@article {pmid41963962,
year = {2026},
author = {Li, Y and Wu, H and Yang, J and Weedor, JG and Ding, H and Cui, W and Cui, B and He, Z and Zhang, W and Xing, Y and Zeng, F and Huang, X and Zheng, K and Shen, Y and Yu, Y and Pan, W and Yang, X},
title = {Clostridium butyricum ameliorates Toxoplasma gondii-induced neuropsychiatric disorders by attenuating glial-mediated synaptic pruning via the gut-brain axis.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41963962},
issn = {1742-2094},
support = {Nos. 202310313083Y//the Training Programs of innovation and Entrepreneurship for College Students in Jiangsu Province/ ; Nos. X202510313020//the Training Programs of innovation and Entrepreneurship for College Students in Jiangsu Province/ ; Nos. X202510313017//the Training Programs of innovation and Entrepreneurship for College Students in Jiangsu Province/ ; No. JC20250007//the Faculty Development Grant of Basic Medical Sciences in Xuzhou Medical University/ ; Nos. 82372283//the National Natural Science Foundation of China/ ; No. QL-YB022//the XZHMU-QL Joint Research Fund/ ; No. 2022M710120//China Postdoctoral Science Foundation/ ; },
abstract = {UNLABELLED: Gut microbiota dysbiosis contributes to Toxoplasma gondii (T. gondii)-induced neuropsychiatric disorders (TNDs); however, the underlying mechanisms remain largely elusive. Here, we identified the critical role of butyrate-producing bacteria in TNDs in mice. Decreased abundance of butyrate-producing bacteria was consistently observed in patients with Alzheimer’s disease and T. gondii-infected mice. Dietary supplementation with Clostridium butyricum (C. butyricum), a gut commensal butyrate-producing bacterium, reversed gut microbiota dysbiosis, ameliorated intestinal barrier disruption and inflammation, and reduced endotoxemia. Coincidentally, C. butyricum administration suppressed microglial and astrocytic activation, rescued synaptic ultrastructure damage and synaptic loss, thus alleviating cognitive impairment and anxiety/depression-like behaviors. Mechanistically, C. butyricum treatment mitigated the abnormal synaptic pruning mediated by glial cells and C1q to prevent the neuropathology induced by T. gondii infection. Importantly, fecal microbiota transplantation from C. butyricum-supplemented mice into antibiotic-treated recipients recapitulated the therapeutic effects on gut and brain pathology observed in infected mice. Together, our findings suggest that C. butyricum ameliorates TNDs by modulating glial cell-mediated abnormal synaptic pruning via the gut-brain axis, highlighting the therapeutic potential efficacy of butyrate-producing bacteria against TNDs.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03761-y.},
}

@article {pmid42199923,
year = {2026},
author = {Putri, VA and Hapsari, RS and Amalia, R},
title = {L-α-GPC in Cognitive Decline: Mechanisms and Clinical Evidence in Neurodegenerative Disorders.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {579603},
pmid = {42199923},
issn = {1176-6328},
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and vascular dementia are characterized by progressive neuronal loss, synaptic dysfunction, and cognitive decline. Despite the widespread use of symptomatic treatments, including acetylcholinesterase inhibitors and dopaminergic agents, these disorders remain incurable and lack disease-modifying therapies. L-α-Glycerylphosphorylcholine (L-α-GPC), a naturally occurring choline-containing phospholipid, has attracted interest for its dual roles as a precursor to acetylcholine biosynthesis and a modulator of neuroprotective signaling pathways. This narrative review summarizes current preclinical and clinical evidence regarding the mechanistic and clinical relevance of L-α-GPC in neurodegenerative disorders associated with cognitive impairment. Preclinical studies suggest that L-α-GPC can cross the blood-brain barrier, enhance cholinergic neurotransmission, upregulate neurotrophic factors such as brain-derived neurotrophic factor (BDNF), and modulate inflammatory responses, including those involving the α7 nicotinic acetylcholine receptor pathway. In animal models, L-α-GPC has been associated with improved cognitive performance, reduced neuroinflammation, and attenuation of amyloid-β and tau-related pathological features. Clinical studies have reported potential benefits of L-α-GPC, either as monotherapy or in combination with agents such as donepezil, in patients with AD, vascular dementia, mild cognitive impairment (MCI), and PD-related cognitive decline. However, the interpretation of these findings should be cautious because the available evidence remains heterogeneous, with notable variability in study design, dosage regimens, treatment duration, and outcome measures. Further well-designed, large-scale randomized controlled trials, together with biomarker-based assessments, are needed to clarify the therapeutic relevance and optimal clinical application of L-α-GPC in cognitive decline and neurodegenerative disorders. Overall, current evidence indicates that L-α-GPC may represent a promising adjunctive approach, although more robust validation is still required.},
}

@article {pmid42201167,
year = {2026},
author = {Bonny, G and Mahfooz, K and Garcia-Rates, S and Hasan, S and Greenfield, SA},
title = {Evaluating the Efficacy of Monoclonal Antibodies Against a Bioactive Peptide Involved in Alzheimer's Disease: A Methodological Approach.},
journal = {Methods and protocols},
volume = {9},
number = {3},
pages = {},
pmid = {42201167},
issn = {2409-9279},
abstract = {Antibody treatment for Alzheimer's disease is an evolving therapeutic strategy that ensures high affinity and specificity to the target antigen; however, current approaches have proven only partially successful. A 14-mer peptide, T14, is twice as high in Alzheimer's brains and has been identified as a primary driver in the neurodegenerative process. Previously, the polyclonal antibody Ab-19 was shown to be as effective as the T14 receptor blocker (NBP-14) in reducing the toxic calcium influx in PC12 cells. The aim of this study was to establish a thorough validation process in order to evaluate the efficacy of respective anti-T14 monoclonal antibodies in T14 detection and rescuing potential from T14-induced toxicity in PC12 cells. Subsequently, we assessed the binding affinity of the most promising antibody, THK-117, via quantitative indirect conjugated T14 ELISA assays. The level of efficacy shown proved to be comparable to the polyclonal antibody, yet with the additional advantage of robust manufacturing reproducibility and high binding specificity toward the T14 epitope. With a notably low EC50, THK-117 can be viewed as a promising candidate for humanization, offering a strong potential as a therapeutic monoclonal antibody for the treatment and prevention of Alzheimer's disease.},
}

@article {pmid41992240,
year = {2026},
author = {Bhargavan, B and Annadurai, N and Kanmogne, GD},
title = {Effects of HIV and azidothymidine on Alzheimer's-like pathology and amyloid beta transporters in hu-PBL-NSG mice, brain endothelial amyloid beta uptake and endothelial barrier integrity.},
journal = {Fluids and barriers of the CNS},
volume = {23},
number = {1},
pages = {},
pmid = {41992240},
issn = {2045-8118},
abstract = {BACKGROUND: Despite increased life expectancy with antiretroviral therapy, people with HIV (PWH) have significantly higher prevalence of comorbid diseases, including neurocognitive impairment. PWH and neurocognitive impairment often show features of Alzheimer’s-like pathologies, including increased brain amyloid-beta (Aβ) and phospho-Tau; it is not known if antiretroviral drugs contribute to the development of these pathologies or potentiate HIV effects. We aimed to investigate whether azidothymidine (AZT), a drug still used by PWH in many resource-limited countries, alters or potentiates HIV-induced Alzheimer’s-like pathologies.

METHODS: Hu-PBL-NSG mice plasma/serum and brain tissues were analyzed to investigate the effects of HIV-1 infection and AZT treatment on viremia, immunosuppression, phospho-Tau, Aβ42, neuronal NeuN, endothelial claudin-5, ZO-1, and Aβ transporters [low-density lipoprotein receptor–related protein-1 (LRP1) and receptor for advanced glycation end-products (RAGE)] transcription, expression, and proteolytic cleavage. In vitro, we assessed the effects of HIV-1 Tat and AZT on Aβ42 aggregation, endothelial LRP1 and RAGE expression, Aβ uptake and transport.

RESULTS: HIV significantly increased brain phospho-Tau (serine199, threonine181, serine396), brain and plasma Aβ42, decreased LRP1, NeuN, claudin-5, ZO-1, and increased RAGE transcription and expression, increased soluble(s)LRP1 and decreased sRAGE. AZT treatment of infected animals decreased blood and brain viremia and reduced HIV-induced immunosuppression but had no effect on HIV-induced brain Aβ42, phospho-Tau, NeuN, claudin-5, ZO-1, LRP1 or RAGE transcription, expression, or cleavage. AZT treatment of non-infected animals significantly increased phospho-Tau in the brain somatosensory cortex, decreased LRP1, NeuN, claudin-5, and ZO-1, and increased RAGE transcription and expression, increased sLRP1 and decreased sRAGE. Tat decreased LRP1 and increased RAGE expression in brain endothelial cells, and AZT accentuated Tat-induced effects. AZT+Tat significantly increased Aβ aggregation and AZT significantly increased endothelial Aβ42 uptake/retention.

CONCLUSIONS: HIV and AZT independently dysregulate NeuN, claudin-5, ZO-1, LRP1 and RAGE transcription, expression, and proteolytic cleavage in hu-PBL-NSG mice. Such dysregulation of neuronal nuclei, endothelial tight junction proteins, and Aβ transporters could contribute to increased neurovascular injury and altered Aβ clearance following HIV infection and/or AZT treatment. In the presence of Tat, AZT increased Aβ aggregation. AZT also increased endothelial Aβ uptake/retention, which suggests that AZT may contribute to brain endothelium impairment and dysfunction.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12987-026-00807-4.},
}

@article {pmid42190844,
year = {2026},
author = {Ma, X and Koppelmans, V and Akcicek, H and Akcicek, EY and Shen, J and Chen, L and Balu, N and Yuan, C and King, JB},
title = {SNAP MRI reveals association between distal cerebral arterial flow and cognitive function in an aging population.},
journal = {Magnetic resonance imaging},
volume = {132},
number = {},
pages = {110702},
doi = {10.1016/j.mri.2026.110702},
pmid = {42190844},
issn = {1873-5894},
abstract = {OBJECTIVE: Impaired blood flow has recently been recognized as a critical contributor to cognitive impairment and dementia. It was reported that cerebral distal arterial flow measured from Simultaneous Non-contrast Angiography and Intraplaque Hemorrhage (SNAP) MRI is associated with post-treatment cognitive function improvement in carotid atherosclerosis patients. In this study, we aim to evaluate the value of SNAP-based measurements in assessing cerebrovascular function in an aging population.

MATERIALS AND METHODS: Neurovascular MRI data were collected on 36 aging participants (22 cognitively unimpaired and 14 impaired; 9 mild cognitive impairment (MCI) and 5 Alzheimer's Disease (AD)). Neurovascular MRI measurements, including white matter hyperintensities (WMH) volumes, cerebral blood flow (CBF), and SNAP-based distal cerebral arterial flow (dCAF) index, were quantified. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

RESULTS: Significant differences in the dCAF index were observed between cognitively unimpaired and impaired groups, and the dCAF index was significantly correlated with the RBANS total score. While CBF was significantly associated with dCAF index, there is no significant correlation of CBF or WMH with the RBANS score in this population.

CONCLUSION: Our findings suggest that the dCAF measured with SNAP MRI is valuable for evaluating the cognition-related cerebrovascular condition in an aging population.},
}

@article {pmid42190921,
year = {2026},
author = {Bhasha, S and Chintada, V and Munikumar, M and Maddineni, J and Nagulavancha, R and Malempati, T and Gadda, SS and Sankepally, KKR and Adi, PJ},
title = {Targeting Tau-Mitochondrial Crosstalk in Alzheimer's Disease: Integrative Multi-Omics and Artificial Intelligence-Driven Tools for the Development of Disease-Modifying Therapeutics.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103186},
doi = {10.1016/j.arr.2026.103186},
pmid = {42190921},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative illness marked by cognitive impairment, synaptic dysfunction and neuronal death. Tau protein abnormalities and mitochondrial dysfunction are key features of its pathogenesis, and both are involved in driving disease development. Emerging evidence suggests that pathogenic tau not only destabilizes microtubules but also directly compromises mitochondrial dynamics, bioenergetics and quality control, ultimately aggravating neurodegeneration. However, the molecular processes by which tau disease causes mitochondrial failure are poorly known. In this review, we discuss the tau-mitochondria interplay in AD and highlight how integrated multi-omics and computational approaches are boosting the development of disease-modifying treatments. We conducted an extensive evaluation of recent literature in key scientific databases related to tau biology, mitochondrial dysfunction, mitophagy, transcriptomics, proteomics, metabolomics, and computational drug development in AD. The results demonstrate that hyperphosphorylated tau leads to inhibition of mitochondrial transport, changes in membrane potential, impairment of oxidative phosphorylation and increased generation of reactive oxygen species (ROS). Multi-omics analyses show coordinated changes in molecular pathways affecting energy metabolism, synaptic maintenance and neuronal survival. Furthermore, computational and AI-based methods have enabled the recognition of novel tau-interacting proteins, mitophagy modulators and treatment candidates. The tau-mitochondrial interaction is a key pathogenic axis in Alzheimer's disease and provides prospective avenues for harnessing multi-omics and computational techniques to create mechanism-based treatments to restore mitochondrial function and synaptic integrity. This integrative paradigm provides a basis for next-generation precision therapies for neurodegenerative network dysfunction.},
}

@article {pmid42191654,
year = {2026},
author = {Isei, MO and Okeowo, OM and Okoye, CN and Sobodu, TO},
title = {Enhancing global Alzheimer's disease drug outcomes by comprehensive African data integration.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452117},
doi = {10.1177/13872877261452117},
pmid = {42191654},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) remains the leading cause of dementia worldwide and continues to pose a substantial therapeutic challenge. Although recent advances in disease-modifying treatments targeting amyloid-β pathology have generated cautious optimism, their translational impact is limited by persistent gaps in population and geographic representation within clinical trials. African populations, the most genetically diverse worldwide, remain markedly underrepresented in AD genomic and therapeutic studies. This gap limits the identification of ancestry-specific genetic risk factors and differential treatment responses and may contribute to the high attrition rates observed across AD drug development pipelines. We examine how the limited inclusion of African cohorts restricts insights into AD pathobiology and reduces the external validity of emerging therapeutic strategies. We highlight opportunities arising from the systematic integration of African population and clinical data, which have the potential to reveal novel biological mechanisms and expand the global relevance of candidate interventions. Persistent barriers, including insufficient research infrastructure and frequent substitution of African American cohorts for indigenous African populations, continue to obscure population-specific variation and hinder the development of a representative evidence base. Advancing the field will require coordinated and context-appropriate recruitment strategies, predictive modeling approaches grounded in region-specific data, and long-term investment in research capacity across the continent. A globally representative scientific framework that captures the full spectrum of human genetic heterogeneity is essential for accelerating progress in AD drug development. Integrating African population and data into clinical research will strengthen scientific rigor, enhance generalizability, and facilitate the development of globally equitable therapeutic strategies.},
}

@article {pmid42191751,
year = {2026},
author = {Okda, M and El-Masry, SM and Helmy, MW and Abbas, H},
title = {Herbosomal nanocarriers using natural-origin surfactants: a quercetin-based strategy for Alzheimer's disease and oxidative-stress-driven neurodegeneration.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42191751},
issn = {2045-2322},
mesh = {*Quercetin/chemistry/pharmacology/administration & dosage ; *Oxidative Stress/drug effects ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Surface-Active Agents/chemistry ; Animals ; Antioxidants/chemistry/pharmacology/administration & dosage ; *Drug Carriers/chemistry ; Neuroprotective Agents ; Polysorbates/chemistry ; *Nanoparticles/chemistry ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by oxidative stress, neuroinflammation, and cholinergic dysfunction. Quercetin (QUE) is a multifunctional flavonoid with potent antioxidant and anti-inflammatory effects and proven neuroprotective, anticancer, antimicrobial, and hepatoprotective potential. However, its therapeutic translation, particularly in the management of Alzheimer's disease, is severely limited by low aqueous solubility, low bioavailability, and rapid metabolism. The current study aims to develop QUE-loaded herbosomes as an advanced phytophospholipid delivery system for AD treatment, with a focus on replacing the synthetic surfactant Tween 80 with natural-origin betaine surfactants to overcome the drawbacks of poor biocompatibility and chronic toxicity associated with conventional surfactants. QUE herbosomes were developed using the thin-film hydration method and evaluated for physicochemical characteristics, stability, and in vitro release behavior. Formulation variables were optimized to obtain herbosomal systems with favorable nanoscale properties and sustained drug release. DSC and FTIR analyses confirmed successful incorporation of quercetin within the vesicular structure. Compared with QUE suspension, the optimized QUE herbosomal formulations (F5 &F6) showed significantly higher effect in aluminum chloride-induced AD as evidenced by Behavioral testing, biochemical, and Histopathological analyses. These findings suggest that the developed QUE herbosomes with natural-origin surfactants offer a safe and biocompatible alternative to synthetic surfactant herbosomes, improving therapeutic outcomes in AD and holding promise for other oxidative stress-related neurodegenerative conditions.},
}

*Quercetin/chemistry/pharmacology/administration & dosage
*Oxidative Stress/drug effects
*Alzheimer Disease/drug therapy/pathology/metabolism
*Surface-Active Agents/chemistry
Animals
Antioxidants/chemistry/pharmacology/administration & dosage
*Drug Carriers/chemistry
Neuroprotective Agents
Polysorbates/chemistry
*Nanoparticles/chemistry

@article {pmid42191803,
year = {2026},
author = {Jalili, M and Babaei, P and Golshekan, M and Abedinzade, M and Andalib, S},
title = {Quercetin-loaded cellulose nanofibers improve memory, learning, and attenuate endoplasmic reticulum stress in a rat model of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-54595-w},
pmid = {42191803},
issn = {2045-2322},
abstract = {Alzheimer's disease (AD) lacks effective disease-modifying therapy. This study evaluated the neuroprotective efficacy of quercetin-loaded cellulose nanofibers (QNP) in a streptozotocin (STZ)-induced AD rat model, focusing on memory impairment and endoplasmic reticulum (ER) stress. Forty-eight male Wistar rats were randomly allocated to six groups (n = 8): Control, AD model (ICV STZ 3 mg/kg on days 1 and 3), STZ + empty cellulose nanoparticles, STZ + free quercetin (10 mg/kg IP), STZ + QNP (10 mg/kg IP, equivalent quercetin dose), and STZ + donepezil (1 mg/kg IP) for 14 days. Morris water maze testing revealed that QNP significantly reduced escape latency during acquisition (31%, P < 0.001 vs. AD model) and increased time spent in the target quadrant during the probe trial (P < 0.01). QNP treatment resulted in significantly greater improvement compared to an equivalent dose of free quercetin (P < 0.05). RT-PCR demonstrated XBP-1 mRNA splicing exclusively in the AD model group, indicating activation of the unfolded protein response (UPR). Both free quercetin and QNP completely prevented this splicing, demonstrating potent suppression of ER stress. Cellulose nanofiber-mediated delivery significantly enhances quercetin's bioavailability and therapeutic efficacy, ameliorating cognitive deficits in AD likely via mitigation of ER stress. QNP represents a promising, biocompatible nano-therapeutic strategy for Alzheimer's disease.},
}

@article {pmid42192197,
year = {2026},
author = {Liang, C and Zhou, Y and Zhuang, K and Wang, S and Zhong, L and Can, D and Lei, A and Li, H and Zhang, J and Leng, L},
title = {Microglial mitochondria transfer to astrocytes via GPNMB-enriched extracellular vesicles alleviates cognitive deficits in tauopathy mice.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42192197},
issn = {1546-1726},
support = {2024J010001 to LL.//Natural Science Foundation of Fujian Province (Fujian Provincial Natural Science Foundation)/ ; },
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by cognitive decline. The precise molecular mechanisms that underlie the pathogenesis of AD remain elusive. Here we show that glycoprotein nonmetastatic melanoma protein B (GPNMB) is produced by microglia and transferred to astrocytes through extracellular vesicles (EVs) in PS19 tau pathology mice. Tau is cleaved in microglia to generate N-terminal fragments that form a complex on mitochondria with Parkin/Nix and GPNMB, promoting the secretion of EVs containing mitochondria. Functional mitochondria transferred to astrocytes via EVs markedly improve astrocytic functions and attenuate the cognitive impairments and pathogenic features in PS19 mice. By contrast, microglial GPNMB deficiency eliminates mitochondrial EV secretion and mitochondrial transfer to astrocytes, thereby impairing astrocytic functions and exacerbating cognitive impairment in PS19-CcKO (CX3CR1 cre Gpnmb floxp) mice. GPNMB-enriched EVs from PS19 mice alleviate the pathological phenotypes of PS19 mice, offering potential insights for AD treatment.},
}

@article {pmid42192211,
year = {2026},
author = {Gaur, A and Wong, M and Chen, JJ and Kang, Y and Tahoulas, D and Jeor, K and Raguram, KH and Gallagher, D and Rapoport, M and Herrmann, N and Lanctôt, KL},
title = {Synaptic biomarkers in Alzheimer's disease dementia and mild cognitive impairment: A systematic review and meta-analysis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71501},
doi = {10.1002/alz.71501},
pmid = {42192211},
issn = {1552-5279},
support = {PTCG-20-700751/ALZ/Alzheimer's Association/United States ; /CAPMC/CIHR/Canada ; //Toronto Rehabilitation Institute/ ; ASRP #21-11//Alzheimer Society Research Program/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/blood ; *Biomarkers/cerebrospinal fluid/blood ; *Cognitive Dysfunction/cerebrospinal fluid/blood ; *Synapses/metabolism ; Synaptosomal-Associated Protein 25/cerebrospinal fluid ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is characterized by synaptopathy, a neuropathological feature that can contribute to underlying cognitive decline. Here, we evaluate potential cerebrospinal fluid (CSF) and blood-based synaptic biomarkers in AD dementia and its earliest clinical stage, mild cognitive impairment (MCI).

METHODS: Articles that measured a subset of CSF and/or blood-based synaptic biomarkers in AD dementia, MCI, and/or healthy controls were included. A random-effects model was used to determine standardized mean differences and 95% confidence intervals.

RESULTS: In total, 65 study cohorts were included for meta-analysis and 12 for qualitative review. Several CSF (synaptosomal-associated protein 25 [SNAP-25], growth-associated protein 43 [GAP-43], neuronal pentraxin receptor, neuronal pentraxin-1, neuronal pentraxin-2, synaptotagmin-1, syntaxin-1B, and vesicle-associated membrane protein 2) and blood-based (SNAP-25, GAP-43, and synaptotagmin-1) synaptic biomarkers were altered in AD dementia and/or MCI.

DISCUSSION: Further evaluation of these identified biomarkers may enrich our understanding of AD pathophysiology and disease trajectory, as well as inform future treatment interventions.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/blood
*Biomarkers/cerebrospinal fluid/blood
*Cognitive Dysfunction/cerebrospinal fluid/blood
*Synapses/metabolism
Synaptosomal-Associated Protein 25/cerebrospinal fluid

@article {pmid42192558,
year = {2026},
author = {Aggad, WS and Ghosh, R and Almohaimeed, HM and Mohammedsaleh, ZM and Saleh, FM and Almars, AI and Jyothi, SR and Panigrahi, R and Kumer, A and Dhara, B},
title = {Exosome-mediated gut-brain axis signaling in neurodegenerative diseases: Mechanisms, experimental evidence, and therapeutic perspectives-A narrative review.},
journal = {Animal models and experimental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/ame2.70226},
pmid = {42192558},
issn = {2576-2095},
support = {PNURSP2026R213//Princess Nourah Bint Abdulrahman University/ ; },
abstract = {The stomach and the brain are connected by a sophisticated two-way communication mechanism called the gut-brain axis. Extracellular vesicles, particularly exosomes, that move bioactive substances between the stomach and the brain, such as proteins, lipids, metabolites, and microRNAs, may improve the gut-brain axis. In the past years, the role of exosome-mediated communication has been recognized as significant in relation to the etiology, continued progression, and potential treatment of neurodegenerative disorders. The authors of this review article present a summary of the current understanding of the relationship of gut microbiome, exosome biogenesis, and the pathophysiological development of neurodegenerative diseases. Evidence from laboratory studies, animal studies, and newly emerging human studies suggests that microbiome-based metabolites and inflammatory mediators may modulate how exosomes are produced, what they carry, and how they interact with the blood-brain barrier. These exosomal signals may impact neuroinflammation, neuronal signaling, and the spread of pathological proteins of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. In addition, they examine some possible ways to target the gut-brain axis from a therapeutic perspective, including manipulating the gut microbiome, providing probiotics and/or prebiotics, performing fecal microbiota transplantation, and/or using engineered extracellular vesicles as vehicles for drug delivery. The authors also outline some of the methodological differences that make it difficult to assess the effects of exosomes.},
}

@article {pmid42192778,
year = {2026},
author = {Ramírez Hernández, E and Netzahualcoyotzi, C and Hurtado-Alvarado, G and Sánchez, JL and Pereyra Morales, A and Arredondo-Zamarripa, D and Hernández-Zimbrón, LF and Papy-Garcia, D and Guevara, J and Gutiérrez Ponce, N and Gomez-Henao, W and Garfias, Y and Ortiz Chavez, G and Zenteno, E},
title = {The Effect of Metabolic Syndrome on Alzheimer's Disease: Physical Activity as a Preventive and Therapeutic Measure.},
journal = {Brain sciences},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/brainsci16050465},
pmid = {42192778},
issn = {2076-3425},
support = {PAPIIT IA208726//Universidad Nacional Autónoma de México/ ; PAPIIT IN222724//Universidad Nacional Autónoma de México/ ; PAPIIT IN204624//Universidad Nacional Autónoma de México/ ; },
abstract = {Epidemiological and clinical research on neurodegenerative diseases has shown that metabolic dysregulations increase the risk of developing Alzheimer's Disease (AD). Many metabolic changes can be grouped into metabolic syndrome (MetS), which is defined as the presence of three or more risk factors, including insulin resistance, hyperglycemia, hypertension, central obesity, and dyslipidemia. These changes cause systemic effects that are crucial in triggering neuroinflammation and neurodegeneration, key factors in AD development. All these factors impair energy metabolism in peripheral tissues and the brain by decreasing glucose utilization, leading to alterations in O-GlcNAcylation, glycosylation, mitochondrial function, oxidative stress, chronic inflammation, synaptic dysfunction, autophagy impairment, and blood-brain barrier (BBB) dysfunction. However, these factors are modified and largely influenced by lifestyle choices. A newer perspective emphasizes that regular exercise is vital for maintaining brain metabolism as we age. Current evidence suggests that engaging in physical activity for individuals with metabolic syndrome reduces their risk of Alzheimer's disease, enhances prognosis, and improves cognitive abilities. This review explores how metabolic syndrome relates to Alzheimer's and highlights possible strategies for prevention and treatment.},
}

@article {pmid42192839,
year = {2026},
author = {Valverde, HP and Clark, BJ and Hogeveen, J and Clark, VP},
title = {Noninvasive Brain Stimulation Techniques and Their Efficacy in Treating Cognition and Memory in Mild Cognitive Impairment and Alzheimer's Disease-A Systematic Review.},
journal = {Brain sciences},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/brainsci16050527},
pmid = {42192839},
issn = {2076-3425},
abstract = {BACKGROUND/OBJECTIVES: The growing aging population is susceptible to cognitive and memory impairment, most commonly due to Alzheimer's disease, with no cures currently available. Noninvasive brain stimulation (NIBS) techniques may serve to improve cognition and delay catastrophic memory loss.

