@article {pmid42668333,
year = {2026},
author = {Kalra, P and Chaturvedi, D and Kumar, A and Grewal, AK and Khan, H and Singh, V and Singh, TG and Singh, T and Ahmad, SF and Attia, SM},
title = {AMBMP Hydrochloride Reverses STZ-Induced Alzheimer-Type Dementia Associated with Wnt/β-catenin/TLR4 Signaling.},
journal = {Neuromolecular medicine},
volume = {28},
number = {1},
pages = {},
pmid = {42668333},
issn = {1559-1174},
support = {ORF-2026-748//King Saud University/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced ; *Toll-Like Receptor 4/physiology/agonists ; Streptozocin/toxicity ; Male ; Mice ; *Wnt Signaling Pathway/drug effects ; *Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Donepezil/therapeutic use/pharmacology ; Disease Models, Animal ; Maze Learning/drug effects ; beta Catenin/physiology ; Acetylcholinesterase/metabolism ; Palmitic Acid/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative disorder with progressive cognitive decline and neuronal loss. This study investigated the neuroprotective effects of AMBMP Hydrochloride, a Wnt/β-catenin agonist, in a streptozotocin (STZ)-induced mice model of AD, elucidating the interplay between dysregulated Wnt/β-catenin signaling and Toll-Like Receptor 4 (TLR4)-mediated inflammation, with Palmitic acid used as a TLR4 pathway modulator. Mice received bilateral intracerebroventricular (i.c.v.) injections of STZ (3 mg/kg) on Day 1 and Day 3, followed by administration of Donepezil (3 mg/kg)/ AMBMP Hydrochloride (5 mg/kg and 10 mg/kg)/Palmitic acid (TLR4 agonist, 20 mg/kg) via the intraperitoneal (i.p.) route from Day 4 to Day 22. STZ-treated mice exhibited significant cognitive dysfunction, characterized by impaired performance in the Morris Water Maze (MWM) task along with increase in acetylcholinesterase (AChE) activity, oxidative stress (thiobarbituric acid reactive substances; TBARS), neuroinflammation [tumor necrosis factor alpha (TNF-α)/Interleukin-6 (IL-6)/Interleukin-1 beta (IL-1β) and nuclear factor kappa B (NF-κB)] and decreased reduced glutathione (GSH) levels. However, AMBMP Hydrochloride significantly improved behavioral and biochemical alterations possibly through modulation of Wnt/β-catenin signaling and attenuation of TLR4-mediated inflammation. Interestingly, Palmitic acid co-treatment was found to counteract these protective effects, further pointing to a role of TLR4 in the pharmacological effect of AMBMP Hydrochloride. In summary, we confirmed that AMBMP Hydrochloride exhibits potent neuroprotective effects associated with modulating Wnt/β-catenin/TLR4 signaling, offering a promising therapeutic approach against Alzheimer-Type Dementia. Future studies should delve deeper into the molecular mechanisms and translational promise of AMBMP hydrochloride, paving the way for its development as a potential candidate for AD management.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced
*Toll-Like Receptor 4/physiology/agonists
Streptozocin/toxicity
Male
Mice
*Wnt Signaling Pathway/drug effects
*Neuroprotective Agents/therapeutic use/pharmacology
Oxidative Stress/drug effects
Donepezil/therapeutic use/pharmacology
Disease Models, Animal
Maze Learning/drug effects
beta Catenin/physiology
Acetylcholinesterase/metabolism
Palmitic Acid/pharmacology

@article {pmid42668348,
year = {2026},
author = {Han, Z and Chen, H and Yao, Y and Bo, X and Ni, X and Liu, H and Bai, M and Li, T and Bao, L and Zhang, D and Dong, W},
title = {Promoting Effect of (+)-Borneol on Alzheimer's Disease Treatment in APP Transgenic Zebrafish and Its Blood-Brain Barrier Permeation Mechanism.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42668348},
issn = {1559-1182},
mesh = {Animals ; *Blood-Brain Barrier/drug effects/metabolism/pathology ; Zebrafish/genetics ; Animals, Genetically Modified ; *Alzheimer Disease/drug therapy/genetics/pathology/metabolism ; *Camphanes/pharmacology/therapeutic use ; *Amyloid beta-Protein Precursor/genetics/metabolism ; Brain/pathology/metabolism/drug effects ; },
abstract = {(+)-Borneol (Bor) has been shown to enhance drug penetration across the blood-brain barrier (BBB); yet its mechanisms of action and adjuvant effects on Alzheimer's disease (AD) drugs remain insufficiently investigated. This study systematically explored the adjuvant effects of Bor and its underlying mechanisms by employing AB wild-type zebrafish and APP transgenic zebrafish models. Results demonstrated that Bor at concentrations of 0.05 mM or lower exhibited no toxicity toward AB wild-type zebrafish, whereas 0.01 and 0.05 mM Bor significantly increased the expression of green fluorescent protein (GFP) in the zebrafish brain. Genetic analyses revealed that Bor downregulated genes encoding tight junction proteins and P-glycoprotein (P-gp). Drug treatment experiments showed that Bor enhanced the efficacy of AD therapeutic agents, including Zhenbaopill (ZBP, a traditional medicinal preparation) and the synthetic drug 8e. Specifically, Bor ameliorated AD-related behavioral impairments, inhibited cerebral apoptosis, restored the expression of AD-associated genes, normalized the activities of acetylcholine (ACh)-related enzymes, and downregulated both the mRNA and protein levels of Claudin 5. In summary, Bor enhances BBB permeability by regulating the expression of genes encoding BBB-related proteins, thereby increasing the brain concentration and bioavailability of AD drugs with anticholinesterase activity. An appropriate dose of Bor may thus contribute to enhancing the therapeutic efficacy of AD drugs.},
}

Animals
*Blood-Brain Barrier/drug effects/metabolism/pathology
Zebrafish/genetics
Animals, Genetically Modified
*Alzheimer Disease/drug therapy/genetics/pathology/metabolism
*Camphanes/pharmacology/therapeutic use
*Amyloid beta-Protein Precursor/genetics/metabolism
Brain/pathology/metabolism/drug effects

@article {pmid42668476,
year = {2026},
author = {Wu, B and Wu, J and Zhu, L and Li, A and Fu, Y and Lei, Z and Wu, D and Peng, W and Xie, L},
title = {Intranasal L-DOPA/TPP-engineered extracellular vesicles deliver icariin to ameliorate mitochondrial dysfunction with associated sphingolipid remodeling in Alzheimer's disease models.},
journal = {Materials today. Bio},
volume = {40},
number = {},
pages = {103563},
pmid = {42668476},
issn = {2590-0064},
abstract = {Alzheimer's disease (AD) is associated with mitochondrial dysfunction, oxidative stress, and disrupted lipid homeostasis, but the therapeutic translation of mitochondrial-protective agents remains limited by inefficient brain delivery, insufficient neuronal selectivity, and poor subcellular precision. Here, we developed an intranasal extracellular vesicle formulation (L-DOPA/TPP-EV-ICA) by loading icariin (ICA) into mesenchymal stem cell-derived extracellular vesicles and post-inserting DSPE-PEG-Levodopa and TPP-PEG-PE to enhance nasal environment, neuronal association, and mitochondria-associated intracellular enrichment. The engineered vesicles retained EV-like morphology, showed measurable ICA encapsulation, and maintained colloidal stability under the tested storage and simulated nasal conditions. In a human nasal epithelial Transwell model, L-DOPA/TPP-EV-ICA showed greater neuronal uptake than unmodified EVs without detectable disruption of epithelial barrier integrity and exhibited preferential colocalization with mitochondria-associated structures after cellular internalization. In Aβ-injured neuronal cells, L-DOPA/TPP-EV-ICA treatment reduced mitochondrial oxidative stress and mPTP opening, improved membrane potential, and enhanced ATP production and redox-related parameters. Following intranasal administration, the engineered formulation generated stronger and more persistent brain-associated fluorescence and showed preferential association with NeuN-positive cells. In APP/PS1 mice, treatment improved cognitive performance, and attenuated histopathological and mitochondrial abnormalities. Integrated proteomic, metabolomic analyses, and protein-level analyses further identified treatment-associated alterations in sphingolipid-related pathways. These findings support L-DOPA/TPP-EV-ICA as a promising preclinical intranasal EV platform for improving mitochondrial function and modulating sphingolipid-associated alterations in AD-related models.},
}

@article {pmid42668611,
year = {2026},
author = {Gao, F and Luo, G and Liu, B and Qiu, X and Bai, J and Wang, R},
title = {Comparative effectiveness of multiple interventions for Alzheimer's disease on ABC syndromes and QoL: A Bayesian network meta-analysis.},
journal = {iScience},
volume = {29},
number = {9},
pages = {117250},
pmid = {42668611},
issn = {2589-0042},
abstract = {Evidence comparing directly pharmacological and non-pharmacological treatments for Alzheimer's disease (AD) is scarce. The ABC symptoms-activities of daily living (ADLs) (A), behavioral and psychological symptoms (BPSs) (B), cognitive function (C), and quality of life (QoL)-are critical for diagnosing and assessing treatment effects in AD. This study aims to evaluate five interventions for AD: pharmacological therapy (PT), photobiomodulation (PBM), cognitive therapy (CT), exercise therapy (ET), and repetitive transcranial magnetic stimulation (rTMS) using a Bayesian network meta-analysis approach. Among 6,450 records screened, 91 randomized controlled trials (RCTs) involving 12,242 participants met the inclusion criteria. PBM and rTMS showed significant benefits for cognitive function in AD patients. PT and CT showed notable effectiveness in enhancing activities of daily living. For QoL, CT and ET were identified as more favorable outcomes. Collectively, each intervention exerts unique merits targeting ABC symptoms and QoL, implying combined pharmacological and non-pharmacological regimens could optimize therapeutic gains for AD management.},
}

@article {pmid42669137,
year = {2026},
author = {Xu, B and Li, X and Dong, S and Zhang, Z and Jin, D and Li, G and Wang, J},
title = {Modulating the Gut-Microbiota-Brain Axis in Alzheimer's Disease: Therapeutic Potential of Nutritional and Metabolic Factors.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {9},
pages = {e71117},
pmid = {42669137},
issn = {1755-5949},
mesh = {Humans ; *Alzheimer Disease/metabolism/diet therapy/microbiology/therapy ; *Gastrointestinal Microbiome/physiology ; Animals ; *Brain/metabolism ; *Brain-Gut Axis/physiology ; Fecal Microbiota Transplantation/methods ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia among the elderly, characterized by a gradual decline in memory and cognitive function. The growing body of evidence highlighting the interaction between the gut microbiota and the central nervous system has positioned the gut microbiota as a key area of research in AD pathogenesis.

METHODS: This review critically evaluates the preclinical evidence and clinical trial outcomes, complemented by mechanistic studies and Mendelian randomization analyses, to assess the therapeutic potential of nutritional interventions targeting the gut-microbiota-brain axis in AD.

RESULTS: Dietary components and patterns regulate the composition and function of the gut microbiota, which in turn influence brain function through the gut-microbiota-brain axis via chemical/metabolic, immune-mediated, and neural pathways. Specific nutrients, microbial metabolites, and dietary patterns have been shown to exert either protective or detrimental effects on AD pathology and cognitive function. Emerging strategies, including precision nutrition, fecal microbiota transplantation, and next-generation microbiome-based therapies, offer new avenues for AD prevention and treatment.

CONCLUSIONS: Nutritional interventions targeting the gut-microbiota-brain axis represent a promising approach for the comprehensive prevention and management of AD. Further mechanistic and clinical studies are warranted to translate these findings into effective therapeutic strategies.},
}

Humans
*Alzheimer Disease/metabolism/diet therapy/microbiology/therapy
*Gastrointestinal Microbiome/physiology
Animals
*Brain/metabolism
*Brain-Gut Axis/physiology
Fecal Microbiota Transplantation/methods

@article {pmid42669176,
year = {2026},
author = {Forsyth, F and Diaz, A and Andersson, V and Haraldsen, IH and Gove, D},
title = {Ethical considerations of fluid biomarker use in alzheimer's disease - a rapid review.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/13607863.2026.2719938},
pmid = {42669176},
issn = {1364-6915},
abstract = {OBJECTIVE: Alzheimer's disease (AD) care has been reshaped by the integration of fluid biomarkers. This review addressed the question "What are the ethical considerations of fluid biomarker use in eligibility assessments for treatment in AD and mild cognitive impairment?"

METHODS: A rapid review following established guidelines was performed. Relevant data were identified and organised within the four pillars of biomedical ethics. Results were reported in line with the PRISMA checklist.

RESULTS: Searches identified 10,611 records; 34 were included following screening. Narrative synthesis suggests there are a greater number of ethical risks over benefits within the current clinical context. However, interpretation is subjective and empirical data is lacking.

CONCLUSIONS: Multiple ethical concerns surround the use of fluid biomarkers in AD treatment decisions, and there is limited empirical evidence to substantiate claims about benefits and harms. Uncertainty in biomarker performance, particularly in underrepresented groups, raises risks to non-maleficence, autonomy, and justice and complicates clinical decision making.},
}

@article {pmid42669622,
year = {2026},
author = {Sun, W and Yang, B and Zheng, H and Wang, Q and Shi, Y and Wang, G and Yin, W and Wang, H and Qi, X and Yao, Y and Wang, J and Cui, S and Cui, K and Mao, J and Xia, Y and Deng, J and Zhao, S and Wang, Z and Liu, F and Yi, M and Ding, J and Le, W and Li, X and Yuan, J and Wan, Y and Zheng, J},
title = {Extracellular matrix remodeling upregulates hippocampal neurogenic niche stiffness and impairs neurogenesis in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71784},
pmid = {42669622},
issn = {1552-5279},
support = {2025ZD0217600//Brain Science and Brain-like Intelligence Technology-National Science and Technology/ ; BMU2022YJ003//Peking University Talent Startup Fund supported by the Fundamental Research Funds for the Central Universities/ ; PKU2026PKULCXQ003//Clinical Medicine Plus X - Young Scholars Project of Peking University, the Fundamental Research Funds for the Central Universities/ ; 2024300CC0020//Scientific Project of Beijing Life Science Academy/ ; 2023000CB0010//Scientific Project of Beijing Life Science Academy/ ; 2023000CA0060//Scientific Project of Beijing Life Science Academy/ ; HBCAD2024-03//Opening Project of Hubei Key Laboratory of Cognitive and Affective Disorders/ ; LGL-2614-02//Lingang Laboratory/ ; 2024302RPIB03//Supporting Project for Principle Investigators of Beijing Life Science Academy/ ; 82671849//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/physiopathology ; *Extracellular Matrix/metabolism ; *Neurogenesis/physiology ; Mice ; Humans ; *Hippocampus/metabolism/pathology ; YAP-Signaling Proteins ; Male ; Mice, Transgenic ; Disease Models, Animal ; *Dentate Gyrus/metabolism ; Up-Regulation ; },
abstract = {INTRODUCTION: Preserving adult hippocampal neurogenesis alleviates cognitive deficits in Alzheimer's disease (AD), yet how biophysical alterations in such as stiffness in the neurogenic niche regulate neurogenesis remains unclear.

METHODS: Stiffness in the hippocampal dentate gyrus subgranular cell zone (SGZ) of 5×FAD mice was measured using atomic force microscopy. Extracellular matrix (ECM) components in mice and AD patients were profiled through proteomics. Hydrogels were supplemented in the SGZ to upregulate local stiffness in wildtype mice, while glycosaminoglycanases was injected to downregulated stiffness in 5×FAD mice. Gene expression in the neurogenic lineage was analyzed through single nucleus sequencing. Conditional knockdown or overexpression of mechanosensors and/or Yes-associated protein 1 (YAP1) were achieved using viral vectors.

RESULTS: We found SGZ stiffening occured early in 3-month 5×FAD mice, associating with ECM remodeling and neurogenesis impairment. Upregulation of tissue stiffness in the SGZ of wild-type mice via supplementing high-density hydrogel suppressed neurogenesis, whereas downregulaion of the niche stiffness in AD mice using hyaluronidase-1 (HAase1) and other glycosaminoglycanases preserved neurogenesis. Single-nucleus transcriptomics reveals that the HAase1 treatment reshaped transcriptome of the neural stem cells (NSCs) lineage. Specifically, we found that the integrin-YAP1 mechanotransduction axis played important roles in the stiffness-induced neurogenesis deficits. Conditional knockdown of both integrin β1 and YAP in the NSC lineage mitigated stiffness-induced deficits. Consistently, the association of ECM remodeling and neurogenesis impairments were also observed in post mortem AD patients.

