverage, lecanemab received traditional approval in 2023, resulting in broader access through Medicare. Despite these developments, the comparative cost-effectiveness of lecanemab and aducanumab has not been fully established. This study aimed to assess whether lecanemab is more cost-effective than aducanumab in the management of early AD.

METHODS: An indirect comparison of cost-effectiveness was performed due to the absence of head-to-head randomized controlled trials. A five-state Markov model was constructed from the perspective of the US healthcare system with a lifetime horizon and a 1-year cycle length. Model outcomes included life-years (LYs), quality-adjusted life-years (QALYs), and costs, all discounted at an annual rate of 3%. Incremental cost-effectiveness ratios (ICERs) were calculated and compared with established willingness-to-pay (WTP) thresholds. One-way sensitivity analyses identified key drivers of model uncertainty, and a probabilistic sensitivity analysis (PSA) with 1,000 Monte Carlo simulations tested the robustness of the findings.

RESULTS: The incremental cost of the lecanemab group compared to the aducanumab group was $30,018.97, with an increase in quality-adjusted life-years (QALYs) of 0.25, resulting in an ICER of $121,678.49 per QALY gained. The result of the one-way sensitivity analysis showed that the utility of the state of mild dementia due to AD had the most important effects on the ICER of the lecanemab group compared to the aducanumab group. The probabilistic sensitivity analysis showed that lecanemab was more cost-effective than aducanumab across various WTP thresholds.

CONCLUSION: Our findings suggest that lecanemab provides greater value than aducanumab; however, at current list prices, neither drug is cost-effective compared with the standard of care. Price reductions are necessary to improve affordability, particularly for lecanemab, which is more widely covered by Medicare. Policy implications remain significant, as under the Inflation Reduction Act (IRA), biologics such as lecanemab are exempt from Medicare price negotiations for 13 years post-approval, limiting short-term opportunities for cost adjustment.},
}

*Alzheimer Disease/drug therapy/economics
Humans
*Cost-Benefit Analysis
*Antibodies, Monoclonal, Humanized/economics/therapeutic use
Quality-Adjusted Life Years
United States
Markov Chains
Aged
Male
Female

@article {pmid41694229,
year = {2026},
author = {Kushnir, CN and Taylor-Bateman, V and Davies, NM and Anderson, EL},
title = {Assessing the repurposing potential of disease-modifying antirheumatic drug targets to reduce Alzheimer's disease risk: a Mendelian randomization study.},
journal = {Brain, behavior, & immunity - health},
volume = {52},
number = {},
pages = {101185},
pmid = {41694229},
issn = {2666-3546},
abstract = {BACKGROUND: Systemic inflammation plays a key role in the development and progression of Alzheimer's disease (AD). However, the repurposing potential of select anti-inflammatory drug targets for AD treatment remains unclear.

METHODS: Two-sample Mendelian randomization (MR) and colocalization analyses were conducted to estimate the effects of select disease-modifying antirheumatic (DMARD) targets on AD risk. We investigated 9 DMARD targets, using blood protein quantitative trait loci (pQTLs) from the UK Biobank Pharma Proteomics Project (n = 54,219). Outcome associations were extracted from the International Genomics of Alzheimer's Project (ncases = 21,982, ncontrols = 41,944).

RESULTS: Our MR estimates suggest that higher levels of FCGR3B, an etanercept target, increased the risk of AD (OR: 1.10; 95% CI [1.02, 1.19]; p = 0.01). We found little evidence that the remaining DMARD targets affected AD risk. Colocalization analysis provided little evidence that target pQTLs, including FCGR3B, colocalized with AD.

CONCLUSIONS: Our findings suggest a causal effect of FCGR3B on AD risk, but not for the remainder of the analyzed DMARD targets. Further research is recommended to elucidate the causal role of FCGR3B in AD and build upon the current literature on viable AD therapeutic targets.},
}

@article {pmid41693920,
year = {2026},
author = {Ebdah, W and Thomas, SD and Eissa, N and Jayaprakash, P and Łażewska, D and Kieć-Kononowicz, K and Sadek, B},
title = {Simultaneous inhibition of cholinesterase and antagonism of histamine H3 receptors alleviates cognitive deficits and mitigates apoptosis in scopolamine-induced amnesia in mice.},
journal = {Frontiers in behavioral neuroscience},
volume = {20},
number = {},
pages = {1722019},
pmid = {41693920},
issn = {1662-5153},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory deficits. Mounting evidence highlights the role of cholinergic and histaminergic neurotransmissions in the pathophysiology of AD. Hence, developing agents that target multiple neurotransmitter systems may provide improved therapeutic benefits.

METHODS: This study investigated the effects of acute systemic administration of E100, a dual-active cholinesterase inhibitor (ChEI) and histamine H3 receptor (H3R) antagonist, on scopolamine (SCO)-induced memory impairment in male C57BL/6 mice. Behavioral assessments, including the Novel Object Recognition Test (NORT), Y-Maze test (YMT), Three-Chamber Test (TCT), Fear Conditioning test (FCT), and Elevated Plus Maze (EPM), were conducted to assess cognitive performance while biochemical analyses assessed apoptotic markers, oxidative stress, neuroinflammation and acetylcholinesterase activity.

RESULTS: Systemic administration of E100 (10 mg/kg, i.p.) significantly improved memory function in SCO-induced amnesia, as evidenced by enhanced short-term memory (STM) (p < 0.001) and long-term memory (LTM) (p < 0.01) performance in the NORT, as well as improved spatial memory in YMT (p < 0.001) and FCT (p < 0.001; for cued fear memory) and (p < 0.001; for contextual fear memory). Additionally, E100 treatment in the TCT, improved social memory (p < 0.001) and alleviated SCO-induced anxiety-related deficits in the EPM (p < 0.001). Moreover, treatment with E100 (10 mg/kg, i.p.) attenuated SCO-induced neuroinflammation by reducing TNF-α and IL-1β levels and mitigated oxidative stress by increasing GSH and SOD while decreasing MDA levels in the hippocampus and cerebellum (p's < 0.001). E100 also reduced caspase-1 activity (p < 0.001), suggesting its anti-apoptotic effect. Furthermore, E100 attenuated the elevated AChE activity observed in SCO-induced amnesic mice (p < 0.01), providing effects comparable to those of the reference drug Donepezil.

DISCUSSION: These findings provide extensive in vivo evidence of the neuroprotective effects of E100, demonstrating its ability to ameliorate memory deficits, mitigate neuroinflammation and restore oxidative as well as AChE activity balance. By targeting both cholinergic and histaminergic dysfunction in the brain, E100 offers a promising therapeutic strategy for AD and related neurodegenerative disorders. This study highlights the potential role of dual-active ChEIs and H3R antagonists in memory impairment, and addressing multiple neuropathological mechanisms underlying AD.},
}

@article {pmid41693328,
year = {2026},
author = {Evans, M and Ritchie, C and Trepel, D and Hahn-Pedersen, JH and Kettle, J and Chan, MS and Bray, BD and Clark, A and Ivkovic, M and Wichmann, CA and Edwards, S},
title = {Estimating the Future Health and Social Care Costs of Alzheimer's Disease Dementia in the UK: Impact of Disease Modifying Therapy Efficacy, Uptake, and Care Model - A Scenario Modelling Study.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {2},
pages = {e70185},
doi = {10.1002/gps.70185},
pmid = {41693328},
issn = {1099-1166},
support = {//Novo Nordisk/ ; },
mesh = {Humans ; *Alzheimer Disease/economics/therapy/epidemiology ; United Kingdom/epidemiology ; *Health Care Costs/trends ; Aged ; Markov Chains ; Male ; Female ; Aged, 80 and over ; },
abstract = {BACKGROUND: To model scenarios exploring potential impacts of disease-modifying therapies (DMTs) for Alzheimer's disease (AD) dementia on future health and social care costs in the United Kingdom.

METHODS: A cohort Markov model was developed using population projections and published AD epidemiological data. Stage-specific transition rates (mild cognitive impairment due to AD and mild, moderate, severe AD dementia) and health and social care cost data were applied to estimate cost outcomes over 2020-2040. Potential proportion of eligible population receiving treatment (uptake) and follow-up care models (primary vs. specialist care) were elicited from expert opinion. Scenarios combined ranges of DMT efficacy estimates, uptake, and care model. DMT price was excluded due to no UK precedent.

RESULTS: Without DMT access, 1,038,405 people (1.5%) were projected to have AD dementia by 2040. Under the various DMT treatment scenarios, the prevalence of AD dementia by 2040 was projected to be 34,000-98,000 cases lower. Associated cumulative cost offsets were higher, £4.4-12.9billion over 2020-2040, in scenarios where most individuals received primary care follow-up, compared with majority specialist care follow-up (-£2.3billion to +£3.2billion). Assuming DMT efficacy of 25%, 58% uptake and majority primary care follow-up cumulative cost offsets increased from £4.4billion to £10.1billion by 2040 but the UK Health Service would need to diagnose and provide DMT for over a million individuals by 2030 and two million by 2040 to achieve this.

CONCLUSIONS: Potential cost offset from DMT are large but highly dependent on the model of healthcare delivery and the ability of healthcare systems to scale up diagnosis and treatment services.},
}

Humans
*Alzheimer Disease/economics/therapy/epidemiology
United Kingdom/epidemiology
*Health Care Costs/trends
Aged
Markov Chains
Male
Female
Aged, 80 and over

@article {pmid41692211,
year = {2026},
author = {Yue, S and Xing, H and Du, X and Wang, Y and Qin, R and He, J and Yu, J and Zhangsun, D and Craik, DJ and McIntosh, JM and Wu, Y and Zhu, X and Luo, S},
title = {α-Conotoxin LvID, an antagonist of α7 nicotinic acetylcholine receptor, mitigates Alzheimer-associated phenotypes by inhibiting Aβ deposition and reactive astrogliosis.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {150933},
doi = {10.1016/j.ijbiomac.2026.150933},
pmid = {41692211},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is the most common form of dementia in older adults. Neuritic plaques and reactive astrogliosis are neuropathological hallmarks of AD. Amyloid beta (Aβ), the major component of neuritic plaques, is derived from amyloid precursor protein (APP) by sequential cleavages by β-secretase and γ-secretase. The dysregulation of α7 nicotinic acetylcholine receptors (α7 nAChRs) is associated with both reactive astrogliosis and Aβ deposition. However, the role of nAChR antagonists in AD pathogenesis and underlying mechanisms remains elusive. In this study, we explored the effect of α-conotoxin LvID, a marine-derived peptide from Conus lividus, acts as a selective antagonist of α7 nAChRs, on AD pathogenesis. We found that LvID rescues learning and memory deficits in AD model mice in Morrios water maze, This led to a doubling of the memory of the AD model mice. Moreover, LvID treatment can reduce it by 50% in Aβ levels and also inhibited the proliferation of reactive astrocytes in AD model mice compared to non-treated AD model mice. Furthermore, the effect of LvID on learning and memory deficits and Aβ generation is mediated by an α7 nAChR‑calcium-CaMKII signaling pathway. These findings suggest that LvID may offer therapeutic potential for AD treatment by modulating α7 nAChR-mediated pathways involved in Aβ production. The work demonstrates that LvID is a potential drug template for AD treatment.},
}

@article {pmid41692154,
year = {2026},
author = {Chen, YC and Chiu, TJ and Wu, YY and Wang, YT and Wu, KH and Yeh, TH and Hsieh, YJ and Chen, WS and Chiu, CC},
title = {ALDH2 activation protects against mutant TOMM40-mediated mitochondrial dysfunction and neurodegeneration in Alzheimer's disease.},
journal = {Life sciences},
volume = {},
number = {},
pages = {124274},
doi = {10.1016/j.lfs.2026.124274},
pmid = {41692154},
issn = {1879-0631},
abstract = {AIMS: TOMM40 (translocase of outer mitochondrial membrane 40) is crucial for mitochondrial protein import. Mutations in TOMM40 increase the risk of Alzheimer's disease (AD) and trigger neuroinflammation. ALDH2 (aldehyde dehydrogenase 2) has neuroprotective effects, but the therapeutic role of ALDH2 activation in targeting neuroinflammation-induced AD remains unclear.

MATERIALS AND METHODS: In this study, it was hypothesized that TOMM40 mutations cause BV2 microglial activation and neuronal loss by impairing mitochondrial functions and that ALDH2 activation by small-molecule activator Alda-1 exerts anti-neuroinflammatory effect on HT22 hippocampal neurons.

KEY FINDINGS: Expression of mutant TOMM40 (F113L or F131L) induced BV2 microglial activation, reduced ALDH2 activity, and impaired mitochondrial function in BV2 microglia. ALDH2 activation by Alad-1 attenuated mutant TOMM40-induced microglial activation, mitochondrial dysfunction, ROS production, and lipid droplet accumulation. Alda-1 also suppressed mutant TOMM40-induced ROS/NF-κB/NLRP3 inflammasome axis and reduced the secretion of IL-1β, IL-6, and TNF-α. Conditioned medium from mutant TOMM40-expressing microglia induced apoptosis, neurite degeneration, and neuronal death in HT22 hippocampal neurons, which were alleviated by Alda-1 treatment.

SIGNIFICANCE: These findings suggest that ALDH2 activation prevents neuroinflammation-induced hippocampal neuronal death by downregulating NLRP3 inflammasome pathway, reducing lipid droplet accumulation, and enhancing mitochondrial function and neurite outgrowth.},
}

@article {pmid41691696,
year = {2026},
author = {Baniasadipour, B and Bagheri, F and Hendudari, F and Koopaee, S and Amini, SM and Kamalabadi, MA and Fatemidokht, A},
title = {Molecular and Microstructural MRI of Neuroinflammation in Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050420458251115070244},
pmid = {41691696},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a leading cause of cognitive decline in older adults, often diagnosed late when pathology and symptoms are established, reducing treatment effectiveness. Both AD and mild cognitive impairment (MCI) trigger neuroinflammation, leading to molecular and microstructural changes, including oxidative stress, mitochondrial dysfunction, glial activation, synaptic and neurotransmitter disturbances, myelin degradation, and white matter dysfunction. The blood-brain barrier (BBB) is also compromised.

METHODS: Advanced magnetic resonance imaging (MRI) techniques, such as magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), magnetization- transfer imaging (MTI), chemical exchange saturation transfer (CEST), contrast-enhanced MRI (CE-MRI), and arterial spin labeling (ASL), offer promise for the early detection of Alzheimer's disease (AD)-related molecular and microstructural changes.

RESULTS: Based on recent studies, advanced MRI modalities-including magnetic resonance spectroscopy, diffusion imaging, contrast-enhanced imaging, and chemical shift imaging-can highlight metabolic dysfunction, white matter degradation, microstructural disruption, blood-brain barrier dysfunction, cerebral hypoperfusion, vascular dysfunction, and pH alterations caused by neuroinflammation in Alzheimer's patients.

DISCUSSION: The integration of advanced MRI modalities into clinical practice could improve the diagnosis and management of Alzheimer's disease (AD). Magnetic resonance spectroscopy and diffusion imaging can identify metabolic and microstructural changes years before brain atrophy occurs, aiding professionals in the early detection of AD. Additionally, perfusion imaging and magnetization transfer imaging can help distinguish between Alzheimer's disease, frontotemporal dementia (FTD), and vascular dementia. Finally, contrast-enhanced MRI can monitor the integrity of the blood-brain barrier to evaluate responses to drug treatments.

CONCLUSION: Despite challenges, such as longer scan times and limited specificity, advanced MRIbased approaches are at the forefront of identifying reliable biomarkers for early detection of Alzheimer's disease and determining optimal management and treatment strategies.},
}

@article {pmid41691694,
year = {2026},
author = {Yang, Z and Tangli, M and Tan, Y and Chen, H and Shu, N and Ke, Z and Hu, Z and Ye, Q and Meng, H and Chen, H and Xu, Y},
title = {Repetitive Transcranial Magnetic Stimulation Alters Brain Communication Networks to Improve the Cognitive Function in Patients with Amnestic Mild Cognitive Impairment - A Clinical Trial.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X389814251019160424},
pmid = {41691694},
issn = {1875-6190},
abstract = {INTRODUCTION: Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive intervention that could effectively enhance the cognitive function in patients with amnestic mild cognitive impairment (aMCI). However, the mechanism and predictive biomarkers for therapeutic response remain poorly understood.

METHODS: Fifty-three aMCI patients underwent either neuro-navigated rTMS (n=28) or sham stimulation (n=25) targeting the left angular gyrus over four weeks (registered in 2021: ChiCTR2100050496). Multimodal MRI and comprehensive neuropsychological assessments were conducted pre- and post-intervention. Changes in brain communication networks and their correlation with cognitive improvements were analysed, with random forest models applied to predict treatment efficacy.

RESULTS: Episodic memory (p<0.001) and general cognitive function (p<0.05) of aMCI patients were significantly improved after intervention. Novel alterations in brain communications networks were identified in 5 sensorimotor areas, executive control regions, and emotion-cognition processing hubs. Communication alterations between the right precentral gyrus and right angular gyrus were positively correlated with the improvements in episodic memory (r=0.38, p=0.046), while the alterations between right precentral gyrus and right angular gyrus were negatively correlated with improvements in general cognitive function (MMSE, r=-0.44, p=0.019; MoCA, r=-0.43, p=0.024). Notably, the random forest model integrating communication network patterns with baseline demographic and neuropsychological data showed strong power in predicting rTMS effects.

DISCUSSION: These findings advance understanding of rTMS mechanisms by linking network plasticity to cognitive gains, addressing critical knowledge gaps.

CONCLUSION: Neuro-navigated rTMS targeting the left angular gyrus may enhance cognitive function in aMCI patients by improving inter-brain regions communication. Baseline communication patterns hold promise as predictive biomarkers, facilitating personalized treatment strategies.},
}

@article {pmid41691677,
year = {2026},
author = {Xinyang, L and Yuling, L and Shuai, M and Jing, H and Jianjun, C and Yang, G and Caixia, L and Ke, H and Yazhen, S},
title = {Network Pharmacology and Experimental Approaches Reveal the Effects of Scutellaria barbata Flavonoids Against Alzheimer's Diseasevia CREB Phosphorylation in Rats.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673417632251125054314},
pmid = {41691677},
issn = {1875-533X},
abstract = {INTRODUCTION: In this study, we investigated the effects and molecular mechanisms by which Scutellaria barbata flavonoids (SBFs) enhance neurogenesis and ameliorate memory impairment mediated by CREB phosphorylation in rats, using a network pharmacology approach.

METHODS: The active ingredients of SBFs and their targets were identified using the Traditional Chinese Medicine Systems Pharmacology platform. An Alzheimer's disease (AD) model was established by intracerebroventricular injection of Aβ25-35 combined with AlCl₃ and RHTGF-β1 (composited Aβ) in rats. The Morris water maze was used to confirm the successful establishment of the AD rat model. Successfully modeled rats were randomly divided into three groups: a model group and two treatment groups receiving either 140 mg/kg SBFs or 0.5 mg/kg Rolipram (positive control). After 38 days, the Morris water maze test was performed to assess learning and memory abilities. Hematoxylin-eosin (HE) staining, immunohistochemistry, quantitative PCR (qPCR), and Western blotting (WB) were conducted to evaluate neuronal morphology, NeuN protein expression, the mRNA levels of TrkB, RSK, CREB, and BDNF, and the protein expression of NeuN, TrkB, RSK, P-CREB-Ser133, and BDNF in the hippocampus and cerebral cortex of the rats.

DISCUSSION: These results indicate that SBFs and Rolipram ameliorate learning and memory impairment, reduce neuropathological changes, promote neurogenesis, and upregulate the BDNF- RSK-CREB signaling pathway through the activation of CREB phosphorylation. The findings suggest that the effects of SBFs are similar to those of Rolipram and that SBFs may also act as activators of CREB phosphorylation. Overall, SBFs promote neurogenesis and improve learning and memory deficits, possibly by enhancing CREB phosphorylation. This study identified the key targets and signaling pathways of SBFs in AD, indicating that SBFs represent a promising multitarget therapeutic candidate for the treatment of AD. However, our research has some limitations. Further studies are needed to determine the absorption route, major active components, and metabolic forms of the bioactive substances in SBFs. In future work, we aim to clarify the potential mechanisms of SBFs in AD by integrating multiple omics approaches and to evaluate the safety and efficacy of SBFs in AD treatment.

RESULTS: Thirty-seven targets were identified based on the intersection between AD-related targets and the components of SBFs. SBFs were involved in anti-AD activity through the MAPK signaling pathway, including the BDNF-RSK-CREB pathway. SBFs attenuated memory impairment, ameliorated neuropathological changes, increased NeuN protein expression, and regulated the mRNA expression of TrkB, RSK, CREB, and BDNF, as well as the protein expression of NeuN, TrkB, RSK, P-CREB-Ser133, and BDNF. Rolipram produced similar effects to SBFs.

CONCLUSION: Network pharmacology analysis and animal experiments confirmed that SBFs promote neurogenesis and ameliorate learning and memory impairment in AD model rats, primarily by facilitating CREB phosphorylation, similar to Rolipram. This study indicates that SBFs may be a promising therapeutic candidate for the treatment of AD.},
}

@article {pmid41691604,
year = {2026},
author = {Zhong, P and Shaker, T and Li, P and Yan, Z},
title = {Compromised synaptic signal from prefrontal cortex to mediodorsal thalamus in Alzheimer's disease models and its rescue by kinase inhibitors.},
journal = {The Journal of physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/JP289018},
pmid = {41691604},
issn = {1469-7793},
support = {AG064656/NH/NIH HHS/United States ; AG067597/NH/NIH HHS/United States ; },
abstract = {One of the most important neural circuits controlling cognitive processes is the projection from prefrontal cortex (PFC) to thalamus. To determine the strength of PFC projections to different thalamic nuclei, we performed optogenetic experiments by injecting channelrhodopsin-2 (ChR2) to medial PFC and recording synaptic responses evoked by light stimulation of ChR2-expressing terminals in thalamic neurons. The mediodorsal thalamus (MD) had markedly larger synaptic currents than neighbouring areas, suggesting that PFC sends prominent signals to MD. To determine whether the PFC to MD pathway is altered at early stages of Alzheimer's disease (AD), we used two mouse models (∼4 months old), transgenic mice carrying the human P301S mutation of microtubule-associated protein tau (Tau), and familial AD mice carrying five mutations on APP and PS1 (5xFAD). Both AD mouse models exhibited a more significant decline in short-term depression (STD) of synaptic responses in response to repeated light stimulation of MD ChR2 signals. Optogenetic imaging showed that Tau mice had significantly reduced ChR2 expression in MD axon terminals innervated by PFC. Next, we inhibited two kinases, serum and glucocorticoid-regulated kinase 1 (SGK1) and glycogen synthase kinase-3 beta (GSK3β), both of which can induce tau hyperphosphorylation and the ensuing disruption of microtubule-based transport in AD. Treatment with SGK1 or GSK3β inhibitor normalized STD of PFC to MD synaptic responses in Tau mice, but not in 5xFAD mice. These results suggest that the synaptic connectivity in the PFC-to-MD pathway is compromised in AD, which may be due to tau kinase-induced disruption of axonal transport. KEY POINTS: Optogenetic recordings reveal the strong connection from prefrontal cortex (PFC) to mediodorsal thalamus (MD). Short-term depression (STD) of PFC to MD synaptic responses is altered in P301S Tau and 5xFAD mouse models of Alzheimer's disease (AD). Optogenetic imaging uncovers the significantly reduced PFC to MD projection in Tau mice. Inhibition of tau kinase SGK1 or GSK3β normalizes STD of PFC to MD synaptic responses in Tau mice, but not 5xFAD mice. These results suggest that the synaptic information transfer from PFC to MD pathway is compromised in AD, probably via tau kinase-induced disruption of axonal transport.},
}

@article {pmid41689888,
year = {2026},
author = {Perry, R and Kipps, C and Soto Martín, ME and Bozzali, M and Logroscino, G and Trafford, S and Dhadda, S and Kanekiyo, M and Goodwin, A and Hodgkinson, M and Hersch, S and Irizarry, M and Kramer, L and Froelich, L},
title = {Lecanemab for treatment of individuals with early Alzheimer's Disease (AD) who are apolipoprotein E ε4 (ApoE ε4) non-carriers or heterozygotes.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {4},
pages = {100507},
doi = {10.1016/j.tjpad.2026.100507},
pmid = {41689888},
issn = {2426-0266},
abstract = {BACKGROUND: Lecanemab, an antibody directed at Aβ-protofibrils and plaque, showed meaningful delay in disease progression and biological effects consistent with disease modification in the phase 3 Clarity AD trial.