METHODS: A systematic review of NIBS research on cognitive impairment was carried out using PubMed, with additional backward citation searching. A total of 81 studies using NIBS were included.

CONCLUSIONS: The reviewed studies show that NIBS holds promise in improving memory deficits in patients with cognitive impairment. While the longevity of benefits from transcranial electrical stimulation appears limited, its short-term effects may provide benefits when used consistently. Transcranial magnetic stimulation appears to provide longer-lasting benefits. Transcranial focused ultrasound stimulation may also provide further benefits through more precise targeting of deeper brain structures compared to other NIBS techniques. Together, these results suggest that NIBS shows promise for the treatment of symptoms related to cognitive and memory impairment, and may help to alleviate some of the growing issues associated with the increasing level of Alzheimer's disease in an aging population.},
}

@article {pmid42193043,
year = {2026},
author = {Zamzuri, ZE and Kamaruzzaman, MA and Teoh, SL and Yahaya, MF},
title = {A Review of the Effect of Peripheral Amyloid β on the Central Nervous System.},
journal = {Current issues in molecular biology},
volume = {48},
number = {5},
pages = {},
doi = {10.3390/cimb48050438},
pmid = {42193043},
issn = {1467-3045},
support = {FF-2025-443//Universiti Kebangsaan Malaysia Faculty of Medicine Fundamental Grants (GFFP)/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder classically defined by cerebral amyloid β (Aβ) plaque deposition and tau pathology. In recent years, AD has increasingly been recognized as a multisystem disorder rather than a purely brain-restricted condition, as mounting evidence indicates that Aβ metabolism is a dynamic, bidirectional process involving both central and peripheral compartments. Peripheral tissues, particularly platelets, liver, kidneys, and the gastrointestinal tract, contribute substantially to circulating Aβ levels and influence cerebral amyloid burden. Platelets are now considered the predominant source of peripheral Aβ, accounting for the majority of plasma Aβ under physiological and pathological conditions, while the liver and kidneys play critical roles in Aβ clearance through receptor-mediated uptake, enzymatic degradation and excretion. Disruption of these peripheral clearance pathways elevates circulating Aβ, increasing its transport into the brain via blood-brain barrier (BBB) mechanisms by enhanced RAGE-mediated influx and impaired LRP1-dependent efflux in AD. Peripheral Aβ entry into the central nervous system exacerbates neuroinflammation, mitochondrial dysfunction, and oxidative stress, thereby accelerating neuronal damage and disease progression. This review synthesizes updated evidence on peripheral sources of Aβ, differences between central and peripheral Aβ pools, mechanisms of Aβ transport across the BBB, pathological consequences of peripheral Aβ on the brain and emerging therapeutic strategies targeting peripheral Aβ metabolism, highlighting the importance of a systemic perspective in AD pathogenesis and treatment.},
}

@article {pmid42193260,
year = {2026},
author = {Virk, JP and Fernando, MG and Asih, PR and Martins, RN},
title = {Translational Feasibility of Curcumin for Treatment of Alzheimer's Disease: A Critical Appraisal of Clinical Challenges.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {5},
pages = {},
doi = {10.3390/antiox15050638},
pmid = {42193260},
issn = {2076-3921},
abstract = {The absence of robust and effective treatments for Alzheimer's disease remains a major challenge in modern medicine. As one of the leading causes of death, its increasing prevalence and complex chronic pathogenesis impose a substantial societal and healthcare burden, intensifying the need for effective therapeutic strategies. Current treatments remain limited, with minimal impact on cognitive decline in symptomatic patients. Curcumin, the bioactive ingredient in turmeric, has taken precedence over other natural products due to its potent antioxidative and anti-inflammatory properties. Numerous publications have extensively reported on the therapeutic effect of curcumin in animal models of Alzheimer's disease. However, no curcumin formulation has demonstrated consistent clinical efficacy against Alzheimer's or other neurodegenerative diseases to date. Over the years, many critics have argued that curcumin's undesirable chemical properties, mainly low bioavailability and rapid metabolism, pose significant barriers to its therapeutic use to target the brain. Considerable funding and research effort on emerging technologies such as nanoparticles and intranasal delivery continue to drive curcumin preclinical and clinical trials, prompting reflection on the rationale for continued investment. This narrative review critically dissects this disconnect, arguing that many purported benefits remain insufficiently substantiated, and identifying important opportunities where future research may hold promise for an effective treatment.},
}

@article {pmid42193907,
year = {2026},
author = {Albensi, BC and Adlimoghaddam, A},
title = {Targeting Mitochondrial Dysfunction in Alzheimer's Disease Neurons: Lithium Boosts Oxidative Phosphorylation.},
journal = {Cells},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/cells15100896},
pmid = {42193907},
issn = {2073-4409},
support = {AARF-22-967198/ALZ/Alzheimer's Association/United States ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/drug therapy ; *Oxidative Phosphorylation/drug effects ; *Mitochondria/metabolism/drug effects/pathology ; *Neurons/metabolism/drug effects/pathology ; Mice ; *Lithium/pharmacology/therapeutic use ; Mice, Inbred C57BL ; Electron Transport Complex IV/metabolism ; Mice, Transgenic ; Energy Metabolism/drug effects ; Oxygen Consumption/drug effects ; Hippocampus/pathology/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid beta (Aβ) and neurofibrillary tangles in brain tissue; however, AD is multifactorial, and different etiopathogenic mechanisms involve factors that can affect mitochondrial function, which are associated with AD. While high-dose lithium is a well-established mood stabilizer, accumulating evidence suggests that low-dose lithium provides significant neuroprotection by reversing AD pathology, cognitive impairment, and inflammation. Despite these findings, there is limited information on how lithium affects brain energy metabolism. In the current study, we investigated the effect of lithium (0, 0.1, 1, and 10 mM) on mitochondrial function in AD neurons. Neuronal cells were isolated from the hippocampi of embryonic day 14-17 (E15-E17) control (C57BL/6) mice and 3xTg-AD mice. Mitochondrial oxygen consumption rate (OCR), mitochondrial Cytochrome C Oxidase (COX) activity, total ATP activity, and the expression of mitochondrial complex protein involved in oxidative phosphorylation (OXPHOS) were measured in control vs. 3xTg-AD in the presence and absence of lithium treatment. In the present study, lithium treatment significantly increased (p < 0.05) mitochondrial OCR, COX, total ATP, and levels of mitochondrial complex protein subunits (Complex I-V) in 3xTg-AD neurons. However, lithium had no effect on energy metabolism in control neurons. Together, these data indicate that lithium improves mitochondrial function under pathological states. Overall, these results have important implications for the treatment of disorders in which brain energy regulation is compromised, including AD. Particularly, our results highlight a role for lithium in regulating bioenergetics in early-stage AD and suggest that neuronal cells may be a crucial therapeutic target for preventing AD.},
}

Animals
*Alzheimer Disease/metabolism/pathology/drug therapy
*Oxidative Phosphorylation/drug effects
*Mitochondria/metabolism/drug effects/pathology
*Neurons/metabolism/drug effects/pathology
Mice
*Lithium/pharmacology/therapeutic use
Mice, Inbred C57BL
Electron Transport Complex IV/metabolism
Mice, Transgenic
Energy Metabolism/drug effects
Oxygen Consumption/drug effects
Hippocampus/pathology/metabolism

@article {pmid42193936,
year = {2026},
author = {Sepehrimanesh, M and Melen, SV and Yeasmin, F and Ojo, VA and Walden, F and Urmee, H and Etheridge, J and Nasu, AK},
title = {Emerging Therapeutic Strategies for Neurodegenerative Diseases: A Comprehensive Review of Recent Advances and Future Directions.},
journal = {Cells},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/cells15100928},
pmid = {42193936},
issn = {2073-4409},
mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Animals ; Neuroprotective Agents/therapeutic use ; Genetic Therapy ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), represent a growing global health burden characterized by progressive neuronal loss and functional decline. Despite decades of intensive research, effective disease-modifying therapies remain limited, underscoring the urgent need for innovative therapeutic strategies. This review highlights recent advances in the understanding of disease etiology and emerging treatment approaches, with a particular focus on modalities with translational potential. We discussed novel disease-modifying interventions, including gene and cell therapies, RNA-targeting strategies, and immunotherapies aimed at clearing misfolded proteins such as amyloid-β, tau, and α-synuclein. In parallel, we examined the evolving recognition of neuroinflammation and mitochondrial dysfunction as actionable therapeutic targets, alongside progress in precision medicine and biomarker-guided approaches that enable early diagnosis and individualized treatment. Additionally, we summarized developments in repurposed pharmacological agents, neuroprotective compounds, and lifestyle interventions, emphasizing the importance of integrative, multimodal strategies. Across AD, PD, and ALS, convergent molecular mechanisms, including protein misfolding, oxidative stress, and disrupted proteostasis, present opportunities for cross-disease therapeutic targeting. Finally, we addressed key challenges and future directions, including translating preclinical efficacy into clinical success, optimizing CNS-targeted delivery systems, and navigating ethical considerations surrounding gene editing and stem cell therapies.},
}

Humans
*Neurodegenerative Diseases/therapy
Animals
Neuroprotective Agents/therapeutic use
Genetic Therapy

@article {pmid42195086,
year = {2026},
author = {André, Z and Kopániová, A and Gaštanová, B and Brandoburová, P and Režnáková, V and Fabian, M and Povinec, P and Hanes, J and Gmitterová, K},
title = {CSF Amyloid and Tau Biomarkers Distinguish Mixed from Vascular Dementia by Identifying Alzheimer's Disease Co-Pathology.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {5},
pages = {},
doi = {10.3390/medicina62050833},
pmid = {42195086},
issn = {1648-9144},
mesh = {Humans ; Biomarkers/cerebrospinal fluid/analysis ; *Dementia, Vascular/cerebrospinal fluid/diagnosis ; *tau Proteins/cerebrospinal fluid/analysis ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; *Amyloid beta-Peptides/cerebrospinal fluid/analysis ; Female ; Male ; Aged ; Mixed Dementias ; Diagnosis, Differential ; Peptide Fragments/cerebrospinal fluid ; ROC Curve ; Aged, 80 and over ; Middle Aged ; },
abstract = {Background and Objectives: Vascular dementia (VaD) and mixed dementia (MD) represent prevalent causes of cognitive decline in the elderly, as they share similar pathological pathways and clinical features. Distinguishing between these two conditions remains a challenge, due to their frequent clinical and neuroimaging overlap. Nevertheless, it is important from a prognostic perspective. Materials and Methods: The study comprised 114 participants, including patients with VaD (n = 33), MD (n = 26), Alzheimer's disease (AD; n = 26), and 29 cognitively healthy controls (C). We evaluated routinely used cerebrospinal fluid (CSF) biomarkers (total tau, p-tau181, Aβ1-42) and their ratios to assess inter-group differences, diagnostic accuracy, and correlations with cognitive score. Results: Patients with MD demonstrated significantly higher levels of t-tau and p-tau181, and lower levels of Aβ1-42, compared to VaD (p < 0.004 for all analyses). With the exception of p-tau181/t-tau, all calculated ratios enabled differentiation between these groups. ROC analysis confirmed the high diagnostic accuracy of CSF Aβ1-42 and t-tau (AUC 0.82 and 0.79 respectively) for detecting AD pathology in dementia patients. Furthermore, the t-tau/Aβ1-42, p-tau181/Aβ1-42 ratios were the most effective in differentiating AD-related from vascular pathologies (AUC 0.78 and 0.80 respectively), and in differentiating MD from VaD (AUC 0.79 and 0.77 respectively). A significant correlation was observed between CSF biomarkers (especially tau markers) and cognitive impairment severity. Conclusions: CSF biomarkers effectively differentiate mixed from vascular dementia by identifying underlying AD pathology independent of the clinical phenotype. This supports the use of CSF biomarkers in clinical practice to reveal the neurodegenerative component in patients with cerebrovascular disease, which is of fundamental importance for emerging disease-modifying treatment strategies in mixed neuropathologies.},
}

Humans
Biomarkers/cerebrospinal fluid/analysis
*Dementia, Vascular/cerebrospinal fluid/diagnosis
*tau Proteins/cerebrospinal fluid/analysis
*Alzheimer Disease/cerebrospinal fluid/diagnosis
*Amyloid beta-Peptides/cerebrospinal fluid/analysis
Female
Male
Aged
Mixed Dementias
Diagnosis, Differential
Peptide Fragments/cerebrospinal fluid
ROC Curve
Aged, 80 and over
Middle Aged

@article {pmid42195382,
year = {2026},
author = {Testa, C and Palmese, F and Boni, S and Domenicali, M and Lauretani, F},
title = {Clinical Trajectories of Neurodegenerative Diseases in Older Adults: A Three-Sphere Framework for Precision Geriatric Neurology.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/life16050827},
pmid = {42195382},
issn = {2075-1729},
abstract = {Neurodegenerative diseases are among the most consequential disorders of later life, not only because of their increasing prevalence, rising from approximately 1-2% at age 65 to over 30% by age 85, but also because they develop within the broader clinical context of ageing, multimorbidity, frailty, and polypharmacy. In older adults, these conditions rarely present as isolated and static diagnostic entities; rather, they unfold as dynamic clinical trajectories involving the progressive interaction of cognitive decline, behavioural-neuropsychiatric symptoms, and extrapyramidal-motor dysfunction. In this review, we propose a trajectory-based framework for the interpretation and management of major neurodegenerative disorders in later life, including Alzheimer's disease, frontotemporal dementia, Parkinson's disease and Parkinson's disease dementia, dementia with Lewy bodies, and vascular cognitive impairment. Building on a conceptual model organized around three major symptom spheres: cognitive, behavioural-neuropsychiatric, and extrapyramidal-motor, we argue that each disorder can be understood according to the relative predominance and temporal evolution of these domains. Alzheimer's disease is typically cognition-led, frontotemporal dementia behaviour-led, and Parkinsonian syndromes motor-led, whereas dementia with Lewy bodies shows early multidomain convergence across all three spheres simultaneously. Vascular and mixed dementias follow more heterogeneous trajectories shaped by lesion burden, network disruption, and copathology. This framework has direct implications for diagnosis, prognostic stratification, and treatment selection, because interventions targeting one sphere may destabilize another and generate prescription cascades, delirium, or functional decline. We further discuss how biomarker-based diagnosis, disease-modifying therapies, non-pharmacological interventions, multidisciplinary care, deprescribing strategies, and palliative planning can be integrated within a trajectory-based approach. Interpreting neurodegeneration through clinical trajectories rather than diagnostic labels alone offers a more realistic and therapeutically useful model for precision geriatric neurology across the full course of disease.},
}

@article {pmid42196209,
year = {2026},
author = {Mouaimi, M and Metaxas, A and Kourti, M},
title = {The Emerging Role of Dimethyl Fumarate in Alzheimer's Disease-A Systematic Review of Available Preclinical Studies.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104227},
pmid = {42196209},
issn = {1422-0067},
mesh = {*Dimethyl Fumarate/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; Humans ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress/drug effects ; Antioxidants/pharmacology/therapeutic use ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; },
abstract = {Dimethyl fumarate (DMF), a fumaric acid ester, is approved for psoriasis and multiple sclerosis due to its antioxidant and anti-inflammatory properties mediated via Nrf2 activation. Nrf2 regulates genes that protect cells from oxidative stress, a key factor in neurodegenerative diseases such as Alzheimer's disease (AD), which is characterized by amyloid-β and tau accumulation and lipid peroxidation. This systematic review aimed to evaluate preclinical evidence for DMF as a potential therapeutic agent in AD models through Nrf2 activation. A comprehensive literature search of PubMed and Scopus (last search: December 2025) identified in vitro, in vivo, and combined preclinical studies assessing DMF in AD models. Studies were screened using predefined inclusion and exclusion criteria, and methodological quality was assessed using established tools. Results were synthesized narratively. Eighteen studies were ultimately included in the analysis. Across the included studies, DMF consistently activated the Nrf2 pathway, enhancing antioxidant and anti-inflammatory gene expression. DMF treatment reduced amyloid-β and tau protein levels, mitigated oxidative stress, and improved cognitive performance in animal models. However, the evidence is limited by heterogeneity in experimental models and methodological variability. In conclusion, preclinical evidence suggests DMF is a promising candidate for AD treatment by targeting oxidative stress and neuroinflammation via Nrf2 activation. Further preclinical studies, particularly on ferroptosis mechanisms, and well-designed clinical studies are warranted to clarify its full therapeutic potential. This review was not registered and the authors received no funding.},
}

*Dimethyl Fumarate/therapeutic use/pharmacology
*Alzheimer Disease/drug therapy/metabolism
Animals
Humans
NF-E2-Related Factor 2/metabolism
Oxidative Stress/drug effects
Antioxidants/pharmacology/therapeutic use
Disease Models, Animal
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism

@article {pmid42196212,
year = {2026},
author = {Jóźwiak-Bębenista, M and Stasiak, A and Sienkiewicz, M and Kwiatkowski, P and Kowalczyk, E},
title = {Psilocybin in Older Adults: Therapeutic Opportunities in Inflammation-Driven Disorders of Aging-From Depression to Neurodegeneration.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104229},
pmid = {42196212},
issn = {1422-0067},
support = {503/1-108-01/503-11-001//Medical University of Lodz/ ; },
mesh = {Humans ; *Aging/drug effects ; *Inflammation/drug therapy ; *Neurodegenerative Diseases/drug therapy ; *Depression/drug therapy ; *Psilocybin/therapeutic use/pharmacology ; Animals ; Aged ; *Hallucinogens/therapeutic use/pharmacology ; },
abstract = {Aging is associated with chronic, low-grade inflammation ("inflammaging"), which contributes to neuropsychiatric and neurodegenerative disorders such as depression, Alzheimer's disease, and Parkinson's disease. Conventional pharmacotherapies often provide limited benefit in older adults and are further complicated by polypharmacy and drug-drug interactions. Psilocybin, a serotonergic psychedelic acting primarily as a partial agonist at the 5-HT2A receptor and currently undergoing accelerated clinical development, has emerged as a potential multimodal therapeutic agent addressing these challenges. Acting via its active metabolite psilocin, 5-HT2A receptor-mediated signaling modulates cortical glutamatergic transmission, enhances tropomyosin receptor kinase B/brain-derived neurotrophic factor (TrkB/BDNF) pathways, and modulates neuroimmune cascades (includingnuclear factor kappa B (NF-κB), with convergent systems-level effects such as reorganization of the default mode network. Human studies report acute reductions in TNF-α with variable effects on IL-6 and CRP, consistent with an immunomodulatory profile. Pharmacokinetically, psilocybin shows properties advantageous in geriatric care: rapid onset, short half-life, and predominant phase-II glucuronidation, reducing interaction risk. Controlled studies demonstrate rapid antidepressant and anxiolytic effects in major depressive disorder, treatment-resistant depression, and existential distress, with emerging feasibility signals in neurodegeneration. Together, these findings support the hypothesis that a time-limited, mechanism-based intervention may improve mood and cognition while attenuating inflammation. This review integrates current evidence on psilocybin's neuroimmune and pharmacokinetic mechanisms relevant to aging, outlining its potential role in inflammation-related disorders and highlighting the need for targeted studies in older adults, who remain underrepresented in psychedelic research.},
}

Humans
*Aging/drug effects
*Inflammation/drug therapy
*Neurodegenerative Diseases/drug therapy
*Depression/drug therapy
*Psilocybin/therapeutic use/pharmacology
Animals
Aged
*Hallucinogens/therapeutic use/pharmacology

@article {pmid42196227,
year = {2026},
author = {Kasprzak, A},
title = {Somatostatin in Aging: Correlations with Selected Central Nervous System and Gastrointestinal Tract Diseases.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104244},
pmid = {42196227},
issn = {1422-0067},
mesh = {Humans ; *Aging/metabolism ; *Somatostatin/metabolism ; Animals ; *Gastrointestinal Diseases/metabolism ; *Central Nervous System/metabolism ; },
abstract = {The hypothalamic-pituitary-somatotropic (HPS) axis, which includes growth hormone (GH) and insulin-like growth factor 1 (IGF-1), is one of three endocrine systems that show a decline in hormone concentration with age. Among the hypothalamic hormones involved in the aging process, GH-releasing hormone (GHRH) and somatostatin (SST) are most affected, resulting in several age-related changes. The pathophysiology of GH decline in the aging process is unclear, specifically, whether it results from decreased GHRH or increased SST levels. Similarly, it is not known whether quantitative changes in hypothalamic peptides (including SST) precede or follow age-related pathological behavioral changes. SST is produced mainly by cells of the central nervous system (CNS) and the gastrointestinal (GI) tract, which are functionally interconnected systems that undergo significant changes during aging. The physical changes in the aging organism are considered physiological, and experimental evidence indicates that a large proportion of these changes are the result of declining hormonal activity (including the SST system). It is particularly important to understand the role of SST in diseases of old age, which affect both cognitive processes and memory (e.g., Alzheimer's and Parkinson's diseases) and the proper functioning of the GI tract and pancreas (e.g., obesity, type 2 diabetes mellitus, and colorectal cancer). This narrative review discusses systemic and peripheral changes in SST production and secretion observed in aging individuals and their potential association with selected diseases of old age, especially CNS and GI tract diseases. Understanding the role of SST expression with age will enable the better application of this neuropeptide in the diagnosis and treatment of diseases of old age (including cancers).},
}

Humans
*Aging/metabolism
*Somatostatin/metabolism
Animals
*Gastrointestinal Diseases/metabolism
*Central Nervous System/metabolism

@article {pmid42196498,
year = {2026},
author = {Bianchi, VE and Visbal, LC and Devesa, J},
title = {Growth Hormone and Brain Regeneration: Evidence from Clinical Studies in Dementia, Traumatic Brain Injury, and Stroke: A Systematic Review.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104521},
pmid = {42196498},
issn = {1422-0067},
mesh = {Humans ; *Brain Injuries, Traumatic/drug therapy/metabolism/physiopathology ; *Stroke/drug therapy/metabolism/physiopathology ; *Dementia/drug therapy/metabolism ; *Growth Hormone/therapeutic use/metabolism/pharmacology ; Animals ; *Brain/drug effects/physiology/metabolism ; Insulin-Like Growth Factor I/metabolism ; *Regeneration/drug effects ; },
abstract = {Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) play essential roles in the brain, influencing neuronal and dendritic growth, as well as neurotransmission. These effects persist throughout life. Numerous studies in animals and humans have demonstrated the beneficial effects of GH therapy on memory and cognitive function, as well as on the restoration of neuronal function following injury. All nerve cells, including neurons, glia, endothelial, epithelial, and perivascular cells, are affected by the actions of GH/IGF-1. IGF-1, in particular, has been associated with cognitive function. The GH-IGF-1 axis increases the proliferation of neuronal progenitor cells and the formation of new neurons, oligodendrocytes, and astrocytes. In this study, we searched databases such as PubMed, Google Scholar, and Embase for human clinical trials evaluating the effect of growth hormone (GH) therapy on dementia, Alzheimer's disease (AD), post-traumatic brain injury (PTI), and stroke. The following search terms were used: "GH and dementia," "GH and Alzheimer's disease," "GH and TBI," and "GH and stroke." Inclusion criteria were all randomized controlled trials and observational studies. Exclusion criteria included the lack of cognitive and memory assessments. We found 28 articles. Most studies show the beneficial effects of GH therapy on memory and recovery of brain function after traumatic injury and stroke; however, consistent data are still lacking. The limited number of clinical trials, the small number of patients, and the lack of data on plasma levels of sex hormones that clearly contribute to brain function are limiting factors. This is the case, for example, with androgens. Other critical factors are dosage and treatment duration. Prolonged administration and supraphysiological doses are more effective in inducing positive clinical changes. Growth hormone (GH) therapy is a very promising intervention for preventing and treating dementia and early-stage Alzheimer's disease, and it contributes significantly to the recovery of brain function in patients after traumatic injury and stroke. Further studies with more robust methodologies are needed to confirm these results.},
}

Humans
*Brain Injuries, Traumatic/drug therapy/metabolism/physiopathology
*Stroke/drug therapy/metabolism/physiopathology
*Dementia/drug therapy/metabolism
*Growth Hormone/therapeutic use/metabolism/pharmacology
Animals
*Brain/drug effects/physiology/metabolism
Insulin-Like Growth Factor I/metabolism
*Regeneration/drug effects