DISCUSSION: ECM stiffness plays as a critical regulator of hippocampal neurogenesis, providing potential targets for pro-neurogenic therapeutics of AD.},
}

Animals
*Alzheimer Disease/metabolism/pathology/physiopathology
*Extracellular Matrix/metabolism
*Neurogenesis/physiology
Mice
Humans
*Hippocampus/metabolism/pathology
YAP-Signaling Proteins
Male
Mice, Transgenic
Disease Models, Animal
*Dentate Gyrus/metabolism
Up-Regulation

@article {pmid42669911,
year = {2026},
author = {Demirbas, ZS and Naharci, MI},
title = {Antiplatelet use in all-cause dementia and dementia subtypes among older adults: a population-based retrospective study.},
journal = {Croatian medical journal},
volume = {67},
number = {4},
pages = {297-305},
pmid = {42669911},
issn = {1332-8166},
mesh = {Humans ; Female ; Retrospective Studies ; Male ; Aged ; *Platelet Aggregation Inhibitors/therapeutic use ; *Dementia/drug therapy/classification ; Aged, 80 and over ; Aspirin/therapeutic use ; Risk Factors ; Clopidogrel/therapeutic use ; },
abstract = {AIM: To evaluate the appropriateness of antiplatelet use across dementia subtypes in older adults and to identify factors associated with inappropriate antiplatelet use.

METHODS: This population-based retrospective study enrolled adults aged ?65 years with dementia evaluated at a tertiary geriatric outpatient clinic at Gulhane Training and Research Hospital between 2016 and 2025. Antiplatelet (aspirin or clopidogrel) use was categorized as appropriate use, underuse, overuse, or appropriate non-use according to the 2021-2024 European Society of Cardiology guidelines. Multivariable logistic regression analyses were performed to identify the factors associated with inappropriate antiplatelet use.

RESULTS: Among 683 older adults with dementia, 40.7% received antiplatelet therapy. Antiplatelet underuse and overuse were observed in 16.8% and 16.1% of the participants, respectively. Underuse was most prevalent in vascular dementia (38.9%), whereas overuse was most prevalent in Alzheimer disease (20.2%) and frontotemporal dementia (19.0%). In multivariable analyses, antiplatelet overuse was independently associated with diabetes mellitus (odds ratio [OR] 4.31; 95% confidence interval [CI] 1.66-11.16) and inversely associated with current smoking (OR 0.06; 95% CI 0.06-0.67). Antiplatelet underuse was independently associated with female sex (OR 4.44; 95% CI 1.52-12.92).

CONCLUSIONS: Our findings highlight the gaps between guideline recommendations and real-world practice and support the need for individualized dementia-sensitive antiplatelet treatment strategies.},
}

Humans
Female
Retrospective Studies
Male
Aged
*Platelet Aggregation Inhibitors/therapeutic use
*Dementia/drug therapy/classification
Aged, 80 and over
Aspirin/therapeutic use
Risk Factors
Clopidogrel/therapeutic use

@article {pmid42670073,
year = {2026},
author = {Ma, J and Wei, Z and Rong, C and He, W and Wang, X and Zhao, D},
title = {The Relationship Between Biomarkers in Blood and Urine and Alzheimer's Disease and Sleep Disorders (Long Sleep): A Mendelian Randomization Study.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050466562260804080255},
pmid = {42670073},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a neurological condition that increases in severity from a gradual start. Previous studies have found an association between long sleep (LS) and AD. To slow its progression, it is important to recognize biomarkers associated with the early stages of both AD and LS.

METHODS: This study aimed to use two-sample Mendelian Randomization (MR) to identify blood and urine biomarkers associated with AD and LS. Thirty-five biomarkers from blood and urine were included as exposures in the MR analysis, while AD and LS were considered the outcomes. The AD dataset included 39,106 patients and 46,828 controls from Europe. Data on sleep duration were obtained from a GWAS in 34,184 cases and 305,742 controls of European ancestry. This study included 35 blood and urine biomarkers across 355,891 participants, including 318,953 white British, 23,582 non-white British, 6,019 African, and 7,338 South Asian participants from the UK Biobank.

RESULTS: Cystatin C, CRP, and Non-Albumin protein showed genetic association with AD and LS. The genetic association results after Bonferroni's correction are significant for Non-Albumin Protein in AD and LS.

DISCUSSION: This study provides further insight into the genetic associations and relationships among AD, LS, and other biomarkers; it also presents several potential candidates for AD and LS diagnosis and treatment. The opposing roles of C-reactive Protein, Cystatin C, and Non-Albumin protein in AD and LS warrant a greater exploration of their differential functions at various ages and in specific brain microenvironments in future studies.

CONCLUSION: This study provides a theoretical basis for the diagnosis and treatment of AD and LS. More experiments are needed in the future to verify this prediction.},
}

@article {pmid42670527,
year = {2026},
author = {Pan, L and Liu, B and Xu, J and Mu, X and Fan, L},
title = {Mesenchymal Stem Cells and Extracellular Vesicles for Neurodegenerative Diseases: Therapeutic Advances and Challenges.},
journal = {International journal of nanomedicine},
volume = {21},
number = {},
pages = {628071},
pmid = {42670527},
issn = {1178-2013},
mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Extracellular Vesicles/transplantation ; *Mesenchymal Stem Cells/cytology ; *Mesenchymal Stem Cell Transplantation/methods ; Animals ; },
abstract = {Mesenchymal stem cells (MSCs), as a type of adult stem cells, exhibit robust self-renewal, multi-lineage differentiation, paracrine and immunomodulatory capacities, demonstrating broad application prospects in the treatment of neurodegenerative diseases. This review systematically summarizes the mechanisms of action, therapeutic advances and comparative analyses of various MSCs and their derived extracellular vesicles (EVs) in Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and discusses the optimization effects of gene modification and pretreatment on therapeutic efficacy. This article not only highlights the advantages of various MSCs and their corresponding EVs, but also provides unique insights into their differentiated therapeutic potential and mechanism of action, which have not been fully elucidated in previous studies. Meanwhile, although current research results are encouraging, this paper also critically points out that existing studies suffer from insufficient elucidation of mechanisms and lack of large-scale clinical trials. Finally, the article prospects future directions of MSC-based therapeutic strategies, including mechanism deepening, treatment optimization and standardization system construction, to promote their translation into clinical application. However, most of the current evidence is still preclinical, and the recognized clinical efficacy in humans is still limited. This is a narrative review. Literature was screened from Web of Science and PubMed by thematic relevance and research quality, without systematic review protocol or meta-analysis.},
}

Humans
*Neurodegenerative Diseases/therapy
*Extracellular Vesicles/transplantation
*Mesenchymal Stem Cells/cytology
*Mesenchymal Stem Cell Transplantation/methods
Animals

@article {pmid42671006,
year = {2026},
author = {Ayuba, M and Che Mohd Nassir, CMN and Abdul Hamid, H and Hein, ZM and Alhaji Modu, B and Mohd Moklas, MA and Mehat, MZ},
title = {Ficus deltoidea preserves neuronal-glial ultrastructure and attenuates neuroinflammation in an Alzheimer's disease-like rat model.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/1028415X.2026.2717205},
pmid = {42671006},
issn = {1476-8305},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) plaques, hyperphosphorylated tau tangles, cognitive decline, neuroinflammation, and neuronal-glial dysfunction, yet effective disease-modifying therapies remain unavailable. Increasing evidence suggests that preservation of neuronal and glial integrity is critical for mitigating disease progression. In the present study, we investigated the neuroprotective effects of Ficus deltoidea Jack (FD) in a D-galactose and aluminum chloride (D-gal/AlCl3)-induced rat model of AD-like neurodegeneration. Adult male Wistar rats were treated with FD (50, 100, and 200 mg/kg) for ten weeks and assessed for cognitive performance, cortical neuronal integrity, hippocampal ultrastructure, and neuroinflammatory signaling. FD treatment significantly improved spatial learning and memory in the Morris water maze without affecting locomotor activity. Histopathological analysis demonstrated dose-dependent preservation of pyramidal neurons in prefrontal cortex and hippocampal layers II (p < 0.0001), III (p < 0.0001), and V (p < 0.0001), with the highest dose of FD producing neuronal viability comparable to donepezil. Importantly, transmission electron microscopy demonstrated that FD markedly preserved the ultrastructural integrity of hippocampal microglia and astrocytes, maintaining mitochondrial morphology, rough endoplasmic reticulum organization, and myelin integrity. Consistent with these structural effects, FD significantly suppressed neuroinflammatory cytokine expression (IL-1β, IL-6, and TNF-α) in the prefrontal cortex. Collectively, this study provides the first integrated ultrastructural and molecular evidence that FD confers multi-level neuroprotection across the cortical-hippocampal axis by preserving neuronal-glial architecture and attenuating neuroinflammation. These findings highlight FD as a promising multi-target natural candidate for mitigating neurodegenerative processes associated with AD.},
}

@article {pmid42671152,
year = {2026},
author = {Otani, K},
title = {From public preferences to clinical tasks in anti-amyloid therapy for Alzheimer's disease.},
journal = {Psychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/pcn.70128},
pmid = {42671152},
issn = {1440-1819},
abstract = {Tajika and colleagues found that, among Japanese respondents willing to consider lecanemab, the median smallest worthwhile difference exceeded the absolute benefit used in their study scenario. This commentary argues that this expectation-efficacy gap should be translated into concrete clinical tasks across the anti-amyloid care pathway, including expectation assessment, biomarker and eligibility counseling, shared decision-making, treatment monitoring, support for non-initiation or discontinuation, and continuing psychosocial care.},
}

@article {pmid42665355,
year = {2026},
author = {Afonso, AS and Schroeder, KM and Mitchell, L and Carragher, N and Casey, C and Patel, N},
title = {Characterising patients with Alzheimer's disease in England: a cohort study using data from Clinical Practice Research Datalink linked to Hospital Episode Statistics.},
journal = {BMJ open},
volume = {16},
number = {8},
pages = {e115438},
doi = {10.1136/bmjopen-2025-115438},
pmid = {42665355},
issn = {2044-6055},
mesh = {Humans ; Female ; *Alzheimer Disease/epidemiology/drug therapy ; England/epidemiology ; Aged, 80 and over ; Male ; Comorbidity ; Aged ; Databases, Factual ; Cohort Studies ; Algorithms ; Middle Aged ; Polypharmacy ; Hospitalization/statistics & numerical data ; },
abstract = {OBJECTIVES: To characterise demographics, comorbidities, co-medications and healthcare resource utilisation (HCRU) in patients newly diagnosed with Alzheimer's disease (AD) in England using published and validated AD algorithms.

DESIGN: Observational cohort study.

SETTING: Real-world data in England from the Clinical Practice Research Datalink Aurum primary care database linked to the Hospital Episode Statistics secondary care database.

PARTICIPANTS: Two disease-based algorithms (Imfeld et al and Douros et al) and one medication-based algorithm (Schroeder et al) were selected from the literature to identify patients with AD. The index period for patient selection was from 1 January to 31 December 2019. Patients were grouped into three non-mutually exclusive cohorts reflecting these algorithms (cohorts A-C), then patients aged ≥60 years were further grouped into three subcohorts (subcohorts 1-3). Subcohort 1 included 9826 patients, subcohort 2 included 10 265 patients and subcohort 3 included 7355 patients.

PRIMARY OUTCOME MEASURES: Demographics, comorbidities, co-medications and HCRU present up to and including the date of cohort qualification were described.

RESULTS: Across subcohorts 1-3, mean age at index ranged from 81 to 83 years, and most patients were female (59%-63%) and White (93%). Common comorbidities were hypertension (67%-71%), asthma and chronic obstructive pulmonary disease (60%-63%) and arthritis and osteoarthritis (51%-53%). Common co-medications were analgesics (87%-89%), systemic corticosteroids (83%-84%) and anti-inflammatory and anti-rheumatic agents (81%-82%). Up to 34% of patients had a specialist referral or visit, with up to 18% involving a neurologist. In the 12 months prior to and including the index date, up to 46% of patients had an emergency department visit or inpatient visit for any cause.

CONCLUSIONS: In England, most newly diagnosed patients with AD were White females in their early 80s with common comorbidities including hypertension, asthma, chronic obstructive pulmonary disease, arthritis and osteoarthritis. This study addresses a critical evidence gap by quantifying the England-specific burden of comorbidity, polypharmacy, and HCRU among patients with AD using multiple validated and published AD algorithms. Findings were broadly consistent across the three subcohorts identified using disease-based and medication-based algorithms, strengthening internal validity of the study and demonstrating that the findings are robust to the method of AD case definition. This study provides a novel insight into the real-world AD population in England, and findings may help healthcare professionals to identify patients living with AD, understand patients' needs and tailor treatment strategies.},
}

Humans
Female
*Alzheimer Disease/epidemiology/drug therapy
England/epidemiology
Aged, 80 and over
Male
Comorbidity
Aged
Databases, Factual
Cohort Studies
Algorithms
Middle Aged
Polypharmacy
Hospitalization/statistics & numerical data

@article {pmid42665452,
year = {2026},
author = {Huang, WL and Wang, LL and Shi, JR and Liu, Q},
title = {Acupuncture for Alzheimer's disease: A systematic review and meta-analysis integrating traditional insights and scientific evidence.},
journal = {Journal of integrative medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.joim.2026.08.002},
pmid = {42665452},
issn = {2095-4964},
abstract = {BACKGROUND: Alzheimer's disease (AD), a leading cause of dementia in the elderly, is characterized by progressive cognitive impairment, and still lacks effective therapeutic interventions.

OBJECTIVE: This systematic review synthesizes the classical theoretical foundations, clinical evidence, and modern mechanistic insights for the use of acupuncture to treat AD.

SEARCH STRATEGY: A meta-analysis was conducted based on a comprehensive literature search of PubMed, Embase, the Cochrane Library, CNKI, VIP information, and Wanfang Data, covering the period from inception until September 2025.

INCLUSION CRITERIA: Eligible randomized controlled trials (RCTs) compared acupuncture (manual or electroacupuncture) with control interventions, including sham acupuncture, donepezil, placebo, or no treatment.

DATA EXTRACTION AND ANALYSIS: Data were extracted by two reviewers working independently and then analyzed using the meta and meta for packages in R (v4.3.2). Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated.

RESULTS: A total of 21 RCTs comprising 1354 participants met the inclusion criteria. Compared with no-treatment controls, acupuncture significantly improved cognitive performance, as measured by the Mini-Mental State Examination (MMSE) (WMD = 3.74, 95% CI: 1.34-6.14), and outperformed placebo controls (WMD = 2.13, 95% CI: 1.39-2.87). Acupuncture showed efficacy comparable to that of donepezil on MMSE and Activity of Daily Living (ADL), suggesting non-inferiority to standard pharmacotherapy. Frequently used acupoints included GV20, ST36, GB20, LR3, and ST40, often combining local (GV24, EX-HN1) and distal (SP10, KI3) points. Reported adverse events were mild and transient, with no significant difference from controls. Biomarker analyses indicated that acupuncture enhanced acetylcholine levels and reduced plasma Aβ1-40, Aβ1-42, and Tau levels, implying modulation of cholinergic transmission and AD-related pathology.