OBJECTIVE: The objective of this paper is to present efficacy and safety results in ApoE ε4 non-carriers or heterozygotes population of Clarity AD.

DESIGN: Clarity AD is an 18-month, randomized study (core) in participants with early AD, with an open-label extension phase (OLE) phase.

SETTING: Academic and clinical centers.

PARTICIPANTS: All eligible ApoE ε4 participants were randomized 1:1 across 2 treatment groups (placebo and lecanemab 10 mg/kg biweekly); the results presented herein are for the ApoE4 heterozygote or non-carrier participants.

MEASUREMENTS: Endpoints included change from baseline at 18 months in the global cognitive and functional scale, CDR-SB, amyloid positron emission tomography (PET), Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14), Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL), and health-related quality-of-life (HRQoL) assessments. Amyloid imaging related abnormalities (ARIA) occurrence was monitored throughout the study by central reading of magnetic resonance imaging. Following 18 months treatment in the Core, eligible participants transitioned to the OLE where they received open-label lecanemab. Clinical outcomes (CDR-SB, ADAS-Cog14, and ADCS-MCI-ADL) were evaluated by examining 'delayed start' (core:placebo followed by OLE:lecanemab) and 'early start' (core:lecanemab followed by OLE:lecanemab) cohorts as well as natural history cohorts. Time to progression to next stage of AD was also evaluated through 36 months.

RESULTS: 1795 participants with early AD were enrolled in Clarity AD, of which 1521 were ApoE ε4 heterozygotes or non-carriers (85 %). Lecanemab significantly reduced clinical decline on CDR-SB at 18 months compared to placebo in the ApoEε4 heterozygotes or non-carriers subgroup. Amyloid PET, ADAS-Cog14, ADCS-MCI-ADL, and HRQoL results were consistent with the CDR-SB findings. In the analysis subgroup, the most common adverse reactions for lecanemab were infusion-related reactions (26 %), ARIA-H (13 %), fall (11 %), headache (11 %), and ARIA-E (9 %). In the OLE, lecanemab-treated participants continued to accrue benefit in CDR-SB through 36 months, with continued separation through 36 months relative to the ADNI natural history cohort. Delayed start results follow a parallel trajectory relative to early start results, but do not catch up, confirming a disease modifying effect and reflecting importance of early treatment initiation. Results were similar for ADAS-Cog14 and ADCS-MCI-ADL. Lecanemab reduced the risk of progression to next stage of AD by 28 % on lecanemab as compared to the ADNI natural history cohort.

CONCLUSION: In the ApoE ε4 heterozygotes or non-carrier subgroup of Clarity AD, lecanemab slowed decline in disease progression and reduced markers of amyloid, with expanding benefit over time.

GOV IDENTIFIER: Clarity AD NCT03887455.},
}

@article {pmid41689668,
year = {2026},
author = {Sui, Y and Zhang, N and Chen, X and Tortorella, MD and He, J},
title = {Entorhinal Cholecystokinin in Alzheimer's Disease: Its Earliest Vulnerability and Rescue Effects Across Different Disease Stages in a Mouse Model.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01689-8},
pmid = {41689668},
issn = {1573-6830},
support = {CityUHK 11103922, CityUHK 11104923, CityUHK 11104524//Hong Kong Research Grants Council, General Research Fund/ ; C1043-21G, C1002-24W//Hong Kong Research Grants Council, Collaborative Research Fund/ ; SRFS2324-1S02//Hong Kong Research Grants Council, Senior Research Fellow Scheme/ ; 09203656//Hong Kong Health Bureau, Health and Medical Research Fund/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. The entorhinal cortex (Ent) is among the earliest affected regions, and its neuropeptide cholecystokinin (CCK) supports neocortical-associated memory. Although our previous work demonstrated that CCK treatment rescues cognition and neuroplasticity in aged AD mice, the correlations among CCK expression, synaptic function, and cognitive decline with aging remain poorly understood. Using 3xTg-AD mice (2-18 months), we performed stereological, histological, and molecular analyses to evaluate brain atrophy, neuronal loss, glial responses, and gene expression. Cognitive function was assessed using the novel object recognition test (NOR), motor learning was evaluated using the rotarod test, and synaptic integrity was measured via electrophysiological recordings. We also investigated the therapeutic potential of CCK-B receptor (CCK-BR) agonists on learning and memory and neuroplasticity across disease stages of AD. In 3xTg-AD mice, the Ent exhibits significant atrophy and excitatory neuronal loss as early as 7 months of age, confirming its role as one of the earliest and most severely affected regions in AD. CCK was downregulated earlier than other synaptic genes in the Ent and other brain regions. Cholecystokinin tetrapeptide (CCK-4) treatment rescued deficits in synaptic plasticity, cognition, and motor learning in 3xTg-AD mice across multiple disease stages. Long-term administration of HT-267, a CCK-BR agonist with a prolonged half-life, in young 3xTg-AD mice delayed cognitive decline, enhanced synaptic scaffolding, and restored long-term potentiation in both the cortex and hippocampus (HPC). Our findings identify CCK downregulation as an early biomarker in AD and demonstrate the therapeutic effects of CCK-BR agonists in mitigating cognitive and synaptic deficits from mild to severe disease stages. The ability of long-term CCK-4 analogue treatment to decelerate AD progression indicates its promise as an early intervention strategy.},
}

@article {pmid41689409,
year = {2026},
author = {Stroud, J and Cummings, JL and Chumki, SR and Such, P and Wang, D and Palma, AM and Zhang, Z and Grossberg, GT},
title = {Brexpiprazole for treating agitation in different groups of people with Alzheimer's dementia: a plain language summary.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/17582024.2026.2623968},
pmid = {41689409},
issn = {1758-2032},
}

@article {pmid41688417,
year = {2026},
author = {Nagata, T and Shinagawa, S and Noto, S and Yamato, K and Mori, N and Onuki, K},
title = {Family Caregiver Burden and Neuropsychiatric Symptoms in Japanese Community-Dwelling People With Alzheimer's Disease: A Cross-Sectional Study Using a Web-Based Questionnaire.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {2},
pages = {e70143},
doi = {10.1111/psyg.70143},
pmid = {41688417},
issn = {1479-8301},
support = {//Otsuka Pharmaceutical/ ; },
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/psychology/nursing/therapy ; *Caregivers/psychology/statistics & numerical data ; Middle Aged ; Aged ; Japan/epidemiology ; Cross-Sectional Studies ; Surveys and Questionnaires ; *Independent Living/psychology ; Adult ; *Caregiver Burden/psychology/epidemiology ; Aged, 80 and over ; *Cost of Illness ; Internet ; East Asian People ; },
abstract = {BACKGROUND: Previous studies of community-dwelling people with Alzheimer's disease (AD) have reported an association between the severe neuropsychiatric symptoms (NPS) of dementia and caregiver burden. We explored the current status of family caregiver burden, NPS of dementia, and care service usage in Japanese community-dwelling people with AD.

METHODS: A web-based questionnaire was administered to cohabitant family caregivers of community-dwelling people with AD from 13 to 27 November 2023. Amongst 8108 participants registered in the panel data, 705 family caregivers (age: 19-79 years) were selected. Participants completed the Japanese version of the Neuropsychiatric Inventory-Brief Questionnaire.

RESULTS: Family caregivers (n = 705) had a mean ± standard deviation (SD) age of 54.6 ± 11.5 years, 56.9% were male, and 84.0% cared for a parent or in-law with AD. Patients with AD had a mean ± SD age of 84.2 ± 8.8 years; 26.2% were male, and 90.6% had NPS, including 73.4% with hyperactivity (agitation, disinhibition, irritability and aberrant motor behaviour). Mean ± SD caregiving time per week was higher for caregivers of patients with NPS versus without NPS (24.1 ± 22.1 vs. 17.6 ± 14.0 h). The dissatisfaction with nursing care support services was higher amongst caregivers of patients with NPS vs. without NPS. To manage hyperactivity, 11.3% of caregivers administered medication and 11.5% relocated patients to a calm environment; 16.6% of the caregivers had no way to cope. Amongst caregivers who responded 'administer medication' in response to hyperactivity, 32.1% had care staff or a medical provider come in and administer oral medication and 18.9% took the patient to a medical facility to receive an injection or intravenous treatment.

CONCLUSIONS: Caregiving for AD patients with NPS (vs. without NPS) was associated with longer duration of caregiving, greater usage of nursing care services and dissatisfaction with nursing care support services.},
}

Humans
Male
Female
*Alzheimer Disease/psychology/nursing/therapy
*Caregivers/psychology/statistics & numerical data
Middle Aged
Aged
Japan/epidemiology
Cross-Sectional Studies
Surveys and Questionnaires
*Independent Living/psychology
Adult
*Caregiver Burden/psychology/epidemiology
Aged, 80 and over
*Cost of Illness
Internet
East Asian People

@article {pmid41688290,
year = {2026},
author = {Wang, C and Liu, X and Fan, Y and Liu, GY and Wu, P and Li, SC and Du, YJ},
title = {Silk fibroin@polydopamine for acupoint catgut-embedding therapy in Alzheimer's disease.},
journal = {Journal of integrative medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.joim.2026.01.010},
pmid = {41688290},
issn = {2095-4964},
abstract = {OBJECTIVE: We developed a novel silk fibroin@polydopamine (SF@PDA) material and investigated the mechanism of SF@PDA acupoint implantation for the treatment of Alzheimer's disease (AD) in a mouse model.

METHODS: In the materials research phase, we characterized the surface morphology and properties of the novel SF@PDA composites and evaluated their safety using the cell counting kit-8 assay. Following the intervention, C57BL/6 mice underwent open-field experiments and the Morris water maze test. We analyzed the collected tissues with hematoxylin-eosin staining, immunofluorescent staining, Western blotting, reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent assay.

RESULTS: After acupoint implantation, SF@PDA reduced amyloid-β (Aβ) deposition and preserve neurons, thereby improving cognitive performance. In particular, SF@PDA can reduce the expression of inflammatory factors, including interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α, and inhibit the inflammatory response, thereby further reducing Aβ accumulation and neuronal damage. The SF@PDA treatment resulted in an increase in exploratory behavior and a decrease in the number of errors in mice. Meanwhile, the number of Aβ plaques in the brain was significantly reduced (P < 0.05), and inflammatory cell infiltration was lessened.

CONCLUSION: SF@PDA acupoint implantation has significant therapeutic effects on AD model mice. The mechanism can be related to the inhibition of inflammatory response, reduction of Aβ deposition, and promotion of nerve regeneration. Please cite this article as: Wang C, Liu X, Fan Y, Liu GY, Wu P, Li SC, Du YJ. Silk fibroin@polydopamine for acupoint catgut-embedding therapy in Alzheimer's disease. J Integr Med. 2026; Epub ahead of print.},
}

@article {pmid41687996,
year = {2026},
author = {Gautam, AS and Anju, K and Singh, RK},
title = {Treatment with Interleukin-17 A antibody restored behavioral and neuronal biomarkers in Amyloid-beta1-42-exposed model of Alzheimer's disease.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {150856},
doi = {10.1016/j.ijbiomac.2026.150856},
pmid = {41687996},
issn = {1879-0003},
abstract = {The neuroinflammation in Alzheimer's disease (AD) is due to amyloid-beta1-42 (Aβ1-42) triggered cytokines release from the brain resident immune cells. Interleukin-17 A (IL-17 A) is one of the crucial cytokines involved in orchestrating neuroinflammation and exacerbating AD pathology. Thus, IL-17 A may be considered as one of the key therapeutic options to control AD progression. This study was conducted using BALB/c mice divided into four groups, such as control group, Aβ1-42 (5 μg) group, Aβ1-42 (5 μg) + IL-17 A neutralizing antibody (1 μg) group, and Aβ1-42 (5 μg) + antibody control (IgG1 isotype, 1 μg) group. The intranasal exposure of either Aß1-42 or vehicle was administered once daily for the first seven consecutive days. The intranasal exposure to anti-mouse IL-17 A neutralizing antibody or isotype control was performed once daily from day 5 to day 7, one hour after Aß1-42 exposure. The memory evaluations were conducted through the Morris water maze, novel object recognition test, and passive avoidance test. The brain IL-17 A cytokine levels were increased >2-fold in Aβ1-42-exposed mice as compared to control. IL-17 A antibody exposure led to significant partial improvement in cognitive memory and significantly reduced the expression of AD biomarkers (amyloid precursor protein, beta secretase, phosphorylated tau) along with a significant suppression of IL-17 A signaling axis, astrogliosis, neuronal damage and cytokines in the brain regions of Aβ1-42-exposed animals. In conclusion, neutralizing IL-17 A prevented Aβ1-42-mediated effects and revealed IL-17 A as a potential therapeutic target involved in the regulation of AD progression and pathology.},
}

@article {pmid41687942,
year = {2026},
author = {Wang, S and Guo, Y and Wang, S and Wang, Y and Huo, S and Li, M and Chen, Q and Zhang, L and Kuang, H and Pan, J and Liu, Y},
title = {Polygonatum Sibiricum polysaccharide ameliorates Alzheimer's disease by alleviating cuproptosis and activating the PI3K/AKT signaling pathway.},
journal = {Journal of ethnopharmacology},
volume = {362},
number = {},
pages = {121359},
doi = {10.1016/j.jep.2026.121359},
pmid = {41687942},
issn = {1872-7573},
abstract = {Defined by the selective loss of central nervous system neurons, a progressive neurodegenerative disorder is what Alzheimer's disease (AD) constitutes. It is recognized as the leading cause of dementia globally. Polygonatum sibiricum, also known as "tiger ginger" and "chicken-head ginseng", was hailed as a "treasure herb" by the ancient Chinese pharmacologist Li Shizhen. As a traditional Chinese medicine, its primary active component, Polygonatum sibiricum polysaccharide (PSP), has demonstrated well-defined neuroprotective effects.

AIM OF THE STUDY: The core objective of the present research was to dissect the molecular mechanisms that underlie the therapeutic actions of PSP in AD.

MATERIALS AND METHODS: PSP was purified through water extraction, alcohol precipitation, decolorization, Sevag method deproteinization, and dialysis. The purified polysaccharide was characterized by ultraviolet and infrared spectroscopy. Spatial learning was evaluated as examined by performance in the Morris water maze. To investigate the pathological processes involved in PSP's effects, a range of techniques were employed, including Nissl staining, biochemical assays, immunohistochemistry, transmission electron microscopy, immunofluorescence, and western blotting. The interaction between PSP and the DLAT protein was examined using the CETSA.

RESULTS: Experimental findings indicated that administration of PSP mitigated cognitive impairments in mice with AD and attenuated the loss of neuronal cells. Furthermore, PSP ameliorated mitochondrial damage, modulated cuproptosis-related proteins, and activated the phosphorylation of PI3K and AKT.

CONCLUSION: The present study demonstrates that PSP improves cognitive impairments in 3 × Tg-AD mice by targeting DLAT and subsequently activating the PI3K/AKT pathway. The findings from in vitro cellular models align with those observed in vivo studies. Consequently, PSP emerges as a promising agent endowed with therapeutic potential for AD treatment.},
}

@article {pmid41687939,
year = {2026},
author = {He, S and Fu, XJ and Sun, YH and Zhou, P and Zhang, S and Wang, ZG},
title = {Haikun Shenxi Capsule Alleviates Alzheimer's Disease by Targeting Mitophagy to Clear Turbidity Toxin.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121367},
doi = {10.1016/j.jep.2026.121367},
pmid = {41687939},
issn = {1872-7573},
abstract = {"Turbidity toxin damages brain" has been identified as a critical etiopathogenetic mechanism in Alzheimer's disease (AD). Haikun Shenxi Capsule (HKSX), a traditional Chinese medicine (TCM) formula with efficacy in dissolving turbidity and eliminating toxicant, is clinically used for chronic renal failure (CRF).

AIM OF THE STUDY: Based on the TCM theory of "treating different diseases with the same therapy", this study aimed to investigated the neuroprotective effects and molecular mechanisms of HKSX on AD.

MATERIALS AND METHODS: SAMP8 mice and N2aApp695 cells were used as AD models, behavioral, pathological assessments, as well as metabolomics, transmission electron microscopy (TEM), immunofluorescence (IF), immunohistochemistry (IHC) and western blot analyses, were conducted to validate HKSX's therapeutic effects and underlying mechanisms on AD.

RESULTS: Behavioral testing results showed that HKSX significantly improved learning and memory impairments of SAMP8 mice in novel object recognition (NOR) test and Morris Water Maze (MWM) test, along with reduced levels of Aβ and p-Tau at Thr231 in hippocampus. In metabolomics profiling, HKSX was demonstrated to modulate 73 metabolites and key metabolic pathways, including unsaturated fatty acid biosynthesis, tricarboxylic acid (TCA) cycle, and D-glutamine/D-glutamate metabolism, which are closely related with mitochondria. TEM showed that HKSX improved mitochondrial swelling and cristae rupture in SAMP8 mice, accompanied by increased autolysosomes. HKSX also enhanced mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) levels, reduced reactive oxygen species (ROS) content, suggesting that it significantly improved mitochondrial structure and function. IHC showed that HKSX administration significantly increased PINK1-positive staining. IF double-labeling results indicated that HKSX promoted the co-localization of Parkin-Tom20, LC-3-LAMP, and mitochondria-lysosomes, providing direct evidence of mitophagy activation. However, inhibition of mitophagy with Mdivi-1 abrogated HKSX-induced activation of PINK1-Parkin signaling, blocked clearance of turbidity toxins, such as Aβ, p-Tau and ROS, and suppressed autophagosome formation in N2a/APP695 cells, confirming that HKSX-mediated neuroprotection is mitophagy-dependent.

CONCLUSIONS: This study established that HKSX alleviated AD-like pathological features and cognitive deficits by activating PINK1-mediated mitophagy pathway. These results suggest that mitophagy may be involved in the cellular process of "eliminating turbidity toxins and detoxification," which provide a novel therapeutic angle for exploring TCM remedies that resolve turbidity in the treatment of AD.},
}

@article {pmid41686995,
year = {2026},
author = {Bacsu, JD and Mero, K and O'Connell, ME and Funk, M and Ménard, A and Norman, M and Blackstock, S and Mann, J and Hulko, W and D'Souza, MS and Fraser, S},
title = {Mapping the Landscape, Knowledge Gaps, and Areas for Innovation in Brain Health and Dementia Research in Canada: Protocol for a Scoping Review of Reviews.},
journal = {JMIR research protocols},
volume = {15},
number = {},
pages = {e79020},
doi = {10.2196/79020},
pmid = {41686995},
issn = {1929-0748},
mesh = {Humans ; Scoping Reviews as Topic ; *Dementia ; Canada ; *Brain ; *Biomedical Research ; Research Design ; },
abstract = {BACKGROUND: Dementia is one of Canada's most pressing public health challenges, with rates expected to surge in response to the country's aging population. Given the rapidly growing issue of dementia, understanding national research efforts is critical to prioritizing and advancing strategic directions in brain health and dementia research. Recently, the Canadian Institutes of Health Research awarded a 1-year funding grant from the Brain Health and Cognitive Impairment in Aging Research Initiative to map the scope of brain health and dementia research in Canada.

OBJECTIVE: This scoping review of reviews protocol aims to address this call by outlining the methodology that will be used for mapping the research landscape, documenting the knowledge gaps, and identifying areas of innovation to advance brain health and dementia research in Canada.

METHODS: Given the large volume of literature, a scoping review of Canadian-led reviews was selected as the most appropriate method because it would allow for a robust synthesis of nationally relevant research while mapping knowledge gaps and innovation. Our scoping review of reviews will follow the framework by Arksey and O'Malley along with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. The search will focus on peer-reviewed literature reviews published between January 1, 2020, and January 1, 2025, to capture the current state of knowledge since the national dementia strategy's publication in 2019. This search will be conducted using 5 electronic databases: CINAHL, PubMed, PsycInfo, Scopus, and Web of Science. Our data extraction table will include the following categories: author, province, and year; aim; review timeline; method; theme; knowledge gaps; innovations; and findings. The data will be analyzed using a combination of deductive and inductive thematic analysis.

RESULTS: This protocol was registered on June 5, 2025, with the Open Science Framework. This study was funded by the Canadian Institutes of Health Research from November 2024 to November 2025. The anticipated timeline for the publication of the full scoping review of reviews is May 2026. The findings from this review will be shared through targeted knowledge mobilization activities such as presentations at national funding agency meetings, academic conferences, and community workshops.