@article {pmid42196596,
year = {2026},
author = {Hasan, I and Tang, X and Xu, J},
title = {Glial Cells in Behavioral and Psychological Symptoms of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104621},
pmid = {42196596},
issn = {1422-0067},
support = {82173798//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/psychology/pathology/metabolism ; *Neuroglia/metabolism/pathology ; Animals ; Microglia/metabolism/pathology ; Astrocytes/metabolism/pathology ; Oligodendroglia/metabolism/pathology ; },
abstract = {Behavioral and psychological symptoms of dementia (BPSD) affect the majority of patients with Alzheimer's disease (AD), substantially increasing caregiver burden and the likelihood of institutionalization. The clinical management of BPSD remains challenging because of its poorly understood pathogenesis, the limited efficacy of conventional interventions, and significant safety concerns associated with current treatments. These limitations underscore the urgent need to identify novel therapeutic targets and develop glia-centered treatment strategies. As essential components of the central nervous system, glial cells maintain neural homeostasis, regulate neurotransmission, and mediate neuroinflammatory responses. Increasing evidence suggests that glial dysfunction contributes to the development of BPSD, thereby linking AD neuropathology and neuropsychiatric symptoms. Aberrant microglial activation, astrocytic dysfunction, and oligodendrocyte injury collectively compromise neural circuit integrity, disrupt neurotransmitter balance, and impair neuron-glia communication, ultimately promoting the progression of diverse BPSDs. Given the critical role of glial cells in regulating neurotransmitter systems, the dysregulation of which is closely associated with BPSD, this review summarizes the involvement of glial cells in BPSD, elucidates the underlying molecular mechanisms, and discusses recent advances in glia-based therapeutic strategies, thereby providing insights into the pathogenesis of BPSD in AD.},
}

Humans
*Alzheimer Disease/psychology/pathology/metabolism
*Neuroglia/metabolism/pathology
Animals
Microglia/metabolism/pathology
Astrocytes/metabolism/pathology
Oligodendroglia/metabolism/pathology

@article {pmid42196607,
year = {2026},
author = {Wind-Mark, K and Kunze, LH and Willem, M and Palumbo, G and Giudici, C and Nuscher, B and Boening, G and Gildehaus, FJ and Lindner, S and Werner, RA and Franzmeier, N and Gnörich, JS and Brendel, M and Zatcepin, A},
title = {Tracking of Neuroinflammation Dynamics During Combined Anti-β-Amyloid Therapy (AAT) and Immunomodulation in a Preclinical Alzheimer's Disease Model.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104632},
pmid = {42196607},
issn = {1422-0067},
support = {EXC 2145 SyNergy - ID 390857198//German Research Foundation/ ; Medical & Clinician Scientist Program (MCSP)//Ludwig Maximilian University of Munich/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/immunology/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; Mice ; Positron-Emission Tomography ; Disease Models, Animal ; Pioglitazone/pharmacology/therapeutic use ; *Neuroinflammatory Diseases/drug therapy/diagnostic imaging ; Receptors, GABA/metabolism ; *Antibodies, Monoclonal/pharmacology/therapeutic use ; *Immunomodulation/drug effects ; PPAR-gamma Agonists ; Mice, Transgenic ; Microglia/metabolism/drug effects ; Brain ; },
abstract = {Neuroinflammation is increasingly recognized as a key modulator of therapeutic response and adverse events in Alzheimer's disease (AD), especially during anti-amyloid-β (Aβ) monoclonal antibody (Aβ-mAb) treatment. We applied longitudinal translocator protein (TSPO) positron emission tomography (PET) to evaluate TSPO-associated neuroinflammatory responses to chronic Aβ-mAb therapy and their modulation by the peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone. App[NL-G-F] knock-in mice underwent TSPO-PET and Aβ-PET imaging at 5, 7.5, and 10 months of age across four treatment arms: placebo, Aβ-mAb, pioglitazone, and combination therapy. TSPO-PET detected early and progressive neuroinflammatory responses to Aβ-mAb that appeared lower with pioglitazone co-treatment. Both mono- and combination therapy were associated with altered temporal and spatial dynamics of the TSPO-PET signal. In addition, we applied a previously validated microglia desynchronization index based on TSPO-PET connectivity, which captured individual variation in regional TSPO-PET organization and correlated with cognitive performance. Together, TSPO-PET and its regional synchronicity can quantify longitudinal, region-specific treatment effects, which may help differentiate harmful from adaptive neuroinflammatory responses. These findings highlight the potential of TSPO-PET as a stratification biomarker to optimize therapeutic interventions. TSPO-PET therefore enables in vivo tracking of treatment-associated neuroinflammatory responses during anti-Aβ immunotherapy and provides a non-invasive framework for evaluating combination strategies targeting amyloid pathology and immune regulation in AD.},
}

Animals
*Alzheimer Disease/drug therapy/immunology/diagnostic imaging/metabolism
*Amyloid beta-Peptides/immunology/antagonists & inhibitors
Mice
Positron-Emission Tomography
Disease Models, Animal
Pioglitazone/pharmacology/therapeutic use
*Neuroinflammatory Diseases/drug therapy/diagnostic imaging
Receptors, GABA/metabolism
*Antibodies, Monoclonal/pharmacology/therapeutic use
*Immunomodulation/drug effects
PPAR-gamma Agonists
Mice, Transgenic
Microglia/metabolism/drug effects
Brain

@article {pmid42198335,
year = {2026},
author = {Lu, H and Yu, Y and Yang, Y and Li, H and Li, Y and Yu, T and Wang, S and Li, F and Cheng, X},
title = {Ginsenoside Rg1 Ameliorates the Learning and Memory Deficits of 5xFAD Mice by Inhibiting CCR3 Activity: Insights from In Vivo and In Vitro Investigations.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {5},
pages = {},
doi = {10.3390/ph19050661},
pmid = {42198335},
issn = {1424-8247},
support = {No.82374062//National Natural Science Foundation of China/ ; YDZX2023003//Central government-guided special fund project for local scientific and technological development/ ; KYZK2024Q24//Shandong University of Traditional Chinese Medicine Youth Science Research Fund Project/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is characterized by amyloid-beta accumulation and neuroinflammation, yet the molecular target of Ginsenoside Rg1 remains elusive. This study aimed to elucidate the neuroprotective mechanism of Ginsenoside Rg1, specifically investigating its interaction with C-C motif chemokine receptor 3 (CCR3). Methods: We utilized 5xFAD transgenic mice and CCR3-overexpressing BV2 microglial cells. Behavioral assessments, enzyme-linked immunosorbent assays, quantitative real-time polymerase chain reaction, molecular docking, and surface plasmon resonance were employed to evaluate cognitive function and molecular pathways. Results: Ginsenoside Rg1 treatment significantly ameliorated spatial learning and memory deficits. Quantitatively, Rg1 reduced cortical amyloid-beta 1-40 levels (p < 0.05) and bound directly to CCR3 with a dissociation constant of 3.599 × 10[-5] mol/L. This inhibition suppressed neuroinflammation and restored neurotrophic factors, including Brain-derived neurotrophic factor. Conclusions: CCR3 is a novel pharmacological target for Ginsenoside Rg1, providing a precise molecular basis for its neuroprotective effects. Future research should focus on clarifying the pharmacokinetic profile and brain bioavailability of Ginsenoside Rg1 to facilitate clinical translation.},
}

@article {pmid42198353,
year = {2026},
author = {Skroban, J and Kruk-Słomka, M and Popiołek, Ł},
title = {Exploring Acylhydrazones' Properties Against Neurodegenerative Diseases and Other Clinical Applications: A Review.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {5},
pages = {},
doi = {10.3390/ph19050679},
pmid = {42198353},
issn = {1424-8247},
abstract = {Neurodegenerative diseases are a serious problem for modern society, and their treatment remains an important issue discussed by the scientific community. One of the promising potential directions for modulating neurodegenerative processes is the use of acylhydrazones, a class of compounds that combine different bioactive fragments linked by an acylhydrazone moiety. So far, the biological properties of these compounds have been proven. They show antibacterial, antiviral, antifungal, antiparasitic, anticancer, anti-inflammatory and antioxidant activity. Many research papers focus on designing acylhydrazones that will find use in the treatment of neurodegenerative diseases by inhibiting the enzymatic activity of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase 1 (BACE1) and monoamine oxidase (MAO), as well as inhibiting β-amyloid aggregation, exhibiting metal chelation and antioxidant properties. Recent studies have described the acylhydrazone-based dual (multi-target) inhibitors, which have demonstrated encouraging outcomes during in vitro evaluations. This review covers recent articles published in the years 2020-2025 and offers a comprehensive overview of the biological properties of the acylhydrazones and their multifunctional derivatives on neurodegenerative processes and/or neuroprotection, while emphasizing their universal nature, structural versatility and role as leading structures in the search for new drugs.},
}

@article {pmid42198361,
year = {2026},
author = {Silva, R and Monteiro, J and Ramalho, MJ and Andrade, S and Loureiro, JA and Pereira, MC},
title = {Advances in Strategies to Transport Nanoparticles Across the Blood-Brain Barrier for Drug Delivery into the Brain for the Treatment of Alzheimer's Disease.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {5},
pages = {},
doi = {10.3390/ph19050685},
pmid = {42198361},
issn = {1424-8247},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive dementia, constituting one of the leading causes of global mortality. Although the current treatments help attenuate the symptoms associated with AD, they are unable to stop the long-term progression of the disease, and consequently, no cure exists. One of the main reasons for the lack of cure and, therefore, one of the biggest challenges in its treatment, is the blood-brain barrier (BBB). This protective barrier limits the entry of foreign substances, including drugs, into the central nervous system. Different types of engineered nanoparticles (NPs) have been demonstrated to be able to penetrate this barrier and serve as efficient drug delivery systems (DDS) into the brain, making them a promising solution for future therapeutic development. Therefore, the purpose of this paper is to provide valuable insights into challenges faced by DDS in treating AD, highlight the nanotechnology-based approach, and discuss the advances in strategies being employed to enhance the crossing of NPs through the BBB. Furthermore, some up-to-date NP systems are presented, along with the latest therapeutic agents targeting AD, and finally, it underscores innovative approaches under investigation. Ultimately, the barriers hindering the clinical translation of NP-based strategies into human patients are discussed.},
}

@article {pmid42198444,
year = {2026},
author = {Badawi, GA and Shaaban, RS and Almutairi, JA and El-Masry, TA and Zaki, HF and Ibrahim, SM},
title = {Physical Exercise Enhances Melatonin Effect in D-Galactose/Aluminum Chloride-Induced Alzheimer's Disease of Ovariectomized Rats: Irisin Induction Associated with Upregulation of PPAR-γ/IGF-1/BDNF and Decreasing TNF-α/p38-MAPK/NLRP3/GFAP Pathway.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {5},
pages = {},
doi = {10.3390/ph19050770},
pmid = {42198444},
issn = {1424-8247},
support = {PNURSP2026R892//Princess Nourah bint Abdulrahman University Researchers Supporting Project/ ; },
abstract = {Background: Postmenopausal women are at high risk of Alzheimer's disease (AD) incidence and progression. Irisin, an exercise-induced myokine, has neuroprotective and antiaging effects against AD, especially in menopausal women suffering from insulin resistance (IR). For the first time, the novel role of irisin induced by melatonin (MTN) or/and physical exercise (PHE) was investigated in the current ovariectomized (OVX)/AD rat model by modulating brain neuroinflammation and IR-related markers. Methods: Fifty female Wistar rats were divided into five groups, with one representing a sham group. AD was induced in the other four bilateral OVX rat groups by daily intraperitoneal injection of D-galactose/AlCl3 (60 and 10 mg/kg, respectively) for 42 days. Group III-V: Animals were exposed to MTN (10 mg/kg/day; i.p.), PHE, and a combination of these, respectively, in the final 14 days of the experiment. Results: The OVX/AD rats showed significant deterioration in learning, memory, neurochemical, and histopathological examinations, while the MTN or/and PHE treatments significantly increased serum and brain irisin, improving memory in a Y-maze assessment. Thus, hippocampal histopathological alterations and IR-related markers decreased. In addition, suppressed hippocampal amyloid-beta protein expression and neuroinflammatory content of tumor necrosis factor-alpha (TNF-α), p38 mitogen-activated protein kinase (p38 MAPK), and NOD-like receptor protein-3 (NLRP3) were associated with an increase in peroxisome proliferator-activated receptor-gamma (PPAR-γ) protein expression and insulin-like growth factor-1 content in hippocampal tissues, collectively suppressing glial fibrillary acidic protein (GFAP) content, leading to an increase in brain-derived neurotrophic factor expression. Conclusions: Irisin induction may serve as a novel avenue in AD/menopause treatment and prevention via modulating the TNF-α/p38 MAPK/PPAR-γ/NLRP3/GFAP pathway.},
}

@article {pmid42199014,
year = {2026},
author = {Hao, L and Xing, Y and Han, Y},
title = {Status of diagnosis, treatment, and care of Alzheimer's disease continuum in China: A survey-based analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261453551},
doi = {10.1177/13872877261453551},
pmid = {42199014},
issn = {1875-8908},
abstract = {BackgroundThe 2018 NIA-AA framework outlines a six-stage continuum from asymptomatic individuals to severe Alzheimer's disease (AD) dementia, but most Chinese research still focuses on dementia or broad diagnostic categories.ObjectiveTo map diagnosis, treatment, and care patterns across all six AD clinical stages in China and identify demographic, clinical, treatment and care-related factors associated with disease stage.MethodsWe conducted a nationwide, open online survey via official media channels targeting patients with clinician-confirmed AD and their caregivers. Data were collected via Questionnaire Star. Descriptive analyses, group comparisons, and ordinal logistic regression were performed to examine factors associated with NIA-AA stage.ResultsA total of 1116 valid responses were analyzed. Most participants were at Stage 2 or higher, with distribution of 0.4%, 9.1%, 16.0%, 24.8%, 26.6%, and 23.0%, across Stage 1-6. Overall, 64.5% had been diagnosed within five years. Neurology (66.4%) and memory clinics (19.2%) were the most frequently visited departments. Donepezil (52.2%) and Memantine (38.8%) were the most common medications, while 34.5% reported engaging in non-pharmacological interventions. Only 1.9% of patients receiving professional dementia institutional care. In logistic regression, disease duration (OR = 0.724, p = 0.006), stage at first outpatient visit (OR= 1.843, p < 0.001), and Donepezil use (OR = 1.394, p = 0.003) were independently associated with current NIA-AA stage.ConclusionsThis study provides the first nationwide, real-world description of diagnosis, treatment, and care across all NIA-AA stages in China. The findings highlight the need for improved primary-care screening, expanded memory-clinic access, and structured caregiver support to promote earlier detection and more equitable, stage-appropriate management of AD.},
}

@article {pmid42199025,
year = {2026},
author = {Wang, Y},
title = {Mesenchymal stem cell-mediated regulation of neuroinflammation and amyloid-β clearance: A promising therapeutic strategy for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261451894},
doi = {10.1177/13872877261451894},
pmid = {42199025},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by cognitive decline. Its pathogenesis is complex, involving multiple pathological processes, including amyloid-β (Aβ) deposition, neuroinflammation, and synaptic dysfunction. In recent years, the role of mesenchymal stem cells (MSCs) in AD therapy has garnered significant attention. MSCs, through their multi-directional differentiation potential and paracrine effects, exhibit remarkable neuroprotective and anti-inflammatory properties, influencing AD progression. This review summarizes the potential mechanisms and effects of MSCs in AD treatment and explores precision therapeutic strategies based on MSC modulation.},
}

@article {pmid42199075,
year = {2026},
author = {Jin, L and Wang, X and Song, F and Hou, J and Bi, Y and Wen, X and Wang, X and Lai, F and Cheng, A},
title = {Quantitative AV-45 PET imaging for assessing treatment response to lecanemab and deep cervical lymphatic-venous anastomosis in Alzheimer's disease.},
journal = {Nuclear medicine communications},
volume = {},
number = {},
pages = {},
doi = {10.1097/MNM.0000000000002184},
pmid = {42199075},
issn = {1473-5628},
support = {no. 82001862//National Natural Science Founda tion of China/ ; },
abstract = {OBJECTIVES: This study aimed to validate the clinical utility of visual and software-based quantitative AV-45 PET analyses and compare treatment effects between lecanemab and deep cervical lymphatic-venous anastomosis (dcLVA).

METHODS: This retrospective cohort study included Alzheimer's disease patients who received 6-month lecanemab therapy or dcLVA surgery between July 2024 and 2025. AV-45 PET was performed 1 week before and 6 months after treatment. Standardized uptake value ratios (SUVRs) and centiloids (CLs) were obtained using visual and quantitative analyses. Agreement was assessed using Cohen's κ and intraclass correlation coefficients (ICC). Receiver operating characteristic (ROC) analysis evaluated diagnostic performance. Logistic regression used Informant Questionnaire on Cognitive Decline in the Elderly score greater than or equal to 3.3 as the outcome.

RESULTS: Baseline characteristics were comparable between groups (all P > 0.05). Visual assessment showed good agreement with centiloid quantification (κ = 0.72, ICC = 0.663). ROC analysis identified ΔCL as the optimal marker (area under the curve = 0.764, P = 0.026), with a cutoff of -11.5%. ΔCL ≥ -11.5% independently predicted cognitive decline in the lecanemab group (odds ratio = 10.281, 95% confidence interval = 1.289-82.005; P = 0.028). Cognitive decline was less frequent in the lecanemab group (23.5 vs. 81.8%; P < 0.001). ΔCL differed significantly between groups (P = 0.006), whereas ΔSUVR did not.

CONCLUSION: Visual and centiloid-based AV-45 PET analyses show good concordance for monitoring Alzheimer's disease treatment response. ΔCL is a robust marker of lecanemab efficacy, which is superior to dcLVA in reducing amyloid-β burden and delaying cognitive decline.},
}

@article {pmid42199126,
year = {2026},
author = {Wang, Y and Wang, Z and Zhao, J and Zhou, Y and Wei, D and Zhao, J and Sun, Z and Jiang, W},
title = {Mitochondrial transfer: A comprehensive analysis of mechanistic insights, preclinical applications, and technological innovations.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01156},
pmid = {42199126},
issn = {1673-5374},
abstract = {Mitochondrial transfer, the intercellular exchange of functional mitochondria, is crucial for maintaining cellular homeostasis and promoting tissue repair, particularly in neurological disorders associated with mitochondrial dysfunction. This review addresses the mechanisms through which mitochondrial transfer occurs, including tunneling nanotubes, extracellular vesicles, gap junction channels, and cell fusion. Mitochondrial transfer and transplantation have demonstrated positive therapeutic effects in various disease models, such as cerebral hemorrhage, ischemic stroke, Alzheimer's disease, and multiple sclerosis. Exogenous mitochondria can integrate into recipient cells, enhancing adenosine triphosphate production, restoring redox balance, and improving cellular survival under stress conditions. However, clinical translation faces significant hurdles, including immune rejection, limited recipient cell uptake capacity, a lack of standardized manufacturing protocols, and unresolved ethical concerns regarding mitochondrial sourcing. To address these challenges, cutting-edge biotechnological strategies, such as mitochondrial surface modification, nanocarrier-based delivery, biomaterial-assisted transplantation, and the use of engineered vesicles, are being developed to enhance the precision, stability, and biocompatibility of mitochondrial delivery. Furthermore, innovative approaches, including CRISPR-based genome editing, 3D-bioprinted tissue models, and artificial intelligence-assisted predictive platforms, are being explored to enhance mitochondrial function and delivery efficiency. Current strategies to harness mitochondrial transfer include pharmacological agents that enhance mitochondrial dynamics, stem cell-based delivery of healthy mitochondria, and the aforementioned bioengineered platforms. In conclusion, the integration of mitochondrial transfer as a groundbreaking treatment option for neurological disorders relies on addressing two to three fundamental challenges. These include the establishment of standardized and scalable protocols for production and quality control, formulating approaches to minimize immune reactions and improve the efficiency of mitochondrial integration, and creating a well-defined ethical and regulatory framework for sourcing and utilizing mitochondria. The primary contribution of this work lies in its integrated analysis of mechanistic insights, preclinical applications, and technological innovations, providing a consolidated roadmap for advancing mitochondrial transplantation from bench to bedside.},
}

@article {pmid42199136,
year = {2026},
author = {Huang, Z and Zhu, Y and Li, X and Lei, X and Tang, L and Wen, D and Yao, S and Gong, J and Zang, G and Guo, Z},
title = {Dopamine, glutamate, and gamma-aminobutyric acid: Key hubs in neurotransmitters, signal transduction, and cognitive dysfunction.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00849},
pmid = {42199136},
issn = {1673-5374},
abstract = {Neurotransmitters such as dopamine, glutamate, and gamma-aminobutyric acid (GABA) play crucial roles in regulating cognitive functions including learning, memory, and executive control. Dysregulation in synthesis, release, and metabolism of these neurotransmitters is implicated in the pathogenesis of various neurological disorders, such as Alzheimer's disease, Parkinson's disease, depression, and schizophrenia, leading to significant cognitive impairment. Recent research highlights that dopamine modulates reward processing, motivation, and memory through its synthesis via tyrosine hydroxylase and reuptake via the dopamine transporter. Glutamate, the primary excitatory neurotransmitter, mediates synaptic plasticity and cognitive processes through ionotropic and metabotropic receptors, while gamma-aminobutyric acid maintains inhibitory balance via GABA A and GABA B receptors. Notedly, interactions among these neurotransmitters, such as dopamine-Glu cross-talk through N-methyl-D-aspartate and dopamine receptors, and GABAergic regulation of dopaminergic activity, are critical for cognitive function. Existing detection techniques, including microdialysis, electrochemical sensors, and genetically encoded indicators, have advanced our understanding but still lack the spatiotemporal resolution needed to fully capture dynamic neurotransmitter interactions in real time. Although pharmacological interventions targeting these systems (e.g., L-3,4-dihydroxyphenylalanine, ketamine, GABAergic modulators) show potential, clinical applications are limited by significant side effects and variable efficacy. In summary, a multi-target approach, combining advanced detection methods with a deeper understanding of neurotransmitter crosstalk, may pave the way for more effective diagnostic and treatment interventions for cognitive disorders.},
}

@article {pmid42182271,
year = {2026},
author = {Shee, S and Huang, M and Baghel, MS and Zheng, Y and Lun, S and Yadav, SK and Yadav, NN and Ruiz-Gonzalez, CE and Tyagi, S and Nuermberger, E and Jain, SK and Bhujwalla, ZM and Slusher, BS and Wong, PC and Bishai, W},
title = {BCG vaccination mitigates tau pathology and restores cognitive function in PS19 mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.12.724591},
pmid = {42182271},
issn = {2692-8205},
abstract = {UNLABELLED: Retrospective studies in patients with non-muscle invasive bladder cancer (NMIBC) have reported a significant reduction in Alzheimer's disease (AD) incidence (12-78%) among Bacillus Calmette-Guérin (BCG) recipients versus controls. To investigate the underlying mechanisms, we evaluated BCG in the PS19 mouse model of tauopathy. We found that BCG administration reduced hippocampal phospho-tau and microgliosis while preserving neuronal markers. In vivo volumetric T2-MRI demonstrated attenuation of brain atrophy accompanied by increased glutamate-weighted CEST-MRI signals. Functionally, BCG-treated mice showed improved performance in the novel object recognition test (NORT), as well as improved body-weight maintenance and survival. Transcriptomic profiling of the hippocampus revealed near complete normalization of the PS19 disease-associated gene expression signature towards that of healthy controls. Flow cytometric profiling of brain myeloid populations demonstrated a reduction in activated resident microglia, but total microglia cells remain elevated. Moreover, an increase of the co-stimulatory marker CD80 on the recruited peripheral myeloid cells ensues following BCG treatment. Consistent with this shift in myeloid state, primary brain myeloid cells from BCG-treated mice also exhibited enhanced phagocytosis of FITC-labeled tau fibrils and increased lactate production. Together, these findings indicate that BCG induces systemic and CNS myeloid cell reprogramming that limits neuroinflammation, enhances tau clearance, and rescues cognitive and neurodegenerative phenotypes in a tauopathy model. BCG is a safe, readily available therapy that merits consideration as a preventive agent against dementia.

ONE SENTENCE SUMMARY: BCG therapy prevents tauopathy in PS19 mouse model.},
}

@article {pmid42182561,
year = {2026},
author = {Iizuka, T and Watanabe, T and Kameyama, M},
title = {Aging modulates amyloid clearance kinetics during anti-amyloid therapy: evidence from real-world serial amyloid PET.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1801267},
pmid = {42182561},
issn = {1663-4365},
abstract = {BACKGROUND: Anti-amyloid antibodies have been shown to reduce cerebral amyloid burden in early Alzheimer's disease (AD), yet considerable interindividual variability in treatment-associated amyloid reduction has been observed. The biological factors underlying this variability remain unclear. In particular, the influence of aging on amyloid clearance dynamics during anti-amyloid therapy has not been well characterized in real-world clinical settings.

METHODS: We conducted a prospective observational study of 23 patients with early-stage AD receiving lecanemab who underwent serial [18]F-flutemetamol amyloid PET at baseline and after 6 and 12 months. Amyloid burden was quantified in centiloid units. Cognitive outcomes were assessed using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Baseline cerebral perfusion was evaluated using [123]I-IMP SPECT with three-dimensional stereotactic surface projection (3D-SSP) analysis.

RESULTS: All participants showed reductions in amyloid burden on serial PET; however, the magnitude of reduction varied substantially across individuals. Older patients tended to exhibit larger and more rapid reductions in amyloid burden, whereas younger patients demonstrated more modest decreases despite comparable baseline amyloid levels and standardized dosing. Amyloid reduction at 6 months strongly predicted the magnitude of reduction at 12 months, suggesting that early PET changes capture subsequent amyloid clearance trajectories. Cognitive decline occurred in a subset of patients despite substantial amyloid reduction and was associated with marked baseline temporo-parietal hypoperfusion on SPECT rather than insufficient amyloid removal.