CONCLUSION: This review highlights acupuncture as a holistic, multi-targeted therapy with promising potential for managing AD. Future research should aim to standardize acupuncture protocols, integrate TCM syndrome differentiation, and adopt neurobiological and imaging techniques to explore mechanisms. Please cite this article as: Huang WL, Wang LL, Shi JR, Liu Q. Acupuncture for Alzheimer's disease: A systematic review and meta-analysis integrating traditional insights and scientific evidence. J Integr Med. 2026; Epub ahead of print.},
}

@article {pmid42665539,
year = {2026},
author = {Lu, H and Hu, C and Fu, Y},
title = {Fabrication of Mesoporous Manganese Nanoparticles Incorporated Aβ-Peptide Inhibits Aβ Aggregation and Alleviates Neuroinflammation Against Alzheimer's Disease.},
journal = {Journal of biomedical materials research. Part B, Applied biomaterials},
volume = {114},
number = {9},
pages = {e70131},
doi = {10.1002/jbm.b.70131},
pmid = {42665539},
issn = {1552-4981},
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Amyloid beta-Peptides/chemistry/metabolism ; Mice ; *Manganese/chemistry/pharmacology ; Humans ; Porosity ; *Nanoparticles/chemistry ; Blood-Brain Barrier/metabolism ; *Neuroinflammatory Diseases/metabolism/drug therapy/pathology ; Protein Aggregation, Pathological ; tau Proteins/metabolism ; Protein Aggregates/drug effects ; },
abstract = {Extracellular amyloid plaques from Aβ accumulation and intracellular neurofibrillary tangles (NFTs) from hyperphosphorylated Tau (p-Tau), both leading to neuronal dysfunction, synapse loss, and cognitive decline. Nonetheless, achieving an effective therapeutic outcome is challenging due to the limited drug bioavailability through the blood-brain barrier (BBB) and the complex microenvironment within the brain. This study proposes MM-TA for the synergistic treatment of AD, utilizing mesoporous manganese (MM) as a nanocarrier to deliver a LK7 (Aβ-inhibiting peptide) and a DAA (amino acid-peptide) that inhibits Tau-related fibrils formation. A biomimetic nanocarrier (MM-LD@4CM termed as MLDC) encapsulated with 4T1 cell membranes (4CM) was developed, inspired by 4T1 cells' ability to facilitate BBB penetration. Following traversal of the BBB, MLDC concurrently prevented Tau phosphorylation and suppressed Aβ aggregation. Furthermore, by leveraging MM's catalase-mimetic properties, MLDC mitigated oxidative stress and altered the microenvironment associated with AD progression. In contrast to the singular therapeutic agent, MLDC ameliorated nerve damage and enhanced cognitive function in AD mice by reducing Aβ oligomers, phosphorylated Tau, and inflammation, thereby providing a synergistic therapeutic approach with significant potential for effective AD treatment.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology
*Amyloid beta-Peptides/chemistry/metabolism
Mice
*Manganese/chemistry/pharmacology
Humans
Porosity
*Nanoparticles/chemistry
Blood-Brain Barrier/metabolism
*Neuroinflammatory Diseases/metabolism/drug therapy/pathology
Protein Aggregation, Pathological
tau Proteins/metabolism
Protein Aggregates/drug effects

@article {pmid42665946,
year = {2026},
author = {Le, N and Anne, N and Shen, C and Pallapothu, R and Liu, Y and Park, C},
title = {Dementias in Older Women With Early-Stage HER2-Negative Breast Cancer Treated With Anthracycline Plus Taxane Versus Taxane-Based Chemotherapy Regimens.},
journal = {Pharmacoepidemiology and drug safety},
volume = {35},
number = {9},
pages = {e70457},
pmid = {42665946},
issn = {1099-1557},
mesh = {Humans ; Female ; *Taxoids/adverse effects/administration & dosage ; Aged ; *Anthracyclines/adverse effects/administration & dosage ; SEER Program/statistics & numerical data ; *Antineoplastic Combined Chemotherapy Protocols/adverse effects/administration & dosage ; *Breast Neoplasms/drug therapy/pathology ; Erb-b2 Receptor Tyrosine Kinases ; *Dementia/epidemiology/chemically induced ; United States/epidemiology ; Aged, 80 and over ; Bridged-Ring Compounds/adverse effects/administration & dosage ; Medicare/statistics & numerical data ; Incidence ; Neoplasm Staging ; Longitudinal Studies ; Alzheimer Disease/epidemiology/chemically induced ; },
abstract = {BACKGROUND: Anthracycline plus taxane (ATAX) regimens are associated with improved survival in HER2-negative breast cancer (HBC) compared to taxane-based (TAX) regimens. However, anthracyclines are known for their cardiotoxicity, which could increase the risk of neurocognitive deficits, raising concerns about neurocognitive safety, particularly in older adults. Limited evidence exists comparing neurocognitive outcomes between these two regimens.

OBJECTIVE: To compare the incidence of Alzheimer's disease and related dementias (ADRD) between ATAX and TAX regimens in neoadjuvant (Trial #1) and adjuvant (Trial #2) settings among older women with early-stage HBC.

METHODS: Using SEER-Medicare data (2010-2021), we identified women aged ≥ 66 years with newly diagnosed HBC and no prior neurocognitive conditions between 2011 and 2021. Patients were longitudinally tracked, and their eligibility for each regimen was evaluated. We applied the clone-censor-weight method and used weighted pooled logistic regression to estimate the 10-year risks of ADRD, Alzheimer's disease (AD), and vascular dementia (VD).

RESULTS: We identified 14 079 and 9321 eligible individuals in Trial #1 and Trial #2, respectively. For ADRD outcome, the 10-year risk difference (RD) was -6.91% (95% CI: -15.60% to 0.91%) for HR+/HER2- cohort and -2.14% (95% CI: -9.57% to 5.46%) for TNBC cohort in Trial #1. The 10-year RD was -1.42% (95% CI: -9.33% to 6.98%) for HR+/HER2- cohort and -2.91% (95% CI: -9.54% to 7.86%) for TNBC cohort in Trial #2.

CONCLUSION: Our findings suggest that ATAX regimens were not associated with increased risks of ADRD, AD, and VD compared to TAX regimens in older women with HBC. However, the risks of AD and VD should be interpreted with caution due to sparse events. These findings may support the continued use of ATAX regimens in this population, while also informing more personalized, risk-adapted treatment strategies.},
}

Humans
Female
*Taxoids/adverse effects/administration & dosage
Aged
*Anthracyclines/adverse effects/administration & dosage
SEER Program/statistics & numerical data
*Antineoplastic Combined Chemotherapy Protocols/adverse effects/administration & dosage
*Breast Neoplasms/drug therapy/pathology
Erb-b2 Receptor Tyrosine Kinases
*Dementia/epidemiology/chemically induced
United States/epidemiology
Aged, 80 and over
Bridged-Ring Compounds/adverse effects/administration & dosage
Medicare/statistics & numerical data
Incidence
Neoplasm Staging
Longitudinal Studies
Alzheimer Disease/epidemiology/chemically induced

@article {pmid42666495,
year = {2026},
author = {Hölscher, C},
title = {GLP-1 and GIP class drugs have neuroprotective properties in Alzheimer's and Parkinson's disease.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1906426},
pmid = {42666495},
issn = {1662-4548},
abstract = {Alzheimer's and Parkinson's disease are two CNS diseases with a large unmet need for disease-modifying therapies. Recently, two phase 3 clinical trials testing the GLP-1 analogue Semaglutide (Wegovy, Ozempic) in patients with Alzheimer's disease did not show improvements. This failure should not have been a surprise, since it has been known for many years that Semaglutide does not cross the blood-brain barrier (BBB) and enters the brain only in very small amounts. It is designed to stay in the blood stream and has a very long half-life in the blood (168 h). The GLP-1 analogue Liraglutide (Victoza), in contrast, has a much shorter half-life (13 h), and a phase 2 clinical trial showed improvements in cognitive tests after 1 year of treatment. GLP-1 receptor agonists have been tested in clinical trials in Parkinson's patients, and a similar picture emerged. Drugs that can cross the BBB well (exenatide, lixisenatide) show good protection, while a drug that cannot cross the BBB showed no effects (NLY01). Clearly, when treating CNS diseases, it is of importance to get the drug into the brain to ensure target engagement. This review will look at the clinical trials that have been conducted in more detail, describe the mode of action as derived from preclinical trials, and discuss novel strategies for getting GLP-1 receptor agonists into the brain to successfully treat CNS diseases.},
}

@article {pmid42667351,
year = {2026},
author = {Yuan, Y and Liu, P and Yin, C and Zhu, J and Xu, J and Xiong, H and Xu, R},
title = {Mechanism and progress of deep brain stimulation in the treatment of neurological and psychiatric disorders.},
journal = {MedScience},
volume = {},
number = {},
pages = {},
pmid = {42667351},
issn = {3091-4981},
abstract = {Deep brain stimulation (DBS) is a reversible and adjustable neurostimulation technique, and has been established as a significant therapeutic modality in functional neurosurgery although its mechanisms are not yet fully understood. The primary indications for DBS include movement disorders such as Parkinson's disease (PD) and dystonia, essential tremor (ET), and Huntington's disease (HD). In recent years, its application has expanded to encompass the treatment of various other neurological and psychiatric conditions, including epilepsy, depression, obsessive-compulsive disorder (OCD), Alzheimer's disease (AD), and Tourette syndrome (TS), although the indications for DBS currently approved by the Food and Drug Administration (FDA) are PD, dystonia, ET, OCD, and epilepsy. In this review, we summarize the prevailing hypotheses regarding the mechanisms through which DBS ameliorates neurological and psychiatric disorders. We also describe the advancements in DBS for treating PD, dystonia, epilepsy, and other brain disorders. Furthermore, we outline the limitations associated with DBS treatment to date. Through this comprehensive analysis, we aim to enhance the understanding of DBS applications in neurological and psychiatric diseases and suggest potential avenues for technological advancement.},
}

@article {pmid42667649,
year = {2026},
author = {O'Neil, LM and Qureshi, HA and Lindemann, L and Cvancara, DJ and Lehmann, AE and Jafari, A},
title = {Cognitive Dysfunction in Chronic Rhinosinusitis: A Scoping Review.},
journal = {International forum of allergy & rhinology},
volume = {},
number = {},
pages = {},
doi = {10.1002/alr.70262},
pmid = {42667649},
issn = {2042-6984},
abstract = {BACKGROUND: Cognitive dysfunction is increasingly recognized as an extra-nasal manifestation of chronic rhinosinusitis (CRS). This scoping review characterizes the primary evidence on cognition in adult CRS, covering measures, treatment response, and incident dementia.

METHODS: We searched EMBASE, PubMed/MEDLINE, Web of Science, the Cochrane Library, CINAHL, and Global Index Medicus through May 2026 using a MeSH and free-text strategy. Inclusion criteria include primary studies of adult CRS with a formal clinical diagnosis (AAO-HNS, EPOS or ICD-coded) reporting at least one validated cognitive measure or recognized cognitive impairment. Two reviewers screened independently. Animal studies, reviews, conference abstracts, and non-CRS populations were excluded. PRISMA-ScR reporting was performed; heterogeneity precluded meta-analysis.

RESULTS: Twenty-four primary studies met inclusion criteria. Adults with CRS perform worse than controls on subjective (Cognitive Failures Questionnaire [CFQ], Neuro-QoL) and objective (Montreal Cognitive Assessment [MoCA], Automated Neuropsychological Assessment Metrics [ANAM], eye movement assessment, P300) cognitive instruments. Deficits correlate with disease-specific QoL severity (SNOT-22, Rhinosinusitis Disability Index [RSDI]). Cognitive measures improve after medical therapy or endoscopic sinus surgery. Two resting-state fMRI analyses identified altered orbitofrontal-precuneus connectivity scaling with sinonasal inflammation. Dementia results are mixed: a UK Biobank analysis (7176 CRS cases among 364,945 participants) reported increased Alzheimer disease risk (HR 1.33), while two Korean cohorts and a 2025 meta-analysis found no association.

CONCLUSION: Adults with CRS show measurable cognitive dysfunction that may improve with treatment, with a plausible neuroinflammatory pathophysiology. Whether this translates to incident dementia is contested. Outcome heterogeneity limits synthesis; therefore, development of a CRS-specific cognitive measurement set is recommended.},
}

@article {pmid42657669,
year = {2026},
author = {Romano, CD and Bratlee-Whitaker, E and Hartry, A and Taylor, J and Callahan, LF and Monks, D and Kremer, I and Lappin, D and Frangiosa, T and Sangodkar, S and Lee, J and Shirneshan, E and Slowiejko, D and DiBenedetti, D and Herring, WL and Bussberg, C and Dardis, GJ and Goss, D and Edwards, T and McLeod, L and Poulos, C and Paulsen, R},
title = {Priorities of people living with Alzheimer's and care partners: What Matters Most?.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71554},
pmid = {42657669},
issn = {1552-5279},
support = {//UsAgainstAlzheimer's/ ; },
mesh = {Humans ; *Alzheimer Disease/psychology ; Female ; Male ; *Caregivers/psychology ; Cross-Sectional Studies ; Aged ; Aged, 80 and over ; Qualitative Research ; Activities of Daily Living ; Middle Aged ; Surveys and Questionnaires ; },
abstract = {INTRODUCTION: Understanding the experience of people living with Alzheimer's disease (PLWAD) and care partners is central to defining meaningful treatment outcomes. The What Matters Most (WMM) research program seeks to identify and measure treatment-related needs, preferences, and priorities across the disease continuum.

METHODS: This mixed-methods, observational, US-based study included qualitative interviews and a cross-sectional, web-based quantitative survey assessing priorities among WMM model concepts and domains.

RESULTS: Racially and ethnically diverse participants represented the full spectrum of disease severity. Qualitative interviews (N = 64) supported a WMM conceptual model of disease comprising 50 concepts across six domains: General Independence, Thought Processing, Communication, Daily Activities, Emotions, and Social Life/Activities. All WMM concepts were deemed important, but the quantitative survey priority ranking (N = 640) identified differences in prioritization among PLWAD and care partners.

DISCUSSION: These findings provide novel, critical insights into the lived experience of Alzheimer's disease (AD) and the identification of meaningful treatment outcomes.},
}

Humans
*Alzheimer Disease/psychology
Female
Male
*Caregivers/psychology
Cross-Sectional Studies
Aged
Aged, 80 and over
Qualitative Research
Activities of Daily Living
Middle Aged
Surveys and Questionnaires

@article {pmid42661318,
year = {2026},
author = {Kiyota, M and Jin, Y and Nemoto, N and Kakikawa, M},
title = {Low-frequency magnetic fields can improve behavioral abnormalities and suppress Aβ accumulation detected by thioflavin T in Caenorhabditis elegans models of Alzheimer's disease.},
journal = {Electromagnetic biology and medicine},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/15368378.2026.2722639},
pmid = {42661318},
issn = {1536-8386},
abstract = {Amyloid β (Aβ) accumulation and Aβ-related senile plaques, the pathological hallmarks of Alzheimer's disease (AD), damage neurons and impair cognitive functions in patients. Previous studies have shown that low‑field magnetic stimulation attenuates Aβ and enhances cognitive performance. In this study, AD models of Caenorhabditis elegans expressing Aβ in the nerves were placed in a low-frequency magnetic field (LFMF) and then subjected to a chemotaxis assay to evaluate attractive behavior. In control C. elegans (CL2122), which do not express Aβ but carried only the vector, the chemotactic behavior was normal and unaffected by LFMF. In contrast, in the AD model expressing Aβ within the nervous system, abnormalities in chemotactic behavior were observed; however, these were improved in a manner dependent on LFMF strength. In addition, the AD model expressing Aβ in the muscle exhibited paralysis, which was significantly attenuated by LFMF. Thioflavin T staining revealed that, in the AD model expressing in muscles, Aβ accumulation declined in the LFMF-treated group compared to that of the non-LFMF group. These results suggest that LFMF can improve abnormal chemotactic behavior and attenuate Aβ-induced paralysis by suppressing the accumulation and aggregation of Aβ in a C. elegans model of AD.},
}

@article {pmid42662336,
year = {2026},
author = {Reinapu, A and Kirss, S and Tõugu, V and Palumaa, P},
title = {Distinct Effects of Copper Ionophores on Intracellular Copper and Cell Viability in Wild-Type and CTR1-Deficient SH-SY5Y Cells.},
journal = {ACS omega},
volume = {11},
number = {33},
pages = {49807-49814},
pmid = {42662336},
issn = {2470-1343},
abstract = {Copper homeostasis is essential for neuronal function, and its dysregulation has been implicated in neurodegenerative disorders. In particular, reduced intracellular copper levels alongside with elevated extracellular copper concentrations have been associated with Alzheimer's disease (AD). Therefore, strategies aimed at restoring intracellular copper levels represent a potential therapeutic approach. In this study, we investigated the effects of selected copper-binding compounds(?)α-lipoic acid (LA), elesclomol (ES), disulfiram (DSF), thiourea (TU), and triapine (3-AP)(?)on copper uptake and cytotoxicity in SH-SY5Y wild-type (WT) and CTR1-deficient (CTR1[-/-]) cells. Intracellular copper levels were quantified using inductively coupled plasma mass spectrometry (ICP-MS), and cell viability was assessed by using propidium iodide assay under various treatment conditions. Among the tested compounds, LA, ES, and DSF significantly increased intracellular copper levels in both WT and CTR1[-/-] cells, whereas TU and 3-AP did not enhance copper accumulation beyond copper-only treatment. Notably, CTR1[-/-] cells exhibited reduced sensitivity to copper-associated toxicity compared to WT cells. Under copper-supplemented conditions, DSF and ES displayed concentration-dependent cytotoxicity, while LA and TU induced only mild effects. In contrast, 3-AP toxicity was abolished in the presence of copper. Furthermore, cotreatment with LA and copper increased cell proliferation and promoted differentiation-associated morphological changes in CTR1[-/-] cells. Overall, our results demonstrate that copper ionophores can enhance intracellular copper levels dependently and independently of CTR1, with distinct effects on cell viability. Among the tested compounds, LA and DSF showed a favorable profile by increasing copper levels while maintaining low cytotoxicity, highlighting their potential for modulating cellular copper homeostasis.},
}

@article {pmid42662931,
year = {2025},
author = {Davis, L and Obisesan, T},
title = {The Shifting Treatment Landscape for Alzheimer's Disease in Primary Care.},
journal = {Federal practitioner : for the health care professionals of the VA, DoD, and PHS},
volume = {42},
number = {Suppl5},
pages = {S37-S42},
pmid = {42662931},
issn = {1078-4497},
}