CONCLUSIONS: Our scoping review of reviews will provide a robust synthesis of the brain health and dementia research landscape, helping document critical knowledge gaps and identify areas for innovation. The results of this research will provide critical data to help inform strategic funding initiatives and future research directions. The findings from our scoping review will have implications for research funders, policymakers, community organizations, and researchers that are working to accelerate brain health and dementia research across Canada.},
}

Humans
Scoping Reviews as Topic
*Dementia
Canada
*Brain
*Biomedical Research
Research Design

@article {pmid41686674,
year = {2026},
author = {Luo, Y and Wen, H and Li, W and Wang, X and Zheng, X and Ge, H and Yin, Y and Chen, L and Wu, X and Hou, W},
title = {Acute deep brain stimulation induces sustained changes in theta and gamma oscillations in Alzheimer's disease model mice.},
journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TNSRE.2026.3664396},
pmid = {41686674},
issn = {1558-0210},
abstract = {Hippocampal theta and gamma oscillations degenerate early in Alzheimer's disease (AD), and may be a critical pathogenic factor and therapeutic target for AD. Deep brain stimulation (DBS) improves abnormal theta and gamma oscillations in AD; however, how these oscillations dynamically change after stimulation remains unclear. Exploring the prolonged neuroregulatory effects of DBS is essential for optimizing parameters and treatment strategies. Therefore, we investigated the sustained changes in the theta and gamma oscillations of the hippocampal cornu ammonis 1 region induced by acute DBS of the entorhinal cortex in APP/PS1 model mice and explored the underlying mechanisms. The results showed that the theta (4-8 Hz), low gamma (30-50 Hz) and high gamma (50-100 Hz) power of DBS-treated APP/PS1 mice exhibited a dynamic increase-decrease-increase trend, and the modulation index of theta and high gamma increased significantly and persisted for three weeks after DBS. Compared with the pre-DBS state, the firing rates of interneurons in APP/PS1 mice decreased significantly, while those of pyramidal neurons increased significantly, and the mean vector lengths of pyramidal neurons and interneurons with theta and gamma oscillations decreased significantly. Furthermore, the expression of CaMKII-α and GAD67 increased significantly. These findings suggest that acute DBS targeting the entorhinal cortex induces compensatory changes in the power of theta and gamma oscillations in APP/PS1 mice potentially by regulating the neuronal excitatory/inhibitory balance, thereby improving neuronal information transmission.},
}

@article {pmid41686334,
year = {2026},
author = {Bautista, JLC and Abellanosa, EAM and Jardiolin, JG and Calpo, RAA and Noriega, CNC and Devanadera, MKP and Lopez, SMM and Guevarra, LA},
title = {Web of Potentials: Neuroactive Components of Spider Venom and Their Emerging Pharmacologic Applications in Neurologic Diseases.},
journal = {BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy},
volume = {},
number = {},
pages = {},
pmid = {41686334},
issn = {1179-190X},
abstract = {Spider venom has emerged as a promising source of neuroactive compounds with potential applications in the treatment of complex neurological disorders. With over 53,000 described species and more yet to be studied, spiders possess one of the most chemically diverse venoms in the animal kingdom. This diversity has evolved through ecological adaptation, enabling spiders to paralyze and manipulate the nervous systems of a wide range of prey. These same mechanisms, which target ion channels, neurotransmitter receptors, and signaling enzymes, coincide with pathways implicated in human neurologic diseases. By examining the structure-function relationships of spider venom components, this review highlights how venom compounds can modulate neuronal excitability, synaptic transmission, inflammation, and neurodegeneration. Evidence of therapeutic relevance is found in diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, stroke, erectile dysfunction, and anxiety, where specific spider-derived components have demonstrated potential disease-modifying effects. Furthermore, by integrating molecular action with disease relevance and ecological context, this review proposes a shift in how spider venom is viewed-not simply as a source of isolated toxins, but as a platform for next-generation therapeutics. This integration of ecological, molecular, and therapeutic dimensions not only synthesizes current knowledge but also charts a path for future interdisciplinary research by revealing critical translational gaps and offering strategies to bridge them toward effective neurotherapeutics.},
}

@article {pmid41685967,
year = {2026},
author = {Ramesh, M and Padmaja, P and Ugale, V and Shirkhedkar, A and Pawara, R and Lokwani, D and Manda, S and Reddy, PN},
title = {Structural Exploration of Pyrazine-1,2,3-Triazole Hybrids as Selective Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.},
journal = {Drug development research},
volume = {87},
number = {2},
pages = {e70249},
doi = {10.1002/ddr.70249},
pmid = {41685967},
issn = {1098-2299},
mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Alzheimer Disease/drug therapy ; *Triazoles/chemistry/pharmacology ; Molecular Docking Simulation ; Acetylcholinesterase/metabolism/chemistry ; Animals ; Structure-Activity Relationship ; *Pyrazines/chemistry/pharmacology ; Humans ; Butyrylcholinesterase/metabolism ; Mice ; Cell Line ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to gradual deterioration of cognitive functions. Cholinesterase enzymes play a critical role in regulating acetylcholine levels in the brain, and their dysfunction leads to impaired cholinergic neurotransmission, which is a primary hallmark of AD and contributes significantly to the cognitive decline and dementia. Here, a series of pyrazine-1,2,3-triazole molecular hybrids incorporating a trifluoromethyl (-CF3) group were synthesized (8a-o). Synthesized compounds were then evaluated in vitro for cytotoxicity and cholinesterase inhibitory activities. All synthesized compounds were found to be nontoxic toward BV-2 cells in the cytotoxicity screening. The in vitro inhibition assays revealed that these derivatives exhibited greater inhibitory potency against acetylcholinesterase (AChE) than butyrylcholinesterase (BuChE). Among them, compound 8h demonstrated the most potent AChE inhibition compared to BuChE (AChE, IC50 = 5.43 µM; BuChE, IC50 = 127.12 µM). The most active compound 8h was further subjected to molecular docking and dynamic simulation (100 ns) to investigate its binding affinity, thermodynamic behavior, and stability within the active site of cholinesterase enzymes. Overall, the findings suggested that the synthesized compounds represent promising drug candidates as selective acetylcholinesterase inhibitors for the treatment of AD.},
}

*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis
*Alzheimer Disease/drug therapy
*Triazoles/chemistry/pharmacology
Molecular Docking Simulation
Acetylcholinesterase/metabolism/chemistry
Animals
Structure-Activity Relationship
*Pyrazines/chemistry/pharmacology
Humans
Butyrylcholinesterase/metabolism
Mice
Cell Line

@article {pmid41685837,
year = {2026},
author = {Jia, X and Guan, Y and Cao, W and Zhang, X and Duan, H and Guo, H and Chen, H and Wang, B and Li, T and Liao, J},
title = {NIR-responsive upconversion nanoplatforms: an anionic drug carrier for ROS amplification induced by β-amyloid fibrils.},
journal = {Dalton transactions (Cambridge, England : 2003)},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5dt03121d},
pmid = {41685837},
issn = {1477-9234},
abstract = {Alzheimer's disease (AD), marked by the misfolding/aggregation of β-amyloid (Aβ), is a major global health challenge. Polyoxometalates (POMs), as anionic therapeutic agents, exhibit potential in depolymerizing Aβ fibrils, inhibiting Aβ fibrillation, and acting as a photocatalyst. To achieve targeted reactive oxygen species (ROS) amplification, we developed a chitosan-modified near-infrared (NIR)-responsive upconversion nanoplatform, UCNPs(Tm/Er)@SiO2@GPS@CH, as a targeted carrier for POMs. The nanoplatform was constructed by sequentially modifying upconversion nanoparticles (UCNPs) with a silica layer, 3-glycidoxypropyltrimethoxysilane (GPS, as a linker), and chitosan (CH, a cationic biomacromolecule). The cationic CH layer enabled efficient loading of anionic POMs through electrostatic interactions with an optimal POM loading capacity of 415.41 μg mg[-1] that positively correlated with CH modification levels. Under NIR irradiation, the nanoplatform triggered a photodynamic effect with abundant ROS. Notably, compared with the control group and Aβ monomer group, the ROS generation in the Aβ fibril group was approximately doubled, which further enhanced the targeted therapeutic efficacy of the system. By integrating NIR responsiveness, cationic chitosan, targeted ROS generation, and low systemic toxicity, the nanoplatform provides a novel strategy for the photooxidative treatment of AD and offers insights into the design of chitosan-modified upconversion nanoparticle-based drug carrier systems.},
}

@article {pmid41685608,
year = {2026},
author = {Clark, HP and Horsley, D and Serpell-Stevens, A and Horton, T and Larsson, AI and Oluwabusola, ET and Ebel, R and De Clippele, LH and Jaspars, M},
title = {New Compounds From the Deep-sea Sponge Mycale lingua.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {2},
pages = {e03519},
doi = {10.1002/cbdv.202503519},
pmid = {41685608},
issn = {1612-1880},
support = {BB/M010996/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; 730984//ASSEMBLE Plus AmpLOPHELIA project/ ; GCBC//Department for Environment, Food and Rural Affairs, UK Government/ ; DEEPEND//Department for Environment, Food and Rural Affairs, UK Government/ ; },
mesh = {*Porifera/chemistry ; Animals ; Molecular Structure ; tau Proteins/metabolism/antagonists & inhibitors ; Humans ; Magnetic Resonance Spectroscopy ; },
abstract = {Three compatible solutes and one compound of unknown ecological function were isolated and characterized from the deep-sea sponge Mycale lingua (Bowerbank, 1866), collected from Tisler reef in Norway. These included the first isolation of asterubine and sulcatin from M. lingua as well as two new sulcatin analogues, sulcatin B and sulcatin C, which have not previously been reported from natural sources. Compound structures were elucidated through high-resolution liquid chromatography-mass spectrometry, and one- and two-dimensional nuclear magnetic resonance spectroscopic methods. All four compounds were tested in tau-tau aggregation assays to determine if they had potential for the treatment of Alzheimer's disease. No activity was displayed in either the cell-free or cell-based tau aggregation assays for any of the compounds.},
}

*Porifera/chemistry
Animals
Molecular Structure
tau Proteins/metabolism/antagonists & inhibitors
Humans
Magnetic Resonance Spectroscopy

@article {pmid41685542,
year = {2026},
author = {Kumar, GA and Pravallika, P and Thirumalai, V and Bukke, SPN and Rao, PBB and Thalluri, C and Chettupalli, AK and Onohuean, H},
title = {Persicaria hydropiper attenuates oxidative stress and reactive oxygen species, and inhibits amyloid-β/tau in SH-SY5Y cell lines via multiple pathways of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418555},
doi = {10.1177/13872877261418555},
pmid = {41685542},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder with progression leading to a decline in cognition. Despite the extensive research, conventional therapies have limited activity and often cause side effects. This demands the need for novel, safer, and effective treatment of AD.ObjectiveThe objective of this study was to determine the phytochemical constituents and determine the anti-Alzheimer's activity of Persicaria hydropiper.MethodsThe total phenol and flavonoid content of the Persicaria (MP) methanol extract was determined, and active principles were identified using GC-MS. The neuroprotective activity was investigated using biochemical assays against Aβ1-42-induced neurodegeneration in SH-SY5Y neuroblastoma cell lines.ResultsPhytochemical analysis revealed the presence of phenols (258.33 mg GAE) and flavonoids (48.31 mg QE). GC-MS identified the anti-inflammatory and antioxidant bioactive compounds. MP exhibited strong ABTS and DPPH radical-scavenging activities and inhibited AChE and BACE1 enzymes. In SHSY5Y cells, MP prevented Aβ1-42 aggregation, restored cell morphology, reduced reactive oxygen species levels, and preserved mitochondrial membrane potential. It suppressed Aβ and tau fibrillation, downregulated Bax and Caspase, upregulated Bcl2, Beclin-1, LC3B-II, and LAMP1, and reduced IL-6, TNF-α, and GSK3β expression, indicating potent neuroprotective, antioxidant, and anti-inflammatory effects.ConclusionsOverall, the results imply that Persicaria hydropiper exhibits protective activity on neuroblastoma cell lines by mitigating oxidative stress, Aβ/tau fibrils, cell death, and inflammation while also inducing autophagy induced by Aβ1-42. Further in vivo studies are needed to validate the findings to establish the plant as a potential source of anti-Alzheimer's drug.},
}

@article {pmid41685429,
year = {2026},
author = {Doring, TH},
title = {TropMol: a cloud-based web tool for virtual screening and early-stage prediction of acetylcholinesterase inhibitors using machine learning.},
journal = {Organic & biomolecular chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6ob00094k},
pmid = {41685429},
issn = {1477-0539},
abstract = {Alzheimer's disease (AD) is the most common type of dementia, accounting for at least two-thirds of dementia cases in people aged 65 and older. Numerous approaches have been studied for the treatment of this disease, including the cholinergic hypothesis. Acetylcholinesterase (AChE) is the most promising target studied within the cholinergic hypothesis for the treatment of AD. Therefore, it is necessary to develop predictive models for the identification of AChE inhibitors. Thus, general drug design models can assist chemical synthesis groups and biochemical testing laboratories by enabling virtual screening and drug design. In this work, the objective is to build a generic molecular screening prediction model for public, online and free use based on pIC50, using a random forest model (RF). For this, a dataset with approximately 16 000 compounds and 134 classes of descriptors was used, resulting in more than 2 000 000 calculated descriptors. Other algorithms were studied, such as gradient boosting, XGBoost, LightGBM, and RF with descriptors from principal component analysis (PCA), but none demonstrated significantly superior results compared to the RF model. The final model studied obtained an R[2] = 0.76 with a 15% test set and obtained an R[2] = 0.73 with a 30% test set, with rigorous Y-scrambling confirming the absence of chance correlation. External validation performed on an independent test set comprising 10% of the data yielded an R[2] of 0.77 and an RMSE of 0.67, statistically confirming that the model retains high predictive accuracy for novel chemical scaffolds and is free from overfitting. It is suggested that compounds containing oxime groups (RR'C = NOH) and those with high structural branching (higher Balaban index) tend to be less potent AChE inhibitors (negative correlation). In addition, some descriptors indicate that electronic charge distribution, molecular surface area, and hydrophobicity play important roles in correlating with the inhibitory activity (pIC50) of the compounds. The presence of linear alkane chains also seems relevant to activity (positive correlation and greater importance). The data and models are available at the following link: (https://colab.research.google.com/drive/1gMcuXAsrqTIBMNnsCEWG9xfkK7aaZAbn?usp=sharing).},
}

@article {pmid41684077,
year = {2026},
author = {Sioufi, MC and Heroiu, I and Wong, S and Le, GH and Dri, CE and Zheng, YJ and Rhee, TG and Lo, HKY and Guillen-Burgos, HF and Teopiz, KM and McIntyre, RS},
title = {The Effect of GLP-1 Receptor Agonists on Autophagy: Insights Gathered from Research Evaluating Neurodegenerative Disorders With These Agents.},
journal = {Acta neuropsychiatrica},
volume = {},
number = {},
pages = {1-36},
doi = {10.1017/neu.2026.10060},
pmid = {41684077},
issn = {1601-5215},
abstract = {OBJECTIVE: Impaired autophagy has been implicated in the pathophysiology of neurodegenerative disorders, such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). Consistent and replicated evidence indicate that Glucagon-like Peptide-1 Receptor Agonists (GLP-1RAs) exert treatment and preventative effects across disparate neurologic and mental disorders, potentially through mechanisms involving autophagy. This systematic review examined the effects of GLP-1RAs on autophagy in cell and animal models of AD and PD, as a proof of concept, to determine if these agents can be repurposed for the prevention and treatment of neurodegenerative and other mental disorders.

METHODS: A systematic search on PubMed, Web of Science, and OVID (Medline, Embase, and APA PsycInfo databases) was conducted from inception to June 17, 2025. Screening was performed independently by two reviewers (MCS and IH) using predefined inclusion and exclusion criteria. Subsequently, a quality assessment was conducted.

RESULTS: The search yielded 142 studies, of which 14 were included. Across studies, GLP-1RAs (e.g., liraglutide, semaglutide, and exendin-4) autophagy-specific markers, including beclin-1, LC3-II/LC3-I, ATG7, ATG3, and LAMP1, while normalizing p62 levels.

DISCUSSION: In addition to promoting neurogenesis, neuroplasticity, and reducing inflammation, GLP-1RAs appear to modulate molecular and cellular systems contributing to autophagy, potentially mediating their broad therapeutic effects. Collectively, these studies present promising findings of GLP-1RAs for neurodegenerative and mental disorders; however, further studies are required to establish their translatability to human populations.},
}

@article {pmid41684018,
year = {2026},
author = {Zhao, Z and Yang, L and Zhang, Z and Song, J and Zhang, C and Duan, X},
title = {3,4-Dihydroxybenzaldehyde Exerts Anti-Alzheimer's Effects by Inhibiting Aβ Protofibril Assembly and Activating Antioxidant Defense Mechanisms.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031599},
pmid = {41684018},
issn = {1422-0067},
support = {82560897//National Natural Science Foundation of China/ ; XDYCQNRC-2022-0284//Xingdian Talent Support Program-Special for Young Talent/ ; 2023-05-007//High-level Talents Projects of Yunnan University of Chinese Medicine-Fifth Level Talents/ ; Zyyzdxk-2023193//National Administration of Traditional Chinese Medicine High-level Key Discipline Construction Project 'Dai Medicine'/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/metabolism/chemistry ; Caenorhabditis elegans/metabolism/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; *Antioxidants/pharmacology/metabolism ; *Benzaldehydes/pharmacology/chemistry ; Caenorhabditis elegans Proteins/metabolism ; Molecular Dynamics Simulation ; Signal Transduction/drug effects ; Forkhead Transcription Factors/metabolism ; Disease Models, Animal ; DNA-Binding Proteins ; Transcription Factors ; },
abstract = {3,4-Dihydroxybenzaldehyde (DBD) is a polyphenolic active constituent derived from Gastrodia elata. Its characteristic phenolic structure is associated with diverse bioactivities, such as anti-inflammatory, antioxidant, and cardioprotective effects. However, its role and underlying mechanisms in combating Alzheimer's disease (AD) remain inadequately elucidated. In this study, we employed computational and experimental approaches to investigate the anti-AD effects of DBD. Molecular dynamics simulations revealed that DBD binds to Aβ fibrils via π-π stacking, hydrophobic interactions, and hydrogen bonds, suggesting its potential to disrupt Aβ fibril stability and thereby inhibit aggregation. In vivo experiments in an AD C. elegans model demonstrated that 2 mM DBD treatment significantly delayed paralysis and extended lifespan. It also improved locomotor activity and pharyngeal pumping rates, while reducing lipofuscin accumulation. These results collectively suggest that DBD promotes healthspan-associated phenotypes. Broad-targeted metabolomics analysis indicated that DBD significantly altered the metabolic profile of the worms. Further mechanistic investigations suggested that the protective effects of DBD are associated with the activation of the DAF-16/FOXO and SKN-1/Nrf2 signaling pathways, accompanied by enhanced resistance to oxidative and thermal stress in nematodes. These findings suggest that DBD exhibits anti-AD potential through multimodal mechanisms, which involve interference with Aβ toxicity and reinforcement of cellular defense. This study supports DBD as a candidate compound and provides a rationale for its further investigation.},
}

Animals
*Amyloid beta-Peptides/metabolism/chemistry
Caenorhabditis elegans/metabolism/drug effects
*Alzheimer Disease/drug therapy/metabolism
*Antioxidants/pharmacology/metabolism
*Benzaldehydes/pharmacology/chemistry
Caenorhabditis elegans Proteins/metabolism
Molecular Dynamics Simulation
Signal Transduction/drug effects
Forkhead Transcription Factors/metabolism
Disease Models, Animal
DNA-Binding Proteins
Transcription Factors

@article {pmid41683895,
year = {2026},
author = {Fernández-Ceballos, MLÁ and Vidal-Nogueira, L and Fernández-Pereira, C and Fortes-González, P and Salgado-Barreira, Á and Ledo-Matos, E and Santana-Muriel, E and Rivera-Baltanás, T and Olivares, JM and Veiga, C and Prieto-González, JM and Agís-Balboa, RC},
title = {Reduced Plasma Aβ Peptides but Stable NfL and GFAP in Major Depressive Disorder.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031474},
pmid = {41683895},
issn = {1422-0067},
support = {PI18/01311//Instituto de Salud Carlos III-ISCIII/ ; PID2022-138936OB-C31//Ministerio de Ciencia e Innovación/ ; PTA2023-023499-I,//Agencia Estatal de Investigación/ ; IN606A-2024/016//Agencia Gallega de Innovación/ ; },
mesh = {Humans ; *Amyloid beta-Peptides/blood ; *Glial Fibrillary Acidic Protein/blood ; *Major Depressive Disorder/blood ; Male ; Female ; *Neurofilament Proteins/blood ; Middle Aged ; Biomarkers/blood ; Adult ; Cross-Sectional Studies ; *Peptide Fragments/blood ; Aged ; Case-Control Studies ; },
abstract = {Major depressive disorder (MDD) has been associated with an increased risk of cognitive decline and neurodegenerative disorders like Alzheimer's disease (AD), prompting interest in peripheral biomarkers related to amyloid metabolism as well as neuroaxonal and astroglial injury. However, evidence regarding circulating markers in MDD remains inconsistent. In this cross-sectional study, we simultaneously assessed plasma levels of amyloid-β peptides (Aβ40 and Aβ42), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in MDD patients and healthy controls (HC) using ultrasensitive single-molecule array (SIMOA) technology. Associations with clinical and cognitive scales were examined. Plasma concentrations of Aβ40 and Aβ42 were significantly lower in MDD patients, whereas no group differences were observed for NfL and GFAP, after correcting for age and sex. However, both Aβ peptides were not significantly associated with depressive symptom severity, whereas the Aβ42/Aβ40 ratio was negatively associated with anhedonia. NfL and GFAP levels were primarily influenced by age. In the absence of a reduced Aβ42/Aβ40 ratio, these findings suggest that reduced plasma Aβ levels in MDD may reflect systemic or metabolic factors associated with MDD, including lifestyle or treatment-related effects. Therefore, these findings should be interpreted with caution and further examined in longitudinal studies to prevent potential confounding factors.},
}

Humans
*Amyloid beta-Peptides/blood
*Glial Fibrillary Acidic Protein/blood
*Major Depressive Disorder/blood
Male
Female
*Neurofilament Proteins/blood
Middle Aged
Biomarkers/blood
Adult
Cross-Sectional Studies
*Peptide Fragments/blood
Aged
Case-Control Studies

@article {pmid41683679,
year = {2026},
author = {Zhang, L and Lu, T and Hua, Z and Peng, S and Du, H and Zhai, X and Cai, Z and Hua, J and Ma, X},
title = {Recent Advances in Polyoxometalates Targeting Proteins Associated with Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Applications.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031257},
pmid = {41683679},
issn = {1422-0067},
support = {202303021211194//Shanxi Province Science Foundation/ ; 2025JG175//Research Project on Educational Reform of Postgraduate Education in Shanxi Province/ ; },
mesh = {*Alzheimer Disease/metabolism/drug therapy ; Humans ; *Tungsten Compounds/chemistry/therapeutic use/pharmacology ; Amyloid beta-Peptides/metabolism ; Animals ; Reactive Oxygen Species/metabolism ; Polyoxometalates ; },
abstract = {Polyoxometalates (POMs) exhibit significant potential for application in Alzheimer's disease (AD) therapeutics owing to their inherent chemical and physical properties and structural tunability. Through transition metal substitution, functional modification, and the construction of POMs-based nanocomposites, POMs can precisely recognize and effectively modulate various key pathogenic proteins involved in Alzheimer's disease. They can also intervene in disease progression through multiple mechanisms, including inhibition of Aβ aggregation, disaggregation of amyloid-β (Aβ), scavenging of reactive oxygen species (ROS), hydrolytic activity, and modulation of enzyme function. In addition, due to their outstanding physicochemical properties, the application of POMs in phototherapy has emerged as a significant direction in AD treatment research. This review systematically summarizes recent advances from 2011 to 2025 in POMs targeting key pathogenic proteins in AD, comprehensively analyzes their specific mechanisms of action across different therapeutic contexts, highlights their significant advantages and broad potential in AD treatment, and provides new insights for the future structural design, functional optimization, and clinical translation of POMs.},
}

*Alzheimer Disease/metabolism/drug therapy
Humans
*Tungsten Compounds/chemistry/therapeutic use/pharmacology
Amyloid beta-Peptides/metabolism
Animals
Reactive Oxygen Species/metabolism
Polyoxometalates