CONCLUSION: In this real-world cohort, aging appeared to influence the observable kinetics of amyloid reduction during anti-amyloid therapy. Early serial amyloid PET may provide useful information regarding longer-term amyloid dynamics, while baseline perfusion imaging may help identify patients with substantial downstream neurodegenerative burden who remain at risk for cognitive decline despite amyloid clearance. These findings highlight biological heterogeneity in treatment response and underscore the value of multimodal imaging for monitoring disease-modifying therapies in AD.},
}

@article {pmid42183357,
year = {2026},
author = {Grabowska, ME and Chen, R and Zhou, Y and Vaidya, AU and Zhong, X and Guardo, C and Dickson, AL and Babanejad, M and Yan, C and Xin, Y and Mundo, S and Peterson, JF and Li, L and Embí, P and Feng, Q and Eaton, J and Wen, Z and Li, B and Wei, WQ},
title = {Integrating genetically predicted transcriptomic signatures with longitudinal real-world data enables scalable drug repurposing for Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9518587/v1},
pmid = {42183357},
issn = {2693-5015},
abstract = {Drug repurposing offers a potential strategy to expand treatment options for conditions with limited therapies, but advancing repurposing candidates toward clinical implementation remains a challenge. Large-scale data, together with advanced genetic and epidemiological methods, may help address this gap. Here, we present an integrative digital medicine approach that combines genetically predicted transcriptomic signatures and perturbation screening for candidate identification with multi-cohort real-world validation for systematic evaluation of prioritized candidates. We applied this approach to Alzheimer's disease (AD), a disease with substantial unmet clinical need and persistent difficulty in developing effective therapies. We constructed AD signatures from genetically predicted expression changes across bulk tissues and microglia, then queried Connectivity Map profiles to identify compounds predicted to oppose these signatures. Aspirin emerged as a reproducible candidate across multiple signatures and underwent further evaluation. We then examined its association with incident AD in longitudinal electronic health record data from Vanderbilt University Medical Center and the NIH All of Us Research Program, as well as national insurance claims data. Across independent cohorts, aspirin initiation before age 65 was consistently associated with lower risk of incident AD, with signals suggesting that cumulative exposure and APOE ε4 status may influence effect size. Transcriptomic analysis of human cortical organoids provided additional experimental support, showing that aspirin more strongly opposed AD-related neuronal pathway alterations in wild-type organoids than in an organoid model of AD. This integrative approach offers a scalable strategy for genetically informed drug repurposing that bridges candidate discovery and clinical evaluation.},
}

@article {pmid42184087,
year = {2026},
author = {Abdelaziz, AM and Shokr, MM and Fathy, MK and Fawzy, MN},
title = {Dysfunction of the CD38-Miro1 Axis Disrupts Astrocyte-neuron Mitochondrial Transfer in Alzheimer's Disease: Mechanisms and Therapeutic Restoration.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {2},
pages = {},
pmid = {42184087},
issn = {1559-1166},
mesh = {*Alzheimer Disease/metabolism/therapy ; Humans ; *ADP-ribosyl Cyclase 1/metabolism ; *Mitochondria/metabolism ; *rho GTP-Binding Proteins/metabolism ; Animals ; *Neurons/metabolism ; *Astrocytes/metabolism ; *Membrane Glycoproteins/metabolism ; *Mitochondrial Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by early bioenergetic failure, contributing to synaptic dysfunction and neuronal vulnerability. This review examines a critical compensatory mechanism, the transfer of functional mitochondria from astrocytes to neurons, and its profound failure in AD. We detail the coordinated molecular cascade of this mitochondrial shunt, initiated by neuronal distress signals that activate astrocytic CD38. CD38-generated cyclic ADP-ribose triggers calcium release, which then binds to the mitochondrial Rho GTPase Miro1, modulating mitochondrial trafficking and promoting peripheral positioning via kinesin motor complexes for intercellular transport through tunneling nanotubes (TNTs). Transient, localized Ca[2+] signals bias mitochondria toward docking at the plasma membrane for export, whereas sustained pathologic Ca[2+] overload impairs trafficking via motor disengagement and Miro1 dysfunction. In AD, this rescue pathway is catastrophically disrupted by NAD+ depletion, Aβ-induced calcium dysregulation, tau-mediated microtubule instability, and oxidative stress, leading to inhibited CD38 signaling, Miro1 dysfunction/impairment, and TNT dismantlement. We systematically explain how this multi-level impairment initiates a vicious cycle of bioenergetic collapse. We also look at promising treatment options that could help restore this shunt, such as NAD+ augmentation to reactivate CD38, Miro1 stabilizers to help with trafficking, and interventions to keep TNT intact. Targeting the astrocyte-neuron mitochondrial shunt may represent an innovative, disease-modifying strategy that could transform the therapeutic framework from simple protein clearance to the proactive restoration of intercellular metabolic support, offering a promising direction for next-generation AD therapeutics.},
}

*Alzheimer Disease/metabolism/therapy
Humans
*ADP-ribosyl Cyclase 1/metabolism
*Mitochondria/metabolism
*rho GTP-Binding Proteins/metabolism
Animals
*Neurons/metabolism
*Astrocytes/metabolism
*Membrane Glycoproteins/metabolism
*Mitochondrial Proteins/metabolism

@article {pmid42184266,
year = {2026},
author = {Ix, M and Dodel, R and Ross, JA},
title = {Alpha-Synuclein-Specific RT-QuIC As a Tool for the Differential Diagnosis of Neurodegenerative Diseases Using Peripheral Tissues.},
journal = {Clinical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1093/clinchem/hvag037},
pmid = {42184266},
issn = {1530-8561},
abstract = {BACKGROUND: The diagnosis of neurodegenerative diseases (NDDs), such as Alzheimer disease (AD), Creutzfeldt-Jakob disease (CJD), Parkinson disease (PD), and other α-synucleinopathies, is traditionally based on clinical signs and symptoms. By the time symptoms emerge, neurodegeneration has already advanced, limiting the window for early treatment and research. Early diagnosis could improve therapeutic outcomes and deepen insights into disease onset, making the search for novel diagnostic tools and early biomarkers a major focus of current research. A key pathological hallmark of these prion-like diseases is the misfolding and aggregation of proteins such as prion protein, α-synuclein (αSyn), and tau, which are detectable early in the preclinical phase and are already used diagnostically.

CONTENT: The real-time quaking-induced conversion (RT-QuIC) assay is a thioflavin T-based in vitro method capable of detecting minute amounts of misfolded proteins in various biofluids with high sensitivity and specificity. It offers a promising approach for the early diagnosis of prion-like diseases. In recent years, RT-QuIC has been further developed, particularly to enhance the detection of αSyn-specific pathologies such as PD and related disorders. Additionally, increasing efforts have aimed to use peripheral and minimally invasive tissues or biofluids, such as skin, saliva, or nasal mucosa, for RT-QuIC analysis to support early and patient-friendly diagnostics.

SUMMARY: This review summarizes recent advances in αSyn-specific RT-QuIC, with a particular focus on peripheral sample materials. The diagnostic potential of this technique for α-synucleinopathies and other NDDs is discussed and its future applications in biomarker discovery are explored.},
}

@article {pmid42184775,
year = {2026},
author = {Feijão, JMS and Oliveira, DS and Chiussi, S and Pêgo, AP and Santos, SD and Moreira, FTC},
title = {NanoGold-enhanced biomimetic sensor for Tau-441 protein detection in serum for Alzheimer's disease diagnosis.},
journal = {Bioelectrochemistry (Amsterdam, Netherlands)},
volume = {172},
number = {},
pages = {109335},
doi = {10.1016/j.bioelechem.2026.109335},
pmid = {42184775},
issn = {1878-562X},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia, and early identification of molecular biomarkers in blood offers a promising avenue for diagnosis and monitoring treatment. Tau-441 stands out as a particularly promising biomarker among the potential molecular targets. This research describes the development of a highly sensitive and cost-effective biomimetic sensor, capable of selectively detecting Tau-441 at femtomolar concentrations. This is achieved through the synergistic combination of gold nanoparticles (AuNPs) with molecularly imprinted polymer (MIP) technology. The MIP layer was sensitised by electropolymerising phenylenediamine (o-PDA) in the presence of Tau-441 and AuNPs onto a gold screen-printed electrode (Au-SPE) using cyclic voltammetry (CV). After polymerisation, the entrapped proteins were removed by proteolytic digestion, generating well-defined imprinted cavities within the polymer matrix. Scanning electron microscopy (SEM) and Raman analysis were conducted to monitor the surface modification of the Au-SPE working electrode. The device displayed linear responses to Tau-441 protein within the range 2.0 pg mL[-1] to 200 ng mL[-1], with a limit of detection of 1.51 fg mL[-1]. The analytical performance of the device was validated in complex matrices, including Cormay serum and cell media from primary cultures of hippocampal neurons, using a competitive assay. The platform showed high sensitivity, good reproducibility, and reliable performance in biologically relevant media, demonstrating strong robustness. Its excellent analytical characteristics, together with the potential for integration into portable electrochemical devices, make this sensor a promising tool for rapid and accurate point-of-care testing, enhancing the detection and monitoring of AD.},
}

@article {pmid42185061,
year = {2026},
author = {Huang, JY and Dong, WG and Guo, WQ and Yang, SM and Huang, ST and Huang, Y and Zhan, SJ and Lin, L and Wang, F and Liu, LL},
title = {[Effect of electroacupuncture on hippocampal myelin and Rac1/PAK1/LIMK1/cofilin signaling pathway in Alzheimer's disease mice].},
journal = {Zhen ci yan jiu = Acupuncture research},
volume = {51},
number = {5},
pages = {614-621},
doi = {10.13702/j.1000-0607.20250434},
pmid = {42185061},
issn = {1000-0607},
mesh = {Animals ; *p21-Activated Kinases/metabolism/genetics ; *Lim Kinases/metabolism/genetics ; *rac1 GTP-Binding Protein/metabolism/genetics ; *Alzheimer Disease/therapy/genetics/metabolism/psychology ; *Hippocampus/metabolism ; Male ; Mice ; Signal Transduction ; *Electroacupuncture ; Humans ; *Actin Depolymerizing Factors/metabolism/genetics ; *Cofilin 1/metabolism/genetics ; *Myelin Sheath/metabolism/genetics ; Neuropeptides ; },
abstract = {OBJECTIVES: To observe the effect of electroacupuncture (EA) on learning-memory ability, hippocampal myelin and RAS-associated C3 botulinum toxin substrate 1 (Rac1)/ P21-activated kinase 1 (PAK1)/ LIM kinase 1 (LIMK1)/ cofilin signaling pathway in senescence-accelerated mouse prone 8 (SAMP8) mice, so as to explore its mechanisms underlying improvement of Alzheimer's disease (AD) from the perspective of the cytoskeleton.

METHODS: Male SAMP8 (AD) mice were randomly divided into model group and EA group, with 9 mice in each group, and 9 male SAMR1 mice of the same age were used as the control group. The mice in the EA group received EA at "Dazhui" (GV14) and "Shenshu" (BL23) and punctured at "Baihui" (GV20) for 20 min, once per day, for 24 d, rest for 2 d after every 8 d of treatment. The Morris water maze test was used to observe the learning-memory ability. The Luxol fast blue (LFB) staining was used to observe the myelin sheath, and the phalloidin staining was used to observe the cytoskeleton in the hippocampus tissue. The mRNA expression levels of Rac1, PAK1, LIMK1, and cofilin were detected using real-time fluorescence quantitative PCR, and the protein expression levels of myelin basic protein (MBP), Rac1, PAK1, phosphorylated (p)-PAK1, LIMK1, p-LIMK1, cofilin, and p-cofilin in the hippocampal tissue were detected using Western blot.

RESULTS: Compared with the control group, the model group showed an obvious increase in the escape latency (P<0.01), and a significant decrease in the number of the original platform-crossing, the swimming time in the original platform quadrant, cytoskeleton fluorescence intensity, mRNA expression levels of Rac1, PAK1, LIMK1, and cofilin, and protein expression levels of MBP and Rac1, and the ratios of p-PAK1/PAK1, p-LIMK1/LIMK1, and p-cofilin/cofilin in the hippocampus tissue (P<0.01). Following EA intervention, the increased level of escape latency and the decreased levels of the number of the original platform-crossing, the swimming time in the original platform quadrant, cytoskeleton fluorescence intensity, and the expression levels of Rac1, PAK1, LIMK1, and cofilin mRNAs, and the expression levels of MBP and Rac1 proteins, and the ratios of p-PAK1/PAK1, p-LIMK1/LIMK1, and p-cofilin/cofilin were reversed (P<0.01, P<0.05). LFB staining showed disordered and loose arrangement of the fibers with vacuoles in the model group. Compared with the model group, the number of myelin fibers was increased with the fibers arranged in relatively regular order in the EA group, suggesting a reduction of the degree of demyelination.

CONCLUSIONS: EA can improve the learning-memory ability of SAMP8 mice, which may be related to its functions in up-regulating the activity of Rac1/PAK1/LIMK1/cofilin signaling, and promoting the cytoskeletal reorganization to improve myelin function.},
}

Animals
*p21-Activated Kinases/metabolism/genetics
*Lim Kinases/metabolism/genetics
*rac1 GTP-Binding Protein/metabolism/genetics
*Alzheimer Disease/therapy/genetics/metabolism/psychology
*Hippocampus/metabolism
Male
Mice
Signal Transduction
*Electroacupuncture
Humans
*Actin Depolymerizing Factors/metabolism/genetics
*Cofilin 1/metabolism/genetics
*Myelin Sheath/metabolism/genetics
Neuropeptides

@article {pmid42188341,
year = {2026},
author = {Buccarello, L and Montagna, C and Di Matteo, S and Mangione, R and Carota, G and Sibbitts, J and Jarosova, R and Lunte, SM and Lazzarino, G and Caruso, G},
title = {The Bright and Dark Sides of Nitric Oxide in Neurodegenerative Diseases.},
journal = {Journal of personalized medicine},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/jpm16050246},
pmid = {42188341},
issn = {2075-4426},
abstract = {Nitric oxide (NO) plays an important role in neuronal communication, synaptic plasticity and vascular regulation. Due to its important function in neuronal homeostasis, NO imbalance is associated with neurodegeneration. Specifically, in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and frontotemporal lobar degeneration (FTLD), an excessive amount of NO, mostly produced by inducible NO synthase (iNOS), reacts with superoxide to form peroxynitrite, driving oxidative/nitrosative stress, mitochondrial dysfunction, and aberrant protein modifications. In AD, NO dysregulation promotes amyloid-β (Aβ) accumulation, tau hyperphosphorylation and synaptic loss, creating a self-perpetuating cycle of neuronal damage. NO's dual role, protective at physiological levels but harmful if overproduced, underscores the therapeutic potential of antioxidant compounds that restore the balance of NO/NOS (especially iNOS) while preserving physiological functions. However, despite the emerging role of antioxidant-based therapeutic approaches, clinical translation is limited by the complexity of NO signaling and the absence of safe, specific NOS inhibitors. By targeting the molecular switch from protective to toxic, NO activity may offer new personalized treatment avenues for neurodegenerative diseases.},
}

@article {pmid42189237,
year = {2026},
author = {Morbelli, SD and Bozzali, M and Cagnin, A and Cecchin, D and Chiti, A and Filippi, M},
title = {Precision pathways: optimising amyloid PET for sustainable Alzheimer's disease care.},
journal = {Journal of neurology},
volume = {273},
number = {6},
pages = {},
pmid = {42189237},
issn = {1432-1459},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism/therapy/drug therapy ; *Positron-Emission Tomography/methods/standards ; *Amyloid beta-Peptides/metabolism ; *Precision Medicine/methods ; Biomarkers/metabolism ; },
abstract = {The approval of anti-amyloid therapies has reshaped Alzheimer's disease from a clinically defined syndrome to a biologically confirmed and treatment-oriented condition. This transition places biomarkers, particularly amyloid positron emission tomography (Aβ-PET), at the centre of diagnostic precision, patient selection, safety governance, and therapeutic monitoring. Aβ-PET provides high specificity for confirming cerebral amyloid pathology, especially in cases with discordant or inconclusive fluid biomarkers, and supports staging through semi-quantitative assessment using standardised Centiloid metrics. In patients considered for anti-amyloid therapies, baseline Aβ-PET refines eligibility and risk-benefit profiling when integrated with MRI and APOE genotyping. During treatment, longitudinal Aβ-PET enables objective assessment of pharmacodynamic target engagement and treatment-related amyloid clearance, supporting response-adapted strategies and, in selected cases, therapy discontinuation. Beyond its clinical role, Aβ-PET has strategic organisational and economic implications. Its value is maximised when embedded within structured, stepwise diagnostic pathways that use scalable fluid biomarkers for triage and reserve Aβ-PET for high-impact decisions. However, implementation is challenged by regional heterogeneity, capacity constraints, and limited harmonisation across centres. Coordinated hub-and-spoke models, quantitative standardisation, and prospective registry-based data collection are essential to ensure the equitable and sustainable integration of anti-amyloid therapies into clinical practice. Aβ-PET has evolved from a confirmatory diagnostic tool to a strategic instrument that enables biologically driven, outcome-oriented care for patients with Alzheimer's disease.},
}

Humans
*Alzheimer Disease/diagnostic imaging/metabolism/therapy/drug therapy
*Positron-Emission Tomography/methods/standards
*Amyloid beta-Peptides/metabolism
*Precision Medicine/methods
Biomarkers/metabolism

@article {pmid42190614,
year = {2026},
author = {Kumar, SN and Abdul Hamid, NAW and Dafik, D and Sunder, R and S, SS and S, A and Kannadhasan, S},
title = {A Voyage on Computer Aided Intelligent Algorithms for the Segmentation of Brain Tissues for Neurodisorder Diagnosis.},
journal = {The International journal of neuroscience},
volume = {},
number = {},
pages = {1-23},
doi = {10.1080/00207454.2026.2680936},
pmid = {42190614},
issn = {1563-5279},
abstract = {Neurodisorders pose a considerable burden to global health, frequently requiring early treatment and diagnosis to avoid irreversible cognitive and motor impairments. Segmentation of brain tissue is an essential task in neurodiagnostics due to its inability to accurately separate grey matter, white matter, and cerebrospinal fluid within imaging modalities like MRI and CT. This article reviews the progress of brain tissue segmentation techniques from manual and semi-automated approaches to sophisticated machine learning and deep learning algorithms. It discusses how these contemporary methodologies enhance segmentation quality, address difficult anatomical variation, and optimize diagnostic accuracy in diseases like Alzheimer's, multiple sclerosis, traumatic brain injury, and stroke. This research work compares supervised, unsupervised, and deep learning paradigms on the basis of their advantages, disadvantages, and potential use in clinical settings. In addition, it presents hybrid and ensemble methods that blend conventional and AI-based approaches to mitigate obstacles such as data heterogeneity, annotation limitations, and interpretability. This survey details the revolutionizing potential of machine learning in neuroimaging and ultimately seeks to facilitate early diagnosis, treatment planning, and individualized healthcare provision for neurological diseases.},
}

@article {pmid42177211,
year = {2026},
author = {Sheikh, S and Shadin, M and Eity, TA and Oni, MIJ and Khatun, MM and Chowdhury, R and Bhuia, MS and Alfaifi, M and Altemani, FH and Altemani, AH and Saleh, N and Islam, MT},
title = {Lenalidomide ameliorates cognitive impairment via putative AChE inhibition: an in silico and in vivo study in a scopolamine-induced cognitive impairment model.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-49461-8},
pmid = {42177211},
issn = {2045-2322},
abstract = {Alzheimer's disease (AD) causes progressive cognitive decline, and current therapies provide limited benefit. This study evaluated the neuroprotective effects of lenalidomide (LLM), a thalidomide derivative, in a scopolamine-induced mouse model of cognitive impairment, with emphasis on its acetylcholinesterase (AChE) inhibitory potential. Mice received LLM (5, 10, and 20 mg/kg), donepezil (DNP) (3 mg/kg), or a combination and were assessed using Y-maze, passive avoidance, novel object recognition, and Morris water maze tests. In silico analysis, including molecular docking, 100 ns molecular dynamics simulation and ADMET profiling were performed to investigate the interaction of LLM with AChE. Memory performance showed a significant and dose-dependent improvement after the treatment of LLM. The 20 mg/kg dose exhibited effects comparable to DNP. LLM and DNP work together to increase effectiveness. Docking and simulation analyses revealed strong, stable binding to AChE while ADMET values indicated good drug-likeness. LLM exhibits neuroprotective and cognition enhancing effects in the scopolamine-induced model. In silico study also shows its potential as an AChE inhibitor. The study's anti-inflammatory mechanisms might also be helpful but need more exploration.},
}

@article {pmid42177528,
year = {2026},
author = {Chen, L and Lin, X and Fu, M and Chen, S and Yan, Z and Diao, Y and Chen, G and Huang, Z and Sun, Y and Lin, Y and Ye, Z and Zhou, Y and Ye, Q},
title = {Engineered neuronal exosomes mediate α-synuclein clearance to ameliorate Parkinson's disease.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04552-6},
pmid = {42177528},
issn = {1477-3155},
support = {2023XH023//the Postdoctoral Research Project Startup Fund of Fujian Medical University Union Hospital/ ; 2024QH2020//the Startup Fund for Scientific Research of Fujian Medical University/ ; 2023Y9008//the Joint Funds for the Innovation of Science and Technology, Fujian Province/ ; 2024ZD01002//the Major Special Project of Fujian Provincial Health Technology Project/ ; U23A20423//the National Natural Science Foundation of China/ ; 2022Y2005//the Clinical Research Center for Precision Diagnosis and Treatment of Neurological Diseases of Fujian Province/ ; },
abstract = {Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. A hallmark pathological feature of PD is the abnormal aggregation of α-synuclein (αSyn) into insoluble Lewy bodies. Consequently, developing strategies to inhibit αSyn aggregation in the brain has been a major research focus for PD treatment. This study developed a therapeutic approach using engineered neuronal exosomes. These exosomes were modified to extend their blood circulation half-life to 3.8 h and enhance targeting, with a 2.15 ± 0.09% brain signal proportion (vs. 0.78 ± 0.07% for free dye). They were then loaded with a self-developed αSyn aggregation-blocking peptide (sPep) as well as the antioxidant pyrroloquinoline quinone (PQQ). We investigated the therapeutic efficacy of this system in both in vitro and in vivo models of PD. Our experiments confirmed that the screened sPep effectively targeted and blocked αSyn aggregation both in vitro and in vivo. Neuronal exosomes, isolated by ultracentrifugation and hybridization, demonstrated strong abilities to cross the blood-brain barrier. In vivo studies revealed that the treatment significantly improved motor and cognitive functions in PD model mice. The underlying neuroprotective mechanisms included reducing αSyn aggregation, enhancing antioxidant capacity, ameliorating mitochondrial dysfunction, and suppressing cell apoptosis, collectively promoting the survival of dopaminergic neurons. These findings demonstrate that the engineered exosome-mediated delivery system exerts a protective effect against PD pathology.},
}

@article {pmid42178013,
year = {2026},
author = {Pattanaik, S and Sahu, PK and Paidesetty, SK and Prusty, SK and Pakeeraiah, K and Panda, PK and Lopamudra, },
title = {Design, synthesis, and inhibition of oxidative, amyloidogenic, and cholinergic dysfunction of Saxagliptin-derived Schiff bases against STZ-induced sporadic AD-like pathology.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178987},
doi = {10.1016/j.ejphar.2026.178987},
pmid = {42178013},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) shares significant pathological convergence with diabetes, primarily through insulin resistance. This leads to oxidative stress, neuronal inflammation, plaque formation, cholinergic dysfunction, and impaired neuronal survival. Herein, we report 10 Saxagliptin (SXG, a potent DPP-IV inhibitor)-derived Schiff base derivatives that were virtually designed and screened. Five leads were prioritized using ADMET profiling and molecular docking, then synthesized via Schiff base condensation with selected aryl aldehydes to target AD progression associated with diabetes. Structural integrity, redox activity, and stability were confirmed by comprehensive characterization, including chromatographic and spectroscopic analyses, DFT calculations, and in vitro antioxidant assays. Neuroprotective potential was thus assessed in vivo by inducing AD-like pathology in rats with a single i.p. dose of STZ at 45 mg/kg, thereby reproducing brain insulin resistance, oxidative-nitrosative stress, and cholinergic dysfunction. Significant neurodegeneration in STZ-treated rats was evidenced by behavioral analyses, biochemical markers (AChE, Aβ42), oxidative stress indices (SOD, CAT, GSH, GPx, MDA, NO, MPO), and hippocampal histology. Treatment with SXG and derivatives at 0.5 mg/kg, orally, resulted in significant restoration of antioxidant defenses, inhibition of lipid peroxidation and NO overproduction, reduction of inflammatory oxidative bursts, and improved cognition in treated groups. Remarkably, derivatives 3c and 3e showed superior free-radical scavenging and greater regulation of redox biomarkers, which were associated with healthy, defined hippocampal cytoarchitecture and reduced neuronal pyknosis and necrosis compared with SXG. Additionally, 3e showed strong therapeutic efficacy by targeting oxidative stress, cholinergic, and amyloidogenic pathways synchronously.},
}

@article {pmid42178051,
year = {2026},
author = {Wang, C and Liu, J and Zhou, Y and Shan, X and Li, S and Ding, S and Zhuo, X and Li, Q and Yang, W and Zhang, X and Gu, L},
title = {Acacetin targets SNX5 to promote autophagy degradation of NLRP3 inflammasome against cognitive impairment in Alzheimer's disease.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118103},
doi = {10.1016/j.bcp.2026.118103},
pmid = {42178051},
issn = {1873-2968},
abstract = {Alzheimer's disease (AD) is a chronic, low-grade inflammatory neurodegenerative disorder. Inhibiting the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is a potential therapeutic strategy for AD, but no approved NLRP3-specific inhibitors are available for clinical use, and current agents often cause significant side effects despite their anti-inflammatory benefits. Acacetin, is a flavonoid compound that can penetrate the blood-brain barrier, with potential for treating AD.The purpose of this study is to clarify the relationship between the anti-AD effect of acacetin and its mechanism of inhibiting NLRP3.acacetin improved cognitive function and reduced neuronal damage in 3xTg mice. Further Acacetin directly binds to sorting nexin-5 (SNX5) and upregulates its expression. This, in turn, activates autophagy to degrade the NLRP3 inflammasome, alleviates inflammationin HT22 cells and BV2 cells. These findings suggest that Acacetin can exert an anti-AD effect by targeting SNX5 to activate autophagy and promote the degradation of the NLRP3 inflammasome, which underscore the importance of targeting SNX5 to suppress NLRP3 inflammasome activation in AD treatment.},
}