@article {pmid42663490,
year = {2026},
author = {Dejgaard, MS and Eide, PK and Tangen, GG and Skovlund, E and Selbæk, G and Wyller, TB},
title = {Cognitive profiles in idiopathic normal pressure hydrocephalus and Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261478264},
doi = {10.1177/13872877261478264},
pmid = {42663490},
issn = {1875-8908},
abstract = {BackgroundIdiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD) are neurodegenerative disorders with partly overlapping clinical features. Since the treatment is different, we need better knowledge about how the cognitive profile differs between these conditions.ObjectiveWe aimed to compare the cognitive profile of iNPH patients with that of a large cohort of confirmed AD patients.MethodsPatients diagnosed with iNPH and accepted for shunt surgery were compared with patients with biomarker verified Alzheimer's disease in The Norwegian Register of Persons Assessed for Cognitive symptoms (NorCog). All patients underwent a standardized cognitive assessment with age and education adjusted z-scores. We used the Clinical Dementia Rating Scale (CDR) to adjust for disease severity. Since the cognitive score distributions were highly skewed, we used nonparametric analyses stratified by CDR stage combined with multinomial logistic regression.ResultsIn total, 276 iNPH patients were compared to 1113 AD patients. iNPH patients performed significantly poorer on phonemic fluency [median z-score difference (AD-iNPH) 0.30, 95% confidence interval (CI) 0.20 to 0.50], but significantly better on other cognitive tests, in particular immediate (median difference -0.35, 95% CI -0.49 to -0.20) and delayed recall (median difference -0.46, 95% CI -0.59 to -0.34). The differences persisted after adjustment for CDR and were most pronounced in early stages of the disease.ConclusionsiNPH seems to affect phonemic fluency more and memory less than AD. As the disease progresses, the cognitive profiles become more similar, and the conditions cannot be distinguished by cognitive tests.},
}

@article {pmid42664573,
year = {2026},
author = {Noguchi-Shinohara, M and Muramatsu, D and Shima, A and Sakashita, Y and Tada, Y and Yamaguchi, H and Komatsu, J and Ikeda, T and Ono, K},
title = {Real-world long-term continuation of lecanemab therapy and the clinical utility of phosphorylated tau 181.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100664},
doi = {10.1016/j.tjpad.2026.100664},
pmid = {42664573},
issn = {2426-0266},
abstract = {This real-world study evaluated the long-term feasibility of lecanemab treatment in 117 patients with early Alzheimer's disease at Kanazawa University Hospital. To assess treatment persistence over a full 18-month course, we focused on the 64 patients who initiated treatment between January and December 2024. Of these 64 patients, 78.1% completed the full 18-month course, and all 48 eligible patients elected to continue beyond 18 months. The overall discontinuation rate was 21.9%, with amyloid-related imaging abnormalities (ARIA) (27.7%), decreased motivation (22.2%), and cognitive decline (11.1%) as the primary reasons. Among all 117 patients, ARIA occurred in 12.9% and was significantly associated with apolipoprotein Eε4 carrier status, elevated baseline cerebrospinal fluid (CSF)-phosphorylated tau (ptau) 181 (ptau181; ≥78.6 pg/ml), ≥2 microbleeds, and Fazekas score≥2 deep white matter hyperintensity. Elevated CSF-ptau181 also independently predicted cognitive decline during treatment and ARIA-related discontinuation. These findings suggest that integrating CSF-ptau181 measurement and baseline MRI into clinical decision-making may support individualized risk stratification and the safe, sustained use of lecanemab in real-world practice.},
}

@article {pmid42665145,
year = {2026},
author = {Yu, X and Gao, P and Yao, Q and Yuan, F and Jing, W},
title = {Polysaccharides targeting organelle network dysfunction in Alzheimer's disease: A review.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {154255},
doi = {10.1016/j.ijbiomac.2026.154255},
pmid = {42665145},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is driven by an interrelated pathological network, which to some extent explains the limited efficacy of single-target therapies and constitutes a significant challenge in current clinical treatment. Emerging evidence indicates that dysfunction and crosstalk among mitochondria, the endoplasmic reticulum, and lysosome-autophagy form a core organelle network that amplifies oxidative stress and exacerbates proteostatic imbalance, neuroinflammation, and synaptic failure. In this review, we summarize natural and engineered polysaccharides as potential multitarget modulators that may influence individual organelle-associated pathways involved in AD-related dysfunction. We discuss how the structural parameters of polysaccharides (e.g., molecular weight, monosaccharide composition, glycosidic linkages, branching, and charge density) are associated with bioactivities through receptor-related signaling pathways, redox and inflammatory regulation, proteostasis/autophagy modulation, and, when applicable, potential gut-brain axis involvement. Furthermore, we highlight rational design strategies (e.g., sulfation and carboxymethylation) and formulation/delivery considerations that may increase efficacy and translational readiness. Finally, key challenges, including heterogeneity, mechanism attribution, brain delivery, and standardization, are outlined to guide the development of polysaccharide-based strategies potentially addressing organelle-associated dysfunction in AD.},
}

@article {pmid42654386,
year = {2026},
author = {Rus Prelog, P and Zupan, M and Šabović, M and Frol, S and Kramberger, MG},
title = {Beyond Amyloid: Systemic and Brain Frailty as Determinants of Response to Anti-Amyloid Therapy in Alzheimer's Disease-A Conceptual Review.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {8},
pages = {},
pmid = {42654386},
issn = {1648-9144},
mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology/complications ; *Frailty/physiopathology/complications ; *Brain/physiopathology ; Antibodies, Monoclonal/therapeutic use ; Biomarkers/analysis ; Aged ; Magnetic Resonance Imaging/methods ; *Amyloid ; },
abstract = {Anti-amyloid therapy (AAT) with monoclonal antibodies (mAbs) modestly slow cognitive and functional decline in early Alzheimer's disease (AD). However, both the magnitude of clinical benefit and the risk of treatment-related complications vary substantially even among patients with similar biomarker profiles. Frailty, both brain and systemic, is highly prevalent in older adults with AD and affects a large proportion of those considered for AAT. Despite this, it has been largely absent from current decision frameworks. Brain frailty, defined by structural and microvascular damage (e.g., small-vessel disease, microbleeds, and atrophy), limits the clinical benefit of amyloid clearance and increases susceptibility to amyloid-related imaging abnormalities. In contrast, systemic frailty, reflecting reduced physiological reserve, mainly affects treatment tolerance and recovery from adverse events. In this narrative, conceptual review, we synthesize evidence that both forms of frailty act as biologically grounded modifiers of AAT efficacy and safety and may limit the clinical benefit while increasing susceptibility to complications and decompensation. Importantly, the precise empirical thresholds at which frailty begins to exert harmful effects remain unknown. We further outline how MRI-based markers of brain frailty, combined with brief systemic frailty measures, could support risk stratification, patient selection, monitoring intensity, and shared decision-making, including deferring treatment when the benefit-risk balance is unfavorable, while avoiding exclusion of patients who may still benefit. Taken together, we propose that future studies should incorporate frailty measures and perform precise assessments of both brain and systemic frailty, as this may improve patient stratification and better characterize the effects of AAT.},
}

Humans
*Alzheimer Disease/drug therapy/physiopathology/complications
*Frailty/physiopathology/complications
*Brain/physiopathology
Antibodies, Monoclonal/therapeutic use
Biomarkers/analysis
Aged
Magnetic Resonance Imaging/methods
*Amyloid

@article {pmid42655989,
year = {2026},
author = {Sayyed, N and Afzal, M and Rafeeq, M and Omer, AB and Al-Abbasi, FA and Rahman, S and Al-Zharani, M and Alzarea, SI and Kazmi, I},
title = {Erucic acid arbitrates neuroprotection in streptozotocin-induced memory deficit via improving oxidative stress/neuroinflammatory indicators/cholinergic activity in rodents.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-23},
doi = {10.1080/1028415X.2026.2718394},
pmid = {42655989},
issn = {1476-8305},
abstract = {BACKGROUND: Erucic acid (EA), a monounsaturated omega-9 fatty acid derived from Raphanus sativus L. seeds, has antioxidant and anti-inflammatory properties. This study investigated its neuroprotective effects against streptozotocin (STZ)-induced diabetes-associated cognitive dysfunction in rats.

METHODS: Male Wistar rats were randomly assigned to five groups: normal control, STZ control (60 mg/kg), STZ + EA (10 mg/kg), STZ + EA (20 mg/kg), and EA (20 mg/kg) per se. EA was administered orally for 38 days. Blood glucose and body weight were measured before STZ administration and at the end of the study. Cognitive function was assessed using the Y-maze and Morris water maze (MWM). Cholinergic function, oxidative stress, neurotransmitters, inflammatory mediators, apoptosis, and cellular energy status were evaluated biochemically, and hippocampal histopathology was performed.

RESULTS: EA treatment significantly reduced hyperglycemia and attenuated diabetes-induced body weight loss. EA improved spontaneous alternation in the Y-maze and spatial learning and memory in the MWM, reducing escape latency and increasing target-quadrant time. EA decreased acetylcholinesterase activity while increasing choline acetyltransferase activity, restored antioxidant defenses, and reduced MDA, ROS, and NO levels. It also normalized neurotransmitter levels, suppressed TNF-α, IL-1β, IL-6, NF-κB, and caspase-3, increased IL-10, and improved the ATP/ADP ratio. Histopathology demonstrated preservation of hippocampal neuronal architecture.

CONCLUSIONS: EA ameliorated diabetes-associated cognitive dysfunction by improving learning and memory, preserving cholinergic neurotransmission, reducing oxidative stress and neuroinflammation, inhibiting neuronal apoptosis, and restoring cellular energy metabolism. These findings support the therapeutic potential of EA for managing cognitive impairment associated with diabetes.},
}

@article {pmid42656799,
year = {2026},
author = {Cecchetto, R and Diani, E and Lotti, V and Palmisano, A and Lagni, A and Mantoan, M and Turrina, S and Raniero, D and Paolone, G and Mazzariol, A and Gibellini, D},
title = {HIV-1 Tat and gp120 as key drivers of neurodegeneration in the central nervous system.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1895162},
pmid = {42656799},
issn = {1664-302X},
abstract = {Combined antiretroviral therapy (cART) has deeply changed the approach to HIV disease treatment. cART tackles HIV replication and improves the life expectancy of HIV-infected people. Notwithstanding the effectiveness of cART in HIV infection control, several observations have determined that 15-50% of HIV-infected people display HIV-associated neurocognitive disorders (HAND) even under long-term viral suppression. Persistent production of the viral proteins Tat and gp120 by central nervous system reservoirs drives chronic neurotoxicity due to their remarkable extracellular stability and efficient uptake by neurons and glial cells. In this review, we will discuss current evidence on the molecular mechanisms by which extracellular Tat and gp120 orchestrate neurodegeneration. Four principal interconnected pathways emerge: (i) mitochondrial dysfunction; (ii) synaptodendritic injury; (iii) chronic neuroinflammation; and (iv) crosstalk with Alzheimer's disease (AD) pathways. Converging data achieved from in vitro models, Tat and gp120-transgenic mice, post-mortem tissue, and cerebrospinal fluid (CSF) biomarkers indicate that these viral proteins contribute to frontostriatal atrophy and hybrid HAND-AD phenotypes increasingly observed in aging HIV patients. Understanding these mechanisms highlights the need for adjunctive neuroprotective strategies targeting CXCR4/CCR5 signaling, mitochondrial quality control, inflammatory pathways, and Aβ/Tau homeostasis derangement and supports the integration of multimodal neuroimaging and CSF proteomics in future longitudinal studies aimed at improving diagnosis and therapeutic development.},
}

@article {pmid42657250,
year = {2026},
author = {Napoleon, T and Akinrinde, D and Femi-Lawal, VO and Adebajo, GO and Yokolo, H and Okei, FU and Alabi, G and Ifeoluwa, OI and Lawal, SO and Abati, SO and Duru, CN and Oluwatosin, O and Sanusi, IO and Solomon, AO and Clement, A and Bello, T and Egwu, EO and Chukwuemeka, EK},
title = {Repetitive Transcranial Magnetic Stimulation in Alzheimer's Disease Cognitive Impairment: A Narrative Review of Clinical Trials.},
journal = {Health science reports},
volume = {9},
number = {9},
pages = {e73104},
pmid = {42657250},
issn = {2398-8835},
abstract = {BACKGROUND AND AIMS: Alzheimer's disease (AD), primarily characterized by cognitive impairment, places an immense burden on patients and caregivers. Non-invasive neuromodulation with repetitive transcranial magnetic stimulation has been proposed to improve cognition in mild to moderate AD. This narrative review aimed to summarize clinical trial evidence on the effects, safety, and tolerability of rTMS for AD-related cognitive impairment and to identify research gaps.

METHODS: A narrative review of clinical trials was performed. PubMed/MEDLINE, Embase, Cochrane Google scholar, and Scopus were searched from inception to January 25, 2025, using terms for "repetitive transcranial magnetic stimulation", "Alzheimer's disease", "cognitive impairment", "clinical trials", and "randomized controlled trial". Clinical trials of active rTMS versus sham or treatment-as-usual in adults with mild to moderate AD that reported validated cognitive outcomes were included. Data on rTMS protocols, cognitive measures, adverse effects, and follow-up were extracted and synthesized narratively without statistical pooling.

RESULTS: 14 trials were included. Across most studies, rTMS delivered at 5-20 Hz for 4 to 12 weeks, at least 5 days per week, was associated with improved cognitive function. Improvements were reported on tools such as the MMSE, CDR-SB, SIB, and ADAS-Cog, with statistically significant differences versus sham in most trials [p < 0.05], and some evidence of sustained benefit at follow-up. rTMS was generally safe and tolerable. Reported adverse effects were mild to moderate and included transient headache, scalp or skin discomfort, pain, and fatigue. Preliminary evidence also suggested potential neuropsychiatric benefits. However, substantial heterogeneity in duration, frequency, treatment plan, targets, and outcome measures limited definitive conclusions.

CONCLUSION: rTMS appears safe in the short term and may be linked to short-term cognitive and neuropsychiatric gains in mild to moderate AD. However, marked protocol heterogeneity, small sample sizes, short follow-up, and risk of bias limit certainty and prevent identification of optimal parameters. rTMS is not ready for routine AD care. Larger, sham-controlled trials with standardized protocols and biomarker or long-term outcomes are needed.},
}

@article {pmid42651126,
year = {2026},
author = {Wang, H and Wang, Y and Lv, Z and Deng, Y and Pan, C and Li, Y and Zhou, Z},
title = {State-Dependent Alterations of Hippocampal Theta-Gamma Coupling in 5xFAD Mice and Their Differential Modulation by Donepezil.},
journal = {Brain sciences},
volume = {16},
number = {8},
pages = {},
pmid = {42651126},
issn = {2076-3425},
support = {2025ZD1801202//National Science and Technology Major Project/ ; },
abstract = {BACKGROUND/OBJECTIVES: Alzheimer's disease (AD) is associated with progressive hippocampal circuit dysfunction, but electrophysiological measures of state-dependent abnormalities and treatment responsiveness remain incompletely characterized. We examined hippocampal theta-gamma coupling in 5xFAD mice across behavioral states and after donepezil.

METHODS: Local field potentials were recorded from CA1 in freely behaving wild-type (WT) and 5xFAD mice during home-cage activity, open-field exploration, and Y-maze testing. Power spectral density and theta-gamma phase-amplitude coupling (PAC) were quantified at the animal level at baseline and after seven days of donepezil.

RESULTS: Untreated 5xFAD mice showed reduced theta-low-gamma coupling during home-cage and open-field activity, but not Y-maze exploration, and elevated theta-high-gamma coupling in all three contexts. Donepezil increased theta-low-gamma coupling during open-field and Y-maze exploration and produced a partial numerical shift toward WT levels in the home cage. For theta-high-gamma coupling, the treated group did not differ significantly from either comparator. Untreated 5xFAD mice also showed reduced center exploration and distance traveled in the open field, while Y-maze spontaneous alternation was unchanged. Theta-high-gamma coupling correlated positively with open-field center time in WT mice only.