@article {pmid41683566,
year = {2026},
author = {Jha, D and Ancona, M and Oplt, F and Farmer, SL and Vagenknecht, M and Vazquez-Otero, A and Prazdnyk, I and Soukup, J and Mathew, RS and Peterson, V and Bitton, DA},
title = {InCytokine, an Open-Source Software, Reveals a TREM2 Variant-Specific Cytokine Signature.},
journal = {International journal of molecular sciences},
volume = {27},
number = {3},
pages = {},
doi = {10.3390/ijms27031137},
pmid = {41683566},
issn = {1422-0067},
mesh = {*Receptors, Immunologic/genetics/metabolism ; *Membrane Glycoproteins/genetics/metabolism ; Humans ; *Cytokines/metabolism/genetics ; Microglia/metabolism/drug effects ; *Software ; Alzheimer Disease/genetics/metabolism ; Animals ; Lipopolysaccharides/pharmacology ; Mice ; Protein Array Analysis ; },
abstract = {Cytokine and chemokine profiling is central to understanding inflammatory processes and the mechanisms driving diverse diseases. We introduce InCytokine, an open-source tool for semiquantitative analysis of cytokine and chemokine data generated by protein array technologies. InCytokine features robust and modular image-processing workflows, including automated spot detection, template alignment, normalization, quality control measures, and quantitative intensity summarization to deliver consistent and reliable readouts from profiling assays. We evaluated InCytokine by profiling wild-type microglia, TREM2 knockout, and Alzheimer's disease-associated TREM2 R47H variant cells in response to lipopolysaccharide and sulfatide exposure. Differential expression analysis revealed unique sulfatide-specific and genotype-specific cytokine signatures in TREM2 variants. We also report an intriguing modulation of DPP4 and a divergent expression pattern of ENA-78 in TREM2 variants in response to lipopolysaccharide and sulfatide treatment. Such distinct expression signatures raise the possibility that TREM2 variants may play a role in modulating inflammatory signaling relevant to cardio-metabolic and Alzheimer's disease. These signatures were corroborated using transcriptional profiling of the same microglia cells, revealing also a good concordance between protein array and RNA sequencing technologies. Taken together, InCytokine is an interactive, user-friendly web application for rapid, reproducible, and scalable analysis of protein array data, proven to generate meaningful insights for drug and biomarker discovery campaigns in pharmaceutical settings.},
}

*Receptors, Immunologic/genetics/metabolism
*Membrane Glycoproteins/genetics/metabolism
Humans
*Cytokines/metabolism/genetics
Microglia/metabolism/drug effects
*Software
Alzheimer Disease/genetics/metabolism
Animals
Lipopolysaccharides/pharmacology
Mice
Protein Array Analysis

@article {pmid41683261,
year = {2026},
author = {Marțiș, GS and Ungur, RA and Pop, A and Bordean, EM and Pașca, C and Borda, IM},
title = {Neuroprotective Herbs Associated with Parkinson's and Alzheimer's Disease.},
journal = {Nutrients},
volume = {18},
number = {3},
pages = {},
doi = {10.3390/nu18030439},
pmid = {41683261},
issn = {2072-6643},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Parkinson Disease/drug therapy ; *Neuroprotective Agents/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; Phytochemicals/pharmacology/therapeutic use ; Animals ; *Phytotherapy ; *Plants, Medicinal/chemistry ; Polyphenols/pharmacology ; Flavonoids ; Plant Extracts/pharmacology/therapeutic use ; },
abstract = {There is currently no treatment for Parkinson's (PD) and Alzheimer's (AD) diseases, and medications that target the blockage of amyloid plaque cascades appear to be the most promising for preventing these diseases. However, it is believed that consuming natural antioxidants, particularly phytochemicals such as phenolic compounds, may help the treatment process for neurodegenerative illnesses. Phenolic substances such as phenolic acids, polyphenols, and flavonoids have been shown to have antioxidant properties in plants and are thought to have a similar impact in humans. This review provides an analysis of the current landscape of PD and AD pathophysiology, paying particular attention to phytochemical-based therapeutic, preventive, and management strategies using disclosed herb candidates in in vivo/vitro studies. We also highlight the herb-derived components that have recently been identified for their effects in the treatment of PD/AD to provide a review and perspectives for the development of the next generation of drugs and preparations for the treatment of PD/AD.},
}

Humans
*Alzheimer Disease/drug therapy
*Parkinson Disease/drug therapy
*Neuroprotective Agents/pharmacology/therapeutic use
Antioxidants/pharmacology/therapeutic use
Phytochemicals/pharmacology/therapeutic use
Animals
*Phytotherapy
*Plants, Medicinal/chemistry
Polyphenols/pharmacology
Flavonoids
Plant Extracts/pharmacology/therapeutic use

@article {pmid41683016,
year = {2026},
author = {Liu, J and Ren, G and Niu, S and Liu, Y and Zhao, Y and Sun, Z and Zhu, Q and Zhang, J and Mao, Y and Liu, Z and Guo, Q and Liu, H},
title = {Probiotics Lactobacillus acidophilus LA4 and Lacticaseibacillus paracasei F5 Alleviate Cognitive Dysfunction in Alzheimer's Disease Models: A Dual-Screening Study in Drosophila and Mice.},
journal = {Foods (Basel, Switzerland)},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/foods15030429},
pmid = {41683016},
issn = {2304-8158},
support = {25YDTPJC00750//Tianjin Science and Technology Plan Project/ ; 25JCQNJC00840//Tianjin Science and Technology Plan Project/ ; },
abstract = {Identifying probiotics that modulate the gut-brain axis is vital for non-pharmacological Alzheimer's disease (AD) therapy. Through a staged screening from transgenic Drosophila to a D-galactose/AlCl3-induced murine model, Lactobacillus acidophilus LA4 and Lacticaseibacillus paracasei F5 were prioritized for their ability to improve climbing indices and reduce Aβ deposition and AChE activity. In AD mice, LA4 and F5 significantly ameliorated cognitive deficits and anxiety-like behaviors. Mechanistically, both strains reduced hippocampal Aβ1-42 and p-Tau levels, inhibited AChE, suppressed pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), and enhanced antioxidant enzymes (SOD, GSH-Px). 16S rRNA analysis revealed restored Firmicutes/Bacteroidetes ratios and enrichment of SCFA-producers (Muribaculaceae, Dubosiella). Metabolomics highlighted remodeled purine and arginine pathways, with strain-specific effects on primary bile acid biosynthesis/sphingolipid metabolism (LA4) and butanoate metabolism/nicotinate and nicotinamide metabolism (F5). Consequently, LA4 and F5 alleviate AD pathology by restructuring microbial and metabolic profiles, thereby mitigating neuroinflammation and oxidative stress. These findings confirm the potential of specific probiotics as functional food ingredients for the prevention and adjuvant treatment of neurodegenerative diseases.},
}

@article {pmid41682879,
year = {2026},
author = {Jang, YJ and Chang, JH and Moon, DU and Jeon, HJ},
title = {Cognitive Impairment, Dementia and Depression in Older Adults.},
journal = {Journal of clinical medicine},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/jcm15031198},
pmid = {41682879},
issn = {2077-0383},
support = {HR21C0885//Ministry of Health & Welfare, Republic of Korea/ ; },
abstract = {This narrative review integrates longitudinal cohort studies, neuroimaging and biomarker research, and major clinical trials to examine how depression and cognitive decline interact across the dementia continuum. Depression and cognitive impairment frequently co-occur in late life and exhibit substantial clinical and biological overlap. Meta-analytic and large population-based cohort studies consistently show that late-life depression increases the risk of mild cognitive impairment and dementia, with stronger associations observed for vascular dementia than for Alzheimer's disease. Neurobiological studies implicate cerebrovascular pathology, neuroinflammation, hypothalamic-pituitary-adrenal axis dysregulation, and fronto-subcortical circuit dysfunction as key mechanisms linking depressive symptoms to later cognitive decline. In a subset of older adults, new-onset depression-particularly when accompanied by executive dysfunction, subjective cognitive decline, or high white-matter hyperintensity burden-are associated with an increased likelihood of near-term cognitive decline and dementia, although evidence for a definitive prodromal state remains limited. Depression is also highly prevalent as part of the behavioral and psychological symptoms of dementia, occurring in 30-50% of individuals with Alzheimer's disease and even higher proportions in dementia with Lewy bodies or frontotemporal dementia. Comorbid depression in dementia accelerates cognitive and functional decline, increases neuropsychiatric burden, and worsens quality of life for patients and caregivers. Therapeutically, antidepressant treatment may confer modest benefits on mood and selected cognitive domains (e.g., processing speed and executive function) in non-demented older adults, whereas in established dementia, antidepressant efficacy is limited. In contrast, cholinesterase inhibitors, memantine, and multimodal non-pharmacological interventions yield small but measurable improvements in depressive or apathy-related symptoms. Emerging disease-modifying therapies for Alzheimer's disease have demonstrated cognitive benefits, but current trial data provide insufficient evidence regarding effects on depressive symptoms, highlighting an important gap for future research. These findings underscore the need for stage-specific, integrative strategies to address the intertwined trajectories of mood and cognition in aging.},
}

@article {pmid41681111,
year = {2026},
author = {Liu, G and Xie, X and Niu, Y and Li, Y and Zhang, J and Jiao, X and Dou, X and Tang, Y and Wang, X and Tang, B},
title = {Aβ-Targeted Theranostic Agent for NIR Fluorescence Imaging Guided Type-I and Type-II Dual Photodynamic Therapy of Alzheimer's Disease.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c07740},
pmid = {41681111},
issn = {1520-6882},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the pathological aggregation of β-amyloid (Aβ), a key contributor to its pathogenesis. Current diagnostic and therapeutic strategies are hindered by limitations such as low sensitivity, high costs, limited efficacy, and severe side effects. In this study, we rationally designed a series of novel theranostic agents integrating Aβ-targeted fluorescence imaging and photodynamic therapy (PDT). Following theoretical calculations and experimental validation, we identified TA-2 as a promising candidate with superior binding affinity, excellent specificity, and a significant NIR fluorescence response to Aβ conformers. Upon NIR light activation, TA-2 generated both O2[•-] and [1]O2 via Type I and II dual mechanisms. This dual ROS generation profile is particularly beneficial for addressing the hypoxic conditions often encountered in Alzheimer's disease (AD) pathology. The photoinduced ROS specifically oxidized critical Aβ residues, disrupting Aβ aggregation and disassembling preformed Aβ fibrils. In vitro, TA-2 demonstrated neuroprotection against Aβ-induced cytotoxicity by alleviating neuronal apoptosis. Following systemic administration, TA-2 easily crossed the blood-brain barrier, bound specifically to Aβ plaques, and enabled real-time monitoring of AD progression and therapeutic efficacy via NIR fluorescence imaging. Meanwhile, PDT with TA-2 resulted in a reduction of cerebral Aβ burden, leading to improved cognitive function in AD mice. These findings position TA-2 as a promising Aβ-targeted theranostic agent, combining both fluorescence imaging and spatiotemporally controlled PDT for AD diagnosis and treatment. This work demonstrates a new paradigm of NIR fluorescence imaging guided PDT for precise AD intervention.},
}

@article {pmid41680984,
year = {2026},
author = {Li, R and Huang, X and Lv, D and Wang, H and Qiao, S and Tan, L and Shi, X and Ren, Y and Wang, H},
title = {Mechanisms and clinical applications of transcranial alternating current stimulation in the treatment of neuropsychiatric disorders: Current evidence and future directions.},
journal = {Chinese medical journal},
volume = {},
number = {},
pages = {},
pmid = {41680984},
issn = {2542-5641},
abstract = {As a noninvasive brain stimulation technique, transcranial alternating current stimulation (tACS) can stimulate cortical neurons with sinusoidal and biphasic alternating current, which is expected to become an innovative neuromodulatory intervention for brain-related diseases. tACS primarily modulates the synchronization and desynchronization of neuronal electrical activity through low-intensity alternating current at specific frequencies, which regulates cortical excitability, alters endogenous cortical rhythms, and subsequently influences brain function. In recent years, tACS technology has been applied in clinical studies targeting various psychiatric and neurological disorders, demonstrating preliminary progress. However, the current research has focused mainly on feasibility studies and case analyses, while the effectiveness and safety of tACS modulation strategies require rigorous scientific validation. In the future, it will be necessary to conduct more high-quality, multicenter, large-sample randomized controlled double-blind trials targeting the different dysfunctions of patients with neuropsychiatric disorders and screen for optimal treatment parameters and stimulation sites to achieve the best neuromodulation effect. This article reviews the potential mechanisms, research progress, and factors influencing the therapeutic efficacy of tACS in the treatment of neuropsychiatric disorders. Furthermore, we discuss the existing challenges and future development trends in this field, aiming to provide novel insights and strategies for the clinical treatment and scientific investigation of neuropsychiatric disorders.},
}

@article {pmid41680609,
year = {2026},
author = {Pourhossein, S and Mianrood, IB and Khatami, SH and Ehtiati, S and Ghasemian, M and Mokhtari, F and Ahmadzade, R and Goudarzi, M and Hamed, N and Namvarjah, F and Karima, S},
title = {Acetyl-11-keto-β-boswellic acid attenuates tau oligomer-induced neurotoxicity in neuroblastoma cell model.},
journal = {BMC neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12868-026-00996-6},
pmid = {41680609},
issn = {1471-2202},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by microtubule destabilization, neuroinflammation, and tau pathology. Among the proposed therapeutic approaches, acetyl-11-keto-β-boswellic acid (AKBA), a bioactive triterpene from Boswellia serrata, has gained attention due to its multiple neuroprotective mechanisms, including microtubule stabilization, anti-inflammatory activity, antioxidant effects, and promotion of neurogenesis. In this study, we aimed to investigate the neuroprotective effect of AKBA against tau oligomer-induced cytotoxicity in SH-SY5Y neuroblastoma cells.

RESULTS: Recombinant human tau protein was expressed, purified, and oligomerized, and the formation of oligomers was confirmed by thioflavin T fluorescence and dynamic light scattering (DLS). SH-SY5Y cells were then treated with AKBA and exposed to tau oligomers. Cell viability was assessed via MTT assay, and apoptosis was evaluated by flow cytometry. The morphology of tau aggregates was visualized using transmission electron microscopy.

CONCLUSIONS: Our findings demonstrated that AKBA significantly reduced tau oligomer-induced cytotoxicity and enhanced cell viability. These results suggest that AKBA, through its multifaceted protective mechanisms, holds promise as a potential therapeutic agent for the treatment of tauopathies such as Alzheimer's disease.

CLINICAL TRIAL NUMBER: Not applicable.},
}

@article {pmid41680597,
year = {2026},
author = {Roh, HW and Chang, YY and Kim, KY and Jeon, SY and Wang, SM and Kim, E and Bae, JN and Ryu, SH},
title = {Evolving Alzheimer's Disease Clinical Practice: Updated Diagnostic Criteria, Fluid Biomarkers, and Special Considerations for Anti-Amyloid Therapies.},
journal = {Psychiatry investigation},
volume = {23},
number = {2},
pages = {183-200},
doi = {10.30773/pi.2025.0400},
pmid = {41680597},
issn = {1738-3684},
support = {//Korean Association for Geriatric Psychiatry/ ; RS-2024-00450828//National Research Foundation of Korea/ ; //Ministry of Science and ICT/ ; },
abstract = {OBJECTIVE: This review overviewed the recent paradigm shifts in the diagnosis and management of Alzheimer's disease (AD), emphasizing the 2024 Alzheimer's Association (AA) revised criteria, advances in cerebrospinal fluid (CSF) and blood-based biomarkers (BBMs), and practical considerations for anti-amyloid monoclonal antibody therapy.

METHODS: We conducted a narrative appraisal of consensus frameworks (2018 National Institute on Aging-Alzheimer's Association [NIA-AA] amyloid, tau, and neurodegeneration [AT(N)] and the 2024 AA criteria), clinical practice guidance from AA released in 2025, regulatory status of CSF and BBMs. Intended-use settings (triage vs. confirmatory) of BBMs and implementation of anti-amyloid anti-body treatments (lecanemab or donanemab) in real-world practice in Korea were also reviewed.

RESULTS: The 2024 AA criteria define AD biologically and designate A and T as core biomarkers; Core 1 biomarkers can establish AD irrespective of symptoms, whereas Core 2 biomarkers refine staging. A two-cutoff BBM strategy (positive/intermediate/negative) reduces misclassification and guides confirmatory CSF/positron emission tomography (PET) or retesting. BBMs now approach CSF/PET accuracy for amyloid detection, enable triage and, in selected settings, confirmation, and show utility for monitoring treatment response. Integration of clinical stages (1-6) with biological stages (A-D) clarifies syndrome-pathology discordance. Special scenarios-maintenance after induction, APOE ε4 homozygotes, Down syndrome, and serious mental illness-require individualized risk-benefit assessment. In South Korea, constrained access to tau PET and some BBMs necessitates Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision-anchored evaluation with selective biomarker testing.

CONCLUSION: Biomarker-oriented diagnosis and anti-amyloid therapies are reshaping AD care. Priorities include rigorous validation of BBMs across populations, equitable access to core biomarkers, safety strategies, and real-world evidence to implement maintenance and special-population care pathways.},
}

@article {pmid41678018,
year = {2026},
author = {Arbaciauskaite, S and Silvestri, S and Luo, P and Krüger, C and Mossmann, ZJ and Allelein, S and Scholz, A and Loeffler, D and Fiorenza, S and Menale, A and Torino, E and Kuhlmeier, D and Peters, O and Lehnardt, S},
title = {Microglia-Derived Extracellular Vesicles from Alzheimer's Disease Patients Carry miRNAs Driving a Neuroinflammatory Response.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {435},
pmid = {41678018},
issn = {1559-1182},
support = {LE 2420/7-1, SFB-TRR167/B03//Deutsche Forschungsgemeinschaft/ ; },
mesh = {*Microglia/metabolism/pathology ; *Alzheimer Disease/genetics/cerebrospinal fluid/pathology/metabolism ; *Extracellular Vesicles/metabolism ; Humans ; *MicroRNAs/metabolism/genetics ; Animals ; Mice ; *Neuroinflammatory Diseases/genetics/pathology/metabolism ; Aged ; Male ; Female ; HEK293 Cells ; Aged, 80 and over ; },
abstract = {Alzheimer's disease (AD) represents the most common cause of dementia and urgently requires sensitive biomarkers and effective therapies. Extracellular vesicles represent membranous nano-sized particles secreted from cells, which serve as intercellular messengers participating in central nervous system (CNS) homeostasis, but also are implicated in AD pathogenesis. In addition, EVs containing disease-specific signatures, such as microRNAs (miRNAs), are considered as potent tools for the diagnosis and treatment of AD and other brain disorders. In this study, we used TMEM119 antibody to immunocapture microglia-derived EVs from cerebrospinal fluid (CSF) of AD patients and control subjects. EVs harvested from these CSF samples contained distinct disease-specific miRNA profiles, as assessed by small RNA sequencing. Using a HEK TLR reporter cell system, we found that these miRNA are potent activators of human TLR8, an established RNA sensor. Out of the miRNAs present in AD-associated EVs, selected oligonucleotides were synthesized and loaded into BV2 microglia-derived EVs. Exposure of primary murine microglia to these miRNA-loaded EVs led to TNF release from these cells, thereby driving a neuroinflammatory response. Taken together, putatively microglia-derived EVs from the CSF of AD patients contain miRNAs, which are capable of activating hTLR8 and inducing an inflammatory response from microglia.},
}

*Microglia/metabolism/pathology
*Alzheimer Disease/genetics/cerebrospinal fluid/pathology/metabolism
*Extracellular Vesicles/metabolism
Humans
*MicroRNAs/metabolism/genetics
Animals
Mice
*Neuroinflammatory Diseases/genetics/pathology/metabolism
Aged
Male
Female
HEK293 Cells
Aged, 80 and over

@article {pmid41677765,
year = {2026},
author = {Kim, H and Hong, JY and Yeo, C and Kim, H and Jeon, WJ and Lee, J and Lee, YJ and Ha, IH},
title = {Neuroprotective Effects of Herbal Formula Yookgong-Dan on Oxidative Stress-Induced Tau Hyperphosphorylation in Rat Primary Hippocampal Neurons.},
journal = {Biology},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/biology15030294},
pmid = {41677765},
issn = {2079-7737},
abstract = {This study sought to evaluate the neuroprotective effects of YGD in an oxidative stress-induced Alzheimer's disease (AD)-like cellular model and to elucidate the underlying molecular pathways, with a focus on tau phosphorylation, Aβ accumulation, and antioxidant defense mechanisms. Rat primary hippocampal neurons were exposed to hydrogen peroxide to induce oxidative stress. The effects of YGD on neuronal viability, neurite outgrowth, and synaptic integrity were assessed using the immunodetection of microtubule-associated protein 2 (MAP2), postsynaptic density protein 95 (PSD-95), and synapsin-1. Levels of phosphorylated tau and Aβ were quantified, and the involvement of extracellular signal-regulated kinase (ERK), glycogen synthase kinase 3β (GSK3β), and nuclear factor-erythroid 2-related factor-2 (Nrf2) pathways was examined. Additionally, in silico molecular docking studies targeting the ATP-binding site of GSK3β were conducted to screen major phytochemicals from the ten medicinal herbs constituting YGD. YGD markedly enhanced neuronal viability under oxidative stress, promoted neurite extension, and increased synaptic marker expression (MAP2, PSD-95, and synapsin-1). Treatment reduced phosphorylated tau by suppressing ERK and GSK3β activation and significantly decreased Aβ accumulation. YGD also upregulated antioxidant defenses via the activation of the Nrf2 pathway. Docking simulations identified oleanolic acid (from Cornus officinalis) as the most potent GSK3β binder (-9.86 ± 0.40 kcal/mol), forming stable interactions with ARG96, ASN95, and GLU97. Additional compounds, including alisol C, drypemolundein B, and friedelin, demonstrated favorable binding energies and engaged key ATP-binding site residues. YGD confers neuroprotection through the integrated modulation of tau phosphorylation, Aβ pathology, and oxidative stress, partly via the multi-target engagement of GSK3β by its constituent phytochemicals. These findings support that YGD attenuates oxidative stress-induced AD-like cellular alterations.},
}