@article {pmid42178053,
year = {2026},
author = {Elkabes, S},
title = {Sexually dimorphic roles of toll-like receptors in the central nervous system.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106830},
doi = {10.1016/j.bbi.2026.106830},
pmid = {42178053},
issn = {1090-2139},
abstract = {Many neurological and psychiatric diseases and disorders show sex differences in prevalence, incidence, disease manifestation and response to treatment. Yet, historically, most clinical and pre-clinical studies have been conducted disproportionately or exclusively in male subjects. In recent years, this research bias has been increasingly addressed through human and animal studies where both sexes are appropriately represented. These investigations have identified sex-specific disease mechanisms driven by a combination of distinct genetic, anatomical, physiological, hormonal and neural factors in males and females. Sexual dimorphism in immune function has long been recognized. Toll-like receptors (TLRs), important mediators of the innate immune response to pathogens and endogenous danger signals, play sex-biased roles in peripheral immunity. Toll-like receptors are also expressed in cells intrinsic to the central nervous system (CNS). They initiate, not only neuroinflammation in CNS infections and disease and injuries, but also influence neurodevelopment and normal aging. Emerging evidence indicates that TLRs expressed in CNS cells contribute to neural pathology in a sex-specific manner, a research area that warrants further investigations. The aim of the present review is to highlight the sex-specific contribution of TLRs expressed in the CNS to chronic pain, neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's Disease and psychiatric disorders including major depressive disorder (MDD). Major findings are highlighted, essential concepts, controversies and knowledge gaps are discussed, and potential future directions are proposed. Attention is drawn to the importance of advancing this research area given that neuroinflammation is a key player in many CNS pathologies and TLRs are the essential drivers of neuroinflammation.},
}

@article {pmid42178337,
year = {2026},
author = {Abaspour, N and Roghani, M and Bagheri, M and Khalili, M},
title = {Pioglitazone protects against trimethyltin hippocampal injury by reducing pyroptosis, mitochondrial dysregulation and ER stress.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-54103-0},
pmid = {42178337},
issn = {2045-2322},
support = {522458//shahed University/ ; },
abstract = {Hippocampus-specific neurotoxic trimethyltin (TMT) is routinely used to mimic a reliable murine phenotype of neurodegeneration as well as cognitive loss and is accordingly appropriate to analyze pathogenesis of the prevalent neurodegenerative disorders, i.e. Alzheimer's disease (AD), and to examine the effectiveness of novel therapeutics. Antidiabetic medication pioglitazone has exhibited neuroprotective effects with promising clinical indications for neurodegeneration-based illnesses. This study was accomplished for studying the neuroprotective effect of pioglitazone against TMT-initiated cognitive decline and allied hippocampal neurodegeneration. For this purpose, rats received intraperitoneal TMT (8 mg/kg) to generate a model of AD-like neurodegeneration and subsequently had oral daily administration of pioglitazone for 3 weeks (20 mg/kg). The acetylcholinesterase inhibitor and certified anti-AD drug donepezil (4 mg/kg) was similarly used as a positive control medicine. Pioglitazone treatment was accompanied by lower cognitive deficits in novel object recognition test and Barnes maze paradigm in addition to mitigation of astrogliosis severity with glial fibrillary acidic protein (GFAP) as its specific indicator and lower CA1 neuronal loss. Furthermore, pioglitazone partially normalized hippocampal factors of oxidative stress and neuroinflammation together with downregulation of pyroptotic parameters comprising caspase 1 and NLR family pyrin domain containing 3 (NLRP3). Moreover, less activity of acetylcholinesterase (AChE) and greater quantity of mitochondrial health-allied factors comprising peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), mitochondrial membrane potential (MMP), mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor γ (PPARγ) were likewise detected after pioglitazone treatment. These advantageous properties of pioglitazone were accompanied by inferior quantity of specific AD-allied markers comprising presenilin1 (PSEN1) and hyperphosphorylated tau (p-tau) as well as downregulation of endoplasmic reticulum (ER) stress, as observed by lower levels of PKR-like ER kinase (PERK), C/EBP homologous protein (CHOP), glucose-regulated protein 78 (GRP78), and inositol-requiring enzyme 1α (IRE1α). While anti-AD donepezil treatment was associated with improvement of cognitive function, however, it was not capable to significantly yield most advantageous effects of anti-diabetic PPARg agonist pioglitazone. This study disclosed the underlying pathways for neuroprotective effect of pioglitazone in TMT neurodegeneration and AD-like phenotype.},
}

@article {pmid42178577,
year = {2026},
author = {Ruthirakuhan, M and Mills, M and Rosenberg, P and Haughey, N and Mintzer, J and Craft, S and Herrmann, N and Lerner, AJ and Levey, AI and Padala, PR and Porsteinsson, A and van Dyck, CH and Shade, D and Lanctôt, KL},
title = {Uncovering lipid biomarkers linked to methylphenidate efficacy in treating apathy in Alzheimer's disease: insights from the ADMET 2 trial.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02055-y},
pmid = {42178577},
issn = {1758-9193},
support = {R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Apathy is a prevalent neuropsychiatric symptom (NPS) in Alzheimer's disease (AD), linked to functional impairment and reduced quality of life. The Apathy in Dementia Methylphenidate Trial 2 (ADMET-2) found methylphenidate (MPH) had modest efficacy for treating apathy, but treatment responses varied. MPH blocks dopamine and noradrenaline transporters, inhibiting dopamine and noradrenaline reuptake. Lipids are closely tied to monamine transporter function through their structural and signaling roles in neurotransmission, neuroinflammation, and synaptic plasticity. This study aimed to identify lipid species associated with MPH response and explore lipid pathway disruptions in responders versus non-responders.

METHODS: Participants from ADMET-2 with baseline lipidomic data were included. Responders were defined by a ≥4-point improvement on the Neuropsychiatric Inventory Apathy subscale (NPI-A), or moderate-to-marked improvement on the ADCS-Clinicians Global Impression-Change (ADCS-CGIC). Baseline plasma samples underwent lipidomic profiling. Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) in the MPH group was used to identify lipid species distinguishing responders from non-responders. Model performance was evaluated by area under the curve (AUC). Identified lipid species were analyzed in MetaboAnalyst for pathway enrichment. A secondary analysis in the placebo group assessed specificity of findings to MPH.

RESULTS: Of the 43 MPH-treated participants, 28 were NPI-apathy responders, and 10 were ADCS-CGIC responders. The PLS-DA model achieved robust discrimination between responders and non-responders (NPI-apathy: AUC = 0.82 +/- 0.05; ADCS-CGIC: AUC=0.84 +/- 0.07). Pathway analysis revealed disruptions in ceramide, phosphosphingolipid, and glycosphingolipid metabolism for NPI-apathy responders, and ceramide and glycosphingolipid metabolism for ADCS-CGIC responders. In 55 placebo-treated participants (30 NPI-apathy responders), an AUC of 0.79 +/- 0.05 was achieved, with pathway analysis indicating disruption in glycosphingolipid metabolism only.

CONCLUSIONS: This study demonstrates the utility of lipidomic profiling in identifying biomarkers of response to MPH in AD patients with apathy. The identified lipidomic species are broadly related to monoamine transporter function, reflecting their role in neurotransmission and synaptic plasticity. While glycosphingolipid metabolism appears broadly linked to changes in apathy, disruptions in ceramide and phospholipid metabolism may be specific to MPH treatment. Further study of these pathways may offer insights into the molecular mechanisms underlying apathy and treatment response, and could inform future biomarker-guided interventions.},
}

@article {pmid42178732,
year = {2026},
author = {Liu, C and Qin, X and Talisa, VB and Wang, J},
title = {Heterogeneous causal mediation analysis using Bayesian additive regression trees.},
journal = {Biometrics},
volume = {82},
number = {2},
pages = {},
doi = {10.1093/biomtc/ujag079},
pmid = {42178732},
issn = {1541-0420},
support = {R21AG087057/NH/NIH HHS/United States ; R01AG080590/NH/NIH HHS/United States ; S10OD028483/NH/NIH HHS/United States ; 2337612//National Science Foundation Faculty Early Career Development Program (CAREER) Award/ ; R305D200031//U.S. Department of Education Institute of Education Sciences Grant/ ; },
mesh = {Bayes Theorem ; Humans ; Computer Simulation ; Alzheimer Disease/genetics/pathology ; Regression Analysis ; *Causality ; *Mediation Analysis ; Apolipoproteins E/genetics ; Models, Statistical ; Genotype ; Biometry/methods ; Cognition ; },
abstract = {Causal mediation analysis provides insights into the mechanisms through which treatments affect outcomes. While mediation effects often vary across individuals, most existing methods focus solely on population-average effects, overlooking individual-level heterogeneity. To address this limitation, we propose a Bayesian regression tree ensemble method that flexibly models nonlinear relationships and captures treatment-by-mediator interactions in the mediation process. Using hierarchical posterior sampling, our approach provides credible intervals with nominal coverage rates for inferring heterogeneous mediation effects. Additionally, we leverage regression tree summaries to identify subgroups with distinct mediation effects and employ SHapley Additive exPlanation values to highlight key moderators and their influence on the mediation process. Comprehensive simulations demonstrate the method's accuracy in estimating and inferring heterogeneous mediation effects. Finally, we apply our method to investigate the heterogeneous mediation role of Alzheimer's disease pathology burden in the effect of apolipoprotein E genotype on late-life cognition.},
}

Bayes Theorem
Humans
Computer Simulation
Alzheimer Disease/genetics/pathology
Regression Analysis
*Causality
*Mediation Analysis
Apolipoproteins E/genetics
Models, Statistical
Genotype
Biometry/methods
Cognition

@article {pmid42179062,
year = {2026},
author = {Li, D and Dai, W and Li, X and Li, H and Li, L and Zhao, Y and Wang, X and Zhang, L},
title = {Amyloid-β suppresses oligodendrocyte differentiation in adult oligodendrocyte precursor cells (OPCs), with inflammatory gene changes distinguishing it from developmental OPCs.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261451403},
doi = {10.1177/13872877261451403},
pmid = {42179062},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) involves white matter deterioration, but how amyloid-β (Aβ) affects oligodendrocyte lineage cells at different maturation stages remains unclear.ObjectiveTo determine whether Aβ impairs oligodendrocyte differentiation and myelination in adult oligodendrocyte precursor cells (OPCs) and to identify molecular correlates via RNA-seq.MethodsOligodendrocyte lineage cells were examined in plaque-associated regions of 8-month-old 5x familial Alzheimer's disease (FAD) mice by immunohistochemistry. Primary OPCs from neonatal and adult rats were cultured with or without amyloid-β1-42 oligomers (oAβ42) to assess differentiation. Myelination was evaluated in organotypic slice cultures. RNA-seq and qPCR were performed to identify oAβ42-induced gene expression changes.ResultsIn 5xFAD mice, Olig2[+] cells were reduced near plaques, with CC1[+] mature oligodendrocytes showing a pronounced decrease, while PDGFRα[+] OPCs remained unchanged. In vitro, oAβ42 inhibited differentiation of both neonatal and adult OPCs, with adult OPCs exhibiting intrinsically slower maturation. Slice cultures revealed selective hypomyelination (reduced myelin basic protein) after oAβ42 treatment. RNA-seq showed that oAβ42 induced a distinct transcriptomic profile in adult OPCs, with upregulated genes enriched in immune/inflammatory pathways. Core inflammatory genes Nr4a1 and Tnf were significantly upregulated, validated by qPCR.ConclusionsoAβ42 plaque pathology is associated with oligodendrocyte maturation blockade. Aβ impairs OPC differentiation in purified cultures accompanied by inflammatory transcriptional changes. These findings highlight oligodendrocyte dysfunction in AD white matter pathology and reveal a specific oAβ42 response in adult OPCs.},
}

@article {pmid42179084,
year = {2026},
author = {Kim, D and Jeong, H and Lim, HK and Ahn, SM and Song, M},
title = {Pharmacological targeting of the integrated stress response by 2BAct improves object recognition memory and reduces neuroinflammation in the 5xFAD model of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261450638},
doi = {10.1177/13872877261450638},
pmid = {42179084},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia. The integrated stress response (ISR) contributes to impaired synaptic plasticity, neuronal dysfunction, and cognitive deficits in AD. However, research targeting the ISR as a therapeutic strategy for AD remains limited due to insufficient mechanistic insight.ObjectiveThis study aimed to evaluate the effects of 2BAct, an ISR inhibitor, on behavioral symptoms, amyloid-β (Aβ) and tau accumulation, and neuroinflammation in 5xFAD mice.MethodsTen-month-old 5xFAD mice received daily intraperitoneal (IP) injections of either 2BAct (10 mg/kg/day), donepezil (2 mg/kg/day; positive control), or vehicle for 23 consecutive days. Anxiety-like behavior and cognitive function were assessed using the open field test (OFT), novel object recognition test (NORT), and Morris water maze (MWM). Amyloid-β (Aβ), tau, and neuroinflammation markers were analyzed by immunofluorescence staining. ISR inhibition was evaluated by examining the phosphorylation level of eukaryotic initiation factor 2 alpha (eIF2α) using immunofluorescence staining and by analyzing ISR-related markers via RNA sequencing.Results2BAct treatment significantly improved object recognition performance and attenuated microglial activation and tau accumulation, without reducing Aβ burden. Reduced levels of phosphorylated eIF2α were also confirmed by immunofluorescence staining.ConclusionsThese findings suggest that 2BAct treatment improves cognitive performance and mitigates neuroinflammation while reducing tau accumulation. Although the therapeutic effects are limited, targeting the ISR with inhibitors such as 2BAct represents a potential therapeutic approach for AD. Further studies are required to elucidate the underlying molecular mechanisms and to address the limitations of ISR-based interventions.},
}

@article {pmid42179740,
year = {2026},
author = {Chen, R and Chiu, SY and DeSimone, JC and Wang, WE and Barmpoutis, A and Mcmillan, CT and Radhakrishnan, H and Irwin, DJ and Clark, L and Kantarci, K and Boeve, BF and Vaillancourt, DE},
title = {Automated Imaging Differentiation for Dementia: Including Alzheimer Disease Dementia and Dementia with Lewy Bodies.},
journal = {Neurology open access},
volume = {2},
number = {2},
pages = {},
pmid = {42179740},
issn = {2998-7601},
abstract = {BACKGROUND AND OBJECTIVES: Differentiation of Alzheimer's disease dementia (ADD) and dementia with Lewy bodies (DLB) remains a challenge. Free-water imaging has been investigated in neurodegenerative diseases and was found to be associated with neurodegeneration and neuroinflammation. This retrospective cohort study tested whether Automated Imaging Differentiation for Dementia (AIDD), combining diffusion free-water imaging (FWI) and support vector machine, predicts ADD vs DLB with high accuracy.

METHODS: Diffusion MRI data was rendered from ADNI, NACC, and PDBP. Free-water and free-water corrected fractional anisotropy were calculated for each participant using a bi-tensor model. Diffusion metrics were randomly assigned to training and testing sets. The primary outcome was the area under the curve (AUC) in the test set. AIDD was paired with antemortem MRI to predict postmortem pathology.

RESULTS: A total of 519 diffusion scans were processed with 258 ADD (mean age 73.7 (8.8), 50% male), 129 DLB (mean age 69.3, 88% male), and 132 controls (mean age 73.6 (6.8), 40% male). The machine learning sample included 387 scans,129 ADD with a mean age of 72.8 (8.7), 52.7% male; 129 DLB with a mean age of 69.3 (8.1), 87.6% male; and 129 controls with a mean age of 73.7 (6.8), 39.5% male). AIDD showed high training AUC for ADD vs DLB = 0.995 (95% CI, 0.985-1.000), ADD vs controls = 0.992 (95% CI, 0.982-1.000), DLB vs controls = 0.991 (95% CI, 0.983-0.999), and controls vs ADD/DLB = 0.990 (95% CI, 0.979-1.000). The testing AUCs were similar: ADD vs DLB = 0.995, ADD vs controls = 0.958, DLB vs controls = 0.939, controls vs ADD/DLB = 0.903. AIDD predictions were confirmed pathologically in a cohort of 13 patients.

DISCUSSION: This study demonstrates that machine learning in combination with free-water imaging can differentiate ADD, DLB, and normal aging with high clinical and pathological accuracy. Advancement in early detection of dementia can lead to more appropriate treatment plans, especially for DLB, and improved disease stratification that have hindered drug development trials.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that Automated Imaging Differentiation for Dementia, combining diffusion free-water imaging and machine learning accurately distinguishes Alzheimer's Disease from Dementia with Lewy bodies.},
}

@article {pmid42179743,
year = {2026},
author = {Yu, Z and Li, H and Wang, Y and Shen, F and Wang, Y},
title = {Aerobic exercise versus acupuncture as adjuncts to acetylcholinesterase inhibitors in Alzheimer's disease: a systematic review and Bayesian network meta-analysis.},
journal = {American journal of clinical and experimental immunology},
volume = {15},
number = {2},
pages = {37-49},
pmid = {42179743},
issn = {2164-7712},
abstract = {Acetylcholinesterase inhibitors (AChEIs) remain the standard therapy for Alzheimer's disease (AD), yet their cognitive and functional benefits are limited, creating a strong need for effective adjunctive treatments. Aerobic exercise and acupuncture have been proposed as promising complements to AChEIs because of their potentially synergistic neurotrophic and cholinergic effects. To compare these treatment combinations, we carried out a Bayesian network meta-analysis (BNMA) of randomized controlled trials (RCTs). These studies were sourced from major English and Chinese databases and examined cognitive and functional outcomes. In total, 37 RCTs were included, covering 2,188 participants. Among all, combined acupuncture (SUCRA = 78.92%) and fire needle therapy (SUCRA = 78%) demonstrated the highest probability of improving Mini Mental State Examination scores, while moderate intensity aerobic exercise ranked best for the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog, SUCRA = 23.3%) and the Barthel Index (SUCRA = 71.1%). Combined acupuncture was ranked highest for the Alzheimer's Disease Assessment Scale-Activities of Daily Living (ADAS-ADL, SUCRA = 94.3%), although its effects did not reach statistical significance. Across analyses, heterogeneity was minimal (I[2] ≤ 4%), model convergence was stable, and no publication bias was detected. Overall, this BNMA suggests that combined or thermal acupuncture offers the strongest cognitive gains alongside AChEIs, whereas moderate-intensity aerobic exercise provides the most reliable functional support. Because overall functional improvements were modest and evidence for some interventions remains limited, the benefits appear selective rather than broad. Larger, standardized trials are needed to clarify these patterns and guide their use in practice.},
}

@article {pmid42179865,
year = {2026},
author = {Arp, AM and Bloom, GS and D'Abreu, A and Fansler, A and Meegan, K and Ratcliffe, S and Kapur, J and Manning, C},
title = {The use of memantine for prevention of Alzheimer's disease: Pilot feasibility study rationale and protocol.},
journal = {Contemporary clinical trials communications},
volume = {51},
number = {},
pages = {101644},
pmid = {42179865},
issn = {2451-8654},
abstract = {BACKGROUND: Alzheimer's disease (AD) affects over 6 million older adults in the Untiled States. Evidence suggests the neuropathology leading to the disorder begins decades earlier, calling for a preventative treatment that can be administered to at risk individuals. Memantine hydrochloride, an NMDA receptor antagonist, is a possible candidate for prophylactic treatment by diminishing excessive NMDA receptor activity.

METHODS: This is a 2-year, double-blind, randomized, placebo-controlled trial of memantine hydrochloride (1:1 randomization allocation using randomly permutated blocks of unequal size). Participants are APOε4 carriers slightly under the average age of AD symptom onset (50-65 years of age) with a positive family history of a first degree relative with AD. Amyloid PET scans are performed pre and post treatment. Cognitive assessments and physical and neurological examinations are completed at regular intervals throughout the feasibility trial.

DISCUSSION: This study will assess the feasibility of the use of memantine hydrochloride for prevention of AD. The primary aim is to determine feasibility of participants who a) enrolled among those found eligible, and b) completed the study among those randomized to a study arm. Exploratory aims include examination of cognitive and safety assessments. Although not powered to determine efficacy, the study will provide direction on design elements needed for a Phase III clinical trial. No formal hypotheses are included in this feasibility trial.

TRIAL REGISTRATION: Clinical Trials NCT05063851.},
}

@article {pmid42180238,
year = {2026},
author = {Wang, Y and Li, H and Zhou, J and Zhao, S and Yang, A and Li, Z},
title = {The clinical value of multimodal neuroimaging in monoclonal antibody therapy for Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1761380},
pmid = {42180238},
issn = {1664-2295},
abstract = {Multimodal neuroimaging plays an indispensable role in the diagnosis, monitoring, and therapeutic evaluation of monoclonal antibody (mAb) therapies for Alzheimer's disease (AD). Structural MRI (sMRI) enables early detection of cerebral atrophy and amyloid-related imaging abnormalities (ARIA), a critical adverse effect associated with anti-Aβ immunotherapies. Positron emission tomography (PET) provides direct visualization and quantification of Aβ plaque clearance, serving as an objective biomarker of target engagement. Functional MRI (fMRI) has been investigated as a means to detect dynamic changes in brain network connectivity following treatment, though the evidence remains preliminary. The integration of these modalities significantly enhances diagnostic accuracy and allows for personalized assessment of treatment response. Furthermore, artificial intelligence (AI) technologies improve the efficiency and predictive power of imaging data analysis, supporting clinical decision-making. Despite these advances, challenges remain regarding the sensitivity and specificity of current imaging techniques, heterogeneity in treatment responses, and the need for long-term safety monitoring. Standardized imaging protocols, combined with multidisciplinary collaboration and robust AI-assisted modeling, are essential to optimize therapeutic outcomes and minimize risks in mAb-based AD treatment.},
}

@article {pmid42180249,
year = {2026},
author = {Miranda, DG and Carrouel, F and Attik, N and Araujo, GF and Lopes, NFDS and Marcucci, MC and Rodrigues, FP and Caires, GA and Vigerelli, H and Godoi, BH and Pacheco-Soares, C and Ramos, LP},
title = {Correction: Juglans regia and Pfaffia paniculata extracts: implications for periodontal disease treatment and correlation with Alzheimer's risk.},
journal = {Frontiers in cellular and infection microbiology},
volume = {16},
number = {},
pages = {1850828},
doi = {10.3389/fcimb.2026.1850828},
pmid = {42180249},
issn = {2235-2988},
abstract = {[This corrects the article DOI: 10.3389/fcimb.2025.1585438.].},
}

@article {pmid42180526,
year = {2026},
author = {Zhang, X and Yu, X and Sha, L and Li, Y and Qiao, Q and Yu, X and Xu, Q},
title = {Reblastatin as a neuroprotective agent in temporal lobe epilepsy and excitotoxic conditions of Alzheimer's disease and Parkinson's disease.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {5},
pages = {2964-2981},
pmid = {42180526},
issn = {2211-3835},
abstract = {Previous studies have shown that heat shock protein 90 (Hsp90) inhibitors can reduce seizures in temporal lobe epilepsy (TLE) by upregulating excitatory amino acid transporter 2 (EAAT2, also known as GLT-1). While the Hsp90 inhibitor 17-AAG is effective, its long-term use raises toxicity concerns. This study aimed to identify a safer Hsp90 inhibitor by screening benzenoid ansamycin derivatives for higher binding affinity and lower toxicity. Among nine natural benzenoid ansamycins and their derivatives screened, reblastatin emerged as the top candidate, exhibiting the highest binding affinity to Hsp90. Compared to geldanamycin and 17-AAG, reblastatin demonstrated significantly lower cytotoxicity in HEK293 and HepG2 cells. Like 17-AAG, reblastatin upregulated EAAT2 levels by disrupting the association among Hsp90, EAAT2, and the 20S proteasome. In a kainic acid-induced TLE mouse model, reblastatin reduced seizure frequency by 50%, with long-term treatment showing toxicity comparable to vehicle controls. Additionally, behavioral tests revealed neuroprotective effects of reblastatin in mouse models of Alzheimer's disease and Parkinson's disease. These findings collectively suggest that reblastatin is a promising Hsp90 inhibitor for treating TLE and excitotoxic conditions associated with neurodegenerative diseases.},
}

@article {pmid42180530,
year = {2026},
author = {Zhao, W and Lai, Y and Li, Z and Yuan, Z and Wen, Z and Zhang, L},
title = {Targeting non-apoptotic regulated cell death (RCD) to treat neurodegenerative diseases.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {5},
pages = {2601-2644},
pmid = {42180530},
issn = {2211-3835},
abstract = {Regulated cell death (RCD) is well-known as a controlled form of cell death regulated by one or more cascading signaling pathways. Over the past few decades, increasing evidence has implicated various non-apoptotic forms of RCD in neurons-including ferroptosis, parthanatos, necroptosis, pyroptosis, autophagic cell death, paraptosis, and cuproptosis-in the pathogenesis of neurodegenerative diseases (NDs) and their associated clinical manifestations. We provide an in-depth analysis of the associations between these RCDs and NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), and highlight the potential of modulating non-apoptotic RCD subtypes as neuroprotective targets. Besides, we highlight the crosstalk mechanisms among different non-apoptotic RCDs in NDs and the key targets regulating the crosstalk, which hold significant promise for developing dual-functional inhibitors that precisely modulate the pathological microenvironment and overcome drug resistance. As our understanding of death signaling networks deepens, such strategies may lead to breakthrough therapies for multiple NDs. Moreover, we further discuss the emerging small molecule compounds targeting non-apoptotic RCDs and their current research progress in clinical trials for the treatment of NDs, which may provide novel directions for related drugs. This comprehensive analysis paves the way for future research and therapeutic strategies aimed at harnessing non-apoptotic RCD pathways to mitigate neurodegeneration and improve patient outcomes.},
}

@article {pmid42180543,
year = {2026},
author = {Yang, Y and Liu, J and Liu, J and Wei, S and Kong, X and Mu, W and Liu, Y and Zhang, N},
title = {Advances in immune cell-based therapeutic agents for the treatment of inflammation-related diseases.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {5},
pages = {2794-2837},
pmid = {42180543},
issn = {2211-3835},
abstract = {Inflammation-related diseases account for over 50% of global disease-associated mortality; the core pathological mechanisms of these diseases are closely linked to functional dysregulation of immune cells such as macrophages and T cells. Aberrantly activated immune cells excessively secrete inflammatory mediators, which drive chronic inflammatory cascades and trigger irreversible tissue damage. In recent years, immune cell-based therapeutic agents (ICTAs) have garnered significant attention due to their inherent targeting specificity and immunomodulatory capabilities, encompassing whole immune cells, cell membranes, or extracellular vesicles serving as active therapeutics or delivery carriers. This review systematically elaborates on strategies for constructing ICTAs through nanoengineering, genetic engineering, and membrane-fused engineering, while outlining their integrating applications with other delivery devices. Furthermore, we summarize the preclinical and clinical trial advancements of ICTAs in various diseases such as tumors, rheumatoid arthritis, diabetes, atherosclerosis, Alzheimer's disease, inflammatory bowel disease, ischemia/reperfusion injury, sepsis, and hemophagocytic lymphohistiocytosis. These insights establish an interdisciplinary design framework for developing clinically applicable ICTAs and propose novel therapeutic approaches for inflammation-related diseases.},
}

@article {pmid41915038,
year = {2026},
author = {Xia, Y and Johnson, K and Fakhri, GE and Guehl, NJ and van de Giessen, E and Coomans, EC and Pijnenburg, YAL and Ossenkoppele, R and Groot, C},
title = {Bayesian modelling demonstrates clinically relevant heterogeneity in Tau PET patterns in Alzheimer's disease.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {53},
number = {7},
pages = {4664-4676},
pmid = {41915038},
issn = {1619-7089},
support = {10510022110010/ZONMW_/ZonMw/Netherlands ; WE.03-2024-06//Alzheimer Nederland/ ; 949570//H2020 European Research Council/ ; 10510022110010/ZONMW_/ZonMw/Netherlands ; },
abstract = {BACKGROUND: Traditionally, subgroups have been used to explore the effects of tau heterogeneity on cognition. However, categorization into rigid, exclusive subtypes, each with their own tau pattern, may overlook the fact that individual tau patterns are complex, and most individuals express features of multiple patterns. Mapping tau patterns in all their complexity has important clinical implications, as it may enable more accurate prognostication and support the development of personalized therapeutic strategies tailored to an individual’s unique tau profile.