CONCLUSIONS: Hippocampal theta-gamma coupling shows frequency- and context-dependent abnormalities in 5xFAD mice. Theta-low-gamma coupling is sensitive to short-term cholinergic modulation during exploration, whereas donepezil's effect on theta-high-gamma coupling remains inconclusive. Animal-level PAC may provide a candidate functional readout, but longitudinal and cross-model validation is required before biomarker claims are justified.},
}

@article {pmid42651656,
year = {2026},
author = {Ding, X and Wang, P and Zhou, L and Li, X},
title = {Revealing the Mechanisms of Alzheimer's, Parkinson's and Huntington's Diseases Through Invertebrate Models.},
journal = {Biology},
volume = {15},
number = {16},
pages = {},
pmid = {42651656},
issn = {2079-7737},
support = {X2026161//College Students' Innovation and Entrepreneurship Training Program/ ; },
abstract = {The neural circuits of the human brain are highly complex (due to the number of neurons and the diversity of synaptic connections), hindering the analysis of the pathological mechanisms of neurodegenerative diseases. Invertebrates with simple yet well-differentiated nervous systems have a natural advantage over mammalian model organisms in the identification of pathogenic genes and functional studies of neurodegenerative diseases. They can provide unique and profound insights into the pathogenesis of complex human neurodegenerative diseases and the formulation of intervention strategies. This article reviews the conserved mechanisms of three neurodegenerative diseases across species, including protein homeostasis imbalance and aggregation toxicity, mitochondrial dysfunction and metabolic abnormalities, axonal transport defects, and loss of synaptic function. Based on research on three invertebrates in the field of neurodegeneration, namely Caenorhabditis elegans (C. elegans), Drosophila melanogaster (D. melanogaster), and Bombyx mori (B. mori), we cover three major types of neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). The aim is to find important inspirations for the future prevention and treatment of neurodegenerative diseases from the aspects of the material basis and existing treatment strategies.},
}

@article {pmid42652920,
year = {2026},
author = {Jehu, DA and Hanson, M and Huang, Y and Soares, A and Hergott, C and Waller, JL and Young, L and Hall, W and Robinson-Johnson, D and Allen, C and Sams, R and Carrick, RM and Fulzele, S and Hamrick, M and Zhu, H and Dong, Y},
title = {Multifactorial Exercise and Inflammatory Responses in Dementia: Findings from a Randomized Controlled Trial Secondary Analysis.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {8},
pages = {},
pmid = {42652920},
issn = {2075-1729},
support = {IGPCT00028//Augusta University/ ; IGPP00033//Augusta University/ ; P01 AG036675 (Core C)//NIA/ ; },
abstract = {The objective of this randomized controlled trial was to evaluate the impact of a multifactorial exercise program on circulating inflammation in people living with dementia (PWD) in residential care. This parallel-group, 6-month assessor-blinded trial (NCT05488951) allocated (1:1) 42 PWD to a multifactorial exercise intervention or usual care alone in residential care settings between July 2022 and January 2023. The exercise group engaged in 30 min of physical therapist-led strength and balance training, followed by 30 min of walking 3 x/week over 6 months, and received usual care. The usual care group only received care from healthcare providers, ongoing medical treatment, and opportunities to participate in social activities. Fasted blood was drawn at baseline and 6 months. Intention-to-treat (ITT) and per-protocol (PP; ≥2 x/week exercise vs. usual care) analyses were conducted. The ITT analysis revealed no differences between groups over time (p > 0.05). In adjusted PP analyses, there was a group-by-time interaction trend resulting in decreases in IL-1β (-3.6; +5.0 pg/mL) and IL-8 (-13.4; +14.0 pg/mL) in the exercise group compared with usual care (IL-1β: p = 0.089; IL-8: p = 0.087). Findings suggest adherence-dependent reductions in pro-inflammatory cytokines, indicating potential benefits of exercise. However, this trial was not powered for this secondary analysis, necessitating the need for larger, adequately powered trials.},
}

@article {pmid42653437,
year = {2026},
author = {Khan, A and Khan, H and Park, IH and Aldahmash, BA and Khan, MS and Yang, G and Kang, KS},
title = {Alkaloids as Emerging Neuroprotective Agents for Neurodegenerative Disorders: Insights into Tryptanthrin and Its Derivatives.},
journal = {International journal of molecular sciences},
volume = {27},
number = {16},
pages = {},
pmid = {42653437},
issn = {1422-0067},
mesh = {Humans ; *Neuroprotective Agents/therapeutic use/pharmacology/chemistry ; *Quinazolines/therapeutic use/chemistry/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Oxidative Stress/drug effects ; *Alkaloids/therapeutic use/pharmacology/chemistry ; },
abstract = {Neurodegenerative conditions are incurable, progressive disorders characterized by the slow and irreversible loss of neurons. This neuronal loss can lead to several neuropsychiatric disorders and long-term complications. Despite significant advances in understanding the mechanisms of neurodegenerative disease, currently, there is no cure for neurodegenerative diseases, highlighting the urgent need for novel neuroprotective strategies. Alkaloids are an important class of bioactive substances that exhibit neuroprotection against several neurodegenerative diseases. Tryptanthrin, an indoloquinazoline alkaloid, shows strong anti-inflammatory, antioxidant, and neuroprotective properties. In this review, we described the pathophysiology of neurodegenerative diseases and summarized several alkaloids' neuroprotective properties. Furthermore, we showed protective benefits of tryptanthrin and its derivatives against neurodegenerative illnesses, focusing on their modulation of oxidative stress, neuroinflammation, neuronal death, and related signaling pathways in cellular and animal models of neurodegenerative diseases. However, various challenges, such as clinical evidence, pharmacokinetic studies, and long-term treatment effects, are not well documented. Future research on tryptanthrin and its derivatives should focus on the optimization of drug delivery methodologies and clinical studies to establish its potential as a therapeutic candidate for neurodegenerative diseases.},
}

Humans
*Neuroprotective Agents/therapeutic use/pharmacology/chemistry
*Quinazolines/therapeutic use/chemistry/pharmacology
*Neurodegenerative Diseases/drug therapy/metabolism
Animals
Oxidative Stress/drug effects
*Alkaloids/therapeutic use/pharmacology/chemistry

@article {pmid42653654,
year = {2026},
author = {Choi, IA and Yun, JH and Lee, J and Choi, DH},
title = {Therapeutic Potential of 2-(2-Benzofuranyl)-2-Imidazoline in Preclinical CNS Models: A Systematic Review of Mechanisms, Disease Models, and Cellular Targets.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {8},
pages = {},
pmid = {42653654},
issn = {1424-8247},
support = {RS-2025-23963199//Ministry of Science and ICT/ ; },
abstract = {Background/Objectives: 2-(2-Benzofuranyl)-2-imidazoline (2-BFI) is a selective imidazoline I2-site ligand that has shown neuroprotective and neuromodulatory effects in preclinical central nervous system (CNS) studies. However, the primary preclinical literature remains fragmented across disease models, outcome types, mechanistic endpoints, and cellular targets, making it difficult to define where its therapeutic-development potential is strongest and how disease- or model-specific functional effects relate to molecular, cellular, tissue, and blood-brain barrier/neurovascular unit (BBB/NVU)-related findings. Methods: This systematic review integrated preclinical evidence from 36 original studies identified in the PubMed, Web of Science, Embase, and Scopus databases through searches last updated on May 19, 2026, to evaluate the strength of evidence for 2-BFI across CNS-related models and to connect functional, molecular, cellular, and neurovascular findings. The evidence categories included ischemic stroke/neurovascular outcomes (n = 13), traumatic CNS injury (n = 2), neuroinflammatory/neurodegeneration-related models (n = 9), behavioral pharmacology (n = 8), and cellular mechanisms (n = 4). Eligible studies were original CNS-related animal, cellular, or behavioral/pharmacological studies that directly evaluated 2-BFI and reported neuroprotective, neurological, cellular, molecular, vascular, inflammatory, neurotransmitter-related, or behavioral outcomes. Findings were synthesized qualitatively, and risk of bias in in vivo animal studies was assessed using SYRCLE's risk-of-bias tool. Results: The most extensive preclinical evidence was found in ischemic stroke and neurovascular injury models, in which 2-BFI attenuated infarct size, neurological deficits, and edema, and suppressed apoptosis-related injury and blood-brain barrier/neurovascular unit (BBB/NVU) disruption. Across models, these effects are best interpreted as modulation of interconnected secondary injury processes involving N-methyl-D-aspartate receptor (NMDAR)/Ca[2+]-dependent excitotoxicity, oxidative and mitochondrial stress, inflammatory amplification, regulated cell death, and neurovascular destabilization. Evidence from traumatic CNS injury, autoimmune neuroinflammation, Alzheimer's disease-related models, chronic epilepsy, and cellular stress models broadened the CNS relevance of 2-BFI but remained less replicated or more mechanistically indirect than the stroke/neurovascular evidence. Behavioral and pharmacological studies additionally indicated that 2-BFI modulates neurotransmitter-related systems associated with pain-, affective-, addiction-, opioid-, and compulsivity-related outcomes, although these findings should be distinguished from disease-modifying neuroprotective evidence. Conclusions: Meta-analysis was not conducted because of heterogeneity in models, dosing regimens, treatment timing, and outcomes. Overall, the current evidence does not yet support definitive dosing, treatment timing, or clinical development recommendations for 2-BFI. The strongest preclinical therapeutic rationale is currently found in ischemic stroke and neurovascular injury settings, whereas other CNS indications require further validation. Future studies should define dose-response relationships, therapeutic windows, pharmacokinetic and safety profiles, sex- and age-related effects, and efficacy in clinically relevant comorbid models before clinical translation is considered. The review was not prospectively registered. Funding was provided by a National Research Foundation of Korea grant funded by the Korean government.},
}

@article {pmid42653713,
year = {2026},
author = {Mendes, GO and Bento, LDP and Oliveira, TM and Barbosa, DB and Tsui, GS and Gomes, EN and Sales, RO and Rocha, MSC and Silva, MPD and Oliveira, TA and Maia, EHB and Falkoski, DL and Marra, IFS and Andrade, LSM and Mendes, LCVP and Fonseca, BS and Oliveira, LMG and Silva, VDAD and Carvalho, PB and Silva, AMD and Taranto, AG and Damázio, LCM and Valle, MS and Leite, FHA},
title = {Design, Synthesis, In Vitro and In Vivo Evaluation of Novel Anti-Alzheimer's (1E,4E)-1,5-Bis[(het)aryl]penta-1,4-dien-3-one Derivatives.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {8},
pages = {},
pmid = {42653713},
issn = {1424-8247},
support = {APQ-04559-22//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; APQ-07852-25//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; APQ-03224-24//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; 305452/2025-8//National Council for Scientific and Technological Development/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is a progressive, multifactorial neurodegenerative condition characterized by neurofibrillary tangles, neuronal loss, cognitive impairment, and accumulation of β-amyloid plaques. Considering the limitations of current treatments, which present adverse effects and only alleviate symptoms without modifying disease progression, there is an urgent need for new therapeutic approaches. This study aimed to investigate the neuroprotective potential of synthetic derivatives of (1E,4E)-1,5-bis[(het)aryl]penta-1,4-dien-3-ones, focusing on the inhibition of the cholinesterase enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), targets directly related to the cholinergic deficit observed in AD. Methods: The compounds were initially synthesized by aldol condensation reactions, with subsequent physicochemical characterization. They were then subjected to in silico assays that demonstrated high binding affinity to the active sites of AChE and BChE. The derivatives were evaluated in vitro for their inhibitory activity on these enzymes and in vivo in an experimental model of AD induced by streptozotocin in Wistar rats. Results: The synthesized derivatives showed favorable predicted interactions with the active sites of AChE and BChE, supporting their potential as cholinesterase inhibitors. In vitro assays demonstrated inhibitory activity against both enzymes, with selected derivatives showing improved activity compared with the parent scaffold. In the in vivo model, treatment with the selected compounds was associated with neuroprotective effects, suggesting preservation of nervous tissue integrity under AD-like conditions. Conclusions: These findings indicate that derivatives may represent promising candidates for further investigation as multitarget agents for AD. The study reinforces the relevance of integrating organic synthesis, molecular modeling, enzymatic assays, and in vivo evaluation in the search for new therapeutic strategies for neurodegenerative diseases.},
}

@article {pmid42654012,
year = {2026},
author = {Karageçili, H and Yerlikaya, E and Ertürk, A and Aslan, K and Akıncıoglu, H and Gülçin, İ},
title = {Comprehensive Evaluation of Peonidin: Antioxidant and Multi-Enzyme Inhibitory Abilities with Molecular Docking Insights.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {16},
pages = {},
pmid = {42654012},
issn = {1420-3049},
mesh = {*Molecular Docking Simulation ; *Antioxidants/chemistry/pharmacology ; *Anthocyanins/chemistry/pharmacology ; Free Radical Scavengers/chemistry/pharmacology ; Humans ; Biphenyl Compounds/chemistry ; Sulfonic Acids/chemistry ; },
abstract = {Anthocyanins are water-soluble plant pigments. They give many plants, fruits, vegetables, and cereal kernels their red, purple, and blue colors. This research aims to reveal the biological properties of peonidin as an anthocyanin. To comprehend the antioxidant capabilities of peonidin, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS[•+]), N,N-dimethyl-p-phenylenediamine dihydrochloride radical (DMPD[•+]), and 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH[•]) scavenging, Fe[3+]-2,4,6-tris(2-pyridyl)-s-triazine (TPTZ), and Cu[2+] reducing assays were recorded. The IC50 values for peonidin against ABTS[•+], DMPD[•+] and DPPH[•] scavenging capabilities were determined to compare with standard antioxidants. ABTS[•+] radical scavenging activity of peonidin had an IC50 value of 15.40 μg/mL, while the IC50 values for BHA, BHT, Trolox, and α-Tocopherol were 12.82, 11.78, 12.67, and 10.83 μg/mL, respectively. DPPH radical scavenging activity of peonidin had an IC50 value of 41.63 μg/mL, while the IC50 values for BHA, BHT, Trolox, and α-Tocopherol were 8.45, 23.10, 6.30, and 18.73 μg/mL, respectively. Enzyme inhibition was studied to investigate the effects of peonidin. The Ki values of peonidin were 114.33, 63.02, 2.99, 9.76, and 15.14 nM toward hCA I, hCA II, AChE, BChE, and α-glycosidase enzymes, respectively. Furthermore, peonidin's interactions with target enzymes BChE, hCA I, hCA II, AChE, and α-glycosidase were investigated by molecular docking. The results suggest that antioxidant-rich peonidin is a plant-based compound with potential use in the treatment of glaucoma, Alzheimer's disease, and diabetes.},
}

*Molecular Docking Simulation
*Antioxidants/chemistry/pharmacology
*Anthocyanins/chemistry/pharmacology
Free Radical Scavengers/chemistry/pharmacology
Humans
Biphenyl Compounds/chemistry
Sulfonic Acids/chemistry

@article {pmid42654104,
year = {2026},
author = {Farias, G and Chahinian, H and Hauchard, N and Brunet, D and Fantini, J and Yahi, N and Fantini, D and Aulas, A},
title = {An Optimal Spray Device for the Nose-to-Brain Delivery of AmyP53, an Adaptive Therapeutic Peptide for Alzheimer's and Parkinson's Diseases.},
journal = {Pharmaceutics},
volume = {18},
number = {8},
pages = {},
pmid = {42654104},
issn = {1999-4923},
abstract = {Background: Nose-to-brain delivery offers a noninvasive route to bypass the blood-brain barrier for the treatment of neurodegenerative diseases. AmyP53 is a first-in-class adaptive 12-mer peptide that prevents the formation of neurotoxic amyloid oligomers by competitively targeting lipid raft gangliosides on brain cell membranes, thereby blocking the shared pathological mechanism underlying both Alzheimer's and Parkinson's diseases. Objective: Here, we report the identification of optimal spray devices for the nose-to-brain delivery of AmyP53, ahead of a planned Phase 1 clinical trial. Method/Results: Among six devices evaluated (four commercial systems and two novel devices specifically engineered for nose-to-brain delivery), two systems were identified as optimal for further clinical development (narrower plume angles and significantly higher deposition in the olfactory region): the Neurospray™ and Neurospray™ Preservative-Free (PF). AmyP53 was quantitatively and reproducibly delivered by both Neurospray™ systems, retaining full recognition of its therapeutic target (gangliosides), as assessed by a surface pressure-based ganglioside-binding assay. In a rabbit preclinical model, intranasal administration of AmyP53 with the Neurospray™ resulted in rapid and sustained brain delivery, detectable at 10 min and persisting at 24 h post-administration, without significant systemic exposure. Conclusions: These results validate the Neurospray™ drug delivery systems as optimal drug delivery systems for the clinical development of AmyP53.},
}

@article {pmid42641765,
year = {2026},
author = {Solfrizzi, V and Lozupone, M and Panza, F},
title = {Anti-amyloid drugs: Integrated clinical pathways for treating older patients with frailty and dementia.},
journal = {Ageing research reviews},
volume = {122},
number = {},
pages = {103331},
doi = {10.1016/j.arr.2026.103331},
pmid = {42641765},
issn = {1872-9649},
abstract = {The introduction of anti-amyloid therapies for Alzheimer's disease challenged current care models, particularly for older adults with frailty. The potential low efficacy of anti-amyloid drugs in these patients may be attributed to chronic inflammation, impaired repair mechanisms, and multisystem dysregulation. Neuropathological studies suggested that the accumulation of common brain pathologies may contribute to progressive physical frailty in older age. At present, there is no certified diagnostic-therapeutic pathway governing the management of patients eligible for anti-amyloid treatment, regardless of the presence of frailty. In the present view point, we argued that frailty should not be treated as an exclusion criterion for anti-amyloid therapies, but as a stratification dimension requiring integrated, multidimensional clinical pathways. Without embedding frailty assessment into eligibility, monitoring, and outcome evaluation, the real-world implementation of disease-modifying therapies risks being ineffective, inequitable, and ethically problematic. Here, we proposed to integrate frailty assessment with biological and neuroimaging criteria to promote ethical, equitable, and clinically-feasible access to disease-modifying treatments in real-world settings.},
}