@article {pmid41677657,
year = {2026},
author = {Dagla, I and Gkikas, F and Gikas, E and Tsarbopoulos, A},
title = {Targeting Amyloid Beta Aggregation and Neuroinflammation in Alzheimer's Disease: Advances and Future Directions.},
journal = {Cells},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/cells15030295},
pmid = {41677657},
issn = {2073-4409},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Animals ; *Neuroinflammatory Diseases/drug therapy ; Blood-Brain Barrier/metabolism ; Drug Delivery Systems ; *Protein Aggregation, Pathological/drug therapy ; Neuroprotective Agents/therapeutic use/pharmacology ; *Protein Aggregates/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly. Among the diverse pathological features of AD, amyloid beta (Aβ) aggregation and neuroinflammation are recognized as central and interlinked mechanisms driving disease progression. This review focuses specifically on these two processes and highlights current pharmacological limitations in modifying disease pathology. Natural products such as curcumin, resveratrol, Ginkgo biloba, epigallocatechin gallate (EGCG), crocin, ashwagandha, and cannabidiol (CBD) have shown promising activity in modulating Aβ aggregation and neuroinflammatory pathways, offering multi-target neuroprotective effects in preclinical studies. However, their therapeutic application remains hindered by poor solubility, instability, rapid metabolism, and limited blood-brain barrier (BBB) permeability. To overcome these barriers, nanotechnology-based drug delivery systems-including polymeric nanoparticles, niosomes, solid lipid nanoparticles, and chitosan-based carriers-have emerged as effective strategies to enhance brain targeting, bioavailability, and pharmacological efficacy. We summarize the mechanistic insights and nanomedicine approaches related to these bioactives and discuss their potential in developing future disease-modifying therapies. By focusing on Aβ aggregation and neuroinflammation, this review provides a targeted perspective on the evolving role of natural compounds and nanocarriers in AD treatment.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/pathology
*Amyloid beta-Peptides/metabolism
Animals
*Neuroinflammatory Diseases/drug therapy
Blood-Brain Barrier/metabolism
Drug Delivery Systems
*Protein Aggregation, Pathological/drug therapy
Neuroprotective Agents/therapeutic use/pharmacology
*Protein Aggregates/drug effects

@article {pmid41677635,
year = {2026},
author = {Acquarone, E and Roy, SM and Staniszewski, A and Watterson, DM and Arancio, O},
title = {The Highly Selective 5-HT2B Receptor Antagonist MW073 Mitigates Aggressive Behavior in an Alzheimer's Disease Mouse Model.},
journal = {Cells},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/cells15030273},
pmid = {41677635},
issn = {2073-4409},
support = {AG066722/GF/NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Aggression/drug effects ; Disease Models, Animal ; Mice ; *Serotonin 5-HT2 Receptor Antagonists/pharmacology/therapeutic use ; Male ; Mice, Transgenic ; *Receptor, Serotonin, 5-HT2B/metabolism ; *Behavior, Animal/drug effects ; *Fluorobenzenes/pharmacology/therapeutic use ; Humans ; Mice, Inbred C57BL ; },
abstract = {Background: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of dementia worldwide. Progressive synaptic dysfunction underlies declines in cognition, daily functioning, and the development of neuropsychiatric syndromes. Neuropsychiatric syndromes that include agitation and aggression affect 40-60% of patients and represent a major source of caregiver burden. Serotonin 5-HT2B receptor levels are increased in the AD patient brain, and thus, treatment of AD animal models with the selective 5-HT2B receptor antagonist MW073 in prevention or disease stage paradigms attenuates Aβ- or tau-induced dysfunction. Methods: We investigated the effects of MW073 treatment on the aggressive behavior of Tg2576 mice in a resident-intruder assay. Results: MW073 treatment significantly reduced aggressive behavior in male Tg2576 mice. Conclusions: MW073 efficacy in treating aggression in Tg2576 mice implicates 5-HT2B receptor-mediated signaling in AD neuropsychiatric symptoms as well as cognitive and behavioral dysfunction.},
}

Animals
*Alzheimer Disease/drug therapy
*Aggression/drug effects
Disease Models, Animal
Mice
*Serotonin 5-HT2 Receptor Antagonists/pharmacology/therapeutic use
Male
Mice, Transgenic
*Receptor, Serotonin, 5-HT2B/metabolism
*Behavior, Animal/drug effects
*Fluorobenzenes/pharmacology/therapeutic use
Humans
Mice, Inbred C57BL

@article {pmid41677117,
year = {2026},
author = {Li, Y and Cheng, Q and Tian, S and Li, X and Chen, Y and Guo, Y and Jiang, Y and Tao, Y and Niu, X and Hu, H and Liu, Y and Li, S},
title = {Oridonin Ameliorates Alzheimer's Disease-Like Pathology in Male Mice Through Inhibition of Receptor-Interacting Protein Kinase 1.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70185},
pmid = {41677117},
issn = {1099-1573},
support = {82404605//National Natural Science Foundation of China/ ; U23A20510//National Natural Science Foundation of China/ ; U24A20806//National Natural Science Foundation of China/ ; 32300318//National Natural Science Foundation of China/ ; BX20220048//National Postdoctoral Program for Innovative Talents/ ; 2022MD723713//China Postdoctoral Science Foundation/ ; 2022NSFSC1362//Natural Science Foundation of Sichuan Province/ ; 2023ZYD0051//Natural Science Foundation of Sichuan Province/ ; 2024NSFSC1324//Natural Science Foundation of Sichuan Province/ ; },
abstract = {Oridonin (Ori) is a bioactive diterpenoid from Rabdosia rubescens that exhibits potent anti-inflammatory and neuroprotective properties. However, its potential role in Alzheimer's disease (AD), especially in modulating receptor-interacting protein kinase 1 (RIPK1)-mediated neuroinflammation and necroptosis, remains unclear. This study aimed to investigate Ori's therapeutic mechanism in AD by targeting RIPK1. We utilized cellular thermal shift assay (CETSA), drug affinity responsive target stability assay (DARTS), and bio-layer interferometry (BLI) to verify the binding of Ori to RIPK1. In vitro, inflammatory and necroptotic responses were assessed in BV2 microglial cells and HT22 neuronal cells using enzyme-linked immunosorbent assay (ELISA), reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blotting, immunofluorescence, and flow cytometry assays. In vivo, we evaluated Ori's therapeutic efficacy in 5× FAD transgenic mice, a well-established AD model, through behavioral analysis using the Morris water maze, along with histological and biochemical assessments of brain tissues. Ori demonstrated a robust interaction with RIPK1 (KD = 533 nM) and significantly increased its thermal and proteolytic stability. Treatment with Ori markedly suppressed the secretion of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα) in microglia by inhibiting the RIPK1-ERK1/2-NF-κB signaling pathway. In neurons, Ori effectively blocked the activation of the RIPK1-RIPK3-MLKL signaling cascade, prevented necrosome formation, and significantly reduced necroptotic cell death. Importantly, in the 5× FAD mouse model, Ori treatment substantially improved spatial learning and memory performance, decreased amyloid-beta (Aβ) plaque deposition, and attenuated inflammatory and necroptotic markers in both cortical and hippocampal regions. Ori as a natural small-molecule inhibitor of RIPK1, capable of concurrently mitigating neuroinflammation and necroptosis-two critical pathological processes underpinning AD. These findings strongly support Ori's potential as a disease-modifying therapeutic for AD.},
}

@article {pmid41676727,
year = {2026},
author = {Tong, M and Mehfooz, F and Zhang, S and Wang, Y and Fang, S and Saykin, AJ and Wang, X and Yan, J and , },
title = {Learning a Continuous Progression Trajectory of Amyloid in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.03.703568},
pmid = {41676727},
issn = {2692-8205},
abstract = {BACKGROUND: Understanding of Alzheimer progression is critical for timely diagnosis and treatment evaluation, but traditional discrete diagnostic groups often lack sensitivity to subtle early-stage changes.

METHODS: We developed SLOPE, an unsupervised dimensionality reduction method that models the amyloid progression in AD on a continuous scale while preserving the temporal order of longitudinal follow-up visits. Applied to longitudinal amyloid PET data, SLOPE generated a two-dimensional trajectory capturing global amyloid accumulation across the AD continuum.

RESULTS: SLOPE-derived staging scores better preserved temporal progression across diagnostic groups and longitudinal follow-up visits and can be generalized to held-out subjects. The learned trajectory revealed biologically consistent amyloid spreading patterns and greater sensitivity to early progression than global amyloid SUVR.

DISCUSSION: SLOPE provides a continuous staging of amyloid pathology that complements global amyloid measures by capturing early localized progression. These properties highlight its potential in disease modeling and monitoring, particularly in early and preclinical stages of AD.},
}

@article {pmid41676487,
year = {2026},
author = {Tagmazian, AA and Schwarz, C and Lange, C and Pitkänen, E and Vuoksimaa, E and , },
title = {petVAE: A Data-Driven Model for Identifying Amyloid PET Subgroups Across the Alzheimer's Disease Continuum.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.02.703218},
pmid = {41676487},
issn = {2692-8205},
abstract = {Amyloid-β (Aβ) PET imaging is a core biomarker and is considered sufficient for the biological diagnosis of Alzheimer's disease (AD). However, it is typically reduced to a binary Aβ™/Aβ+ classification. In this study, we aimed to identify subgroups along the continuum of Aβ accumulation including subgroups within Aβ- and Aβ+. We used a total of 3,110 of Aβ PET scans from Alzheimer's Disease Neuroimaging Initiative (ADNI) and Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) datasets to develop petVAE , a 2D variational autoencoder model. The model accurately reconstructed Aβ PET scans without prior labeling or pre-selection based on scanner type or region of interest. Latent representations of scans extracted from the petVAE (11,648 latent features per scan) were used to visualize, analyze, and cluster the AD continuum. We identified the latent features most representative of the continuum, and clustering of PET scans using these features produced four clusters. Post-hoc characterization revealed that two clusters (Aβ-, Aβ-+) were predominantly Aβ negative and two (Aβ+, Aβ++) were predominantly Aβ positive. All clusters differed significantly in standardized uptake value ratio (p < 1.64×10 [-8]) and cerebrospinal fluid (CSF) Aβ (p < 0.02), demonstrating petVAE's ability to assign scans along the Aβ continuum. The clusters at the extremes of the continuum (Aβ-, Aβ++) resembled to the conventional Aβ negative and Aβ positive groups and differed significantly in cognitive performance, Apolipoprotein E (APOE) ε4 prevalence, and Aβ, tau and phosphorylated tau CSF biomarkers (p < 3×10 [-6]). The two intermediate clusters (Aβ-+, Aβ+) showed significantly higher odds of carrying at least one APOE ε4 allele compared with the Aβ-cluster (p < 0.026). Participants in Aβ+ or Aβ++ clusters exhibited a significantly faster rate of progression to AD compared to Aβ-group (Hazard ratio = 2.42 and 9.43 for groups Aβ+ and Aβ++, respectively, p < 1.17×10 [-7]). Thus, petVAE was capable of reconstructing PET scans while also extracting latent features that effectively represented the AD continuum and defined biologically meaningful clusters. By capturing subtle Aβ-related changes in brain PET scans, petVAE -based classification enables the detection of preclinical AD stages and offers a new data-driven framework for studying disease progression.},
}

@article {pmid41676474,
year = {2026},
author = {Rossitto, LM and Foo, J and Di Silvestri, JM and Lehmann, L and Brunelli, M and Nie, Y and Muñoz-Mayorga, D and Xiao, Q and Dai-Liu, AY and Jati, S and Rossi, M and Daneman, R and Kelly, JW and Newman, JC and Myers, SA and Chen, X},
title = {Ketone body β-hydroxybutyrate restores neuronal Tau proteostasis via ketolysis-independent mechanism.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.30.702936},
pmid = {41676474},
issn = {2692-8205},
abstract = {Metabolic interventions that induce ketosis, including ketogenic diets, caloric restriction, intermittent fasting, and exercise, show promise in the treatment of Alzheimer's disease (AD) and related tauopathies. β-hydroxybutyrate (βHB), the primary ketone body produced during ketosis, reproduces key features of these metabolic interventions, but the molecular mechanism underlying its neuroprotective properties is not fully understood. Here, we demonstrate that a βHB precursor diet is sufficient to ameliorate Tau pathophysiology in a tauopathy mouse model. Furthermore, across in vitro , ex vivo , and in vivo models, we find that βHB enhances neuronal Tau proteostasis and reduces Tau aggregation and secretion. Importantly, these effects are independent of βHB's oxidation for ATP production, as its ketolysis-resistant enantiomer reproduces these benefits, indicating that ketolysis is dispensable for these effects. Overall, these data position βHB as a novel therapeutic avenue for AD and tauopathy and elucidate a novel mechanism of action of metabolic interventions in neurodegenerative disease.},
}

@article {pmid41676156,
year = {2026},
author = {Weng, Y and He, T and Li, M and Zhou, Q and Xie, J and Wei, L and Wang, X and Wang, JZ and Zhong, M and Li, S},
title = {Microglial histone H3K18 crotonylation promotes STAT1 expression and induces cognitive deficit in Alzheimer disease.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1744375},
pmid = {41676156},
issn = {1664-3224},
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics ; *Histones/metabolism ; Mice ; *Microglia/metabolism ; *STAT1 Transcription Factor/metabolism/genetics ; *Cognitive Dysfunction/metabolism/etiology ; Disease Models, Animal ; Hippocampus/metabolism ; Male ; Protein Processing, Post-Translational ; Mice, Transgenic ; Amyloid beta-Peptides ; Humans ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, yet the epigenetic mechanisms underlying its pathogenesis remain incompletely understood. Histone crotonylation, a novel post-translational modification, has been implicated in neuroinflammation. However, its role in AD-related cognitive impairment has not been elucidated.

METHODS: Histone crotonylation was examined in 5xFAD and Aβ42-injected mice. Crotonic acid was administered intracerebroventricular (ICV) to elevate hippocampal histone crotonylation in wild-type mice. Cognitive function was assessed using behavioral tests. Synaptic integrity was evaluated via western blotting and Golgi staining. Microglial activation and co-localization of H3K18cr were determined by immunofluorescence. Transcriptomic analysis identified differentially expressed genes and enriched pathways. The role of signal transducer and activator of transcription 1 (STAT1) was validated in BV2 microglial cells using the STAT1 inhibitor fludarabine.

RESULTS: Hippocampal pan-histone H3 crotonylation (H3Kcr) and H3K18cr were significantly upregulated in both 5xFAD and Aβ42-injected mice compared to controls. ICV injection of crotonic acid markedly elevated hippocampal H3Kcr and H3K18cr levels and induced significant cognitive deficits, shown by impaired novel object recognition and fear conditioning performance. Crotonic acid treatment resulted in synaptic dysfunction, including reduced synaptic markers (SYN1, SYT, GluA2, GluN2B) and decreased CA1 dendritic spine density. Crotonic acid also induced microgliosis with elevated Iba1 expression. H3K18cr was specifically upregulated in microglia, with no significant changes observed in neurons or astrocytes. Transcriptomic analysis identified 478 differentially expressed genes enriched predominantly in immune-related pathways, with STAT1 highlighted as a key upstream transcription factor. In BV2 cells, crotonic acid significantly increased total and phosphorylated STAT1 (Tyr701) levels via a JAK1-independent mechanism. Treatment with fludarabine effectively suppressed STAT1 expression and attenuated the production of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β.

CONCLUSION: This study provides the first evidence that elevated microglial H3K18cr contributes to AD-related cognitive impairment by promoting STAT1 expression and subsequent neuroinflammation. These findings identify microglial histone crotonylation as a novel epigenetic mechanism in AD pathogenesis and suggest that targeting the H3K18cr-STAT1 axis may represent a potential therapeutic strategy for AD.},
}

Animals
*Alzheimer Disease/metabolism/genetics
*Histones/metabolism
Mice
*Microglia/metabolism
*STAT1 Transcription Factor/metabolism/genetics
*Cognitive Dysfunction/metabolism/etiology
Disease Models, Animal
Hippocampus/metabolism
Male
Protein Processing, Post-Translational
Mice, Transgenic
Amyloid beta-Peptides
Humans

@article {pmid41675725,
year = {2026},
author = {Patel, T and Henna, F and Sharif, I and Javed, I and Mustafa, F and Sharif, H and Nasir, F and Javaid, M and Usman, SF and Hanani, C and Anand, N},
title = {A narrative review on the therapeutic potential of stem cells in neurodegenerative diseases: advances, insights, and challenges.},
journal = {Annals of medicine and surgery (2012)},
volume = {88},
number = {2},
pages = {1441-1453},
pmid = {41675725},
issn = {2049-0801},
abstract = {BACKGROUND: Neurodegenerative diseases (NDs) such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) are set apart by progressive neuronal loss and concomitant functional decline. Traditional therapies are equipped with only symptomatic relief, devoid of neurorestorative properties. Stem-cell-based therapies have the potential to revolutionize neurological care by replenishing lost cells, mitigating inflammation, and fostering a neuroprotective environment.

OBJECTIVES: This narrative review aims to appraise the treatment potential of various stem cell types in managing NDs, highlighting their functional pathways, delivery methods, and current experimental validation.

METHODS: A comprehensive literature search was carried out based on data retrieved from PubMed, The Cochrane Library, and ClinicalTrials.gov. Thirty-one studies that fulfill PICO criteria and only English-language publications are incorporated in this review. No part of the study design, data collection, analysis, or interpretation was conducted using artificial intelligence.

RESULTS: Stem cells, including embryonic stem cells, mesenchymal stem cells (MSCs), induced pluripotent stem cells, and neural stem cells, possess distinctive regenerative properties. MSC-derived exosomes can traverse the blood-brain barrier and improve nerve cell longevity. Administration routes such as intravenous, intranasal, and direct brain transplantation are being studied. Neurodegenerative conditions such as PD, AD, HD, and ALS have been widely studied for therapeutic benefits.

CONCLUSION: Regardless of their potential, stem cell therapies raise health risks, including neoplastic growth and immunological incompatibility, alongside bioethical issues. Developments in genetic modification, nanotechnology, and preconditioning strategies are being analyzed to optimize outcomes. Long-term research, harmonization of protocols, and extended patient follow-up are essential for the safe and effective development of medical applications.},
}

@article {pmid41675591,
year = {2026},
author = {Malliou, G and Reus, LM and Pijnenburg, YAL and van der Flier, WM and de Wit, NM and Chornyi, S and Kooij, G and de Vries, HE and Teunissen, CE and Visser, PJ and Ophoff, RA and Tijms, BM},
title = {Distinct CSF lipidomic profiles are associated with five proteomic subtypes in patients with Alzheimer's disease.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {11},
pmid = {41675591},
issn = {3059-4944},
abstract = {BACKGROUND: Alzheimer's disease (AD) is molecularly heterogeneous. In our previous cerebrospinal fluid (CSF) proteomic study in AD, we identified and validated five distinct molecular subtypes characterized by neuronal hyperplasticity (subtype 1), innate immune activation (subtype 2), RNA dysregulation (subtype 3), choroid plexus dysfunction (subtype 4) and blood-brain barrier impairment (subtype 5). These subtypes also differed in the CSF levels of proteins involved in lipid metabolism, suggesting that lipid dysregulation in AD might be subtype specific.

METHODS: We performed untargeted lipidomics on CSF samples from 601 individuals in the Amsterdam Dementia Cohort who were previously included in our proteomic study (n = 416 AD, 185 controls). Using the CSH-QTOF platform for complex lipids, 3,532 lipids were detected in CSF, 270 of which could be mapped to 13 different lipid classes. Lipid levels were compared between each AD subtype and controls using linear regression models adjusted for age and sex (R v4.2.1). Lipids with significantly different levels (p < 0.05) were included for pathway enrichment analysis with MetaboAnalyst6.0.

RESULTS: We observed alterations in the levels of 1,893 lipids, with the majority associated with a single AD subtype. Subtype 3 (RNA dysregulation) exhibited the most pronounced alterations, with altered CSF levels of 669 lipids, including triglycerides and fatty acids, which were reduced compared to controls. Subtype 4 (choroid plexus dysfunction) and subtype 5 (blood-brain barrier dysfunction) both had alterations in the same set of 150 lipids, but with changes occurring in opposite directions (i.e., decreased in subtype 4, and increased in subtype 5). These lipids were associated with sphingolipid metabolism and lipid transport. Subtype 1 (neuronal hyperplasticity) and subtype 2 (innate immune activation) had less pronounced differences compared to the other subtypes. Subtype 1 had increased levels of several phospholipids, indicating neuronal membrane remodeling, and subtype 2 decreased arachidonic acid levels, a precursor of immunoregulatory oxylipins.

CONCLUSION: Our findings reveal subtype-specific lipid metabolism alterations in AD. Currently, five lipid-targeting drugs are in phase 1 and 2 trials. Our results suggest that treatment efficacy may vary by subtype. Understanding these molecular differences can inform trial design and analysis, advancing the development of tailored therapies for AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s44477-026-00018-z.},
}

@article {pmid41618453,
year = {2026},
author = {Swain, A and Soni, ND and Gaspar, RB and Davis, JG and Liu, F and Juul, H and Nanga, RPR and Baur, JA and Reddy, R},
title = {In vivo imaging of glutamate uncovers the neuroprotective effects of nicotinamide riboside on excitotoxicity in an Alzheimer's mouse model.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {37},
pmid = {41618453},
issn = {1758-9193},
support = {R01 DK098656/DK/NIDDK NIH HHS/United States ; R01 AG063869/AG/NIA NIH HHS/United States ; P41 EB029460/EB/NIBIB NIH HHS/United States ; R01 DK098656/DK/NIDDK NIH HHS/United States ; R01 AG063869/AG/NIA NIH HHS/United States ; P41 EB029460/EB/NIBIB NIH HHS/United States ; },
abstract = {BACKGROUND: Nicotinamide adenine dinucleotide (NAD[+]) precursors, such as nicotinamide riboside (NR), have gained interest as potential therapeutics for alleviating Alzheimer’s disease (AD) pathology. Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) can provide insights into the effects of NR on AD by virtue of its sensitivity to monitoring the metabolic status of tissue in vivo.

METHODS: This study used glutamate-weighted CEST (GluCEST) MRI to monitor glutamate-associated metabolic changes following NR treatment in the 5xFAD mouse model of AD. Drinking water was supplemented with NR or provided as is to animals over the course of expected disease progression prior to imaging experiments. Following imaging, an immunohistochemical assay to monitor the expression of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba1) was performed to assess the extent of neuroinflammatory glial responses. A two-way ANCOVA with interaction was performed for statistical analysis of both CEST and IHC data.

RESULTS: Results from GluCEST revealed significantly higher glutamate levels in the hippocampal dentate gyrus of AD mice compared to WT, with a significant reduction following treatment. GFAP staining mirrored this trend, implicating reactive astrogliosis as a mechanism for elevated glutamate. Similar patterns were observed in the cerebral peduncles, a white matter bundle, in which GFAP and Iba1 supported GluCEST findings and suggested neuroinflammation in axonal tracts. Our findings are in concordance with studies reporting elevated glutamate associated with reactive gliosis and morphological changes disrupting glutamate imbalance. Interestingly, NR restores glutamate homeostasis and alleviates neuroinflammatory processes, thus rescuing tissue from excitotoxic insults.