METHODS: We applied a data-driven Bayesian model using Latent Dirichlet Allocation (LDA) to identify four covarying tau PET patterns in amyloid-positive individuals with symptomatic Alzheimer’s disease (AD) from the Amsterdam Dementia Cohort (ADC, N = 93, mean age = 65.3). The four latent tau spatial patterns identified via LDA were designated as follows: Limbic (Factor 1), characterized by predominant involvement of the limbic regions; Left TPC (Factor 2), centered on the left temporo-parietal cortex (TPC); Posterior (Factor 3), reflecting a posterior neocortical distribution; and MTL-sparing (Factor 4), showing relative sparing of limbic regions with diffuse neocortical tau deposition. Associations between individual loadings on each of these factors and cognitive domain scores were assessed using linear regression analyses. We then applied the ADC-derived model to an independent validation sample from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, N = 162, mean age = 72.7) to extract individual factor loadings. Associations between factor loadings and contemporaneous cognitive performance were again tested using linear regression, and linear mixed-effects models were used to additionally explore associations with cognitive decline. All analyses were adjusted for age, sex, education, and clinical diagnosis.

RESULTS: In both the discovery and validation cohort, we identified distinct associations between tau factor loadings and cognitive performance. Higher loading on Factor 1: limbic tau was generally associated with relatively better baseline cognition and slower cognitive decline. Factor 2: left TPC tau was linked to worse baseline scores and faster decline in memory, MMSE and language scores but only in the ADNI cohort. Factor 3: posterior tau was associated with worse baseline MMSE in the ADC cohort and to worse visuospatial performance both cross-sectionally and longitudinally in the ADNI cohort. Factor 4: MTL-sparing tau was related to better longitudinal memory in the ADNI cohort.

CONCLUSION: This data-driven approach identified overlapping tau patterns that relate to distinct cognitive domains. The findings highlight the value of continuous factor modeling in understanding heterogeneity in Alzheimer’s disease. Such a refinement of quantifying tau heterogeneity may improve patient stratification, refine prognostic accuracy, and ultimately guide the development of individualized treatment strategies.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-026-07868-5.},
}

@article {pmid42172309,
year = {2026},
author = {Unruh, D and Todtleben, J and Johnson, K and Schlichtmann, B and Szabo, M and Holland, M and Carlson, C and Hinson, J and Levin, S},
title = {Analytical and Clinical Validity of a High-Throughput, Fully Automated Immunoassay for Plasma Neurofilament Light Chain.},
journal = {The journal of applied laboratory medicine},
volume = {},
number = {},
pages = {},
doi = {10.1093/jalm/jfag052},
pmid = {42172309},
issn = {2576-9456},
abstract = {BACKGROUND: Neurofilament light chain (NfL) has emerged as a promising blood-based biomarker for neuroaxonal damage across neurological disorders. Clinical utility has been correlated with disease activity, treatment response, and prognosis. However, routine clinical laboratory implementation requires comprehensive analytical validation to ensure reliability and accuracy.

METHODS: A fully automated Access NfL research use only (RUO) immunoassay was evaluated on the DxI 9000 Immunoassay Analyzer from Beckman Coulter. Analytical validation in plasma assessed precision, analytical sensitivity, linearity, analytical specificity (interference), calibrator and sample stability, and method comparison to the Quanterix Simoa NfL assay. Clinical validity included comparisons of Alzheimer disease (Ad, N = 20) in plasma and multiple sclerosis (MS, N = 16) in serum, vs healthy controls (N = 20 and N = 23, respectively). Plasma-serum equivalence was validated.

RESULTS: The NfL assay met analytical criteria, with precision demonstrating coefficients of variation <3% across runs, a lower limit of quantification of 3.10 pg/mL, linearity with <12% deviation, and <10% interference. Plasma NfL samples remained stable for 18 h at room temperature (<7% difference) and refrigerated (<5%), and through 5 freeze-thaw cycles (<8%). Method comparison yielded high correlation (R2 = 0.981) with positive systematic proportional bias (Passing-Bablok slope = 3.02). Ad patients showed significantly elevated NfL levels (median 49.3 pg/mL, IQR: 28.9-67.8) vs controls (median 29.1 pg/mL, IQR: 22.6-33.8; P = 0.02). MS patients similarly demonstrated higher NfL (median 27.7 pg/mL, IQR: 22.5-50.6) vs controls (median 19.2 pg/mL, IQR: 15.1-25.6; P = 0.003).

CONCLUSIONS: The high-throughput Access NfL assay demonstrated analytical and clinical validity, supporting implementation in research and clinical laboratories.},
}

@article {pmid42172661,
year = {2026},
author = {Motisi Bertulli, A and Bezzio, C and Marsano, S and Corradini, I and Stranges, S and Matteoli, M and Armuzzi, A},
title = {Does inflammatory bowel disease play a role in cognitive decline? A systematic review.},
journal = {Journal of Crohn's & colitis},
volume = {20},
number = {5},
pages = {},
doi = {10.1093/ecco-jcc/jjag057},
pmid = {42172661},
issn = {1876-4479},
mesh = {Humans ; *Inflammatory Bowel Diseases/complications/psychology ; *Cognitive Dysfunction/etiology/epidemiology ; },
abstract = {BACKGROUND & AIMS: Inflammatory bowel disease (IBD) has been increasingly linked to cognitive impairment (CI) and dementia, yet the underlying mechanisms driving this association remain poorly understood and population, clinical and experimental studies show controversial results. Among others, factors such as chronic inflammation, gut-brain axis dysfunction, and psychological comorbidities have been proposed as contributors to cognitive deficits in IBD patients. The objective of this systematic review was to evaluate the existing literature on the relationship between IBD and cognitive function, considering observational and preclinical studies, with the aim to identify key factors influencing CI and potential clinical implications. The main focus of this review is on the use of IBD treatments, which may have a potential impact on CI.

METHODS: We conducted a systematic review according to PRISMA guidelines. PubMed and Scopus were searched from database inception up to August 30, 2024, for studies assessing cognitive performance in individuals with IBD. Clinical and epidemiological studies, genetic investigations (Mendelian Randomization and Genome-wide Association studies), and preclinical models examining memory, attention, and executive functions were included. Two reviewers independently extracted data and assessed methodological quality and risk of bias.

RESULTS: The research yielded 66 included studies, including 31 populations studies, 13 genetics studies, and 22 preclinical research studies. Our findings suggest that patients with IBD may exhibit impaired cognitive function, particularly in memory, attention, and executive processing. Disease activity, chronic inflammation and psychological stress appear to contribute to these deficits, while some treatment strategies seem to mitigate the risk of CI.

CONCLUSION: IBD is associated with CI and increased dementia risk, with biologics potentially mitigating neuroinflammation-related decline. More longitudinal studies and randomized clinical trials, also on intermediate endpoints, are needed to clarify the neuroprotective role of some therapies and optimize treatment strategies.},
}

Humans
*Inflammatory Bowel Diseases/complications/psychology
*Cognitive Dysfunction/etiology/epidemiology

@article {pmid42172854,
year = {2026},
author = {Copeland, EN and Mohammad, A and Baranowski, BJ and Marcella, BM and Beaudette, SM and MacPherson, REK and Fajardo, VA},
title = {Voluntary wheel running combined with low-dose lithium supplementation improves novel object recognition in male DBA/2 J mdx mice.},
journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)},
volume = {95},
number = {},
pages = {127893},
doi = {10.1016/j.jtemb.2026.127893},
pmid = {42172854},
issn = {1878-3252},
abstract = {BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by a mutation to the dystrophin gene. Cognitive dysfunction is a lesser-known symptom of DMD; however, approximately one-third of patients experience it. Though the mechanisms underlying these dysfunctions are unknown, research points towards an Alzheimer's disease (AD)-like pathology in clinical and preclinical work. In a recent study, we previously demonstrated that inhibiting glycogen synthase kinase 3 (GSK3) through a combination of low-dose lithium supplementation and voluntary wheel running (VWR) improved muscle quality and function in the mdx mouse model of DMD. Interestingly, both VWR and GSK3 inhibition with lithium can exert neuroprotective effects against Alzheimer's pathology; however, whether this treatment can also benefit cognitive function in mdx mice remains unknown.

METHODS: Here, we conducted a brief follow-up study to determine whether inhibiting GSK3 with a combination of low-dose lithium supplementation and VWR would enhance novel object recognition in mdx mice, while also investigating potential mechanisms, including beta-secretase activity, Tau phosphorylation, and sarco(endo)plasmic reticulum calcium ATPase (SERCA) activity.

RESULTS: Our findings show that lithium and VWR treatment, on average, improved novel object recognition in mdx mice-a result that may be linked to enhanced SERCA activity within the hippocampus but not to any changes in beta-secretase activity or tau phosphorylation.

CONCLUSION: Taken together, these data point to the potential benefits of Li and VWR on cognitive function in mdx mice, highlighting the need for future research aimed at teasing out the potential mechanisms.},
}

@article {pmid42172936,
year = {2026},
author = {Li, Y and Li, H and Xu, Z and Zhou, SK and , },
title = {CLIS: Causality-inspired Longitudinal Image Synthesis and its application to Alzheimer's disease characterization.},
journal = {Medical image analysis},
volume = {112},
number = {},
pages = {104126},
doi = {10.1016/j.media.2026.104126},
pmid = {42172936},
issn = {1361-8423},
abstract = {Clinical decision-making relies heavily on causal reasoning and longitudinal analysis of clinical variables, which include demographic variables, biomarkers, measurements, etc., often stored in a tabular format, and visual medical images. For example, for a patient with Alzheimer's disease (AD), how might brain gray matter atrophy evolve over a year under a hypothetical change in the Aβ42 biomarker level in cerebrospinal fluid? Answering such hypothetical questions is important for diagnosis and follow-up treatment, yet these medical images are neither readily acquired nor effectively predicted by correlation-based image synthesis models. Hence, a Causality-inspired Longitudinal Image Synthesis (CLIS) model is valuable. Building such a CLIS model faces three primary challenges: mismatched dimensionality between high-dimensional images and low-dimensional tabular variables, inconsistent intervals in follow-up data, and the complexity of medical causal mechanisms. In this paper, we propose a CLIS model that addresses these challenges via a novel integration of generative imaging, continuous-time modeling, and structural causal models combined with a neural network. Specifically, we first depict dependencies among tabular variables - including demographics, clinical biomarkers, and brain volumes - using a tabular causal graph (TCG), and then extend this to a tabular-visual causal graph (TVCG) to synthesize brain MRIs in a causality-inspired manner. An independent variable is also introduced to explicitly model time intervals. We train our CLIS on the ADNI dataset and evaluate it on two additional AD datasets, demonstrating that the synthesized images are both high-quality and interpretable. Furthermore, the generated MRIs provide insights for AD characterization, illustrating the model's potential utility in clinical applications.},
}

@article {pmid42174650,
year = {2026},
author = {Dakhel, A and Vestin, J and Giedraitis, V and Nyholm, D and Ingelsson, M and Erlandsson, A},
title = {Characterization of a distinct form of vimentin in the neurodegenerative brain.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {42174650},
issn = {2051-5960},
mesh = {*Vimentin/metabolism ; Humans ; *Brain/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology ; *Parkinson Disease/metabolism/pathology ; Female ; Male ; Aged ; Astrocytes/metabolism ; Aged, 80 and over ; Middle Aged ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by brain accumulation of aggregated proteins, leading to neuronal and glial dysfunction. Compelling data indicate that changes in vimentin expression, structure, and localization reflect alterations in cellular homeostasis and may correlate with disease progression. Yet, the involvement of abnormal vimentin in AD and PD remains unclear. Here, we have thoroughly characterized the distribution of modified, disease-associated vimentin in the AD and PD brain parenchyma, as well as in cerebrospinal fluid (CSF), hiPSC-derived astrocytes and organoids. For this purpose, we used the form-specific vimentin antibody [84-1], originally generated to recognize abnormal vimentin on the surface of sarcoma cells. The 84-1 vimentin reactivity pattern was characterized through immunohistochemistry and proximity ligation assay. Moreover, proteomic analysis, Western blot, and ELISA were performed to quantify 84-1 vimentin levels and gain insights into its molecular features. Our data demonstrate that 84-1 can identify a distinct population of vimentin in the human brain that shows low affinity to commonly used vimentin antibodies. The 84-1 vimentin is enriched in disease conditions and forms distinct deposits in the affected regions of the AD and PD brain, often colocalizing with pathological protein aggregates. Interestingly, the 84-1 vimentin pool consists mainly of cleaved proteoforms and reduction-resistant aggregates. Moreover, 84-1 vimentin levels are elevated in the CSF of AD and PD patients as well as in the culture medium of human astrocytes exposed to αSyn or Aβ fibrils. Taken together, our data highlights the importance of modified vimentin in neurodegeneration and presents 84-1 vimentin as a potential biomarker and future treatment target for AD and PD.},
}

*Vimentin/metabolism
Humans
*Brain/metabolism/pathology
*Alzheimer Disease/metabolism/pathology
*Parkinson Disease/metabolism/pathology
Female
Male
Aged
Astrocytes/metabolism
Aged, 80 and over
Middle Aged

@article {pmid42174734,
year = {2026},
author = {Xue, H and Bi, S and Wang, M and Zhu, X and Wang, F and Wang, Y and He, Y and Wang, Y and Liu, X and Cui, B and Li, N and Zhao, Z and Zhang, C and Wu, L and Qi, Z and Yan, S and Lu, J},
title = {Optimizing cutoffs for clinical interpretation of brain amyloid status using PET/MRI: a multisite study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02071-y},
pmid = {42174734},
issn = {1758-9193},
abstract = {BACKGROUND: Amyloid-β PET (Aβ-PET) imaging is playing an increasingly important role in the diagnosis and treatment of Alzheimer's Disease (AD). The Centiloid (CL) scale has been developed to standardize the measurements of Aβ PET imaging. Previous CL threshold settings were based on PET/CT, while our team's preliminary study found that CL values from PET/MRI are higher than those from PET/CT. Therefore, there is an urgent need to establish clinical interpretation cutoffs for Aβ status via PET/MRI to facilitate application in clinical practice.

METHODS: The clinical performance of Aβ PET/MRI and cerebrospinal fluid biomarkers were evaluated in a multisite cohort of 720 participants. Aβ-PET scans were visually read and quantified using CL method. A two-cutoff approach identified thresholds maintaining > 90% sensitivity/specificity and ≤ 20% intermediate cases, selected by maximal Youden index. Group comparisons of cerebrospinal fluid biomarkers and cognition used generalized linear models adjusted for age and sex.

RESULTS: The two-cutoff approach categorized Aβ-PET status as negative (CL ≤ 18.7), gray-zone (18.7-44.2), and positive (CL > 44.2). In Xuanwu cohort, it achieved an accuracy of 94.1%, a positive predictive value of 97.4%, a negative predictive value of 86.1%. In External cohort, the accuracy was 97.4%, positive predictive value 98.5%, negative predictive value 90.8%. Patients in the gray-zone group had lower cerebrospinal fluid(CSF) Aβ-42, Aβ-42/40 levels and a higher P-tau/Aβ-42 ratio.

CONCLUSIONS: This study established optimal CL-cutoff, providing a clinically applicable framework for interpreting Aβ PET/MRI findings. Incorporating a two-cutoff system facilitates the tracking of the AD continuum and supports individualized therapeutic decision-making.},
}

@article {pmid42175737,
year = {2026},
author = {Liang, S and Zhang, Q and Wang, X and Peng, L and Ji, X and Wang, J and Zhang, Y and Huang, J and Yang, J and Zhan, S and Xiao, Y and Liu, W and Chen, L},
title = {Electroacupuncture Improves the Learning and Memory by Modulating Hippocampal Glucose Metabolism through IGF1/IGF1R Signaling in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e14241},
doi = {10.1002/advs.202514241},
pmid = {42175737},
issn = {2198-3844},
support = {82004440//National Natural Science Foundation of China/ ; 2024J09044//Fujian Provincial Natural Science Foundation of China/ ; 2025Y9600//Joint Funds for the innovation of science and Technology, Fujian Province/ ; 2024Y9533//Joint Funds for the innovation of science and Technology, Fujian Province/ ; 2023ZQNZD015//Health Service Research of Fujian Province/ ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline and cerebral glucose hypometabolism. Emerging evidence suggests that modulating brain glucose metabolism represents a promising therapeutic strategy for AD. Here, we demonstrate that electroacupuncture (EA) improves cognitive function in 5×FAD mice by enhancing glucose metabolism in the hippocampus. EA treatment significantly attenuated learning and memory deficits and reduced β-amyloid (Aβ) deposition in 5×FAD mice. Further analysis revealed that these improvements were associated with enhanced hippocampal glucose metabolism and optimized information processing in the brain metabolic network. In addition, EA specifically activated the IGF1/IGF1R signaling pathway in the hippocampus, which promoted membrane translocation of GLUT3 and consequently enhanced neuronal glucose uptake. The glucose metabolic enhancement boosted tricarboxylic acid cycle activity and improved synaptic plasticity. Our findings establish a novel mechanism by which EA improves the learning and memory through the IGF1/IGF1R pathway, providing both theoretic and experimental support for the clinical application of EA in AD treatment.},
}

@article {pmid42175774,
year = {2026},
author = {Lin, Z and Jiang, Z and Chen, D and Liu, Y and He, Z and Ning, W and Wang, S and Guan, L},
title = {Novel Donepezil-Chalcone Hybrids as Potential Multifunctional Anti-Alzheimer's Disease Agents: Design, Synthesis, Computational Simulation, and In Vitro/In Vivo Biological Evaluation.},
journal = {Chemical biology & drug design},
volume = {107},
number = {5},
pages = {e70316},
doi = {10.1111/cbdd.70316},
pmid = {42175774},
issn = {1747-0285},
support = {22567024//The National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Amyloid beta-Peptides/metabolism/chemistry ; *Donepezil/chemistry/pharmacology/therapeutic use ; Molecular Docking Simulation ; Mice ; Humans ; *Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use ; Drug Design ; Peptide Fragments/metabolism ; Acetylcholinesterase/metabolism/chemistry ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use/chemical synthesis ; Molecular Dynamics Simulation ; Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors ; Butyrylcholinesterase/metabolism/chemistry ; Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors ; *Chalcone/chemistry/pharmacology ; Male ; Protein Aggregates/drug effects ; },
abstract = {A novel series of donepezil-chalcone including pyridine, piperazine, phenylamide skeleton hybrids were designed, synthesized, and evaluated for their inhibitory activities against AChE and BChE. Subsequently, a subset of these derivatives was investigation to inhibit Aβ1-42 aggregation and promote Aβ1-42 disaggregation effects. Among them, compounds 8b, 8c, 8j, and 8ab possessing good activity were further assayed for their inhibitory effects on BACE-1 and GSK3β, as well as their PI displacement activity. 8b (AChE, IC50: 0.11 μM; BChE, IC50: 0.18 μM; Aβ1-42 aggregation, IC50: 3.40 μM; their ability to promote Aβ1-42 disaggregation, IC50: 4.53 μM; BACE-1, IC50: 1.82 μM; GSK3β, IC50: 0.98 μM) exhibited prominent bioactivities across the above assays. Meanwhile, the molecular docking and the molecular dynamics simulations were performed to analyze the interactions between 8b and the key amino acid residues of the target proteins, which verified the stability of the corresponding protein ligand complexes. Furthermore, 8b significantly attenuated the cytotoxicity induced by Fe[3+] and Cu[2+] in BV-2 microglial cells, L-Glu in HT-22 hippocampal neuronal cells, and Aβ1-42 in both BV-2 and SH-SY5Y neuroblastoma cells. Additionally, 8b reduced the levels of intracellular ROS and NO in LPS-stimulated BV-2 cells, demonstrating potent anti-inflammatory and neuroprotective properties. Acute toxicity tests in mice confirmed the safety profile of 8b. In in vivo studies, compound 8b effectively protected against neuroinflammation 8b ameliorated cognitive deficits in mice induced by AlCl3 combined with L-galactose, which was associated with the upregulation of p-GSK3β and the downregulation of p-Tau expression. In conclusion, 8b holds great potential as a promising multitarget-directed new lead compound for the treatment of AD.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology
Amyloid beta-Peptides/metabolism/chemistry
*Donepezil/chemistry/pharmacology/therapeutic use
Molecular Docking Simulation
Mice
Humans
*Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use
Drug Design
Peptide Fragments/metabolism
Acetylcholinesterase/metabolism/chemistry
*Neuroprotective Agents/chemistry/pharmacology/therapeutic use/chemical synthesis
Molecular Dynamics Simulation
Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors
Butyrylcholinesterase/metabolism/chemistry
Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors
*Chalcone/chemistry/pharmacology
Male
Protein Aggregates/drug effects

@article {pmid42176081,
year = {2026},
author = {Ibrahim, RW and AlSheikh, MH},
title = {Model Validation Pipeline Against Longitudinal Alzheimer's Biomarker Data.},
journal = {Neuroinformatics},
volume = {24},
number = {2},
pages = {},
pmid = {42176081},
issn = {1559-0089},
mesh = {*Alzheimer Disease/metabolism/diagnostic imaging ; Humans ; Biomarkers/metabolism ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; *Brain/metabolism ; *Models, Neurological ; Longitudinal Studies ; Connectome/methods ; Computer Simulation ; },
abstract = {This study develops a fractional-order model of Alzheimer's disease using a [Formula: see text]-generalized Atangana-Baleanu-Caputo (ABC) operator to capture the spatiotemporal dynamics of amyloid-beta and tau protein spread, coupled with a neuron regeneration mechanism. The fractional parameters α, [Formula: see text], and τ control memory depth, deformation of the kernel, and temporal scaling, respectively. Numerical simulations demonstrate that: (i) intermediate fractional orders [Formula: see text] produce biologically realistic propagation delays, (ii) lower [Formula: see text] values enhance nonlocal interactions and accelerate tau diffusion across the connectome, and (iii) increasing the scaling parameter τ slows accumulation, mimicking effective clearance or treatment response. Incorporating a treatment term with drug diffusion and decay reveals that sustained low decay rates ([Formula: see text]) markedly reduce tau concentrations and protect neuron populations. These findings show that the [Formula: see text]-ABC framework not only captures the hereditary and memory effects of Alzheimer's progression but also provides a flexible platform for simulating therapeutic interventions and predicting disease trajectories using real brain connectome data.},
}

*Alzheimer Disease/metabolism/diagnostic imaging
Humans
Biomarkers/metabolism
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
*Brain/metabolism
*Models, Neurological
Longitudinal Studies
Connectome/methods
Computer Simulation

@article {pmid42176392,
year = {2026},
author = {Baron, KG and Alcántara, C and López, I and Euler, M and Baucom, BRW and Bermudez, B and Arones, Y and Carbajal-Salisbury, S and Fabian, G and Grandner, M and Gorovoy, S and Lopez, S and Parthasarathy, S and Troxel, W},
title = {Protocol for Nuestro Sueño: A randomized trial of a couples-based intervention to improve PAP adherence and sleep health among Hispanic patients beginning positive airway pressure (PAP) and their partners.},
journal = {Sleep medicine},
volume = {145},
number = {},
pages = {109019},
doi = {10.1016/j.sleep.2026.109019},
pmid = {42176392},
issn = {1878-5506},
abstract = {BACKGROUND: Obstructive sleep apnea (OSA) is more common among Hispanic individuals and contributes to risk for cardiometabolic diseases, dementia and poor quality of life. Positive airway pressure (PAP) improves sleep and quality of life, and culturally adapted interventions are promising for increasing treatment engagement. The goal of this study is to test Nuestro Sueño, a culturally adapted couples-based intervention to promote positive airway pressure adherence and sleep health for Hispanic couples in which one partner is recently diagnosed with OSA.

METHODS: We are conducting a two-arm, parallel group, single blind, randomized controlled pilot/feasibility trial to compare our novel culturally adapted treatment to an information control (IC). Nuestro Sueño is a culturally adapted dyadic behavioral intervention based on a transdiagnostic model. The digital health program involves 3- weekly sessions delivered via telehealth with a community health worker. Content is focused on education about OSA and PAP, improving both partner's sleep quality, increasing partner support and communication, and couple-level goal-setting around sleep and PAP use. The IC includes standardized patient educational materials. Both groups receive the usual follow-up care. Assessments will be completed pre-treatment, 1 and 3 months after starting PAP. Our main outcomes are feasibility and treatment satisfaction. Secondary outcomes include comparing Nuestro Sueño to IC for PAP adherence, sleep quality (self-report and objective) and cognitive measures of memory, processing speed and verbal fluency.