@article {pmid42642009,
year = {2026},
author = {Wright, KA and Horta, M and Hayes, A and Ebner, NC},
title = {Oxytocin as regulator of stress and inflammation in aging.},
journal = {Neuroscience and biobehavioral reviews},
volume = {190},
number = {},
pages = {106924},
doi = {10.1016/j.neubiorev.2026.106924},
pmid = {42642009},
issn = {1873-7528},
abstract = {Chronic stress and inflammation are potent determinants of negative health trajectories across adulthood, contributing to the progression of neurodegenerative diseases. In aging, these processes become increasingly intertwined, forming a feedforward loop in which chronic stress activates pro-inflammatory cascades in the brain and body, while pro-inflammatory cytokines stimulate stress-response pathways. Together, these interactions accelerate neuronal vulnerability, cognitive decline, and even Alzheimer's disease and Related Dementia (ADRD) pathology. The neuropeptide oxytocin (OT), a modulator of neurophysiological and social-affiliative processes, may buffer against stress and inflammation. There is evidence suggesting that OT dampens hypothalamic-pituitary-adrenal (HPA) axis reactivity, reduces pro-inflammatory cytokines, and promotes adaptive behaviors that restore physiological balance and promote healthy coping. OT can be synthetically produced and delivered via intranasal administration (IN-OT), providing a potential means of enhancing OT signaling. Understanding OT's role in aging, however, remains limited but of high relevance, also given the convergence of stress and inflammatory cascades in ADRD. This narrative review integrates previously distinct lines of research to delineate proposed pathways through which OT regulates stress and inflammation in aging and ADRD. Using systematic search strategies, this review also provides a structured synthesis of recent studies to evaluate evidence for IN-OT as a therapeutic for mitigating stress and inflammation, with discussion of its potential application in aging and ADRD. Research gaps and future directions are offered regarding OT's mechanisms of action, moderators of IN-OT's treatment response, and enhanced attention to midlife in IN-OT research on stress and inflammation in older adults as well as individuals with ADRD.},
}

@article {pmid42643714,
year = {2026},
author = {Budson, AE and Ljubenkov, PA and Ritter, A and Leahy, C and Ramanan, VK and Brosch, J and Burke, A and Matthews, BR},
title = {Considerations for using amyloid-targeting therapies for the treatment of early symptomatic Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1863897},
pmid = {42643714},
issn = {1664-2295},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/diagnostic imaging ; *Amyloid/metabolism ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Amyloid beta-Peptides/metabolism ; },
abstract = {Amyloid-targeting therapies (ATTs), including donanemab and lecanemab, are FDA-approved disease-modifying therapies for Alzheimer's disease in the mild cognitive impairment or mild dementia stages. Early initiation is important for optimal outcomes. This article summarizes practical strategies for implementing ATTs in clinical practice, focusing on leadership alignment and infrastructure development, as well as patient identification, diagnosis, and monitoring protocols. Key recommendations include establishing appropriate patient tracking systems, infusion and imaging protocols, and interprofessional collaboration. Approaches for systematic patient routing (e.g., hub-and-spoke models, fast-track mechanisms) and biomarker-integrated assessments are critical to facilitating timely diagnosis and treatment. Education for patients, care partners, and clinicians is crucial for managing the risks associated with amyloid-related imaging abnormalities. Successful ATT implementation requires coordinated systems, timely diagnosis, and robust safety monitoring. These measures can enable frameworks for ATT administration to optimize outcomes for patients, care partners, and health systems.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/diagnostic imaging
*Amyloid/metabolism
*Antibodies, Monoclonal, Humanized/therapeutic use
*Amyloid beta-Peptides/metabolism

@article {pmid42643819,
year = {2026},
author = {Jiang, S and Sydney, EJ and Runyan, AM and Serpe, R and Srikanth, M and Figueroa, HY and Yang, M and Myeku, N},
title = {Correction: 5-HT4 receptor agonists treatment reduces tau pathology and behavioral deficit in the PS19 mouse model of tauopathy.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1945844},
doi = {10.3389/fncel.2026.1945844},
pmid = {42643819},
issn = {1662-5102},
abstract = {[This corrects the article DOI: 10.3389/fncel.2024.1338502.].},
}

@article {pmid42643967,
year = {2026},
author = {Shaik, NS and Balya, H and Ramamurthy, S and Pandiyan, B and Elias, JM and Gunturu, S},
title = {Evaluating the safety of investigational anti-Alzheimer's drugs: a comprehensive meta-analysis in the past to current decade.},
journal = {Dementia & neuropsychologia},
volume = {20},
number = {},
pages = {e20250472},
pmid = {42643967},
issn = {1980-5764},
abstract = {UNLABELLED: Alzheimer's disease is a progressive illness that results in the degeneration of neurons with considerable burden. The pharmacological treatments for Alzheimer's disease include cholinesterase inhibitors, monoclonal antibodies, NMDA receptor antagonists despite having different adverse drug reactions (ADR) alongside the health benefits. Limited data exists for the complete safety evaluation across different classes of anti-Alzheimer's drugs.

OBJECTIVE: The meta-analysis evaluated the severity, frequency and variability of ADR as a result of Alzheimer's drugs to determine relative safety across various classes.

METHODS: This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with studies derived from the United States National Library of Medicine (PubMed), Embase, Scopus and ClinicalTrials.gov that focus on randomized controlled trials (RCTs) and observational studies which detailed ADRs of anti-Alzheimer's drugs. Jeffrey's Amazing Statistics Program (JASP) software was used to conduct heterogeneity assessment (I2), risk ratio (RR) and publication bias analysis in addition to meta-regression.

RESULTS: 31 studies were utilized. The studies with cholinesterase inhibitors exhibited more gastrointestinal ADRs and monoclonal antibodies exhibited amyloid-related imaging abnormalities (ARIA-H and E). The BACE1 inhibitors showed liver toxicity that led to increased patient drug discontinuation. A random-effects model was used for the analysis due to heterogeneity (I[2]>50%). The meta-regression analysis indicated drug class as a predictor for the type of ADR.

CONCLUSION: The research demonstrates considerable variations in the safety of Alzheimer's drugs that need tailored treatment supported by post-approval monitoring systems. The literature needs extended investigations of safety evaluation as well as practical treatment investigations in actual clinical settings. Unlike conventional reviews focusing solely on currently approved therapies, this study provides a cross-generational analysis of adverse drug reactions across both historical and investigational anti-Alzheimer's agents, offering insights into mechanism-related safety patterns that may inform the development and clinical use of emerging therapies.},
}

@article {pmid42644303,
year = {2026},
author = {Brookfield, N and Hauck, PM and Doty, EG and Zimmer, JA and Yang, F and Chen, YF and Ardayfio, P and Khanna, R and Ye, W and Tockhorn-Heidenreich, A and Patel, N},
title = {Donanemab for early symptomatic AD in the UK-indicated population: safety and efficacy in those who are non-carriers or heterozygous for APOE ε4.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/17582024.2026.2723524},
pmid = {42644303},
issn = {1758-2032},
abstract = {BACKGROUND: Licensing of donanemab in the United Kingdom (UK) for the treatment of early symptomatic Alzheimer's disease is limited to adults who are Apolipoprotein E (APOE) ε4 non-carriers or heterozygotes.

AIM: To assess safety and efficacy of donanemab in the UK-indicated population.

METHODS: Post-hoc analysis of APOE ε4 non-carriers or heterozygotes from a pooled TRAILBLAZER-ALZ and TRAILBLAZER-ALZ 2 population and the TRAILBLAZER-ALZ 2 population assessed safety and efficacy, respectively.

RESULTS: By 76 weeks, 13/825 (1.6%) and 170/816 (20.8%) participants in the placebo and donanemab arms experienced amyloid-related imaging abnormalities (ARIA)-edema/effusion, 96/825 (11.6%) and 218/816 (26.7%) participants experienced ARIA-microhemorrhages/superficial siderosis and 3/825 (0.4%) and 67/816 (8.2%) participants experienced infusion-related reactions, respectively. Donanemab significantly slowed disease progression versus placebo across multiple clinical scales, including a 40.3% (p < 0.0001) lower risk of progression to the next stage as measured by the Clinical Dementia Rating-Global score. Amyloid clearance occurred in 80.8% of donanemab-treated participants.

CONCLUSIONS: In the UK-indicated population, excluding APOE ε4 homozygotes reduced, but did not eliminate, ARIA risk with donanemab. Treatment slowed disease progression and reduced brain amyloid plaque by 76 weeks. Therefore, donanemab treatment requires structured risk-benefit discussion and appropriate monitoring.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03367403, https://clinicaltrials.gov/study/NCT03367403 (TRAILBLAZER-ALZ) and NCT04437511, https://clinicaltrials.gov/study/NCT04437511 (TRAILBLAZER-ALZ 2).},
}

@article {pmid42644373,
year = {2026},
author = {Jiyah, A and Bulama, I and Onu, A and Gimba, AY and Abbas, AY and Saidu, Y and Bilbis, LS and Muhammad, SA},
title = {Turmeric nanovesicles loaded with vitamins C and E attenuate oxidative stress and improve cognitive outcomes in rats with memory deficits.},
journal = {Therapeutic delivery},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/20415990.2026.2715894},
pmid = {42644373},
issn = {2041-6008},
abstract = {AIM: Oxidative stress (OS) contributes to Alzheimer's disease (AD) pathology. Vitamins C and E target OS, but their efficacies are limited by poor intracellular delivery. Encapsulation in nanovesicles (NVs) may improve targeted delivery for AD treatment.

METHODS: Forty-five rats were randomly assigned to nine groups (n = 5 per group): normal control, scopolamine control, vitamin C, vitamin E, vitamin C + E, turmeric NVs (TNV), TNV-C, TNV-E, and donepezil. Treatment was administered intraperitoneally (IP) for one week before induction of the AD-like model using daily IP administration of scopolamine and continued for two weeks. During this time, behavioral activities were conducted, and brain tissues were collected for analysis.

RESULTS: Vitamins C and E showed encapsulation efficiencies of 12.36 ± 1.01% and 55.24 ± 5.82%, with loading capacities of 14.34 ± 1.37% and 40.70 ± 3.52, respectively. TNV-C and TNV-E increased brain levels of vitamins E and C, enhanced antioxidant defense and cognitive abilities, and reduced acetylcholinesterase activity in dementia rats. TNV-C and TNV-E also protected against neuroinflammation and neuritic plaque formation. Vitamin-loaded TNVs were more effective than free vitamins in improving antioxidant status and cognitive outcomes in AD rats.

CONCLUSION: This study highlights the potential of vitamin-loaded NVs as therapeutics for AD.},
}

@article {pmid42644414,
year = {2026},
author = {Hendrix, S and Mallinckrodt, C and Abschneider, RM and Atri, A and Bendtsen, MD and Colombo, TL and Feldman, HH and Johannsen, P and Cummings, J},
title = {Estimating treatment effects in clinical studies of Alzheimer's disease: What are estimands and why do we need them?.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71676},
pmid = {42644414},
issn = {1552-5279},
support = {//Novo Nordisk/ ; },
mesh = {*Alzheimer Disease/drug therapy ; Humans ; Semaglutide ; Antibodies, Monoclonal, Humanized/therapeutic use ; *Clinical Trials as Topic ; Treatment Outcome ; *Research Design ; },
abstract = {In clinical studies, it is scientifically important, and a regulatory expectation, that objectives be translated into key clinical questions by specifically defining treatment effects to be estimated. Estimands are part of a structured framework, as presented in International Council for Harmonisation (ICH) E9(R1), by which study objectives are linked to a suitable study design and tools for estimation. Estimands are constructed using five attributes: treatment, population, variable (or endpoint), population-level summary for the variable, and intercurrent events (ICEs). ICEs occur after treatment initiation and can affect the existence or interpretation of the measurements. In Alzheimer's disease (AD), potential ICEs include additional AD medication use, discontinuation of treatment, and death. We describe estimands in recent clinical studies of anti-amyloid therapies, including gantenerumab, lecanemab, and donanemab, in AD and use the evoke and evoke+ studies of semaglutide in early-stage symptomatic AD as examples of estimand application in AD trials.},
}

*Alzheimer Disease/drug therapy
Humans
Semaglutide
Antibodies, Monoclonal, Humanized/therapeutic use
*Clinical Trials as Topic
Treatment Outcome
*Research Design

@article {pmid42645044,
year = {2026},
author = {Gao, F and Liu, L and Li, J and Chen, S and Yi, X},
title = {Overview in Electrochemical and Electrical Biosensors for Determining Blood Protein Biomarkers of Alzheimer's Disease.},
journal = {Biosensors},
volume = {16},
number = {8},
pages = {},
pmid = {42645044},
issn = {2079-6374},
mesh = {*Alzheimer Disease/blood/diagnosis ; Humans ; *Biosensing Techniques ; *Biomarkers/blood ; *Electrochemical Techniques ; *Blood Proteins/analysis ; Amyloid beta-Peptides/blood ; },
abstract = {Early diagnosis of Alzheimer's disease (AD) can facilitate the establishment and implementation of therapeutic interventions. The currently used diagnosis methods for AD mainly include cerebrospinal fluid analysis and positron emission tomography imaging. Due to their high invasiveness, high cost, and limited accessibility, these technologies are difficult to meet the needs of large-scale population screening, grading diagnosis, and treatment, thereby limiting the popularization of early diagnosis of AD. The detection of blood biomarkers has become an important breakthrough in early screening and diagnosis of different diseases due to its non-invasive, low-cost, and easy-to-operation advantages. Recently, blood proteins such as amyloid-beta (Aβ), total and phosphorylated Tau, light chain neurofilaments (NFL), and glial fibrillary acidic protein (GFAP) have been considered promising biomarkers for the diagnosis of AD. However, there is currently no effective, minimally invasive, and easily accessible detection method for clinical diagnosis and risk prediction of AD. Electrochemical and electrical biosensors are highly sensitive, simple, fast, and cost-effective analytical tools for disease monitoring, drug development, and target detection. In this work, we comprehensively and systematically overview the progress of various electrochemical and electrical techniques for determining AD-related blood protein biomarkers, mainly including electrochemistry, electrochemiluminescence, photoelectrochemistry, quartz crystal microbalance, field-effect transistor, and organic electrochemical transistor. This work can provide guidance for researchers to develop novel electrochemical and electrical biosensors for early and accurate diagnosis of AD.},
}

*Alzheimer Disease/blood/diagnosis
Humans
*Biosensing Techniques
*Biomarkers/blood
*Electrochemical Techniques
*Blood Proteins/analysis
Amyloid beta-Peptides/blood

@article {pmid42645215,
year = {2026},
author = {Saitta, A and Basilotta, R and Lanza, M and Scuruchi, M and Casili, G and Giovani, P and Copani, A and Esposito, E and Oddo, S and Caccamo, A},
title = {Isoserine Improves Spatial Memory and Remodels Synaptic and Inflammatory Gene-Expression Programs in APP/PS1 Mice.},
journal = {Cells},
volume = {15},
number = {16},
pages = {},
pmid = {42645215},
issn = {2073-4409},
support = {2022B7AFK2//Ministero dell'università e della ricerca/ ; },
mesh = {Animals ; *Spatial Memory/drug effects ; *Synapses/drug effects/metabolism/genetics ; Mice ; *Amyloid beta-Protein Precursor/metabolism/genetics ; Mice, Transgenic ; Alzheimer Disease/genetics/drug therapy ; Male ; *Inflammation/genetics ; *Gene Expression Regulation/drug effects ; *Presenilin-1/metabolism/genetics ; Disease Models, Animal ; Receptors, N-Methyl-D-Aspartate/metabolism ; Maze Learning/drug effects ; },
abstract = {Synaptic dysfunction is a major contributor to cognitive decline in Alzheimer's disease (AD) and represents an attractive therapeutic target. Here, we investigated whether chronic isoserine treatment improves cognition and alters the expression of synaptic-related genes in APP/PS1 mice. Isoserine was well tolerated and did not adversely affect body weight. In the Morris water maze, isoserine improved probe-trial performance in APP/PS1 mice, significantly reducing latency to the first platform-location crossing, while time spent in the target quadrant showed a directionally consistent but non-significant increase. To identify molecular correlates, we profiled 84 synaptic-related genes using a targeted RT[2] Profiler PCR Array. Gene-level factorial analyses identified several nominal treatment-associated effects, but no individual isoserine effect in APP/PS1 mice remained significant after false-discovery-rate correction. In contrast, module-level analyses identified False-discovery rate (FDR)-significant changes in NF-κB/inflammatory, synaptic-maintenance, and glutamatergic-signaling gene-expression modules, with significant genotype × treatment interactions for the NF-κB/inflammatory and synaptic-maintenance modules. Exploratory heatmap and principal component analyses further illustrated disease-context-dependent expression patterns. Western blot analyses showed that isoserine reduced nuclear factor kappa B (NF-κB p65) and NMDA receptor subunit GluN2B (GluN2B) and increased postsynaptic density protein 95 (PSD-95) levels in APP/PS1 mice. These findings suggest that isoserine improves spatial memory retention and coordinately remodels synaptic and inflammatory molecular programs in APP/PS1 mice.},
}

Animals
*Spatial Memory/drug effects
*Synapses/drug effects/metabolism/genetics
Mice
*Amyloid beta-Protein Precursor/metabolism/genetics
Mice, Transgenic
Alzheimer Disease/genetics/drug therapy
Male
*Inflammation/genetics
*Gene Expression Regulation/drug effects
*Presenilin-1/metabolism/genetics
Disease Models, Animal
Receptors, N-Methyl-D-Aspartate/metabolism
Maze Learning/drug effects

@article {pmid42645689,
year = {2026},
author = {Wu, Z and Kong, N},
title = {Exosomes: Mechanisms, Diagnosis, and Therapeutic Progress in Vascular Cognitive Impairment.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42645689},
issn = {1559-1182},
mesh = {*Exosomes/metabolism ; Humans ; Animals ; *Dementia, Vascular/diagnosis/therapy/metabolism ; *Cognitive Dysfunction/diagnosis/therapy/metabolism ; },
abstract = {Vascular cognitive impairment and dementia (VCID) is a cognitive impairment syndrome triggered by cerebrovascular lesions and their associated risk factors, representing the second most prevalent cognitive disorder after Alzheimer's disease (AD). Currently, there are no disease-modifying therapies available for VCID. In recent years, significant progress has been made in the study of exosomes in the context of neurodegenerative diseases (NDs). Given the shared pathophysiological features and underlying heterogeneity between VCID and neurodegenerative disorders, it is hypothesized that exosomes may play a critical role in the pathogenesis, diagnosis, and treatment of VCID. This review systematically summarizes recent advances in the study of exosomes in VCID, elaborates on the potential mechanisms by which exosomes influence the onset and progression of VCID, and highlights their promising applications in the diagnosis and treatment of the condition. In conclusion, exosome-based research offers novel perspectives and strategies for the clinical diagnosis and intervention of VCID, potentially leading to more effective options for affected patients.},
}

*Exosomes/metabolism
Humans
Animals
*Dementia, Vascular/diagnosis/therapy/metabolism
*Cognitive Dysfunction/diagnosis/therapy/metabolism

@article {pmid42646579,
year = {2026},
author = {Calabrò, RS and Calderone, A and Ravi, D and Galipò, C and Crupi, MF and Quartarone, A},
title = {Hospital-to-Home Neurological Transition Care: A Scoping Review Across Selected Chronic Neurological Disorders.},
journal = {Medical sciences (Basel, Switzerland)},
volume = {14},
number = {4},
pages = {},
pmid = {42646579},
issn = {2076-3271},
mesh = {Humans ; *Nervous System Diseases/therapy ; *Transitional Care ; Multiple Sclerosis ; Hospitalization ; Chronic Disease ; Amyotrophic Lateral Sclerosis ; },
abstract = {BACKGROUND: Returning home after neurological hospitalization, rehabilitation, or specialist care transfers responsibility to patients, caregivers, and community services. We mapped mechanisms and gaps across dementia/Alzheimer's disease and related dementias (ADRD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).