CONCLUSION: Overall, this study demonstrates the potential of NR to mitigate glutamate-driven excitotoxicity in AD pathology, and highlights GluCEST as a sensitive in vivo, clinically translatable biomarker for neuroinflammation and excitotoxicity.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-01958-0.},
}

@article {pmid41673679,
year = {2026},
author = {Liao, J and Mou, H and Luo, S and Shen, L and Jiao, B},
title = {Microbiota and Alzheimer's disease: mechanistic insights from a multi-organ perspective.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {3},
pmid = {41673679},
issn = {2047-9158},
support = {82371434//National Natural Science Foundation of China/ ; 2024JJ2097//Outstanding Youth Fund of Hunan Provincial Natural Science Foundation/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder driven by multifactorial mechanisms. Increasing evidence suggests that dysbiosis, a term denoting an imbalance in the composition of the microbiota, may play a pivotal role in the pathogenesis of AD across multiple bodily sites, including the gut, oral cavity, nasal passages, lungs, and skin. Microbial imbalances may promote neuroinflammation, immune dysfunction, and metabolic disturbances through complex host-microbiota networks. This review synthesizes current advances in the understanding of microbiota-driven modulation of AD, introduces the "Multi-Axis Co-Regulation" concept, and evaluates microbial biomarkers for early diagnosis. Finally, the translational potential of microbiota-targeting interventions, including probiotics, dietary modulation, fecal microbiota transplantation, and oral microbiome-based therapies, are discussed, which represent novel strategies for precision prevention and treatment of AD.},
}

@article {pmid41673254,
year = {2026},
author = {Nazli, D and Ipekgil, D and Poyraz, YK and Can, K and Okmen, I and Turhanlar-Sahin, E and Sert Serdar, B and Kocturk, S and Ozhan, G},
title = {Epigallocatechin Gallate and Punicalagin Combination Reduces Aβ Aggregation and Promotes Neurogenesis in Adult Zebrafish Brain.},
journal = {Journal of neuroscience research},
volume = {104},
number = {2},
pages = {e70119},
doi = {10.1002/jnr.70119},
pmid = {41673254},
issn = {1097-4547},
support = {2021.KB.SAG.018//Dokuz Eylül Üniversitesi/ ; 121Z900//Türkiye Bilimsel ve Teknolojik Araştırma Kurumu/ ; IG 3024//European Molecular Biology Organization/ ; },
mesh = {Animals ; Zebrafish ; *Catechin/analogs & derivatives/pharmacology/administration & dosage ; *Hydrolyzable Tannins/pharmacology/administration & dosage ; *Amyloid beta-Peptides/metabolism ; *Neurogenesis/drug effects ; *Brain/drug effects/metabolism ; *Neuroprotective Agents/pharmacology/administration & dosage ; Alzheimer Disease/metabolism/drug therapy ; Disease Models, Animal ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and behavioral alterations. The pathogenesis of AD involves the accumulation of amyloid-beta (Aβ) plaques and the hyperphosphorylated tau proteins, which disrupt neuronal function and trigger neuroinflammation. This study explores the therapeutic potential of epigallocatechin gallate (EGCG) and punicalagin (PU) in mitigating Aβ-induced toxicity using an adult zebrafish model of AD. Our results demonstrate that the EGCG + PU combination significantly reduces Aβ accumulation, protects against cellular damage, suppresses acetylcholinesterase (AChE) activity, and normalizes the expression of amyloidogenic and AD-related genes. Additionally, EGCG + PU treatment alleviates neuroinflammation by suppressing glial activation, including reductions in L-plastin and proinflammatory cytokine expression, while promoting neuronal recovery through mechanisms of neurogenesis and neuroprotection. Notably, the combination treatment restored neuronal density and improved behavioral outcomes by alleviating anxiety- and aggression-like behaviors associated with Aβ toxicity. These results underscore the synergistic neuroprotective effects of EGCG + PU, highlighting their potential as a novel therapeutic approach for mitigating the pathological, behavioral, and inflammatory aspects of AD.},
}

Animals
Zebrafish
*Catechin/analogs & derivatives/pharmacology/administration & dosage
*Hydrolyzable Tannins/pharmacology/administration & dosage
*Amyloid beta-Peptides/metabolism
*Neurogenesis/drug effects
*Brain/drug effects/metabolism
*Neuroprotective Agents/pharmacology/administration & dosage
Alzheimer Disease/metabolism/drug therapy
Disease Models, Animal

@article {pmid41672403,
year = {2026},
author = {Fenton, L and Aslanyan, V and Jacobs, DM and Salmon, DP and Brewer, JB and Rissman, RA and Shadyab, AH and Harrison, TM and Evans, AC and LaCroix, AZ and Feldman, HH and Baker, LD and Pa, J},
title = {Relationships between fine memory discrimination and tau burden in two independent cohorts of older adults.},
journal = {Neuropsychologia},
volume = {},
number = {},
pages = {109393},
doi = {10.1016/j.neuropsychologia.2026.109393},
pmid = {41672403},
issn = {1873-3514},
abstract = {Cognitive assessments sensitive to the integrity of the medial temporal lobe, an area vulnerable to early tau deposition, may serve as low-cost adjunctive markers of underlying tau pathology in older adults. The Mnemonic Similarity Task (MST) is a fine memory discrimination task designed to assess hippocampal integrity. The current cross-sectional study utilized baseline data from two AD prevention trials (the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study and the Exercise in Adults with Mild Memory Problems (EXERT) trial) to examine relationships between MST performance, amyloid-beta, tau, and hippocampal volume. We additionally explored relationships between performance on a traditional memory test, Logical Memory, and AD-related brain measures. Poorer fine memory discrimination was associated with higher tau as assessed by PET in A4 (N=407, 59% female, mean age=71.66, age range=65-85) and CSF (p-tau181, total tau) in EXERT (N=41, 61% female, mean age=74.10, age range=65-89). Poorer fine memory discrimination was also associated with higher amyloid PET in A4 and smaller hippocampal volume in EXERT. Poorer delayed recall on Logical Memory was associated with higher tau and amyloid burden in A4 and with lower hippocampal volume in EXERT. Poorer retention on Logical Memory was associated with higher tau in Braak I and amyloid in A4 and with CSF tau and lower hippocampal volume in EXERT. These results support the potential of fine memory discrimination as measured by the MST as an adjunctive, accessible screening measure associated with higher tau in cognitively normal, amyloid positive older adults and older adults with amnestic MCI.},
}

@article {pmid41672382,
year = {2026},
author = {Khan, S and Imam, A and Singh, S and Ahmed, A and Hassan, MI and Shahid, M and Athar, F and Islam, A},
title = {Exploring the intersection of Alzheimer's disease and comorbidities: a review of the interplay between multiple chronic conditions.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {},
number = {},
pages = {168190},
doi = {10.1016/j.bbadis.2026.168190},
pmid = {41672382},
issn = {1879-260X},
abstract = {Alzheimer's disease (AD) represents degenerative brain disorder that impairs both cognitive functions and daily living activities gradually. It is frequently linked with other disorders such as psychosis, cardiovascular disorders, diabetes, and depression, all of which may influence the disease's onset, trajectory, and treatment approaches. These comorbidities can affect the onset, progression, and management of AD. This review focuses to explore the interplay of AD and comorbidities, and to examine the interplay between multiple chronic conditions. The review found that AD and comorbidities have a complex and bidirectional relationship. Comorbidities can affect the onset, progression, and management of AD, and AD can also affect the management and outcomes of comorbidities. The review also found that comorbidities may have an impact on caregiver burden, healthcare utilization and mortality. The findings suggest that the management of AD should take into account the presence and management of comorbidities to improve the overall outcomes for patients with AD. The literature also suggests that the management of comorbidities should be integrated in the management of AD patients. Furthermore, the review highlights the critical role of timely detection and treatment of comorbidities in AD patients to delay onset and mitigate disease progression. Additionally, it is crucial to consider the influence of comorbidities when selecting treatment options and the management of side effects and adverse events in AD patients. The literature reviewed in this article suggests that a multidisciplinary approach is needed in managing AD patients with comorbidities, which includes regular screening, early detection, and management of comorbidities in addition to managing AD.},
}

@article {pmid41672293,
year = {2026},
author = {Ge, Y and Weng, Y and Chen, Y},
title = {Elucidating the toxicological impact and mechanism of plasticizers exposure on Alzheimer's disease through network toxicology and molecular docking.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {},
number = {},
pages = {116005},
doi = {10.1016/j.fct.2026.116005},
pmid = {41672293},
issn = {1873-6351},
abstract = {This study aimed to explore the underlying mechanisms and key targets of widely used plasticizers, including dimethyl phthalate (DMP), diethyl phthalate (DEP), and dioctyl phthalate (DOP), to the pathogenesis of Alzheimer's disease (AD). Network toxicology, molecular docking, and dynamics simulation screened candidate targets for plasticizer in increasing AD risk. Three machine learning algorithms and two microarray datasets identified key targets, whose immune relevance was assessed by CIBERSORT. An Aβ42-induced BV2 microglia model validated their role. We identified 83 plasticizer targets relevant to AD, which were enriched in KEGG pathways like apoptosis and neuroactive ligand-receptor interaction. CDK5, SLC2A1, and STAT3 were confirmed as key targets, showing consistent differential expression in two AD datasets. Their expression correlated with M1 macrophage infiltration. Molecular docking and dynamics simulations demonstrated that plasticizers stably bind these targets with high affinity. In Aβ42-induced BV2 microglia, phthalate treatment elevated inflammatory factors (TNF-α, IL-1β, IL-6) and STAT3 expression. This study demonstrated the possible mechanistic associations between plasticizers exposure and AD, and STAT3 might be key target of plasticizers.},
}

@article {pmid41672268,
year = {2026},
author = {de Melo Silva, JG and de Medeiros Barros, W and Lopes, NMCP and Bellozi, PMQ},
title = {Alzheimer's disease: Current therapeutic strategies and emerging perspectives for multifactorial intervention.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111640},
doi = {10.1016/j.pnpbp.2026.111640},
pmid = {41672268},
issn = {1878-4216},
abstract = {Alzheimer's Disease (AD) is a progressive, multifactorial neurodegenerative condition and the most common form of dementia, affecting millions globally. Its incidence increases with age and is characterized by cognitive decline, functional impairments, and behavioral disturbances. Although its etiology remains unclear, AD is believed to result from a complex interaction between genetic, environmental, and lifestyle factors. Several hypotheses have been proposed to explain its pathogenesis, including the amyloid cascade, tau neurofibrillary tangle formation, cholinergic and glutamatergic dysfunctions, and, more recently, lipid invasion. Current treatment strategies involve both pharmacological and non-pharmacological interventions. In Brazil, acetylcholinesterase inhibitors and memantine are widely used. Recently, efforts have focused on developing new therapies, such as monoclonal antibodies, with three representatives already approved by the FDA, in addition to innovative approaches such as the use of technology and virtual reality for cognitive therapies. However, there is still a need for research that enables early diagnosis, interventions with fewer adverse effects, and the development of therapies targeting multiple mechanisms. Therefore, the pursuit of more effective and personalized treatments is essential to mitigate the societal impacts of AD.},
}

@article {pmid41672134,
year = {2026},
author = {Maneu, V and García, AG},
title = {P2X7 receptors as targets for neuroprotection.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110877},
doi = {10.1016/j.neuropharm.2026.110877},
pmid = {41672134},
issn = {1873-7064},
abstract = {In this review we explore the potential of P2X7 receptor blockers to elicit neuroprotection. This conjecture is based on a reasonably well-established role of this receptor in activating glial cells to maintain a chronic low-level neuroinflammatory state in the brain of patients suffering some neurodegenerative diseases (NDDs). In this context we briefly discuss evidence supporting the role of P2X7 receptors (P2X7) in the pathogenesis of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. From a pathogenic point of view these diseases have specific features but all share a low level neuroinflammatory state with microglia activation and enhanced P2X7 expression. Next, we comment on available P2X7 blockers with central nervous system (CNS) target engagement. Then, we deal with the proof-of-concept concerning the potential of some blockers to mitigate the neuroinflammatory state in preclinical models of the target diseases above mentioned. We follow with a discussion of the scarce number of clinical trials done with some P2X7 blockers in inflammatory diseases. Finally, we discuss the current discrepancy between promising preclinical data and the limited number of clinical trials exploring P2X7 antagonists in NDDs. We provide some clues that may boost clinical trials with single P2X7 blockers but particularly, with their association with other medicines currently being used or that are intended to be prescribed in the treatment of NDDs.},
}

@article {pmid41671691,
year = {2026},
author = {da Silva, AMP and de Deus, O and Januário Campos Cardoso, L and Virgilio Ribeiro, F and Froelich Meldola, P and Rodrigues Menezes, I and Lee Han, M and Quiroga, DG and James Almeida, K and Haddad Santos, D and Perry, G and Høilund-Carlsen, PF and de Souza Franco, E and de Sousa Maia, MB},
title = {Efficacy, safety, and ARIA risk of anti-β-amyloid antibodies in early Alzheimer's disease: a systematic review, meta-analysis, and meta-regression.},
journal = {Expert opinion on biological therapy},
volume = {},
number = {},
pages = {},
doi = {10.1080/14712598.2026.2631536},
pmid = {41671691},
issn = {1744-7682},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent cause of dementia and has been closely linked to β-amyloid accumulation. However, the efficacy and safety of anti-β-amyloid monoclonal antibodies remain debated.

METHODS: We systematically searched PubMed, Embase, and Cochrane databases for RCTs comparing anti-β-amyloid monoclonal antibodies with placebo in early-stage AD. Eligible trials enrolled participants with biomarker-supported AD and reported global, cognitive, or safety outcomes, including the CDR-SB, ADAS-Cog 13/14, ARIA, and brain volumetric measures.

RESULTS: Six RCTs including 7837 participants were analyzed. Mean age ranged from 69.8 to 75.4 years, and 57.4% were APOE ε4 carriers. Anti-β-amyloid therapy was associated with small differences in global and cognitive outcomes, best described as a modest slowing of decline on the CDR-SB and ADAS-Cog scales. Treatment was associated with increased risks of ARIA-E (RR, 9.40; 95% CI, 6.98-12.66) and ARIA-H (RR, 2.40; 95% CI, 2.08-2.78), as well as greater ventricular enlargement and hippocampal atrophy.

CONCLUSION: In early AD, anti-β-amyloid monoclonal antibodies are associated with modest slowing of decline accompanied by increased ARIA risk and unfavorable structural brain changes, limiting clinical applicability.

PROTOCOL REGISTRATION: http://www.crd.york.ac.uk/prospero identifier is CRD420251071393.},
}

@article {pmid41671614,
year = {2026},
author = {Li, Z and Tan, B and Dong, K and Yu, X and Zhang, SW and Luo, L and Yao, W and Qin, Z and Wu, F},
title = {Cobrotoxin mitigates neuroinflammation and cognitive impairment by suppressing CD8[+] T cell-microglia interactions in male 5 × FAD mice.},
journal = {Biochemical pharmacology},
volume = {247},
number = {},
pages = {117779},
doi = {10.1016/j.bcp.2026.117779},
pmid = {41671614},
issn = {1873-2968},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline accompanied by chronic neuroinflammation. Emerging evidence implicates T-cell infiltration and microglial activation as key immune events that accelerate AD pathology, yet therapeutic approaches targeting this neuroimmune interface remain scarce. Cobrotoxin (CTX), a short-chain neurotoxin derived from Naja atra venom, exhibits potent anti-inflammatory and immunomodulatory properties and is clinically approved in China for the treatment of chronic pain syndromes. Here, we investigated whether CTX could alleviate neuroinflammation and cognitive deficits in 5 × FAD mice, a transgenic model of AD. Intranasal CTX administration for nine weeks enhanced spatial learning and memory in the Morris water maze without altering amyloid-β burden. Flow cytometry and immunofluorescence revealed that CTX markedly reduced brain-infiltrating CD8[+] T cells and downregulated chemokines implicated in T cell-microglia communication, including Cxcl9, Cxcl10, Cxcl16, and Ccl5. Consistent with this, CTX attenuated microglial activation and pro-inflammatory cytokine release while preserving plaque-associated microglia (disease-associated microglia, DAM). Morphological and electrophysiological analyses demonstrated that CTX restored dendritic complexity, spine density, and hippocampal long-term potentiation (LTP), indicating improved synaptic integrity. Collectively, these findings identify CTX as a potent modulator of neuroimmune signaling that mitigates neuroinflammation and synaptic dysfunction in AD, suggesting its potential for repurposing as an immunomodulatory therapy for neurodegenerative diseases.},
}

@article {pmid41670689,
year = {2026},
author = {Abedi, A and Foroutan, T and Dargahi, L},
title = {Intranasal CM-hMSCs modulate brain gene expression linked to glucose metabolism and inflammation in male and female rats exposed to maternal and post-weaning high-fat diets.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41670689},
issn = {1432-1912},
support = {4001774//Iran National Science Foundation (INSF)/ ; 26822//Research Affairs of Shahid Beheshti University of Medical Sciences/ ; },
abstract = {Peripheral metabolic disorders, which drive brain insulin resistance, increase the risk of cognitive impairment, a key contributor to Alzheimer's disease. Conditioned media derived from human mesenchymal stem cells (CM-hMSCs) have shown potential for modulating neurological pathways. Male and female offspring exposed to maternal and post-weaning high-fat diet (HFD) were treated with CM-hMSCs. Spatial memory and anxiety-like behaviors were assessed along with hippocampal markers of glucose metabolism, inflammation, and Alzheimer's disease-related pathways. In male offspring, CM-hMSCs partially improved molecular pathways involved in brain glucose metabolism, as indicated by increased hippocampal mRNA expression of Glut1, Glut4, and IDE, and elevated BDNF levels. CM-hMSC treatment also modulated the inflammatory profile, with increased IL-10 and reduced IL-1β in the hippocampus. However, CM-hMSCs did not produce significant improvements in behavioral outcomes. CM-hMSCs exert early, region-specific molecular effects on hippocampal glucose metabolism and inflammatory responses in HFD-exposed male offspring.},
}

@article {pmid41670187,
year = {2026},
author = {Bourgeat, P and Fripp, J and Lebrat, L and Xia, Y and Feizpour, A and Cox, T and Zisis, G and Gillman, A and Goyal, MS and Tosun, D and Benzinger, TL and LaMontagne, P and Breakspear, M and Lupton, MK and Short, C and Adam, R and Robertson, JS and Sperling, R and O'Bryant, SE and Johnson, SC and Jr, CRJ and Schwarz, CG and Barkhof, F and Farrar, G and Bollack, A and Collij, LE and Landau, S and Koeppe, R and , and , and , and , and , and , and , and , and , and , and , and Morris, JC and Weiner, MW and Villemagne, VL and Masters, CL and Rowe, CC and Dore, V},
title = {AI-enhanced Centiloid quantification of amyloid PET images.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71162},
doi = {10.1002/alz.71162},
pmid = {41670187},
issn = {1552-5279},
support = {GA16788//National Health and Medical Research Council/ ; R01-AG058676-01A1/NH/NIH HHS/United States ; },
mesh = {Humans ; *Positron-Emission Tomography/methods ; *Alzheimer Disease/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/metabolism ; Male ; *Deep Learning ; Female ; Aged ; *Brain/diagnostic imaging/metabolism ; *Neuroimaging/methods ; Australia ; },
abstract = {INTRODUCTION: The Centiloid scale is the standard for amyloid (Aβ) PET quantification in research and clinical settings. However, variability between tracers and scanners remains a challenge.

METHODS: This study introduces DeepSUVR, a deep learning method to correct Centiloid quantification, by penalizing implausible longitudinal trajectories during training. The model was trained using data from 2,129 participants (7,149 Aβ positron emission tomography [PET] scans) in the Australian Imaging, Biomarkers and Lifestyle Study of ageing (AIBL)/Alzheimer's Disease Neuroimaging Initiative (ADNI) and validated using 15,807 Aβ PET scans from 10,543 participants across 10 external datasets.

RESULTS: DeepSUVR increased correlation between tracers, and reduced variability in the Aß-negatives. It showed significantly stronger association with cognition, visual reads, neuropathology, and increased longitudinal consistency between studies. DeepSUVR also increased the effect size for detecting small treatment related slowing of amyloid accumulation in the A4 study.

DISCUSSION: DeepSUVR substantially advances Aβ PET quantification, outperforming all standard approaches, which is particularly important for clinical decision making and to detect subtle or early changes in Aβ.