DISCUSSION: Nuestro Sueño is a novel culturally adapted intervention focused on improving PAP adherence and sleep health among couples in which one partner is recently diagnosed with OSA. Results of this study will be used to inform the design of a subsequent fully adequately-powered clinical trial. If successful, this intervention could significantly advance current clinical practice in the treatment of OSA and sleep health more comprehensively as well as promote sleep health equity among Hispanic patients, who are more likely to face challenges to obtaining diagnosis and treatment for OSA.

TRIAL REGISTRATION: Clinicaltrials.gov, NCT06649929.},
}

@article {pmid42168776,
year = {2026},
author = {van Dyck, CH},
title = {Letter to the editor response for: "Schneider LS, Kennedy RE, Cutter G. Caution in interpreting disease-modification claims with lecanemab: selective reporting and causal inference. Alzheimer's & Dementia. 2026".},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71485},
doi = {10.1002/alz.71485},
pmid = {42168776},
issn = {1552-5279},
}

@article {pmid42170124,
year = {2026},
author = {Patel, D and Patel, T and Patel, PN},
title = {Integrative Analysis of Pharmacological and Non-pharmacological Interventions in Alzheimer's Dementia.},
journal = {Cureus},
volume = {18},
number = {4},
pages = {e107386},
pmid = {42170124},
issn = {2168-8184},
abstract = {Alzheimer's dementia is a progressive neurodegenerative disorder in which cognitive decline, neuropsychiatric symptoms, and functional dependence emerge from a long preclinical and prodromal phase. Effective care increasingly requires an integrative approach: (1) disease-modifying pharmacology for selected patients early in the symptomatic course, (2) symptomatic pharmacotherapy for cognition and behavioral symptoms when benefits outweigh harms, and (3) non-pharmacological interventions that meaningfully affect quality of life, caregiver burden, safety, and functional outcomes across all stages. Recent advances, particularly anti-amyloid monoclonal antibodies, have reshaped early Alzheimer's treatment while raising new implementation challenges around biomarker confirmation, monitoring for amyloid-related imaging abnormalities (ARIA), and health-system capacity. Evidence also supports structured non-pharmacological strategies (e.g., cognitive stimulation, physical activity, caregiver programs, and environmental and behavioral approaches for agitation) as core therapies rather than "adjuncts." This narrative review synthesizes the evidence base and offers a practical, stage-based framework for combining pharmacological and non-pharmacological therapies, emphasizing person-centered goals, safety, feasibility, and equity.},
}

@article {pmid42171909,
year = {2026},
author = {Hammad, MO and Shady, T and Moanes, B and El-Sharkawy, AR and Galal, AM and Tawfeek, AE and El-Sisi, AEM and Sameh, A and Mahrous, S and Atya, N and Essam, A and El-Desouky, S and Abd El-Aziz, MH},
title = {Quinoa seed (Chenopodium quinoa W.) extract attenuates Alzheimer's disease-like neurodegeneration: Targeting the SLC7A11/GPX4 pathway.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42171909},
issn = {1573-4978},
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; *Chenopodium quinoa/chemistry/metabolism ; Rats ; Male ; *Plant Extracts/pharmacology ; Disease Models, Animal ; Oxidative Stress/drug effects ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; Seeds/chemistry ; Hippocampus/metabolism/drug effects/pathology ; Antioxidants/pharmacology/metabolism ; Aluminum Chloride ; Signal Transduction/drug effects ; Cognitive Dysfunction ; Maze Learning/drug effects ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and hippocampal neuronal loss. Targeting ferroptosis-related pathways represents a promising therapeutic strategy.

OBJECTIVE: This study aimed to investigate the potential effect of quinoa (Chenopodium Quinoa W.) seed extract in an aluminum chloride (AlCl₃)-induced rat model of AD, with a particular focus on the SLC7A11/GPX4 antioxidant axis and NCOA4-mediated ferritinophagy.

METHODS: Adult male rats were randomly divided into four groups (n = 6): GI (Control), GII (AD), GIII (Quinoa + AD), and GIV (Alzemenda + AD). AD was induced by oral AlCl₃ administration. Quinoa extract and Alzemenda were administered concurrently with AlCl₃ throughout the experimental period. Behavioral performance was evaluated using the Morris Water Maze and Open Field Test. Oxidative stress markers, iron parameters, gene expression, and histopathological changes in the hippocampus were assessed.

RESULTS: GII exhibited significant cognitive impairment, increased lipid peroxidation, depletion of antioxidant defenses, downregulation of SLC7A11, and marked hippocampal iron deposition compared with GI. Treatment with quinoa (GIII) significantly improved learning and memory, restored GPX4 activity and GSH levels, upregulated SLC7A11 expression, and attenuated hippocampal iron deposition. GIV showed comparable behavioral and histological improvement. Systemic iron indices, as well as hippocampal FPN1 and NCOA4 expression, did not differ significantly among groups.

CONCLUSION: Quinoa seed extract exerts ameliorating effects in AlCl₃-induced AD by suppressing oxidative stress-associated neurodegeneration through preservation of the SLC7A11/GSH/GPX4 axis rather than modulation of iron export or ferritinophagy pathways.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/chemically induced
*Chenopodium quinoa/chemistry/metabolism
Rats
Male
*Plant Extracts/pharmacology
Disease Models, Animal
Oxidative Stress/drug effects
*Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism
Seeds/chemistry
Hippocampus/metabolism/drug effects/pathology
Antioxidants/pharmacology/metabolism
Aluminum Chloride
Signal Transduction/drug effects
Cognitive Dysfunction
Maze Learning/drug effects

@article {pmid42171931,
year = {2026},
author = {Shukla, S and Singh, RK},
title = {Crosstalk between death-associated protein kinase 1-regulated mechanisms and dysfunctions in alzheimer's disease.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42171931},
issn = {1573-4978},
mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; Humans ; *Death-Associated Protein Kinases/metabolism/genetics ; Amyloid beta-Peptides/metabolism ; Neurons/metabolism/pathology ; Animals ; Signal Transduction ; Cell Death ; Reactive Oxygen Species/metabolism ; tau Proteins/metabolism ; Brain/metabolism ; Autophagy ; },
abstract = {Alzheimer's disease (AD) is a chronic progressive neurocognitive disorder manifested by increased production and deposition of amyloid beta (Aβ), abnormal tau phosphorylation, and formation of neurofibrillary tangles (NFTs). In addition, the disease progression is found to be associated with neuronal cell death, elevated levels of reactive oxygen species, mitochondrial dysfunction, and loss of synaptic plasticity in specific regions of the brain. AD is seventh leading cause of death and over more than 70%-80% of 57 million people having dementia develop AD worldwide. The disease population is also severely increasing at an alarming rate globally. The currently available treatment strategies remain insufficient to cure the disease because AD involves very complex pathways during its progression. Death-associated protein kinase 1 (DAPK1) is identified as a promising next-generation therapeutic drug target for the management of AD. It belongs to a family of serine/threonine kinases that influences different hypotheses involved in AD pathogenesis, such as tauopathies, Aβ hypothesis, redox, and autophagy pathways. In this review, we highlight the involvement of DAPK1 in various molecular pathways associated with AD pathogenesis and the crosstalk between DAPK1 and synaptic dysfunction and neuronal cell death implicated in AD. Moreover, the various small molecules, microRNAs, and phytoconstituents have been discussed, which have the potential to be developed as a treatment strategy targeting DAPK1-related pathological pathways in AD.},
}

*Alzheimer Disease/metabolism/pathology/genetics
Humans
*Death-Associated Protein Kinases/metabolism/genetics
Amyloid beta-Peptides/metabolism
Neurons/metabolism/pathology
Animals
Signal Transduction
Cell Death
Reactive Oxygen Species/metabolism
tau Proteins/metabolism
Brain/metabolism
Autophagy

@article {pmid42172039,
year = {2026},
author = {Han, X and Xue, J and Zhang, Q and Li, R and Guo, X and Duan, Q and Sang, S},
title = {Nitric oxide-enhanced blood-brain barrier penetration and mitochondria-targeted antioxidant carbon dots for Alzheimer's disease.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6tb00133e},
pmid = {42172039},
issn = {2050-7518},
abstract = {Alzheimer's disease (AD) involves a complex pathogenesis in which the β-amyloid (Aβ) cascade and oxidative stress hypotheses interact through mitochondrial dysfunction, forming a vicious cycle that underscores the need for multi-targeted therapeutic strategies. In this study, multifunctional carbon dots (EMA-CDs) were rationally designed and synthesised via a simple one-pot hydrothermal approach to integrate antioxidant activity, nitric oxide (NO) release capability, and mitochondrial targeting. EMA-CDs exhibited potent reactive oxygen species (ROS) scavenging abilities, efficiently eliminating hydroxyl radicals, superoxide anions, and DPPH radicals with rates exceeding 80%. Their mitochondrial specificity further alleviated intracellular oxidative stress and neuroinflammation. Notably, EMA-CDs at low concentrations (80 µg mL[-1]) markedly inhibited Aβ42 aggregation and promoted fibril disassembly, achieving inhibition and depolymerisation efficiencies of approximately 97.1% and 99.4%, respectively. In addition, EMA-CDs promoted NO production, which in turn modulated the expression of MMP-9 and ZO-1 proteins. This led to a reversible and transient opening of the blood-brain barrier (BBB), resulting in an enhanced penetration efficiency with a cumulative rate of 65.4% over 12 h. Furthermore, in the C. elegans CL2006 model, EMA-CDs significantly alleviated Aβ42 plaque deposition and reduced intracellular ROS levels by approximately 55%. Moreover, EMA-CDs extended the mean lifespan of the worms by about 6 days and enhanced reproductive capacity to 1.25-fold of the control, demonstrating potent in vivo neuroprotective and antioxidative stress effects. Collectively, this study demonstrates that EMA-CDs function as a versatile therapeutic platform for AD treatment and provide a promising avenue for the development of multi-target nanotherapeutics and novel AD intervention strategies.},
}

@article {pmid41965633,
year = {2026},
author = {Mansel, CO and Ghisays, V and Mahnken, JD and Swerdlow, RH and Reiman, EM and Karnes, JH and Denny, JC and Veatch, OJ},
title = {Downward bias in the association between APOE and Alzheimer's disease using prevalent and by-proxy disease sampling in the All of Us research program.},
journal = {BMC medical genomics},
volume = {19},
number = {1},
pages = {},
pmid = {41965633},
issn = {1755-8794},
support = {R01 HL156993/HL/NHLBI NIH HHS/United States ; OT2 OD026549/OD/NIH HHS/United States ; 1OT2OD026549/NH/NIH HHS/United States ; R01 HL158686/HL/NHLBI NIH HHS/United States ; OT2 OD036485/OD/NIH HHS/United States ; P30 AG035982/NH/NIH HHS/United States ; R21 HL172036/HL/NHLBI NIH HHS/United States ; P30 AG072973/NH/NIH HHS/United States ; ZIA HG200417/NH/NIH HHS/United States ; P30 AG072973/NH/NIH HHS/United States ; P30 AG072973/NH/NIH HHS/United States ; P30 AG035982/NH/NIH HHS/United States ; 1OT2OD026549/NH/NIH HHS/United States ; ZIA HG200417/NH/NIH HHS/United States ; P30 AG035982/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Recent genome-wide association studies for Alzheimer’s Disease and related dementias (ADRD) have increased statistical power via larger analysis datasets from biobanks by (1) including non-age-matched controls and prevalent cases, and/or (2) including individuals who report a family history of ADRD as proxy cases. However, these methods have the potential to increase noise and distort genetic associations which are important for genomic-informed prevention and treatment of ADRD. Here, we sought to understand how the effect sizes of genetic associations in ADRD could be sensitive to these methodological choices, using APOE genotypes as an example.

METHODS: Participants in the All of Us Research Program over the age of 49 at enrollment (n = 229,722) were assigned one of four categories: incident ADRD (developed after enrollment in All of Us), prevalent ADRD (present on enrollment), proxy ADRD (participant noted a family history of ADRD), and control (no history or diagnosis of ADRD). ADRD diagnoses were determined using available electronic health records and APOE genotype was determined using whole-genome sequencing. Effect sizes for the associations between APOE risk alleles and ADRD diagnoses were compared using polychotomous logistic regression and presented as adjusted generalized ratios (AGR).

RESULTS: The mean age of the cohort was 64 ± 9 years, and it was 57% female; 65% clustered predominantly with European genetic reference populations. Among the participants, 733 (0.3%) had prevalent ADRD, 684 (0.3%) had incident ADRD, and 19,186 (8.4%) reported a family history of ADRD (proxy ADRD). The effect size for APOE ε4 heterozygote was similar for proxy ADRD (AGR [95% CI]: 2.10 [1.96–2.24]) but attenuated for prevalent ADRD (1.38 [1.17–1.63]) compared to incident ADRD (2.13 [1.81–2.50]). For APOE ε4 homozygotes, the effect sizes were significantly attenuated in both proxy (3.53 [2.93–4.26]) and prevalent (3.12 [2.20–4.45]) ADRD. Furthermore, APOE and ADRD association effect sizes increased when restricting the control (no ADRD) group to older age brackets.

CONCLUSIONS: Our study highlights how genetic associations with ADRD can be sensitive to how cases are defined in biobanks like All of Us, with effect sizes downwardly biased when using prevalent or by-proxy cases compared to incident cases.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12920-026-02362-1.},
}

@article {pmid42164617,
year = {2026},
author = {Garnier-Crussard, A and Dadar, M and Villain, N and Charidimou, A and Boulouis, G and Cotton, F and Brickman, AM and Chételat, G},
title = {White matter hyperintensities in Alzheimer's disease in the era of anti-amyloid therapies.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {},
pages = {e70349},
pmid = {42164617},
issn = {2352-8729},
abstract = {White matter hyperintensities (WMHs) are highly prevalent in Alzheimer's disease (AD) and arise from interacting vascular pathologies (including hypertensive small vessel disease and cerebral amyloid angiopathy) alongside inflammatory and neurodegenerative processes. In the era of anti-amyloid monoclonal antibodies, this heterogeneity is increasingly relevant for both treatment efficacy and safety. WMHs may signal mixed AD-vascular pathology that dilutes the cognitive benefit of amyloid-targeting therapies and may also index vulnerability of the neurovascular unit that predisposes to amyloid-related imaging abnormalities (ARIAs), although direct evidence remains limited. In this perspective, we synthesize current knowledge on the origins of WMHs in AD, review advanced magnetic resonance imaging and biomarker approaches that aim to refine lesion characterization in vivo, and discuss how WMHs should be interpreted in memory clinic practice when considering anti-amyloid therapies. We conclude with a research roadmap to integrate WMH phenotyping into precision risk-benefit assessment and ARIA prediction .},
}

@article {pmid42164658,
year = {2026},
author = {Liu, X and Jia, L and Wu, K and Chen, M and Sun, J and Yang, C and Xu, C and Sun, J and Wang, J and Dai, L},
title = {Exploring and Targeting the Connection of Iron and Copper Homeostasis to Neurodegenerative Diseases.},
journal = {MedComm},
volume = {7},
number = {},
pages = {e70766},
pmid = {42164658},
issn = {2688-2663},
abstract = {Iron (Fe) and copper (Cu) are vital micronutrients that regulate many critical physiological processes in the human body, with their homeostasis in the central nervous system (CNS) being essential for proper neuronal function. Disruptions in their metabolism and regulatory pathways have been associated with the pathogenesis of various forms of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD). Despite growing research on metal homeostasis, the intricate molecular mechanisms that link iron and copper metabolism to the initiation and progression of NDDs remain insufficiently elucidated. In this review, we provide a systematic overview of the metabolic processes of iron and copper in the body and CNS, highlighting their interactions with many metal-binding proteins, including transporters, storage proteins, and important intrinsically disordered proteins (e.g., amyloid β-protein, tau, and alpha-synuclein) involved in NDDs. We further dissect the downstream effects of metal ion dyshomeostasis on cellular redox balance, neuroinflammation, autophagy, organelle interaction network, and cell death. Additionally, we discuss current therapeutic strategies aimed at targeting iron and copper dyshomeostasis, as well as the emerging role of artificial intelligence in this field of research. By integrating metal metabolism, metal-protein interactions, the effect of metal dyshomeostasis on downstream biological processes, and potential intervention strategies, this review serves as a comprehensive reference for understanding the pathogenesis of NDDs and offers new perspectives for developing effective therapeutics. Overall, this review underscores the significance of reinstating metal balance for the treatment of neurodegeneration.},
}

@article {pmid42166005,
year = {2026},
author = {Kariminejad-Farsangi, H and Kariminejad-Farsangi, H and Mir, Y and Sheibani, V and Joushi, S},
title = {Mechanistic insights into mesenchymal stem cell therapy for cognitive impairments in Alzheimer's disease models: a systematic review and meta-analysis.},
journal = {Molecular and cellular biochemistry},
volume = {},
number = {},
pages = {},
pmid = {42166005},
issn = {1573-4919},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options that primarily offer symptomatic relief. Mesenchymal stem cells (MSCs) have shown promise in preclinical studies due to their neuroprotective, immunomodulatory, and regenerative properties. This systematic review and meta-analysis aimed to assess the effects of MSC therapy on cognitive performance and molecular pathology in animal models of AD.A systematic search was conducted in PubMed, Web of Science, Scopus, Embase, ProQuest, and gray literature sources. This study included in vivo interventional animal studies that evaluated the effects of MSCs on cognitive outcomes in Alzheimer's disease models using the Morris Water Maze test. The standardized mean difference (SMD) was used as the effect size, and data were synthesized using a random-effects model. Study quality was assessed using the SYRCLE risk of bias tool. Publication bias was evaluated through funnel plots, Egger's test, and the trim-and-fill method. Sensitivity analysis was performed using the leave-one-out method and further supported by a risk-of-bias-based approach.A total of 51 studies met the inclusion criteria, of which 37 were included in the meta-analysis. The findings indicated that MSC therapy significantly reduced escape latency (SMD = -1.18, 95% CI -1.46 to-0.89, I[2] = 56.81%, P = 0.00) and increased time spent in the target quadrant (SMD = 1.93, 95% CI 1.46 to 2.40, I[2] = 78.63%, P = 0.00). MSC treatment also led to an increase in hippocampal BDNF levels and a reduction in Aβ deposition and pro-inflammatory cytokines such as IL-1β and TNF-α. However, the effect on IL-6 levels was not statistically significant.MSCs Improve cognitive function and modulate pathological features in AD animal models. Further high-quality studies with standardized protocols and broader literature inclusion are needed to support clinical translation.},
}

@article {pmid42166031,
year = {2026},
author = {Xu, X and Ni, Z and Wang, YB and Fan, SS and Du, Y and Wang, X and Meng, XY},
title = {Decoding shared pathogenic networks of oxidative stress in neuropsychiatric disorders to prioritize multi-target therapeutics from natural products.},
journal = {Cell biology and toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10565-026-10208-w},
pmid = {42166031},
issn = {1573-6822},
support = {2508085QC099//Natural Science Foundation of Anhui Province of China/ ; 2025AHGXZK40182//Natural Science Research Project for Youth of Higher Education Institutions of Anhui Province/ ; },
abstract = {BACKGROUND: Neurodegenerative and psychiatric disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and schizophrenia (SZ), are characterized by progressive neuronal loss and synaptic dysfunction. Despite their severity, effective disease-modifying treatments remain unavailable, largely due to the elusive nature of their underlying molecular mechanisms.

METHODS: To elucidate these mechanisms, we conducted an integrative systems biology analysis incorporating transcriptomic datasets, in silico proteomic networks, and inferred metabolomic profiles. Machine learning (ML) and deep learning (DL) models were employed to identify regulatory networks associated with oxidative stress, immune response, and synaptic signaling. Furthermore, network pharmacology approaches were applied to explore multi-target intervention strategies using bioactive compounds from traditional Chinese medicine (TCM).

RESULTS: Our integrative analysis revealed extensive overlap in dysregulated biological processes across all four disorders, particularly involving oxidative stress and immune activation. We identified TP53, NFE2L2, and PPP3CA as central regulatory hubs driving these pathologies. Notably, computational predictions highlighted that TCM-derived compounds, specifically stigmasterol and dodecanoic acid, exhibit promising multi-target effects for modulating these oxidative and inflammatory responses. Subsequent in vivo experimental validation was performed exclusively to corroborate the disease-associated pathways and core gene dysregulation in an Aβ42-induced AD model. These findings demonstrated molecular and behavioral phenotypes consistent with our multi-dimensional computational predictions, establishing a robust mechanistic rationale that merits future in vivo pharmacological validation for the predicted bioactive compounds.

CONCLUSION: This study highlights the utility of a multi-disease, multi-dimensional framework in uncovering shared pathogenic signatures. By integrating computational analytics with pharmacological modeling and experimental validation, we identified key regulatory genes and natural compounds with therapeutic potential. These findings provide a theoretical foundation for the development of multi-target, personalized treatment strategies against neurodegeneration.},
}

@article {pmid42166820,
year = {2026},
author = {Czarnota-Łydka, K and Kucwaj-Brysz, K and Cios, A and Mordyl, B and Głuch-Lutwin, M and Jastrzębska-Więsek, M and Partyka, A and Honkisz-Orzechowska, E and Karcz, T and Pakulska, J and Satała, G and Żesławska, E and Dąbrowska, M and Starek, M and Więcek, M and Kurowska, K and Pyka, P and Brunetti, L and Leuci, R and Piemontese, L and Nitek, W and Wesołowska, A and Carrieri, A and Handzlik, J},
title = {New chalcogen-optimized 1,3,5-triazines as dual 5-HT6R/FAAH modulators: A versatile approach to neurodegenerative disorders.},
journal = {European journal of medicinal chemistry},
volume = {315},
number = {},
pages = {118966},
doi = {10.1016/j.ejmech.2026.118966},
pmid = {42166820},
issn = {1768-3254},
abstract = {The clinical failure of selective serotonin 5-HT6 receptor (5-HT6R) antagonists in Alzheimer's disease (AD) highlights the need for multitarget therapeutic strategies addressing the multifactorial nature of neurodegeneration. Building upon our pioneering discovery of the first-in-class dual 5-HT6R/FAAH (fatty acid amide hydrolase) modulators among O-ether triazine compounds, we here report a comprehensive lead-optimization campaign centered on the triazine-based compound MR3b, identified as a promising lead in the search for AD treatment. Structural modifications based on scaffold contraction and chalcogen bioisosterism generated a focused library of 1,3,5-triazine derivatives with diversified GPCR and FAAH profiles. Several compounds displayed nanomolar affinities for 5-HT6R, 5-HT2AR, and D2R, alongside improved FAAH inhibition and antioxidant properties. Sulfur and selenium substitutions markedly enhanced receptor affinity and reduced cytotoxicity compared to the oxygen-containing lead. Selected compounds demonstrated significant neuroprotective effects in cellular models of AD-related pathology, including mitochondrial dysfunction, amyloid-β, and glutamate-induced toxicity. Furthermore, the thio-analogue 4c effectively reversed memory deficits in vivo, showing superior CNS penetration (Kp,brain = 0.78), an expanded therapeutic window (NOR test), and improved safety relative to MR3b. This study identified compound 4c as a second-generation lead and underscores the potential of multitarget triazine-based ligands combining serotonergic modulation and FAAH inhibition as potential disease-modifying candidates for AD and related neurodegenerative disorders.},
}

@article {pmid42167685,
year = {2026},
author = {Lee, YW and Cho, YE and Kim, SY and Cho, SY and Lee, SJ and Do, YJ and Lee, NH and Kim, DH and Ryu, JH and Bae, HJ and Park, SJ},
title = {Paeonol ameliorates scopolamine- and β-amyloid 1-42 oligomer-induced cognitive impairments through modulation of the TGR5-PKA-cAMP response element-binding-brain-derived neurotrophic factor pathway and inhibition of acetylcholinesterase.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106188},
doi = {10.1016/j.neuint.2026.106188},
pmid = {42167685},
issn = {1872-9754},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, synaptic dysfunction, and cholinergic signaling deficits. Paeonol (2-hydroxy-4-methoxyacetophenone), a phenolic compound derived from Paeonia suffruticosa, has well-documented neuroprotective activity, but potential cognitive benefits and the underlying mechanisms have not been widely examined. Here, we investigated the potential of paeonol to improve cognitive function in scopolamine- and Aβ1-42 oligomer-induced mouse models of AD. Paeonol significantly improved the performance of both models in the Y-maze, novel object recognition, and passive avoidance tests, particularly at 10 mg/kg. Western blotting of excised brain tissue revealed that paeonol treatment reversed scopolamine- and Aβ1-42 oligomer-induced suppression of hippocampal PKA and cAMP response element-binding (CREB) phosphorylation and concomitantly enhanced brain-derived neurotrophic factor (BDNF) expression. Notably, paeonol also reversed scopolamine- and Aβ1-42-induced downregulation of Takeda G-protein-coupled receptor 5 (TGR5), an upstream regulator of the PKA-CREB-BDNF pathway, and molecular docking simulations predicted a possible paeonol-TGR5 interaction. Moreover, paeonol suppressed scopolamine-induced elevation of acetylcholinesterase activity with efficacy comparable to the clinical inhibitor donepezil. These findings support the potential of paeonol as a naturally sourced multitarget therapeutic agent for AD.},
}

@article {pmid41965687,
year = {2026},
author = {Hamed, FM and Mady, MS and Elgayed, SH and Mansour, YE and Mahgoub, S and Lai, KH and Lin, CY and Elsayed, HE and Moharram, FA},
title = {Carpoxylon macrospermum leaf extract and its phenolic compounds: a multi-targeted therapeutic remedy for Alzheimer's disease.},
journal = {BMC complementary medicine and therapies},
volume = {26},
number = {1},
pages = {},
pmid = {41965687},
issn = {2662-7671},
support = {MOST 111-2320-B-038-040-MY3, 113-2628-B-038-009-MY3, and 113-2321-B-255-001//National Science and Technology Council of Taiwan/ ; },
abstract = {BACKGROUND: Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder with a significant impact, especially on elderly people. Although no current treatment is available for AD, several studies have been conducted to discover alternative remedies capable of managing its symptoms and slowing the progression. Accordingly, herein we analysed the phenolic composition and investigated the defatted aqueous methanol extract (DAE) of Carpoxylon macrospermum H.Wendl. & Drude (Family Arecaceae) leaves against key enzymes in addition to oxidative and inflammatory markers involved in AD progression.