METHODS: Following JBI guidance and PRISMA-ScR, eligibility was derived using population-concept-context. We included empirical reports involving adults with a target condition, a post-discharge, return-home, rehabilitation, telehealth, caregiver, treatment, respiratory, or palliative continuity component, and post-transition patient, caregiver, service, safety, rehabilitation, equity, or implementation outcomes. Five databases were searched through to 11 May 2026. Two reviewers independently screened records; charting and classification were verified by R.S.C., A.C., and A.Q.

RESULTS: Of 24,417 records, 69 reports were included: Dementia/ADRD, 28; PD, 10; MS, 9; and ALS, 22. Eighteen were core transition reports (26.1%), 14 return-home/community re-entry reports (20.3%), 16 adjacent continuity reports (23.2%), and 21 companion/secondary reports (30.4%). Dementia/ADRD provided discharge-anchored evidence; PD and MS mapped functional carry-over; ALS mapped adjacent respiratory, telehealth, and palliative continuity.

CONCLUSIONS: The main contribution is an operational cross-disease framework separating direct discharge, return-home, adjacent-continuity, and companion evidence while linking mechanisms to disease-specific pathways. This framework maps disease-specific functions, not comparative effectiveness. The proposed frameworks are author-derived and hypothesis-generating. Future studies should use explicit anchors, standardized outcomes, longer follow-up, and equity-sensitive implementation measures addressing caregiver workload, digital access, feasibility, and sustainability. They inform testable, context-sensitive intervention designs for future neurological transition-care research and practice.},
}

Humans
*Nervous System Diseases/therapy
*Transitional Care
Multiple Sclerosis
Hospitalization
Chronic Disease
Amyotrophic Lateral Sclerosis

@article {pmid42648539,
year = {2026},
author = {Shi, K and Luo, XY and Liu, TT and Liu, WZ and Dong, YF and Zheng, FB and Zhou, X and Xing, JS and Sun, ZH and Chen, QQ and Jiang, L and Tan, CC and Tan, L and Xu, W and , },
title = {Cerebral amyloid-β burden and white matter injury: associations, clues for underlying mechanisms, and implication on cognitive trajectory after lecanemab therapy.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.08.057},
pmid = {42648539},
issn = {2090-1224},
abstract = {INTRODUCTION: White matter hyperintensities (WMH) are linked to cognitive decline and risk of Alzheimer's disease (AD).

OBJECTIVES: To test whether amyloid-β (Aβ) deposition contributes to white matter injury and whether WMH dynamics can modulate the clinical efficacy of the anti-Aβ therapy.

METHODS: Twenty patients with early AD who are receiving lecanemab and a matched cohort of 110 untreated AD patients were followed. Linear mixed-effects models were used to examine the interplay between WMH trajectories and lecanemab on cognitive decline. The roles of Aβ burden in predicting baseline severity and progression rates of WMH were evaluated in a larger cohort of 1,031 adults. Finally, cerebrospinal fluid (CSF) proteomic and bioinformatic analyses were performed to identify potential candidate mediators and pathways linking Aβ to WMH progression.

RESULTS: Following lecanemab treatment (median = 13 times), 80 % of patients showed WMH reductions, predominantly in periventricular and frontoparietal regions. Compared to the reference cohort, WMH progression is significantly slower among those with anti-Aβ therapy. WMH trajectory significantly modified the relationship between anti-Aβ therapy and cognitive decline, with greater cognitive improvement observed among those with smaller WMH reductions. The levels of Aβ burden were correlated with higher burden and accelerated rates of WMH. Eight proteins in CSF were identified as candidate mediators linking WMH to Aβ. They were enriched in vascular-endothelial, neuro-cytoskeletal, and neuroinflammation pathways.

CONCLUSION: The interplay of Aβ with white matter integrity contributes to cognitive decline in the context of Alzheimer's disease.},
}

@article {pmid42650743,
year = {2026},
author = {Zhou, Y and Diao, Y and Yan, Z and Shui, X and Huang, Z and Sun, Y and Wang, S and Xia, Y and Lee, TH and Wang, L},
title = {Development of a Novel AAV-Mediated microRNA Gene Therapy for Spatial Suppression of BACE1 to Improve Cognitive Function in Alzheimer's Disease Model Mice.},
journal = {Biomolecules},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/biom16081075},
pmid = {42650743},
issn = {2218-273X},
support = {82401642, 82404101, 82271449 and 82571556//National Natural Science Foundation of China/ ; 2022J01666//Fujian Provincial Department of Science and Technology/ ; 2025Y9117, 2024Y9094 and 2023Y9008//Fujian Provincial Department of Science and Technology/ ; },
mesh = {Animals ; *MicroRNAs/genetics/metabolism ; *Alzheimer Disease/therapy/genetics/metabolism ; *Amyloid Precursor Protein Secretases/genetics/metabolism/antagonists & inhibitors ; *Aspartic Acid Endopeptidases/genetics/metabolism/antagonists & inhibitors ; *Dependovirus/genetics ; *Genetic Therapy/methods ; Mice ; Disease Models, Animal ; Humans ; *Cognition ; Gene Therapy Agents ; Hippocampus/metabolism ; Male ; },
abstract = {The beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a promising and rational target for Alzheimer's disease (AD), but current clinical trials have been disappointing. Consequently, utilizing the intrinsic regulatory mechanisms of BACE1 during AD pathogenesis might provide valuable insights into the treatment of this devastating disease. In this study, we proposed a combination of AAV delivery and microRNA therapeutics targeting AD at its root by sustained and spatial inhibition of BACE1 with a single therapeutic injection. We demonstrate that upregulation of BACE1 is correlated with downregulation of miR-143-3p in the hippocampus of individuals with AD, and miR-143-3p can directly target BACE1 to inhibit Aβ generation. In the brains of 5×FAD model mice, BACE1 levels are found to be elevated with age in the cornu ammonis 1 (CA1) subfield of the hippocampus. AAV-mediated miR-143-3p restoration in the hippocampal CA1 subfield of AD mice can improve cognitive performance, attenuate BACE1 expression, reduce Aβ levels, induce microglia polarization toward the anti-inflammatory phenotype, modulate neural-related genes including Gal3, and promote synaptic functions. Collectively, the AAV-mediated microRNA gene therapy approach developed for spatial suppression of BACE1 can effectively enhance cognitive performance in AD model mice, offering an attractive therapeutic option for AD treatment with long-lasting efficacy.},
}

Animals
*MicroRNAs/genetics/metabolism
*Alzheimer Disease/therapy/genetics/metabolism
*Amyloid Precursor Protein Secretases/genetics/metabolism/antagonists & inhibitors
*Aspartic Acid Endopeptidases/genetics/metabolism/antagonists & inhibitors
*Dependovirus/genetics
*Genetic Therapy/methods
Mice
Disease Models, Animal
Humans
*Cognition
Gene Therapy Agents
Hippocampus/metabolism
Male

@article {pmid42651097,
year = {2026},
author = {Heath, S and Ruzicka, M and McLoon, T and Gupta, D and Emeri, O and Nnabugwu, Z and Adeniji, A and Brackett, C and Slack, S and Agbowuro, A},
title = {The Role of the NMDA Receptor in the Treatment of Psychiatric and Neurological Diseases.},
journal = {Brain sciences},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/brainsci16080786},
pmid = {42651097},
issn = {2076-3425},
abstract = {The N-methyl-D-aspartate receptor (NMDAR) is an ionotropic glutamate receptor widely expressed in the CNS and in peripheral tissues where it mediates crucial physiological functions and its dysregulation has been linked to a host of neurological and psychiatric disorders including Alzheimer's disease, schizophrenia, epilepsy, and chronic pain. This work highlights the therapeutic potential in targeting the NMDAR in these disease states by providing a holistic analysis of the existing literature focused on the molecular role of the receptor in applicable disease conditions. While several drugs targeting the NMDAR have been approved for clinical use, many more are in clinical and preclinical development. A significant part of this review assesses the chemical and pharmacological attributes of these molecules and provides a prognostic perspective for their use.},
}

@article {pmid42634953,
year = {2026},
author = {Du, L and Yan, S and Ren, X and Hassan, SSU and Sun, Y and Gan, Y and Xiao, X and Li, S and Jin, H},
title = {Breaking Alzheimer's Disease Barrier: The Role of Xanthoceras sorbifolia Bunge Oil in Gut-Brain Axis and TLR4/Myd88/MAPK Pathway Inhibition.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70432},
pmid = {42634953},
issn = {1099-1573},
support = {81830117//National Natural Science Foundation of China/ ; 2020YFC2003100//National Key R&D Program of China/ ; U22A20365//Joint Funds of National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with cognitive decline and neuroinflammation. Xanthoceras sorbifolia Bunge oil (XSBO), a woody plant oil rich in bioactive fatty acids, has shown potential health benefits. This study aimed to investigate the neuroprotective effects and underlying mechanisms of XSBO in AD. A scopolamine-induced AD rat model was established to evaluate the effects of XSBO on cognitive function, pathological changes, and neuroinflammation. Gut microbiota alterations were analyzed by 16S rDNA sequencing. Fecal microbiota transplantation (FMT) and short-chain fatty acid (SCFA) supplementation experiments were performed to explore the role of gut microbiota-derived metabolites. The TLR4/MyD88/MAPK signaling pathway was further examined. XSBO treatment improved cognitive deficits, reduced neuronal damage and neuroinflammation, and enhanced intestinal barrier integrity in AD rats. XSBO restored gut microbiota dysbiosis and increased SCFA-producing bacteria. FMT and SCFA supplementation confirmed that microbiota-derived metabolites contributed to XSBO-mediated cognitive improvement and neuroprotection. Mechanistically, XSBO inhibited lipopolysaccharide-induced neuroinflammation by suppressing TLR4/MyD88/MAPK signaling activation. XSBO alleviates AD-related cognitive impairment and neuroinflammation by modulating the gut microbiota-SCFA axis and inhibiting TLR4/MyD88/MAPK-mediated inflammatory responses. These findings suggest that XSBO may serve as a promising dietary intervention for neurodegenerative disease management.},
}

@article {pmid42635855,
year = {2026},
author = {Gönüllü, S and Dalkılınç, E and Çelik, O and Çelik, H and Küçükler, S and Topal, A and Akay, R and Yıldız, MO and Alım, B and Özdemir, S},
title = {Therapeutic Effects of miR-29b-Enriched Nanovesicles on Mitochondrial Injury and Neuroinflammatory Processes in Alzheimer's Disease.},
journal = {Neurotoxicity research},
volume = {44},
number = {5},
pages = {},
pmid = {42635855},
issn = {1476-3524},
mesh = {*MicroRNAs/administration & dosage ; Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Mitochondria/drug effects/metabolism/pathology ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Oxidative Stress/drug effects/physiology ; Cell Line, Tumor ; Amyloid beta-Peptides/toxicity ; *Extracellular Vesicles/metabolism ; },
abstract = {Alzheimer's disease (AD) is defined by the accumulation of extracellular amyloid-β plaques and intracellular neurofibrillary tangles, which drive neuronal and synaptic impairment. In AD, the accumulation of protein aggregates leads to neuroinflammation, increased oxidative stress, and mitochondrial damage, resulting in neuronal loss and cognitive impairment. Emerging evidence highlights that microRNAs (miRNAs) modulate AD-related pathological pathways and may offer opportunities for therapeutic intervention. In this study, we investigated the therapeutic potential of microRNA-29b (miR-29b) delivered via small extracellular vesicles (sEVs) in an in vitro neuroblastoma model of AD. Four experimental groups were established using SH-SY5Y neuroblastoma cells: (1) untreated control cells, (2) Aβ-treated cells to model AD-like pathology, (3) cells treated with unloaded sEVs, and (4) cells treated with miR-29b-loaded sEVs (sEV-miR-29b). To evaluate treatment effects, we assessed markers of oxidative stress (ROS, LDH, SOD, MDA, GPX1), neuroinflammation (BDNF, ICAM1, TNF-α, NfL, MIF, VEGFA, MCP-1), mitochondrial dysfunction (Cytc, TFAM, PINK1, DNM1L), synaptic integrity (CPLX2, ROR1), and AD pathology (Amyloid-β, Total Tau, pTau181, pTau217). Our findings demonstrate that treatment with sEV-miR-29b attenuated Aβ-induced oxidative stress, reduced pro-inflammatory signaling, and improved mitochondrial homeostasis compared with Aβ-only and sEV-only groups. Moreover, sEV-miR-29b treatment partially restored synaptic protein expression and decreased pathological tau phosphorylation. These results indicate that miR-29b plays a regulatory role in neuroinflammation, oxidative stress, and mitochondrial function, suggesting that sEV-mediated delivery of miR-29b represents a promising therapeutic strategy for modulating AD-related neurodegenerative mechanisms. This study highlights the potential of miR-29b-loaded sEVs as a therapeutic approach for AD.},
}

*MicroRNAs/administration & dosage
Humans
*Alzheimer Disease/metabolism/drug therapy
*Mitochondria/drug effects/metabolism/pathology
*Neuroinflammatory Diseases/metabolism/drug therapy
Oxidative Stress/drug effects/physiology
Cell Line, Tumor
Amyloid beta-Peptides/toxicity
*Extracellular Vesicles/metabolism

@article {pmid42636218,
year = {2026},
author = {Nasir, AB and Kilani, Y and Aldiabat, M and Abdelghany, O and Hafez, Y and Desai, N and Madi, MY and Wade, FG and Qureshi, K and Frey, LJ and Farmer, AD and Syn, WK},
title = {Antidiabetic medications and risk of cognitive disorders in type 2 diabetes: A retrospective cohort study.},
journal = {PloS one},
volume = {21},
number = {8},
pages = {e0356138},
pmid = {42636218},
issn = {1932-6203},
mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy/complications ; Female ; Retrospective Studies ; *Hypoglycemic Agents/therapeutic use/adverse effects ; Metformin/therapeutic use/adverse effects ; Middle Aged ; Male ; Aged ; Insulin/therapeutic use/adverse effects ; Adult ; *Cognitive Dysfunction/epidemiology/chemically induced ; Alzheimer Disease/epidemiology ; Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects ; Incidence ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/adverse effects ; *Cognition Disorders/epidemiology ; Glucagon-Like Peptide-1 Receptor Agonists ; Dementia, Vascular/epidemiology ; },
abstract = {OBJECTIVE: To evaluate the associations between commonly used antidiabetic regimens and incidence of mild cognitive disorder, Alzheimer disease, and vascular dementia in adults with type 2 diabetes.

This retrospective cohort study used the TriNetX US Collaborative Network of electronic health records from 2010 to 2024. Adults aged 40-69 years with type 2 diabetes and at least 1 year of follow-up were included. Propensity score matching was applied to balance covariates.