HIGHLIGHTS: Novel artificial intelligence (AI)-method that penalizes biologically implausible longitudinal trajectories, enabling the model to learn standardized uptake value ratios (SUVR) correction factors without requiring longitudinal data at inference time. Improves Centiloid consistency across tracers and studies, significantly enhancing cross-sectional and longitudinal amyloid positron emission tomography (PET) quantification. DeepSUVR-derived Centiloids show stronger associations with cognition, visual reads, and neuropathology. Longitudinal variability is reduced three- to five-fold, enabling more reliable tracking of amyloid accumulation and better detection of treatment effects. Novel reference and target masks derived from DeepSUVR replicate most of the model's performance, offering a practical alternative for integration into existing pipelines.},
}

Humans
*Positron-Emission Tomography/methods
*Alzheimer Disease/diagnostic imaging/metabolism
*Amyloid beta-Peptides/metabolism
Male
*Deep Learning
Female
Aged
*Brain/diagnostic imaging/metabolism
*Neuroimaging/methods
Australia

@article {pmid41668753,
year = {2026},
author = {Giff, AE and Wruble Clark, M and Bhattacharyya, S and Sage, PT and Madore, B and Guenette, JP and Miyawaki, EK},
title = {Deep cervical lymph node analysis in central nervous system inflammatory disease.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1747114},
pmid = {41668753},
issn = {1664-3224},
mesh = {Humans ; *Lymph Nodes/immunology/pathology ; Animals ; *Neuroinflammatory Diseases/immunology ; Glymphatic System/immunology ; },
abstract = {A previously espoused notion that the brain is an immune-privileged organ has been challenged by evidence of bidirectional communication between the central nervous system and the periphery. A well-described "glymphatic" system in the brain and the meningeal lymphatic system serve as conduits through which antigens, immune cells, and metabolic waste travel from the brain to the deep cervical lymph nodes. These nodes, which are more than passive drainage points, serve as locales where dendritic cells, T cells, and B cells interact with central nervous system-derived signals and modulate immune responses that can influence the brain itself. Disruption of clearance mechanisms to deep cervical nodes-due to intracranial vascular disease, aging, poor sleep, chronic inflammation, or other etiologies-may lead to immune dysregulation. Abnormalities in lymphatic drainage can also alter the presentation of antigens from the central nervous system, affect lymphocyte trafficking, and contribute to the aggregation of proteins like β-amyloid, tau, and α-synuclein. This review synthesizes current knowledge on glymphatic and meningeal lymphatic anatomy and function, highlights how impaired drainage contributes to disorders including multiple sclerosis, Alzheimer disease, and Parkinson disease, and discusses the emerging role of deep cervical lymph node imaging and immunophenotyping in assessing neuroinflammation. Finally, we consider how modulation of meningeal lymphatic and nodal function, through pharmacologic or physical interventions, may impair or restore drainage and alter the course of disease in various ways. The integration of advanced imaging with immunological analysis ultimately may enhance the diagnosis, monitoring, and treatment of neuroinflammatory and neurodegenerative diseases. We propose that deep cervical lymph nodes represent an understudied locale, and, potentially, a therapeutic target for peripheral interventions to influence brain disease trajectories.},
}

Humans
*Lymph Nodes/immunology/pathology
Animals
*Neuroinflammatory Diseases/immunology
Glymphatic System/immunology

@article {pmid41668551,
year = {2026},
author = {Gao, C and Li, Y and Zhou, B and Liu, Y and Hao, MQ and Sun, H and Jin, Z and Li, LL and Yang, XF and Guo, XL and Yin, Y},
title = {The application of exosomes derived by mesenchymal stem cell from different tissues in the management of Alzheimer's disease.},
journal = {Nanomedicine (London, England)},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/17435889.2026.2629030},
pmid = {41668551},
issn = {1748-6963},
abstract = {With the intensifying global trend of population aging, the treatment of Alzheimer's disease (AD) faces significant challenges. Current therapeutic approaches can only temporarily alleviate symptoms without halting or reversing disease progression. Numerous studies on mesenchymal stem cell-derived exosomes (MSC-Exos) suggest that, compared to stem cell therapy, MSC-Exos offer considerable advantages in the treatment of AD. This review examines the various mechanisms by which exosomes produced from MSCs function as therapeutic agents for AD. Additionally, it provides a concise overview of the research conducted on MSC-Exos for AD, categorized by tissue source. The text also provides an account of the ongoing clinical trials involving MSC-Exos and examines their benefits, drawbacks, and potential avenues for future research.},
}

@article {pmid41668547,
year = {2026},
author = {Zhang, Y and Wang, J and Yuan, J and Li, S and Sun, Y},
title = {FA-2-b-β modulates HMGB1/NF-κB/NLRP3 signaling to alleviate neuroinflammation in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418300},
doi = {10.1177/13872877261418300},
pmid = {41668547},
issn = {1875-8908},
abstract = {BackgroundFA-2-b-β, an extract derived from traditional Chinese medicine (TCM), has been suggested as a potential neuroprotective agent.ObjectiveThis study aimed to elucidate its role in modulating HMGB1-mediated inflammation and pyroptosis in Alzheimer's disease (AD), with a particular emphasis on the interaction between FA-2-b-β and HMGB1.MethodsAD cell and animal models were used to examine the effect of FA-2-b-β on HMGB1/NF-κB/NLRP3 signaling pathway. Protein expression levels were detected by western blotting, and enzyme-linked immunosorbent assay (ELISA), respectively. Immunofluorescence staining was performed to determine the cellular localization of key proteins. The role of HMGB1 in amyloid-β (Aβ)-induced neuroinflammation and pyroptosis was examined through siRNA-mediated HMGB1 knockdown. Behavioral tests were conducted in AD animal models to evaluate cognitive improvements following FA-2-b-β treatment.ResultsIn cellular models, FA-2-b-β significantly suppressed Aβ-induced overexpression HMGB1 and inhibited the activation of NF-κB, which consequently led to a reduction in the formation of the NLRP3 inflammasome. This suppression resulted in decreased of activation caspase-1 and lower levels of IL-1β and IL-18, thereby alleviating pyroptosis and neuroinflammation. The knockdown of HMGB1 further corroborated its role in mediating Aβ-induced inflammatory responses. In AD animal models, treatment with FA-2-b-β attenuated neuroinflammation, preserved neuronal integrity, and enhanced cognitive function.ConclusionsFA-2-b-β exhibits a capacity to modulate the HMGB1/NF-κB/NLRP3 signaling pathway, thereby mitigating neuroinflammation and pyroptosis, highlighting its potential as a therapeutic intervention for AD.},
}

@article {pmid41668529,
year = {2026},
author = {Wang, W and Chen, Y and Xiong, Z and Wang, Z and Ye, W and Li, X},
title = {Donepezil Research in Cognitive Impairment: A Bibliometric and Scientometric Analysis of Global Trends and Pharmacological Perspectives.},
journal = {Brain and behavior},
volume = {16},
number = {2},
pages = {e71251},
doi = {10.1002/brb3.71251},
pmid = {41668529},
issn = {2162-3279},
support = {//Neurosurgery First-class Discipline Funding Project of the Second Affiliated Hospital of Harbin Medical University/ ; },
mesh = {*Donepezil/therapeutic use/pharmacology ; Humans ; *Bibliometrics ; *Cognitive Dysfunction/drug therapy ; Alzheimer Disease/drug therapy ; Cholinesterase Inhibitors/therapeutic use/pharmacology ; *Nootropic Agents/therapeutic use/pharmacology ; Biomedical Research ; },
abstract = {BACKGROUND: Cognitive impairment (CI) greatly affects global health and quality of life. Donepezil, a widely used treatment for CI, particularly in Alzheimer's disease, has been extensively studied; however, a comprehensive bibliometric analysis summarizing global research trends remains limited.

METHODS: Relevant English-language articles and reviews published between 2000 and 2025 were retrieved from the Web of Science Core Collection. CiteSpace and VOSviewer were employed to analyze publication trends, collaborative networks, journal distribution, co-citation patterns, and keyword co-occurrence.

RESULTS: A total of 1907 publications were identified. The United States led in both output and citation impact, with the University of Toronto emerging as the most influential institution. The U.S. Department of Health and Human Services provided the greatest funding support. The Journal of Alzheimer's Disease was the primary publishing outlet, and Etsuro Mori was the most prolific and influential author. Keyword analysis revealed "Donepezil," "Alzheimer's disease," and "Mild cognitive impairment" as dominant terms. Recent hotspots-such as "acetylcholinesterase," "oxidative stress," "neuroinflammation," "tau protein," and "mechanism"-reflect a shift toward mechanistic and preclinical research.

CONCLUSION: Research on donepezil for CI has shown consistent growth, evolving from clinical application toward mechanistic exploration and disease modification. Future studies are expected to focus on individualized therapy, combination strategies, and underexplored CI subtypes, aiming to enhance the therapeutic potential and clinical value of donepezil.},
}

*Donepezil/therapeutic use/pharmacology
Humans
*Bibliometrics
*Cognitive Dysfunction/drug therapy
Alzheimer Disease/drug therapy
Cholinesterase Inhibitors/therapeutic use/pharmacology
*Nootropic Agents/therapeutic use/pharmacology
Biomedical Research

@article {pmid41668484,
year = {2026},
author = {Wang, Q},
title = {[Current status and future perspectives on age-related hearing loss and cognitive impairment].},
journal = {Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology head and neck surgery},
volume = {40},
number = {3},
pages = {220-225},
doi = {10.13201/j.issn.2096-7993.2026.03.002},
pmid = {41668484},
issn = {2096-7993},
mesh = {Humans ; Aged ; *Presbycusis ; *Cognitive Dysfunction ; *Cognition Disorders ; *Hearing Loss ; Aging ; },
abstract = {Objective:Age-related hearing loss（ARHL） is one of the most common sensory degenerative disorders in the elderly, characterized by high prevalence, insidious onset, and progressive deterioration. Recent studies indicate that ARHL not only impairs communication and quality of life in older adults, but is also significantly associated with the development of cognitive impairment and Alzheimer's disease. However, its underlying pathogenesis remains incompletely understood, and the relationship between clinical phenotypes of ARHL and cognitive decline has yet to be clearly defined. ARHL occupies a pivotal position in geriatric health management and in the prevention of neurodegenerative diseases, yet it has not been systematically conceptualized or mechanistically examined. In this review, we summarize the current research progress on ARHL and cognitive impairment, analyze possible mechanisms linking the two conditions, evaluate the potential cognitive protective effects of hearing interventions, and propose priority directions for future research and clinical practice. With advances in multidisciplinary collaboration and technological innovation, the prevention and treatment of ARHL are expected to enter a new era of greater precision and efficiency, offering novel opportunities to reduce the risk of cognitive impairment and improve overall health in older populations.},
}

Humans
Aged
*Presbycusis
*Cognitive Dysfunction
*Cognition Disorders
*Hearing Loss
Aging

@article {pmid41669706,
year = {2024},
author = {Hoang, B and Pang, Y and Dodge, H and Zhou, J},
title = {Translingual Language Markers for Cognitive Assessment from Spontaneous Speech.},
journal = {Interspeech},
volume = {2024},
number = {},
pages = {977-981},
pmid = {41669706},
issn = {2958-1796},
abstract = {Mild Cognitive Impairment (MCI) is considered a prodromal stage of dementia, including Alzheimer's disease. It is characterized by behavioral changes and decreased cognitive function, while individuals can still maintain their independence. Early detection of MCI is critical, as it allows for timely intervention, enrichment of clinical trial cohorts, and the development of therapeutic approaches. Recently, language markers have been shown to be a promising approach to identifying MCI in a non-intrusive, affordable, and accessible fashion. In the InterSpeech 2024 TAUKADIAL Challenge, we study language markers from spontaneous speech in English and Chinese and use the bilingual language markers to identify MCI cases and predict the Mini-Mental Status Examination (MMSE) scores. Our proposed framework combines the power from 1) feature extraction of a comprehensive set of bilingual acoustic features, and semantic and syntactic features from language models; 2) careful treatment of model complexity for small sample size; 3) consideration of imbalanced demographic structure, potential outlier removal, and a multi-task treatment that uses the prediction of clinical classification as prior for MMSE prediction. The proposed approach delivers an average of 78.2% Balanced Accuracy in MCI detection and an averaged RMSE of 2.705 in predicting MMSE. Our empirical evaluation shows that translingual language markers can improve the detection of MCI from spontaneous speech. Our codes are provided in https://github.com/illidanlab/translingual-language-markers.},
}

@article {pmid41667430,
year = {2026},
author = {Rossini, PM and Pappalettera, C},
title = {Should all MCI with Alzheimer's biological diagnosis receive anti-amyloid therapy?.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08456-z},
pmid = {41667430},
issn = {2041-4889},
abstract = {Our perspective addresses one of the most pressing and timely debates in contemporary neurology and health policy: whether the recent approval of anti-amyloid monoclonal antibodies for Alzheimer's disease should extend to all individuals with mild cognitive impairment (MCI; a large population of tens of millions of individuals worldwide mainly represented in Countries with aged population) who test positive for amyloid biomarkers, despite wide variability in prognosis and therapeutic response and the epidemiological demonstration that only about half of them manifest symptoms of dementia. The manuscript highlights three central themes. First, while epidemiological and meta-analytic data confirm that MCI significantly increases the risk of dementia, more than half of affected individuals-many of whom are biomarker-positive for amyloid/tau-do not progress to dementia even over long- term follow-up. Second, recently approved anti-amyloid therapies, although representing a landmark in disease-modifying treatments, carry high costs, non-negligible risks (particularly amyloid-related imaging abnormalities), and uncertain long-term real-world benefits. Third, indiscriminate prescription of these agents risks exposing large numbers of subjects to unnecessary harm while placing unsustainable burdens on healthcare systems. We argue that the field should urgently move to identify and validate accurate and sustainable instruments for risk-stratified treatment pathways, integrating genetic, clinical, neuropsychological, neuroimaging, and fluid biomarker data including risk and resilience factors to refine prognostication. In addition, we call on the scientific community, journals, and policymakers to foster dialog that bridges neurology, geriatrics, bioethics, health economics, and patient advocacy, so that clinical innovation is matched by ethical responsibility and equitable implementation.},
}

@article {pmid41667287,
year = {2026},
author = {Casper, A and Bolin, J},
title = {Alzheimer Disease and the Utility of PET.},
journal = {Journal of nuclear medicine technology},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnmt.125.271758},
pmid = {41667287},
issn = {1535-5675},
abstract = {Alzheimer disease (AD) is the most common cause of dementia and one of the leading causes of death in adults age 65 y or older in the United States. AD presents with symptoms of cognitive impairment that worsen with disease progression, ultimately affecting an individual's functional abilities, independence, and overall health. Historically, treatment has relied on the mitigation of the adverse effects of the disease; however, the recent development of antiamyloid monoclonal antibodies allows for the targeting of pathologic factors that drive the progression of disease. Nuclear medicine has established itself as a useful tool in the evaluation of AD through the use of PET tracers, which target pathologic biomarkers such as amyloid-β and tau proteins, as well as metabolic processes reflective of neurodegenerative damage. Amyloid-β PET imaging and quantification have recently gained interest for their ability to more effectively diagnose AD and identify patients eligible for treatment with new antiamyloid therapies.},
}

@article {pmid41667282,
year = {2026},
author = {Grabher, BJ},
title = {Centiloids in Amyloid PET: A Practical Guide to Quantitation Interpretation.},
journal = {Journal of nuclear medicine technology},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnmt.125.271823},
pmid = {41667282},
issn = {1535-5675},
abstract = {The approval of disease-modifying antiamyloid therapies has expanded the clinical role of amyloid PET beyond diagnostic confirmation to include baseline characterization and longitudinal monitoring of treatment response. Although visual interpretation remains the clinical standard for amyloid PET, it may be limited in borderline cases and when assessing subtle changes in amyloid burden over time. Quantitative amyloid PET provides objective measures that complement visual assessment, with z scores, SUV ratios, and Centiloid scaling offering increasing clinical utility. The Centiloid scale standardizes amyloid PET quantification across tracers, scanners, and institutions by anchoring measurements to biologically defined reference points, enabling consistent interpretation and comparison. This article describes the principles of amyloid PET quantification, explains the origin and interpretation of Centiloids, and discusses their role in therapy monitoring and clinical decision-making. Understanding quantitative amyloid PET and its limitations is essential for nuclear medicine professionals in the evolving landscape of Alzheimer disease imaging.},
}

@article {pmid41667280,
year = {2026},
author = {Skyles, T and Bouchal, SM and Giarratana, A and Wengler, J and Hart, I and Greig, E and Singh, H and Huang, SS and Martinez, F and Nguyen, B and Shin, CH and Yang, M and Parent, E and Robb, WH and Franceschi, AM and Burkett, B and Johnson, D and Koran, ME},
title = {PET Imaging in Alzheimer Disease in the Era of Antiamyloid Therapy in the United States: Clinical Utility, Quantification, and Policy Landscape.},
journal = {Journal of nuclear medicine technology},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnmt.125.271835},
pmid = {41667280},
issn = {1535-5675},
abstract = {Alzheimer disease (AD) is increasingly diagnosed using molecular imaging biomarkers. PET imaging provides the opportunity to visualize amyloid and tau aggregates and in vivo neurodegenerative changes. These techniques provide exciting new avenues toward diagnosis, disease staging, and therapeutic monitoring of AD. Methods: This review details recent advances in amyloid PET, tau PET, and [18]F-FDG PET as they relate to the diagnosis, staging, and treatment of AD. The increasing roles of PET in the biologically based diagnosis of AD and antiamyloid immunotherapy response monitoring are addressed. Results: Amyloid PET enables improved detection of amyloid-β plaques within the brain. Amyloid PET is increasingly vital for confirming AD diagnoses given the emergence of antiamyloid immunotherapies, which require biomarker-verified amyloid positivity to initiate treatment. Tau PET provides a direct measure of neurofibrillary tangle pathology and is useful for disease staging, the interpretation of atypical clinical presentations, and treatment decision-making. [18]F-FDG PET plays a vital role in distinguishing AD from other dementia subtypes. Expanded reimbursement policies for amyloid and tau PET have increased accessibility to these modalities. Finally, quantitative methods facilitate interscan reproducibility and permit therapeutic monitoring. Conclusion: Molecular neuroimaging is poised to play a central role in the biologic definition, diagnosis, staging, and management of AD. Integrating amyloid, tau, and FDG PET with clinical assessments and fluid biomarkers provides earlier and more accurate diagnoses, opening the door to personalized treatment.},
}

@article {pmid41666775,
year = {2026},
author = {Chaudhari, S and Shinde, A and Salunke, M and Bairagi, S and Dhage, A and Patel, P and Rathod, V and Pathare, S and Altwaijry, N and Khan, MS},
title = {Investigating the anti-Alzheimer potential of biogenic compounds from Zinc15 database as NMDA antagonist: An in-silico approach.},
journal = {Journal of molecular graphics & modelling},
volume = {144},
number = {},
pages = {109277},
doi = {10.1016/j.jmgm.2026.109277},
pmid = {41666775},
issn = {1873-4243},
abstract = {Alzheimer's disease is an unavoidable neurological disorder in which the death of brain cells brings on memory loss, cognitive decline, and eventual dementia. There is no recognized treatment for Alzheimer's illness. By the year 2050, it is expected that the global population will witness approximately 100 million cases of Alzheimer's disease (AD). Despite recognizing AD as a formidable illness for over a century, no effective cure has been discovered thus far. Synaptic dysfunction could result from disturbed synaptic calcium handling caused by excessive activation of glutamate receptors, particularly the N-methyl-D-aspartate receptors (NMDARs). Glutamate serves as the brain's primary excitatory neurotransmitter, acting on ionotropic and metabotropic glutamate receptors. In recent years, several pharmacologically active substances derived from plants, animals, and microbes have shown promise in treating AD by focusing on various pathogenic processes. Initially, we used virtual screening to assess natural product-like compounds against NMDA receptors. In this research study, we have screened a natural compound database derived from zinc15. The best candidate was then validated through molecular dynamics simulation (MDS). The results revealed that out of 4221 compounds tested, only 165 showed superior binding interactions compared to native ligands, making them inhibitors for protein. Further analysis using ADMET indicates favorable drug-like properties, particularly for CNS drug-likeness. The MDS results, including RMSD, RMSF, Rg, and residue interactions, indicated a strong and stable association between top molecules and target protein. This confirms that top molecules can effectively remain within the binding pockets of the target proteins, forming stable protein-ligand complexes.},
}

@article {pmid41666521,
year = {2026},
author = {Qin, Z and Wang, Z and Gao, C and Yong, X and Hua, Y and Zhou, Y and Xie, J},
title = {Ultrasound-mediated blood-brain barrier opening for targeted neurological drug delivery.},
journal = {Biomaterials advances},
volume = {183},
number = {},
pages = {214754},
doi = {10.1016/j.bioadv.2026.214754},
pmid = {41666521},
issn = {2772-9508},
abstract = {Neurological disorders represent a devastating global health crisis, and the blood-brain barrier (BBB) remains a major obstacle for their treatment. Conventional strategies for BBB opening, including direct intracranial injection, osmotic disruption, receptor-mediated transcytosis, and nanoparticle carriers, often suffers from surgical invasiveness, systemic toxicity, poor biodistribution, and off-target effects. Ultrasound-mediated drug delivery has emerged as a revolutionary non-invasive technology for transient and targeted BBB opening, enabling enhanced penetration of therapeutic agents into the central nervous system. This review comprehensively summarizes the mechanisms underlying ultrasound-based delivery with focus on current delivery platforms including microbubble (MB)-assisted, nanoparticle-based, and MB-nanoparticle composite strategies. Furthermore, we highlight recent advances in the application of focused ultrasound (FUS) combined with MBs for the treatment of Alzheimer's disease, Parkinson's disease, and glioma. Finally, we discuss emerging technologies such as sonodynamic therapy and ultrasound-controlled magnetic nanorobots, while also addressing current challenges in this field. This review underscores the transformative potential of ultrasound-mediated drug delivery as a versatile platform for precision neurology. It also prospects future directions for advancing multidisciplinary research and clinical translation.},
}

@article {pmid41666126,
year = {2026},
author = {Yue, J and Jones, B and Tran, KH and Deen, M and Holicek, V and Cheng, WH and Michalik, M and Power, S and Wellington, CL and Watson, NV and Vocadlo, DJ},
title = {Pharmacological inhibition of O-GlcNAcase reduces pS129-α-synuclein positive aggregates in the substantia nigra of mThy1-hSNCA mice.},
journal = {Journal of Parkinson's disease},
volume = {},
number = {},
pages = {1877718X251410291},
doi = {10.1177/1877718X251410291},
pmid = {41666126},
issn = {1877-718X},
abstract = {BackgroundThe aggregation and spread of α-synuclein within brain are associated with the loss of dopaminergic neurons and the formation of Lewy bodies as seen in Parkinson's disease. Blocking the initiation of α-synuclein aggregation, or the spread of such aggregates, may offer disease-modifying approaches to slow disease progression. Previous studies have demonstrated that modification of aggregation prone proteins, including α-synuclein, with O-linked β-N-acetylglucosamine (O-GlcNAc) reduces their aggregation. Small molecule inhibitors of the enzyme O-GlcNAcase (OGA), which removes O-GlcNAc from proteins, confers neuroprotective benefits in various preclinical disease models of Alzheimer's and Parkinson's diseases.ObjectiveThis study investigates the effects of long-term pharmacological enhancement of O-GlcNAcylation in a transgenic mouse model of Parkinson's disease overexpressing human α-synuclein.MethodsThiamet-G was orally administered to mThy1-hSNCA and wild-type (WT) mice for ten months. Behavioral assessments were conducted to examine changes in locomotion and cognition. Histological analyses were performed to analyze α-synuclein aggregates and dopaminergic neurons in brain sections. Immunoblot and ELISA analyses were performed to analyze O-GlcNAc and soluble α-synuclein using brain lysates, respectively.ResultsThiamet-G increased the level of O-GlcNAc in the brain of both mThy1-hSNCA and WT mice. The levels of total α-synuclein in the brain were unaltered. However, Thiamet-G strongly attenuated the deposition of pS129-immunoreactive α-synuclein aggregates within the substantia nigra, prior to observable neurodegeneration. Thiamet-G also protected against locomotor decline.ConclusionsThese results support OGA inhibition as a therapeutic approach to block the pathological formation of toxic α-synuclein as a disease-modifying treatment against Parkinson's disease.},
}

@article {pmid41666058,
year = {2026},
author = {Zhang, H and Wang, D and Yang, J and Zhao, Y and Liu, Y and Zhu, R and Wang, L and Song, R and Zhang, W},
title = {Unsupervised Disentanglement of Brain Heterogeneity for Identifying Subtypes of Alzheimer's Disease.},
journal = {IEEE transactions on bio-medical engineering},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TBME.2026.3663181},
pmid = {41666058},
issn = {1558-2531},
abstract = {Neuroanatomical heterogeneity in Alzheimer's disease (AD) hinders precision diagnosis and treatment, as distinct brain phenotypes may correspond to different disease subtypes. However, MRI-based subtype classifications are often confounded by co-occurring pathologies and non-AD factors, such as genetic predisposition and environmental influences, limiting their clinical interpretability. We propose 3D-DisAD, an unsupervised deep learning framework that disentangles AD-specific neuroanatomical variations from unrelated influences and clusters patients into subtypes with homogeneous brain phenotypes. The framework comprises two synergistic networks: (1) Contrastive Disentanglement Network, which separates AD-specific variations from those shared by AD patients and healthy controls; and (2) Transformation Generation Network, which refines these disease-specific variations by transforming healthy brain representations into realistic, pathology-consistent anatomies via diffusion-based generative modeling. Evaluated on four public datasets, 3D-DisAD reveals strong correlations between the disentangled AD-specific variations and diverse clinical and biological profiles, validating their relevance. Using these variations, we identify four AD subtypes with significant differences in biomarkers, cognitive trajectories, and genetic signatures, and uncover distinct longitudinal progression patterns that suggest potential windows for early intervention. By disentangling AD-specific variations, our method enables more precise patient stratification and personalized treatments, particularly in the early stage of AD. Code is available at: https://github.com/cnuzh/3D-DisAD.},
}