METHODS: NMR and mass spectrometry elucidated the phenolic compounds. Human carbonic anhydrase (hCA), human acetyl cholinesterase (AChE), and cyclo-oxygenase 2 (COX-2) inhibitor screening kits were used to assess the enzyme-inhibitory potential. Lipo-poly saccharide (LPS)-induced murine macrophage (RAW 264.7) in vitro model was used to test the anti-inflammatory effect. Molecular docking studies were conducted using AutoDock Vina.

RESULTS: Chlorogenic acid (1), rutin (2), hesperidin (3), vanillic acid (4), and p-hydroxybenzoic acid (5) have been isolated. The DAE and compounds 2 and 4 significantly inhibited hCA enzyme with IC50 equivalent to 0.160 ± 0.008, 0.243 ± 0.012, and 0.290 ± 0.015 µg/mL, and AChE enzyme with an IC50 corresponding to 3.732 ± 0.13, 0.868 ± 0.03, and 0.597 ± 0.02 µg/mL, respectively. Additionally, they demonstrated potent anti-inflammatory activity by inhibiting the COX-2 enzyme with IC50 values of 4.602 ± 0.17, 2.806 ± 0.10, and 0.849 ± 0.03 µg/mL, respectively. The DAE, 2 and 4 reduced IL-2 to 3.49 ± 0.12—7.018 ± 0.24 pg/mL; IL-4 to 6.019 ± 0.21–12.07 ± 0.41 pg/mL, and TNF-α to 323.65 ± 11.10–501.88 ± 17.21 pg/mL, respectively. Western blotting revealed a decrease in iNOS protein expression. Rutin showed improved docking scores (-8.92 and -7.92 kcal/mol) with AChE and hCA, while 100 ns Molecular Dynamc Simulations (MDS) showed that rutin maintained stable interactions with the proteins throughout the simulations.

CONCLUSION: C. macrospermum extract and its phenolics are promising candidates for AD management, though additional in vivo and clinical studies are needed.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12906-026-05365-8.},
}

@article {pmid42158158,
year = {2026},
author = {Pozuelo Moyano, B and Orgeta, V and von Gunten, A and Vandel, P and Ma, R and Stewart, R and Mueller, C},
title = {Late-life difficult-to-treat depression and dementia subtypes: a naturalistic cohort study using electronic health records.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1795874},
pmid = {42158158},
issn = {1664-0640},
abstract = {INTRODUCTION: Late-life difficult-to-treat depression (LL-DTD) and dementia frequently coexist in later life, but it remains unclear whether clinical and sociodemographic characteristics, as well as medication exposure patterns, differ across dementia subtypes among older adults with both conditions.

METHODS: We analysed anonymised electronic health records from a south London catchment area. We included patients aged ≥60 years at first recorded depression diagnosis with a dementia diagnosis. LL-DTD was defined as inadequate response to ≥2 antidepressant trials. Dementia diagnoses were classified as Alzheimer's disease (AD), vascular dementia (VD), mixed AD/VD, dementia with Lewy bodies (DLB), or other/unspecified dementia. Around the index depressive episode, we captured sociodemographics, depressive symptoms, physical comorbidity, and medication indicators. We used multivariate logistic regression to examine cross-sectional correlates distinguishing dementia subtypes (with AD as reference) within the LL-DTD and dementia sample. We conducted stratified analyses comparing non-AD versus AD dementia by the temporal order of dementia and depression diagnoses.

RESULTS: Among 890 older adults with LL-DTD and dementia, AD was the most common subtype (33.9%), followed by mixed AD/VD (22.5%), VD (22.2%), other/unspecified dementia (15.2%), and DLB (6.2%). Depressive symptom profiles and psychotropic treatment history were broadly similar across subtypes. Compared with AD, VD was associated with greater functional impairment, while greater physical comorbidity burden was more evident in VD and mixed AD/VD.

DISCUSSION: Somatic multimorbidity and functional impairment provided the clearest clinical separation between subgroups, while depressive symptom patterns and medication exposure appeared largely non-specific across dementia subtypes. This underscores the importance of multimorbidity and physical health burden in understanding heterogeneity of dementia outcomes in LL-DTD.},
}

@article {pmid42158310,
year = {2025},
author = {Jain, SK and Sharma, S and Singh, VK and Matreja, PS},
title = {Transplantation of human glial cells into murine brains: A systematic review of efficacy and safety in neurodegenerative disorders.},
journal = {Current journal of neurology},
volume = {24},
number = {2},
pages = {154-167},
pmid = {42158310},
issn = {2717-011X},
abstract = {Background: Neurodegenerative diseases impact millions of individuals globally. Over the years, brain research has predominantly focused on neurons, but attention is now shifting to glial cells, the brain's support cells, which play a vital role in neurodegenerative disorders. Therefore, glial cell transplantation represents a groundbreaking treatment approach for various neurodegenerative disorders, with the potential to restore neuronal function. We evaluated the evidence on the therapeutic effectiveness of human glial cell transplantation in neurodegenerative disorders. Methods: The literature review was performed in PubMed, Scopus, and Web of Science from 2000 to 2024. The authors independently reviewed the screened articles. The study outcomes on cell differentiation, long survival restoration of neuron function, and adverse outcomes were analyzed. Results: Study results highlight promising findings, including astrocytes improving motor function and slowing disease progression in neurodegenerative animal models through neurotrophic factor secretion and reduced inflammation. Similarly, microglia transplantation has demonstrated effectiveness in reducing α-synuclein toxicity in Parkinson's disease (PD), removing amyloid-β plaques in Alzheimer's disease (AD) models, and enhancing neuronal survival. Additionally, in demyelinating pathologies like multiple sclerosis (MS), oligodendrocyte transplantation promotes remyelination, restoring axonal conduction and enhancing functional outcomes. Cografting astrocytes with neuro progenitor cells significantly improved dopamine neuron engraftment and survival for at least 6 months post-transplantation. Conclusion: The transplantation of human glial cells offers promising therapeutic potential for neurodegenerative disorders, improving neuronal survival, restoring damaged circuits, and reducing disease progression.},
}

@article {pmid42159155,
year = {2026},
author = {Cummings, JL and Atri, A and Sano, M and Zetterberg, H and Scheltens, P and Knop, FK and Johannsen, P and Wichmann, CA and Abschneider, RM and Leon, T and Taylor, J and Feldman, HH},
title = {Plain language summary: the evoke(+) studies of semaglutide for early Alzheimer's disease.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/17582024.2026.2666332},
pmid = {42159155},
issn = {1758-2032},
}

@article {pmid42159271,
year = {2026},
author = {Shi, J and Du, Y and Wang, H and Zhang, N and Chen, W and Ni, J and Lu, X and Sun, Y and Wang, G and Liu, J and Zhang, W and Wei, M and Li, T and Zhou, B and Li, F and Wei, C and Yao, L and Xie, H and Tian, J and , },
title = {A paradigm of the diagnosis and treatment for the whole process of Alzheimer's disease.},
journal = {Annals of medicine},
volume = {58},
number = {1},
pages = {2672193},
doi = {10.1080/07853890.2026.2672193},
pmid = {42159271},
issn = {1365-2060},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; *Medicine, Chinese Traditional/methods ; Biomarkers ; Disease Progression ; Early Diagnosis ; Severity of Illness Index ; Practice Guidelines as Topic ; },
abstract = {INTRODUCTION: The clinical management of Alzheimer's disease (AD) is still constrained by the fact that its incompletely understood pathogenesis, difficulty in early diagnosis and the limited long-term treatment benefits so far. This article summarizes a regional perspective on the diagnosis and treatment of AD from the Alzheimer's Disease Chinese (ADC) guideline working group, aiming to improve the whole-process management of AD.

DISCUSSION: The article presents a comprehensive overview of a proposed diagnostic and therapeutic paradigm for AD, consisting of a three-dimensional diagnostic framework and a sequential therapy concept. Crucially, while biological biomarkers of AD are present at all stages, they may be unrelated to clinical severity. To address this, the diagnostic framework combines core clinical criteria with early-changing biomarkers, syndrome staging and traditional Chinese medicine (TCM)-based pattern phenotyping. This integrated, simplified and practical approach enhances diagnostic certainty and its correlation with clinical severity. This sequential therapy is a stage-adaptive treatment plan adjusted according to the disease progression, utilizing a dynamic, multi-target combination therapy. Unlike the existing unchanging single-target therapies, this approach provides specific mechanistic interventions tailored to each stage to prolong efficacy and delay disease progression.

CONCLUSIONS: This paradigm provides a whole-process, stage-oriented approach to AD diagnosis and management that may improve translational relevance, clinical applicability and continuity of care in real-world settings. Future cohort-based validation studies are needed to confirm its diagnostic performance and clinical benefits, and to refine its implementation.},
}

Humans
*Alzheimer Disease/diagnosis/therapy
*Medicine, Chinese Traditional/methods
Biomarkers
Disease Progression
Early Diagnosis
Severity of Illness Index
Practice Guidelines as Topic

@article {pmid42159313,
year = {2026},
author = {Tajika, A and Omae, K and Sahker, E and Luo, Y and Takekita, Y and Furukawa, TA},
title = {Public acceptance and expectations for Lecanemab: Insights from a Smallest Worthwhile Difference study.},
journal = {Psychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/pcn.70082},
pmid = {42159313},
issn = {1440-1819},
abstract = {AIM: To determine the smallest worthwhile difference (SWD) for lecanemab, a disease-modifying drug for Alzheimer's disease (AD), among the general Japanese population using a benefit-harm trade-off method.

METHODS: We conducted an online survey with 658 participants to evaluate their preferences for the treatment effect of lecanemab, given its associated risks and high cost. We calculated SWD as the minimum required increase in the possibility of maintaining cognitive function (relative to the 50% without lecanemab) that patients would accept in exchange for the burdens of treatment (adverse effects, costs, other inconveniences). We examined the median SWD for two scenarios: a family member (SWD-families) and others (SWD-others), and analyzed subgroup differences.

RESULTS: The median SWD revealed a 15% increase for SWD-families and SWD-others. This value exceeds the drug's actual efficacy of an 8% increase. Notably, 17% of respondents reported zero SWD, driven by an intense fear of AD and possibly high expectations from media coverage. Including these participants, nearly half of the respondents considered the current effect worthwhile. No noticeable difference was found between the SWD-families and SWD-others.

CONCLUSION: Based on Japanese clinical scenarios, the public's median expectation for lecanemab exceeds its efficacy, though its current benefit remains acceptable to nearly half the population. These findings underscore that the SWD is shaped by psychological drivers, including fear and hope, rather than just reasoned evaluation. Clinicians must manage these expectations, accounting for highly heterogeneous treatment preferences. Future research should account for emotional factors that can overshadow a rational assessment of treatment value.},
}

@article {pmid42160117,
year = {2026},
author = {Chen, H and Wang, T and Xia, K and Li, X and Yao, X and Huang, W},
title = {Emerging Nanoreactors for Precision Disease Treatment: From Principles to Biomedical Applications.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e73859},
doi = {10.1002/smll.73859},
pmid = {42160117},
issn = {1613-6829},
support = {BK20251864//Basic Research Program of Jiangsu/ ; 62288102//Natural Science Foundation of China/ ; //Disciplinary Fund of the School of Pharmaceutical Sciences/ ; 20250285//Nanjing Tech University Teaching Reform Project/ ; },
abstract = {Inspired by natural cellular compartments, nanoreactors are spatially confined nanostructures that precisely regulate chemical and biological reactions and act as high-performance catalytic nanocontainers. Multifunctional integration of these systems surmounts the inherent limitations of conventional therapeutic modalities. This review focuses on recent breakthroughs in organic and organic-inorganic hybrid nanoreactors, highlighting three core effects: (1) the spatial confinement effect, which elevates the reactant concentration, accelerates mass transfer, lowers activation energy, modulates electronic states, and boosts reaction rates by orders of magnitude; (2) the synergistic effect of active sites, which enables efficient cascade reactions via spatially segregated or hierarchical catalytic architectures; (3) the stimuli-responsive effect, which dynamically controls catalysis and cargo release under endogenous (pH, enzymes, ROS) or exogenous (light, temperature) cues. Typical nanoreactors (liposomes, polymeric micelles/vesicles, mesoporous silica, protein cages, and organic-inorganic hybrids) are systematically discussed regarding structural merits and biomedical applications in treating diabetes, rheumatoid arthritis (RA), chronic wound healing, cancer, and Alzheimer's disease (AD). Current challenges and future perspectives are also addressed. Intelligent nanoreactors are expected to offer immense potential for disease diagnosis and therapy.},
}

@article {pmid42160848,
year = {2026},
author = {Zheng, M and Yang, M and Su, W and Tian, L and Gao, W},
title = {Targeting microglia: A new strategy for the treatment of Alzheimer's disease.},
journal = {Journal of neuroimmunology},
volume = {418},
number = {},
pages = {578966},
doi = {10.1016/j.jneuroim.2026.578966},
pmid = {42160848},
issn = {1872-8421},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and chronic neuroinflammation, remains without curative therapies. Emerging evidence underscores microglia, the brain's resident immune cells, as pivotal players in AD pathogenesis, exerting dual roles in neuroprotection and neurotoxicity. This review synthesizes current knowledge on microglial dynamics, including their heterogeneous activation states (e.g., disease-associated microglia), metabolic reprogramming, aging-related dysfunction, and subset heterogeneity, which collectively influence Aβ clearance, tau propagation, and synaptic integrity. We highlight the interplay between microglial receptors-such as TREM2, APOE, and neurotransmitter receptors (e.g., cholinergic, glutamatergic, and cannabinoid receptors)-and AD pathology, emphasizing their roles in modulating neuroinflammation, phagocytosis, and neuronal excitotoxicity. Furthermore, we evaluate therapeutic strategies targeting microglia, including pharmacologic modulation of neuroinflammatory pathways, metabolic interventions, and cell transplantation, which aim to restore homeostatic microglial functions. Challenges in clinical translation, such as temporal specificity of interventions and microglial plasticity, are critically discussed. By integrating recent advances in single-cell genomics and neuroimmunology, this review provides a roadmap for developing microglia-centric therapies to disrupt the vicious cycle of neuroinflammation and neurodegeneration in AD, offering novel insights for future research and therapeutic innovation.},
}

@article {pmid42160956,
year = {2026},
author = {Yan, Y and Hu, D and Kong, L and Li, K and Su, J and Wu, Y and Zhan, H and Zhang, H and Sun, Y and Dou, X and Huang, P and Zhou, J},
title = {Reductions in neuropsychiatric symptoms after lecanemab treatment and their associations with imaging markers of β-amyloid clearance.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100600},
doi = {10.1016/j.tjpad.2026.100600},
pmid = {42160956},
issn = {2426-0266},
abstract = {BACKGROUND: Anti-amyloid-β (Aβ) therapies can slow cognitive decline and reduce cerebral amyloid burden in Alzheimer's disease (AD). Neuropsychiatric symptoms (NPS) are highly prevalent across the disease course and substantially contribute to disability and caregiver burden. However, whether Aβ clearance translates into improvements in NPS remains unclear.

METHOD: We enrolled 144 individuals with AD-related mild cognitive impairment or AD dementia who received intravenous lecanemab infusions. Standardized clinical rating scales, including the Neuropsychiatric Inventory, and amyloid PET were assessed at baseline (V0), 6 months (V1), and 12 months (V2). Longitudinal changes in clinical function and amyloid burden were analyzed.

RESULTS: Lecanemab treatment was associated with robust reductions in amyloid PET biomarkers and significant short-term reductions in NPS scores in patients who completed follow-up. Longitudinal analyses showed that reductions in total NPI scores were significantly associated with amyloid-β clearance in the insular cortex. Reductions in the hyperactivity subsyndrome were associated with amyloid reduction across a broader network, including the frontal and temporal lobes, striatum, and insular cortex.

CONCLUSIONS: In this real-world cohort, lecanemab was associated with short-term reductions in NPS. Changes in NPS severity were linked to regional amyloid-β clearance.},
}

@article {pmid42161225,
year = {2026},
author = {McNamara, O and Delany, T and Kwakowsky, A},
title = {Bumetanide as a potential treatment for neurodegenerative and neurodevelopmental disorders: A systematic review.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {200},
number = {},
pages = {119533},
doi = {10.1016/j.biopha.2026.119533},
pmid = {42161225},
issn = {1950-6007},
abstract = {Neurological disorders represent a major global health burden, affecting an estimated 3.4 billion individuals worldwide. Bumetanide, a clinically approved loop-diuretic and antagonist of the Na[+] -K[+]-Cl[-] cotransporter NKCC1, has recently emerged as a candidate for repurposing in the treatment of neurological disorders. Disrupted excitation-inhibition balance, driven in part by depolarizing GABAA receptor signaling resulting from altered chloride homeostasis, has been implicated across multiple neurodegenerative and neurodevelopmental conditions. This systematic literature review evaluated preclinical and clinical evidence for the efficacy of bumetanide across a range of neurological disorders, including Alzheimer's, Parkinson's, and Huntington's disease, autism spectrum disorder, schizophrenia, tuberous sclerosis, fragile X syndrome, Down syndrome, and Angelman syndrome. Across in vivo and ex vivo models, bumetanide frequently restored hyperpolarizing GABAergic activity and attenuated behavioral and cognitive abnormalities, although translational relevance is constrained by limited central nervous system penetration following systemic administration. Clinical evidence mainly comes from autism spectrum disorder, where some studies have reported modest improvements in behavioral outcomes and measurable neurophysiological changes, although findings remain inconsistent. Collectively, these findings suggest that NKCC1 inhibition represents a mechanistically relevant but clinically unproven therapeutic strategy. Further research is required to clarify the cellular mechanisms underlying bumetanide responsiveness, optimize delivery to the central nervous system, and identify biomarkers to stratify patients most likely to respond to treatment.},
}

@article {pmid42161327,
year = {2026},
author = {Vallikivi, JK and Kooyman, M and , and Kirby, J and Nigel Leigh, P and Iacoangeli, A and Al-Chalabi, A and Al Khleifat, A},
title = {CYP2D6 variants in amyotrophic lateral sclerosis: an association study of risk and survival.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag178},
pmid = {42161327},
issn = {1460-2156},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapeutic options. Riluzole remains the only widely available disease-modifying treatment for ALS, yet its survival benefit is modest and likely to vary substantially between patients. Cytochrome P450 2D6 (CYP2D6), is a highly polymorphic enzyme that contributes to interindividual variability in the metabolism of many drugs. CYP2D6 is also expressed in the brain, and experimental and translational studies indicate that brain CYP2D activity can influence local metabolism of neuroactive compounds. Accordingly, CYP2D6 poor function variants have been examined as susceptibility modifiers in the development of other neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease, with heterogenous evidence; however, the role of CYP2D6 in ALS has not been established.},
}

@article {pmid42161537,
year = {2026},
author = {Fernández-Romero, L and Díez-Cirarda, M and Delgado-Alonso, C and Cabrera-Martin, MN and González-Rosa, JJ and Sanz-Nieto, C and Pérez-Macías, N and Balugo, P and Gómez-Ruiz, N and Matias-Guiu, J and Portolés-Pérez, A and Matias-Guiu, JA},
title = {Long-term effect of transcranial magnetic stimulation and transcranial electrical stimulation in primary progressive aphasia: study protocol for a randomised, double-blind clinical trial (RECONNECT-PLUS).},
journal = {BMJ open},
volume = {16},
number = {5},
pages = {e112999},
doi = {10.1136/bmjopen-2025-112999},
pmid = {42161537},
issn = {2044-6055},
mesh = {Humans ; Double-Blind Method ; *Transcranial Direct Current Stimulation/methods ; *Transcranial Magnetic Stimulation/methods ; *Aphasia, Primary Progressive/therapy ; Female ; Aged ; *Language Therapy/methods ; Male ; Randomized Controlled Trials as Topic ; Treatment Outcome ; Middle Aged ; },
abstract = {INTRODUCTION: Primary progressive aphasia (PPA) is a neurodegenerative syndrome associated with Alzheimer's disease and frontotemporal degeneration. Non-invasive brain stimulation (NIBS) is a promising treatment, especially associated with language therapy, but comparative efficacy and long-term effects between the different techniques (transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS)) remain unknown. The present study aims to investigate the effects of non-invasive brain stimulation, alone or associated (tDCS/TMS/tDCS plus TMS) combined with language therapy delivered during a period of 6 months, in the progression of language impairment in PPA, compared with sham stimulation combined with language therapy.

METHODS AND ANALYSIS: The study is a randomised, double-blinded, parallel, sham-controlled clinical trial. Patients with PPA in early stages (global Clinical Dementia Rating equal to or less than 1) are eligible. They are to be randomised to one of the four treatment arms of the study (active tDCS-active TMS, active tDCS-sham TMS, sham tDCS-active TMS, sham tDCS-sham TMS). All patients will receive language therapy immediately after each session of NIBS, for 6 months. The primary outcome is the Mini-Linguistic State Examination. The secondary outcomes are naming of trained items, Addenbrooke's Cognitive Examination, Interview for Deterioration in Daily Living Activities, Clinical Dementia Rating including behaviour and language domains, Neuropsychiatric Inventory and regional brain metabolism. Exploratory substudies will be conducted including blood biomarkers, quantitative electroencephalography and spontaneous speech assessment.

ETHICS AND DISSEMINATION: The study is registered (ClinicalTrials.gov: NCT07158216) and approved by the Ethics Committee of the Hospital Clinico San Carlos (code 25/309-IC_P_CE). Patients will be enrolled after signing an informed consent form. Study outcomes will be disseminated through presentations at scientific conferences, publications in peer-reviewed journals and other academic forums.

TRIAL REGISTRATION NUMBER: NCT07158216.},
}

Humans
Double-Blind Method
*Transcranial Direct Current Stimulation/methods
*Transcranial Magnetic Stimulation/methods
*Aphasia, Primary Progressive/therapy
Female
Aged
*Language Therapy/methods
Male
Randomized Controlled Trials as Topic
Treatment Outcome
Middle Aged

@article {pmid42161925,
year = {2026},
author = {Kim, DY and Kim, SM and Lee, C and Han, IO},
title = {O-GlcNAcylation reprograms microglial inflammatory states and attenuates Alzheimer's disease pathology.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08862-3},
pmid = {42161925},
issn = {2041-4889},
support = {RS-2024-00346770//National Research Foundation of Korea (NRF)/ ; },
abstract = {Chronic neuroinflammation, primarily driven by microglia, is a hallmark and key contributor to Alzheimer's disease (AD) progression. O-GlcNAcylation, a nutrient-sensitive post-translational modification, has emerged as a key regulator of cellular stress and inflammation, yet its role in microglial activation in AD remains unclear. We observed that hippocampal tissue from AD patients exhibits a marked reduction in O-GlcNAcylation, accompanied by enhanced pro-inflammatory M1 microglial polarization, elevated NF-κB signaling, and NLRP3 inflammasome activation. In an LPS-induced neuroinflammation model exhibiting AD-relevant inflammatory and cognitive features, as well as in in vitro microglial cultures, LPS exposure led to a pronounced decrease in O-GlcNAcylation, particularly within Iba1-positive microglia. Systemic or in vitro treatment with glucosamine (GlcN) effectively restored O-GlcNAc levels, suppressed M1-associated inflammatory pathways, and promoted an anti-inflammatory M2 phenotype. Mechanistically, GlcN enhanced O-GlcNAcylation of NF-κB subunits p65 and c-Rel, limiting their nuclear translocation and downstream pro-inflammatory gene expression. Notably, GlcN treatment ameliorated LPS-induced memory deficits and neuronal loss in mice. Collectively, these findings suggest that O-GlcNAcylation acts as a modulatory regulator of microglial activation and neuroinflammation in AD, and that enhancing O-GlcNAcylation may represent a potential therapeutic strategy to preserve immune homeostasis and neuronal integrity.},
}

@article {pmid42162073,
year = {2026},
author = {Zamani, NISM and Hamezah, HS and Mediani, A and Ghazali, M and Sadikan, MZ and Jam, FA},
title = {Selective elimination of amyloid-β-induced senescent neuroblastoma cells by Moringa oleifera leaf extract.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-53311-y},
pmid = {42162073},
issn = {2045-2322},
support = {Fundamental Research Grant Scheme (FRGS/1/2024/SKK10/MUCM/02/1)//Ministry of Higher Education, Malaysia/ ; (MUCM-MRB/001/2024)//MUCM-MRB joint seed grant/ ; },
abstract = {Accumulation of senescent cells (SnCs) in the ageing brain contributes to Alzheimer's disease (AD) progression by secreting a senescence-associated secretory phenotype (SASP) that exacerbates neuroinflammation and neurodegeneration. Senolytic agents that selectively eliminate SnCs have emerged as a potential therapeutic strategy; however, safer natural alternatives remain underexplored. In this study, we aimed to investigate the senolytic potential of Moringa oleifera leaf extract (MOL) in an in vitro AD-senescence model using SH-SY5Y cells exposed to amyloid-β (Aβ1-42) oligomers. SH-SY5Y cells exposed to 20 µM Aβ oligomers exhibited a senescent phenotype, characterised by increased senescence-associated β-galactosidase (SA-β-gal) positivity and upregulated nuclear expression of p21, p16, and γH2AX. Treatment with 300 µg/mL MOL significantly reduced the number of cells expressing senescence-associated molecular markers and induced apoptosis in SnCs, while attenuating the secretion of pro-inflammatory SASP cytokines, including IL-8 and TNF-α. Overall findings suggest that MOL extract preferentially targets SnCs and mitigates SASP-associated inflammation. These results support the potential of MOL as a natural compound with senolytic activity and provide a foundation for further development into its therapeutic relevance in AD.},
}