@article {pmid41665751,
year = {2026},
author = {Voronova, AD and Karsuntseva, EK and Shishkina, VS and Chadin, AV and Fursa, GA and Gurin, PI and Kuznetsova, TV and Reshetov, IV and Shport, SV and Stepanova, OV and Chekhonin, VP},
title = {Clinical Trials of Cell Products for the Treatment of Alzheimer's Disease (Review).},
journal = {Bulletin of experimental biology and medicine},
volume = {},
number = {},
pages = {},
pmid = {41665751},
issn = {1573-8221},
abstract = {Existing approaches to the treatment of Alzheimer's disease are ineffective because they do not stop neurodegenerative processes in the brain and do not promote the regeneration of the nervous tissue. Cell therapy is a promising strategy for the treatment of this disease. This review discusses clinical studies of cell-based therapies for Alzheimer's disease, evaluates their therapeutic potential, and proposes strategies for developing safe, accessible, and effective cell products.},
}

@article {pmid41665706,
year = {2026},
author = {Giacomini, PS and Voss, P and Devonshire, V and Schneider, R and Macaron, G and Hussein, S and Blanchette, F and de Villers-Sidani, É},
title = {Eye tracking as a digital biomarker in neurodegenerative diseases.},
journal = {Journal of neurology},
volume = {273},
number = {2},
pages = {133},
pmid = {41665706},
issn = {1432-1459},
mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/physiopathology/complications ; Biomarkers ; *Eye-Tracking Technology ; *Eye Movements/physiology ; },
abstract = {Oculomotor abnormalities are a common finding in neurodegenerative diseases due to degeneration of neural pathways and brain regions involved in controlling eye movements. Pathological changes to the dorsolateral prefrontal cortex, basal ganglia, superior colliculus and cerebellum produce subtle changes in eye-movement metrics that may not be detected by clinical examination. The present review addresses the potential use of eye-movement biomarkers in neurodegenerative conditions such as multiple sclerosis, Parkinson's disease, Alzheimer's disease and other dementias, and amyotrophic lateral sclerosis. Eye-movement metrics such as saccades, anti-saccades, fixation and smooth pursuit are prognostic of disease progression, can differentiate pathologic subtypes as an aid to diagnosis, and enable clinicians to evaluate early worsening of motor and cognitive function. The cost of medical technologies limits their optimal use and accessibility in clinical practice. The shortage of subspecialist neurologists further limits access to care. New eye-tracking technologies incorporated into widely-accessible digital devices such as smart phones and tablets now permit detailed assessments with minimal equipment requirements, providing an important non-invasive and potentially cost-effective method for patient evaluation in routine clinical practice and as an aid to treatment decision-making. Digital biomarkers can be readily employed by healthcare professionals such as family physicians, nurses and pharmacists to bridge the care gaps, potentially providing them with powerful tools that can be broadly adopted to improve the delivery of care to patients with neurodegenerative conditions.},
}

Humans
*Neurodegenerative Diseases/diagnosis/physiopathology/complications
Biomarkers
*Eye-Tracking Technology
*Eye Movements/physiology

@article {pmid41664707,
year = {2026},
author = {Xiang, Q and Shi, RL and Huang, YX and Liu, LN and Tao, JS and Li, XH and Li, XD},
title = {Oligodendrocyte: Development, Plasticity, Biological Functions, Diseases, and Therapeutic Targets.},
journal = {MedComm},
volume = {7},
number = {2},
pages = {e70618},
pmid = {41664707},
issn = {2688-2663},
abstract = {In the past few years, the incidence rate of central nervous system (CNS) diseases is still growing. Meanwhile, the molecular mechanism on the pathogenesis of neurological diseases remains elusive. Oligodendrocyte progenitor cells (OPCs) are distributed in the whole CNS and represent a population of migrating and proliferating adult progenitor oligodendrocytes that can be differentiated into oligodendrocytes (OLs). The main function of OLs is to produce myelin, the membrane wrapping tightly around the axon, which are associated with the myelination and remyelination. During regeneration, the new OLs from OPCs can regenerate lost myelin, which prevents axonal degeneration and restores its plasticity and function. Considering these energy-consuming processes, the high metabolic turnover OLs are susceptible to neurotoxic factors and its excitatory toxicity. Thus, the pathogenesis of OPC and OL are proven in neurological diseases, such as multiple sclerosis, Alzheimer's disease, major psychiatric diseases, and epilepsy. The current study reviewed the development, plasticity as well as application of OPCs and OLs researches on CNS diseases. Additionally, the effective methods and bioengineering technologies as well as biomaterials relevant to regenerative medicine are also discussed, which could provide the novel insight into the therapeutic treatment of those diseases, exploring new pathological clues, identifying the key molecules and targets as well as the potential biomarkers.},
}

@article {pmid41664517,
year = {2026},
author = {Silva Fernandes, A and Barbosa de Souza, Á and Benvindo de Souza, M and Madureira Almeida, L and Luiz Franco, O and Luiz Cardoso Bailão, EF and Borges, LL and Sérgio Nakao de Aguiar, A},
title = {DNA damage induced by fungicides triadimefon, triadimenol, and their mixture in human lymphocytes: cytogenotoxicity and computational analysis of metabolic pathways.},
journal = {Drug and chemical toxicology},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/01480545.2026.2626753},
pmid = {41664517},
issn = {1525-6014},
abstract = {Triadimefon (TF) and triadimenol (TN) are triazole fungicides widely used to prevent fungal infections in cereals, fruits, and other economically important crops. Their harmful effects on non-target organisms have been reported. This study investigated the cytogenotoxic effects of TF and TN, isolated and combined, at environmentally relevant concentrations (TF: 0.006, 0.012, and 0.024 mg/mL; TN: 1.5, 3.0, and 6.0 mg/mL; and 0.012 mg/mL TF + 3.0 mg/mL TN) on human lymphocytes using the trypan blue exclusion test and the comet assay. Additionally, in silico tools, BioTransformer and DIGEP-Pred, were employed to elucidate metabolic pathways more effectively for detoxifying these xenobiotics and to evaluate their putative effects on gene transcription, respectively. Exposure to TF and TN, either alone or in combination, did not affect lymphocyte viability at the tested concentrations. However, both compounds induced an increase in the percentage of DNA strand breaks after treatment. The in silico predictions suggested that the interaction with the cytochrome P450 isoforms (CYP1A2, CYP2A6, CYP2C9, and CYP2D6) differed for each compound analyzed. Gene expression prediction indicated that TF and TN may up-regulate genes involved with hormonal alterations, Alzheimer's disease risk, and cancer progression (SF1, SPON1, ADGRF5, and RORB). While they may down-regulate a gene involved with changes in heart rhythm and neurotoxicity (HCN1). In conclusion, our findings reinforced that the triazole fungicides TF and TN, while effective in agriculture, may pose risks to genomic stability in humans, highlighting the importance of biomonitoring studies in exposed populations.},
}

@article {pmid41664331,
year = {2026},
author = {Siddiqui, S and Tufail, P and Khan, F and Khalid, MF and Khalid, F},
title = {Protocatechuic Acid Alleviates Neurodemyelination by Modulating PKCα-p38/MAPK Pathways in an LPC-Induced Model of Neurodegeneration.},
journal = {Current protein & peptide science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892037385148251207081917},
pmid = {41664331},
issn = {1875-5550},
abstract = {INTRODUCTION: Neuroinflammation, axonal damage, and alterations in extracellular matrix (ECM) protein expression are hallmarks of neurodegenerative diseases. Therapies that enhance recovery from brain injury are of significant clinical value. Therefore, this study investigated the antiinflammatory properties of protocatechuic acid (PCA).

METHODS: Neuroglial cocultures were prepared from P0-P1 rats. Demyelination was induced using LPC (0.003%). The effects of PCA (10 and 25 μg) on neurite outgrowth were assessed using morphometry software. Expression of COX-2, NF-κβ, PKC-α, and p38/MAPK was examined through immunostaining, SDS-PAGE, and Western blotting. Expression intensities were quantified using ImageJ software. Sustained repetitive neuronal firing was evaluated using the patch-clamp technique.

RESULTS: PCA increased neurite outgrowth in LPC-treated cultures after 72 hours in vitro. LPCinduced upregulation of ECM proteins TN-C, LN, and CSPGs was significantly reduced by PCA treatment compared with LPC controls. Similarly, PCA decreased the expression intensities of the pro-inflammatory markers NF-κβ and COX-2 relative to LPC controls. Furthermore, PCA reversed the sustained neuronal firing pattern observed in untreated LPC-exposed neurons.

DISCUSSION: Purified bioactive compounds commonly present in everyday foods show therapeutic potential for Parkinson's and Alzheimer's diseases due to their lower toxicity compared with conventional drugs. Artificial intelligence tools, such as AlphaFold and RoseTTAFold, further support drug development by predicting PCA binding modes with PKCα and P38/MAPK, thereby contributing to the design of personalized therapeutics and advancing neuroscience research.

CONCLUSION: PCA alleviated neuroinflammation by reducing phosphorylation of PKCα and p38/MAPK.},
}

@article {pmid41618017,
year = {2026},
author = {Beccherle, M and Amato, S and Facci, E and Stefanescu, G and Bertagnoli, S and Francesco, VD and Fontana, G and Gambina, G and Moro, V},
title = {Patterns of cognitive and motor decline in Alzheimer's Disease (AD) and ageing in healthy populations.},
journal = {Aging clinical and experimental research},
volume = {38},
number = {1},
pages = {74},
pmid = {41618017},
issn = {1720-8319},
abstract = {BACKGROUND: Various patterns may apply to an individual’s health-span, with quality of life deriving from a balance between physical conditions, motor and cognitive abilities (i.e. psychomotor capabilities).

METHODS: In this study, the Italian version of the Éxamen Geronto-Psychomoteur was administered to a sample of Alzheimer’s Disease (AD) patients (n = 94) and a group of healthy older adults (n = 333) to compare the patterns of psychomotor decline in pathological and physiological ageing. Three domains were considered to integrate bodily and cognitive dimensions: cognitive functions, motor abilities, and muscular tone alterations (physical constraints). Potential correlations with general cognitive functioning, autonomy in daily life, mood and nutritional status were also investigated.

RESULTS: A correlation between cognitive, motor and physical dimensions is confirmed, and the results show that the patterns relating to healthy and pathological ageing are not only quantitatively but also qualitatively different. Besides the cognitive functions, the deterioration in AD also affects the physical components, precociously. Specifically, hypertonia may be present since the initial phases of illness. In healthy subjects, body representations decline early, while verbal memory, temporal and space representation resist over time. Malnutrition correlates with hypertonia in AD and with a reduction in daily life abilities in healthy people.

CONCLUSIONS: The results highlight the importance of adopting an integrated psychomotor approach in the screening, diagnosis and treatment of ageing and AD to investigate early motor and bodily indicators, which are often not fully considered in clinical practice.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40520-026-03327-1.},
}

@article {pmid41527082,
year = {2026},
author = {Du, Y and Wu, L and Mao, Y and Chen, S and Gao, X},
title = {IL-27, a metabolic regulator secreted by astrocytes in response to GLP-1RA OHP2, modulates microglial reprogramming in Alzheimer's disease by regulating cGAS lactylation.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {58},
pmid = {41527082},
issn = {1742-2094},
support = {82473834//National Natural Science Foundation of China,China/ ; 82373780//National Natural Science Foundation of China,China/ ; CPU2022PZQ10//"Double First-Class" University Project/ ; },
abstract = {UNLABELLED: Microglia-mediated neuroinflammation, considered one of the most plausible pathogenic hypotheses underlying Alzheimer’s disease (AD), plays a pivotal role in the initiation and progression of this devastating condition. Recently, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated promising neuroprotective effects in both preclinical and clinical studies. Previously, we developed an orally-administered GLP-1RA peptide called OHP2, which is capable of crossing the blood-brain barrier for the treatment of AD. OHP2 has been shown to effectively reduce brain inflammation in AD mouse models. In this study, we discovered that OHP2 treatment induced IL-27 secretion from astrocytes and modulated microglial reprogramming from the neurotoxic M1 phenotype to the neuroprotective M2 phenotype through glycolysis/cGAS lactylation clock/mTOR pathway, thereby alleviating excessive neuroinflammation. These findings provide a rationale for further pharmacological investigations into OHP2 and suggest that IL-27 may hold significant implications for AD therapy as a metabolic regulator.

GRAPHICAL ABSTRACT: [Image: see text]

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03683-1.},
}

@article {pmid41663779,
year = {2026},
author = {Roy, KK and Kumari, R and Upadhyay, AK and Mohanty, S},
title = {Tailoring treatments: pharmacogenomics in the management of neurodegenerative diseases.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {41663779},
issn = {2240-2993},
abstract = {Neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis are growing more common worldwide, yet treatment is still poor. Conventional therapies can have unforeseen side effects, produce poor medication reactions, and take longer to work. This persistent treatment gap highlights the need for novel approaches to these disorders' complex distinctions. Pharmacogenomics, which examines how genetic differences affect drug response, is a promising new subject and an urgent solution. Pharmacogenomics tailors medicine selection and administration to each patient's genetic profile, addressing the main causes of poor treatment response and preventable side effects. This research has enabled precision medicine that can improve neurodegenerative disease therapy and reduce harm. In this in-depth research, we examine neurodegenerative disease management issues, pharmacogenomics breakthroughs, and how incorporating genetics to clinical practice can improve outcomes. We examine the latest evidence that genetics affect drug breakdown, efficacy, and toxicity. We also discuss the challenges and opportunities of applying this knowledge. Pharmacogenomic approaches must be widely applied to make medicines for these awful disorders safer, more effective, and really suited to patient needs, according to our compilation.},
}

@article {pmid41662806,
year = {2026},
author = {Zhang, H and Zhang, H and Zhao, M and Luo, W and Chen, S and Wang, P and Liu, X and Xu, S},
title = {Da-Bu-Yin-Wan rescues cognitive deficits in aging and Alzheimer's disease models by Wnt/β-catenin-dependent restoration of lysosomal acidification.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {153},
number = {},
pages = {157916},
doi = {10.1016/j.phymed.2026.157916},
pmid = {41662806},
issn = {1618-095X},
abstract = {BACKGROUND: Lysosomal acidification deficits are increasingly recognized as a convergent pathological mechanism driving both age-related cognitive decline (ARCD) and early Alzheimer's disease (AD) progression, creating a self-reinforcing cycle of cellular aging and Aβ dyshomeostasis. Despite demonstrated neuroprotective effects of Da-Bu-Yin-Wan (DBYW) in Parkinson's disease models, its therapeutic potential for lysosomal dysfunction in ARCD and AD remains an uncharted area of investigation.

PURPOSE: This present work aimed to elucidate the mechanistic basis by which DBYW mitigates both ARCD and AD pathology through functionally rescuing impaired lysosomal acidification.

METHODS: Cell-based D-galactose and Aβ-induced in BV2 cells to study lysosomal acidification. Molecular analyses combined immunofluorescence localization studies with quantitative immunoblotting of lysosomal and Wnt signaling proteins. In vivo, DBYW treatment effects were systematically evaluated in both D-gal-induced and APP/PS1 transgenic models using cognitive behavioral followed by immunohistochemical and biochemical assessment of brain tissues lysosomal parameters and Wnt signaling activity.

RESULTS: DBYW attenuated the mechanistic basis of ARCD and AD pathology by functionally rescuing impaired lysosomal acidification. Overexpression of β-catenin could modulate D-galactose or Aβ-induced dysregulation of the Wnt/β-catenin pathway and restore lysosomes with abnormal acidification, while DBYW could regulate lysosomal function by promoting Wnt/β-catenin signaling. In addition, in D-gal-induced aging and AD model mice, DBYW treatment activated Wnt/β-catenin signaling to restore lysosomal acidification, while spatial memory deficits in ARCD and AD models were improved, and pathology in mouse attenuation and APP/PS1 mouse brain tissue was inhibited.

CONCLUSION: DBYW shows a potential dual efficacy in improving cognitive decline in ARCD and AD models. It makes DBYW a promising disease-modifying intervention targeting the shared lysosomal pathophysiology of aging-associated neurodegeneration.},
}

@article {pmid41662521,
year = {2026},
author = {Boskovic, P and Shalita, R and Gao, W and Vernon, H and Deng, YL and Colonna, M and Majzner, RG and Amit, I and Kipnis, J},
title = {Engineering chimeric antigen receptor CD4 T cells for Alzheimer's disease.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {7},
pages = {e2530977123},
doi = {10.1073/pnas.2530977123},
pmid = {41662521},
issn = {1091-6490},
support = {R01AG078667//HHS | NIH | National Institute on Aging (NIA)/ ; R61AG090394//HHS | NIH | National Institute on Aging (NIA)/ ; no number//Carol and Gene Ludwig Family Foundation/ ; no number//Cure Alzheimer's Fund (CAF)/ ; no number//Fred and Ginger Haberle Charitable Fund at East Texas Communities Foundation/ ; },
mesh = {*Alzheimer Disease/therapy/immunology/pathology ; *CD4-Positive T-Lymphocytes/immunology/metabolism/transplantation ; Animals ; *Receptors, Chimeric Antigen/genetics/immunology/metabolism ; Mice ; Humans ; Amyloid beta-Peptides/metabolism/immunology ; *Immunotherapy, Adoptive/methods ; Disease Models, Animal ; Brain/pathology/immunology/metabolism ; },
abstract = {Alzheimer's disease (AD) is the prevailing cause of age-associated dementia worldwide. Current standard of care relies on antibody-based immunotherapy. However, antibody-based approaches carry risks for patients, and their effects on cognition are marginal. Increasing evidence suggests that T cells contribute to AD onset and progression. Unlike the cytotoxic effects of CD8[+] cells, CD4[+] T cells capable of regulating inflammation show promise in reducing pathology and improving cognitive outcomes in mouse models of AD and in aging. Here, we sought to exploit the beneficial properties of CD4[+] T cells while circumventing the need for TCR and peptide-MHC antigen discovery, thereby providing a potential universal therapeutic approach. To achieve this, we engineered CD4[+] T cells with chimeric antigen receptors (CARs) targeting fibrillar forms of aggregated amyloid-β. Our findings demonstrate that optimized CAR-T cells can alter amyloid deposition in the dura and reduce parenchymal pathology in the brain. Furthermore, we observed that CAR-T treatment promotes the expansion and recruitment of endogenous CD4[+] T cells into the brain parenchyma and leptomeninges. In summary, we established the feasibility of amyloid plaque-specific CAR-T cells as a potential therapeutic avenue for AD. These findings highlight the potential of CD4[+] CAR-T therapy not only to modify amyloid pathology but also to reshape the immune landscape of the CNS, paving the way for future development of cellular immunotherapies for neurodegenerative disease.},
}

*Alzheimer Disease/therapy/immunology/pathology
*CD4-Positive T-Lymphocytes/immunology/metabolism/transplantation
Animals
*Receptors, Chimeric Antigen/genetics/immunology/metabolism
Mice
Humans
Amyloid beta-Peptides/metabolism/immunology
*Immunotherapy, Adoptive/methods
Disease Models, Animal
Brain/pathology/immunology/metabolism

@article {pmid41661364,
year = {2026},
author = {Li, L and Kong, J and Fan, R and Yuan, Y and Zhu, L},
title = {Correction: Role of tRNA-Derived Fragments and Their Modifications in the Pathogenesis and Treatment of Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {429},
doi = {10.1007/s12035-026-05713-2},
pmid = {41661364},
issn = {1559-1182},
}

@article {pmid41660277,
year = {2026},
author = {Fang, Y and Han, Z and Yang, S and Chen, J and Li, R and Zhang, Z and Song, J and Wang, D and Ban, Y},
title = {Ferroptosis and Alzheimer's disease: unraveling the molecular mechanisms and therapeutic opportunities.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1758041},
pmid = {41660277},
issn = {2296-634X},
abstract = {Ferroptosis is a novel form of regulated cell death. Compared with other types of cell death, it shows great differences in structure and biochemistry. This type of cell death is receiving increasing attention. For example, studies have found that it plays a key role in the development of neurodegenerative diseases underlying brain atrophy, such as Alzheimer's disease (AD). AD is a chronic and worsening neurodegenerative disease. It poses a serious threat to the health and quality of life of the elderly. The pathology of AD is mainly the presence of extracellular beta-amyloid (Aβ) plaques and intracellular tau-based nerve fiber entanglement (NFTs). Although there are a large number of studies and interventions for AD, so far, no clinical drugs have been found that can stop the pathological progression of AD or cure it. Currently, treatment strategies for this disease only focus on alleviating clinical symptoms and do not achieve slowing disease progression or curing it. Ferroptosis is gradually considered to play a key role in the occurrence and development of AD. Research based on the AD model confirms that neuronal ferroptosis can be inhibited through pharmacology to reverse cognitive disorders. In this review, we first describe the key molecular mechanisms of ferroptosis, and then discuss how these mechanisms operate and develop in AD. Then, we give a detailed introduction to the latest treatments for AD, including iron chelators, antioxidants, and specific ferroptosis inhibitors. What is noteworthy is that this article emphasizes the analysis of the mechanisms of iron metabolism disorders, as well as the introduction of new drugs for the prevention, rather than the alleviation of AD.},
}

@article {pmid41659595,
year = {2026},
author = {Chaggar, P and Vogel, JW and Thompson, TB and Aldea, R and Strandberg, O and Stomrud, E and Palqmvist, S and Ossenkoppele, R and Jbabdi, S and Magon, S and Klein, G and , and Mattson-Carlgren, N and Hansson, O and Goriely, A},
title = {Dynamical A β -Tau-Neurodegeneration Model Predicts Alzheimer's Disease Mechanisms and Biomarker Progression.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.27.701320},
pmid = {41659595},
issn = {2692-8205},
abstract = {UNLABELLED: Alzheimer's disease is characterised by the pathological interaction of two proteins, amyloid-beta (Aβ) and tau, which collectively drive neurodegeneration and cognitive decline. The progression of Aβ, tau, and neurodegeneration biomarkers is captured by the ATN framework, which is a powerful tool for disease classification. However, since the ATN framework is mainly descriptive, it cannot quantify or predict relationships between biomarkers over time. We address this limitation by introducing a dynamical ATN (dATN) model that mechanistically simulates the spatiotemporal progression of Aβ, tau, and neurodegeneration. The dATN model integrates mechanisms of prion-like protein aggregation of Aβ and tau, network-based tau propagation, Aβ-driven catalysis of tau progression, and tau-driven neurodegeneration. We calibrated the model using multimodal longitudinal imaging data from both the ADNI and BioFINDER-2 cohorts and show that it accurately fits longitudinal regional Aβ, tau, and neurodegeneration data. Using the dATN model, we show that Aβ-induced effects predict Braak-like cortical tau progression, that the spatial colocalisation of Aβ and tau is a crucial biomarker of disease acceleration, and that tau-driven atrophy strongly correlates with observed neurodegeneration. Furthermore, by integrating the disease progression model with pharmacokinetic-pharmacodynamic simulations, we present a powerful tool that facilitates regional evaluation of therapeutic strategies targeting Aβ, identification of critical intervention windows, and prediction of heterogeneous treatment effects across brain regions. This framework unifies mechanistic understanding with clinical imaging biomarkers, offering a quantitative approach for forecasting disease progression, testing mechanistic hypotheses, and optimising personalised treatment strategies in AD.

ONE SENTENCE SUMMARY: Colocalisation of A β and tau predicts regional tau progression and optimal A β -targeted intervention windows, while tau predicts neurodegeneration.},
}