EXPOSURE: Patients were classified into 5 treatment groups: metformin only (reference), metformin plus DPP-4 inhibitors, metformin plus GLP-1 receptor agonists, metformin plus SGLT-2 inhibitors, and insulin monotherapy. Exposure was defined by first recorded prescription and continued use during follow-up.

MAIN OUTCOMES AND MEASURES: Primary outcomes were incident mild cognitive disorder, Alzheimer disease, and vascular dementia, identified using ICD-10 codes. Hazard ratios with 95% confidence intervals were estimated from Cox proportional hazards models, with landmark analyses for follow-up shorter and longer than 5 years.

RESULTS: Among 1,528,885 adults with type 2 diabetes (mean age, 58 years; 49.2% women), GLP-1 receptor agonists plus metformin were associated with lower incidence of vascular dementia (HR, 0.46; 95% CI, 0.37-0.57), mild cognitive disorder (HR, 0.79; 95% CI, 0.66-0.95), and Alzheimer disease (HR, 0.46; 95% CI, 0.31-0.70). SGLT-2 inhibitors plus metformin reduced vascular dementia risk (HR, 0.68; 95% CI, 0.54-0.87) but not other outcomes. Insulin monotherapy was associated with higher incidence of vascular dementia (HR, 3.27; 95% CI, 3.03-3.52), mild cognitive disorder (HR, 1.71; 95% CI, 1.56-1.87), and Alzheimer disease (HR, 1.56; 95% CI, 1.32-1.84).

CONCLUSIONS AND RELEVANCE: GLP-1 receptor agonists and SGLT-2 inhibitors combined with metformin were associated with reduced risk of cognitive decline. Insulin monotherapy was associated with higher incidence of all three outcomes; however, this association is likely influenced by confounding by indication, unmeasured markers of diabetes severity (including diabetes duration, cardiovascular and renal disease severity, and microvascular and macrovascular complications), and shorter follow-up among insulin users, and should not be interpreted as a direct drug effect. Because standard Cox models do not account for death as a competing event, reported hazard ratios reflect cause-specific hazards and may not directly correspond to cumulative incidence, particularly for the insulin group, in which mortality and censoring were substantially higher. Antidiabetic medication choice may influence long-term cognitive outcomes and should be considered in diabetes management.},
}

Humans
*Diabetes Mellitus, Type 2/drug therapy/complications
Female
Retrospective Studies
*Hypoglycemic Agents/therapeutic use/adverse effects
Metformin/therapeutic use/adverse effects
Middle Aged
Male
Aged
Insulin/therapeutic use/adverse effects
Adult
*Cognitive Dysfunction/epidemiology/chemically induced
Alzheimer Disease/epidemiology
Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects
Incidence
Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/adverse effects
*Cognition Disorders/epidemiology
Glucagon-Like Peptide-1 Receptor Agonists
Dementia, Vascular/epidemiology

@article {pmid42636356,
year = {2026},
author = {Chen, H and Mcintyre, MK and Aktay, S and Yen, M and Gunawardane, S and Lakhani, DA and Malhotra, A and Colasurdo, M and Gandhi, D},
title = {Endovascular thrombectomy versus medical management in patients with dementia and acute ischaemic stroke.},
journal = {Age and ageing},
volume = {55},
number = {8},
pages = {},
doi = {10.1093/ageing/afag241},
pmid = {42636356},
issn = {1468-2834},
mesh = {Humans ; *Thrombectomy/methods/adverse effects ; Female ; *Ischemic Stroke/therapy/complications/mortality ; *Endovascular Procedures/methods/adverse effects ; Male ; Aged ; Retrospective Studies ; Aged, 80 and over ; *Dementia/complications ; Treatment Outcome ; Length of Stay/statistics & numerical data ; Hospital Mortality ; United States/epidemiology ; },
abstract = {OBJECTIVE: While pre-existing dementia is a known negative predictor for good endovascular thrombectomy (EVT) outcomes, comparative efficacy and safety data of EVT versus best medical management (BMM) for large vessel occlusion (LVO) patients with dementia are limited. This study compares hospitalisation outcomes of EVT versus BMM for LVO patients with underlying dementia.

METHODS: Using the US Nationwide Readmissions Database from 2016 to 2022, we retrospectively identified adult patients with dementia who presented with LVO stroke. The primary outcome was discharge to home. Secondary outcomes included in-hospital mortality, length-of-stay and complications. Patients who underwent EVT were compared to those who received BMM after propensity score matching. Interaction and subgroup analyses assessed treatment effect heterogeneity associated with age and dementia type.

RESULTS: Among 37 298 patients included, 6618 EVT and 13 092 BMM patients remained after propensity score matching. Home discharge rates were similar between groups (27.1% vs 26.4%, P = .51). EVT was associated with longer length-of-stay (median 7 vs 6 days, P < .001) and increased intracranial haemorrhage (23.9% vs 11.1%, P < .001), with no significant difference in mortality (15.0% vs 14.9%, P = .87). Patient age significantly moderated EVT effectiveness (interaction P < .001), and EVT among patients <75 years old was significantly associated with higher rates of home discharge (36.7% vs 26.8%, P < .001). Additionally, EVT appeared more effective for patients with vascular dementia (vs Alzheimer's disease, interaction, P = .014), among whom EVT was associated with significantly higher rates of home discharge (32.7% vs 25.2%, P = .007).

INTERPRETATION: Treatment response to EVT among LVO stroke patients with dementia was heterogeneous, and EVT was beneficial for patients <75 years old and those with vascular dementia.},
}

Humans
*Thrombectomy/methods/adverse effects
Female
*Ischemic Stroke/therapy/complications/mortality
*Endovascular Procedures/methods/adverse effects
Male
Aged
Retrospective Studies
Aged, 80 and over
*Dementia/complications
Treatment Outcome
Length of Stay/statistics & numerical data
Hospital Mortality
United States/epidemiology

@article {pmid42636468,
year = {2026},
author = {Ranganathan, M and Jakob, S and Cerrato, F and Urban Spillane, L and Daryoush, TS and Shuster, S and Dokholyan, K and Herrera, S and Koo, BB and Markowitz, C and Deng, P and Rush, S and Calkins, ME and Troyan, S and Ruparel, K and Gur, RC and Reynolds, H and Wegel, C and Johnson, MB and Hom, L and Bryant, S and Mair, RW and Buckner, RL and , and Birnbaum, R and Birnbaum, R and Kohler, CG and Corcoran, CM and Gur, RE and Hyman, SE},
title = {Schizophrenia Spectrum Biomarkers Consortium: Establishment of a Biorepository for the Discovery of Quantitative Fluid Biomarkers.},
journal = {Schizophrenia bulletin},
volume = {52},
number = {5},
pages = {},
pmid = {42636468},
issn = {1745-1701},
support = {//Stanley Center for Psychiatric Research/ ; },
mesh = {Humans ; *Schizophrenia/blood/cerebrospinal fluid/diagnosis/physiopathology ; Biomarkers/cerebrospinal fluid/blood ; Female ; Male ; Adult ; Pilot Projects ; *Biological Specimen Banks ; Middle Aged ; Longitudinal Studies ; *Psychotic Disorders/cerebrospinal fluid/blood/physiopathology ; Feasibility Studies ; },
abstract = {BACKGROUND AND HYPOTHESIS: Schizophrenia spectrum disorders (SSDs) produce severe symptoms, disability, and premature mortality, but only partially effective symptomatic treatments exist. Treatment development is impeded by lack of insight into disease mechanisms or objective biomarkers for clinical trials. Advances in genetics and neurobiology have converged on strong pathogenic hypotheses for SSDs centered on synapse dysfunction and excessive pruning, pathogenic processes that may produce measurable proteomic evidence in cerebrospinal fluid (CSF). Leveraging design precedents from successful fluid biomarkers discovery for Alzheimer's disease, we undertook a pilot study to test the feasibility of repeated CSF and blood samples collection from individuals with SSDs. Here we report on successful implementation of longitudinal bio-behavioral phenotyping in SSDs and establishment of a repository to permit broad sample and data sharing.

STUDY DESIGN: The Schizophrenia Spectrum Biomarkers Consortium (SSBC) study principles included longitudinal study design, paired CSF and plasma collection associated with robust phenotypic characterization, at 3 academic sites and the establishment of a biorepository. Participants underwent clinical and cognitive assessments, neuroimaging, blood draws, and CSF collection via lumbar puncture (LP) every 6 months.

STUDY RESULTS: SSBC successfully enrolled 48 SSD and 41 Healthy Controls with a 73% longitudinal retention. Clinical, cognitive, and neuroimaging results were consistent across sites and with existing studies. Study procedures were well tolerated, and almost all LPs (99%) resulted in either no or minor headache/backache that resolved without medical interventions.

CONCLUSIONS: The pilot SSBC study demonstrates that a multi-site, longitudinal study with repeat CSF collection is feasible, with excellent participant acceptability and retention.},
}

Humans
*Schizophrenia/blood/cerebrospinal fluid/diagnosis/physiopathology
Biomarkers/cerebrospinal fluid/blood
Female
Male
Adult
Pilot Projects
*Biological Specimen Banks
Middle Aged
Longitudinal Studies
*Psychotic Disorders/cerebrospinal fluid/blood/physiopathology
Feasibility Studies

@article {pmid42638207,
year = {2026},
author = {Li, X and Zhou, Q and Ding, S and Pan, W and Liu, R and Yan, Y and Huang, C},
title = {Shape-Based Partially Linear Single-Index Cox Model for Alzheimer's Disease Conversion.},
journal = {Statistics in medicine},
volume = {45},
number = {20-22},
pages = {e70708},
pmid = {42638207},
issn = {1097-0258},
support = {12288201//National Natural Science Foundation of China/ ; 12322113//National Natural Science Foundation of China/ ; 11901599//National Natural Science Foundation of China/ ; 71991474//National Natural Science Foundation of China/ ; 72495122//National Natural Science Foundation of China/ ; XDA0500400//Chinese Academy of Sciences/ ; 2025A1515012189//GuangDong Basic and Applied Basic Research Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging ; Cognitive Dysfunction/pathology/diagnostic imaging ; *Disease Progression ; Proportional Hazards Models ; Computer Simulation ; Neuroimaging ; Aged ; Female ; Corpus Callosum/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; },
abstract = {Alzheimer's disease (AD) is the major cause of dementia in the elderly, and characterizing the time to conversion to AD is crucial in preventative treatment. While existing statistical methods have proven effective in modeling AD conversion involving various clinical, genetic, and neuroimaging predictors, limited research has explored scenarios where these predictors are shapes derived from the shape space, a nonlinear Hilbert space. In addition, the linear relationship assumption in existing methods may be violated, leading to substantial efficiency losses in real-world applications. To address these challenges, we propose a shape-based partially linear single-index Cox (SPLS-Cox) model that accommodates both scalar and shape predictors. This new development is motivated by establishing the likelihood of conversion to AD in 372 patients with mild cognitive impairment (MCI) enrolled in the Alzheimer's Disease Neuroimaging Initiative, leveraging the early shape-based markers of conversion extracted from the brain white matter region, corpus callosum (CC). These 372 MCI patients were followed over 48 months, during which 161 progressed to AD. Our SPLS-Cox model establishes both the estimation procedure and the pointwise confidence band. Simulation studies are conducted to evaluate the finite-sample performance of our SPLS-Cox. The real application reveals that the CC contour shape is a significant predictor for AD conversion.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging
Cognitive Dysfunction/pathology/diagnostic imaging
*Disease Progression
Proportional Hazards Models
Computer Simulation
Neuroimaging
Aged
Female
Corpus Callosum/pathology/diagnostic imaging
Magnetic Resonance Imaging

@article {pmid42639707,
year = {2026},
author = {Najmi, AK and Yaduvanshi, D and Aggarwal, R and A, S and Aqil, M and Mujeeb, M and Akhtar, M},
title = {Targeting the NLRP3 inflammasome pathway associated with neuroinflammation mediated Alzheimer's disease: pre-clinical and clinical status of emerging therapeutics.},
journal = {Expert opinion on therapeutic targets},
volume = {},
number = {},
pages = {},
doi = {10.1080/14728222.2026.2723488},
pmid = {42639707},
issn = {1744-7631},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a rising global health problem, but current treatments only target symptoms rather than fixing their underlying root causes. A major pathological feature is neuroinflammation, which is specifically driven by the Nucleotide-binding domain, Leucine-rich-repeat and Pyrin domain-containing 3 (NLRP3) inflammasome cascade, which acts as a 'molecular switch' that causes immune cells in the brain to trigger robust secretion of pro-inflammatory cytokines (e.g. IL-1β, IL-18) and pyroptosis, causing systemic inflammation, thereby the neuroinflammation.

AREAS COVERED: This review breaks down the pathways triggered by immune cells activation (neurotoxic microglial phenotype) and majorly focusing over the NLRP3 inflammasome neuroinflammation pathway. It explores the promising therapeutic potential of specific bioactive phytochemicals, repurposed and novel synthetic drugs/agents, to shut-down this molecular switch i.e. NLRP3 inflammasome pathway.

EXPERT OPINION: To truly stop AD, we must shift our focus from treating merely the symptoms, by stopping the disease at its roots. While discovering the novel NLRP3 inflammasome inhibitors is exciting, but the biggest hurdle is getting them into the brain. Future of AD treatment relies on combining these targeted drugs with advanced nanotechnology, like nano-particles, to successfully cross the blood-brain barrier (BBB) and safely deliver the drugs exactly where they are needed.},
}

@article {pmid42639919,
year = {2026},
author = {Morató, X and Hinojosa-Calleja, A and Jofresa, S and Calm, B and Cano, A and Blazquez-Folch, J and Alarcón-Martín, E and Montrreal, L and Muñoz-Morales, Á and Olivé, C and Bayón, P and Sotolongo-Grau, O and Orellana, A and Sanz-Cartagena, P and Montalban, X and Marquié, M and Fernandez, MV and Ruiz, A and Boada, M and Valero, S},
title = {When treatment becomes risk: polypharmacy and inappropriate prescribing in cognitive impairment in 2379 consecutive patients from a memory clinic.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71708},
pmid = {42639919},
issn = {1552-5279},
support = {//Lilly through an Investigator-Initiated Trial/ ; 77225//Eli Lilly and Company/ ; },
mesh = {Humans ; *Polypharmacy ; Female ; *Inappropriate Prescribing/statistics & numerical data ; Aged ; *Cognitive Dysfunction/drug therapy/chemically induced ; Retrospective Studies ; Male ; Aged, 80 and over ; Spain ; Alzheimer Disease/drug therapy ; },
abstract = {BACKGROUND: Polypharmacy, potentially inappropriate medications (PIMs), and drugs associated with drug-induced cognitive impairment (DICI) are highly prevalent in older adults and may affect cognitive decline.

METHODS: This observational retrospective study included 2379 patients evaluated at Ace Alzheimer Center Barcelona. Medication data were extracted from electronic health records using a large language model (LLM). Polypharmacy (≥5), hyperpolypharmacy (≥10), PIMs, and DICI drugs were analyzed across cognitive stages, Alzheimer's disease biomarkers, ApoE subtype, and estimated glomerular filtration rate.

RESULTS: Among patients with cognitive impairment (Clinical Dementia Rating [CDR] ≥ 0.5), 67% presented polypharmacy and 21% hyperpolypharmacy. Higher odds of polypharmacy were observed across the CDR scale, while higher education showed a protective effect. Altered renal function was found in 20.8% of patients with polypharmacy. Indeed, significant differences were found between amyloid beta-positive and negative (Aβ[+]/Aβ[-]) subjects and between the whole population and subjects participating in clinical trials.

DISCUSSION: Polypharmacy is extremely common in patients attending memory clinics. LLMs could facilitate systematic structured medication reviews.},
}

Humans
*Polypharmacy
Female
*Inappropriate Prescribing/statistics & numerical data
Aged
*Cognitive Dysfunction/drug therapy/chemically induced
Retrospective Studies
Male
Aged, 80 and over
Spain
Alzheimer Disease/drug therapy

@article {pmid42640603,
year = {2026},
author = {Pereira da Silva, AM and Santos do Nascimento, MDV and Menegucci, G and Caruso Novaes Tudella, G and Silva Cabeça, L and Ribeiro Gonçalves, O and Vieira Nogueira, B and Oliveira Franco, J and Haddad Santos, D and Silveira Duarte, F and Perry, G and de Souza Franco, E and Bernadete de Sousa Maia, M},
title = {Pioglitazone and Cognitive Outcomes in Mild Cognitive Impairment and Alzheimer Disease: A Systematic Review and Meta-Analysis of Randomized Trials.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000744},
pmid = {42640603},
issn = {1546-4156},
abstract = {BACKGROUND: Cognitive impairment is increasingly recognized among older adults with metabolic disorders, including type 2 diabetes. Metabolic dysfunction and insulin resistance have been implicated in neurodegenerative processes. Pioglitazone, an insulin-sensitizing agent widely used in the treatment of type 2 diabetes, has been investigated for potential effects on cognitive outcomes. This systematic review and meta-analysis evaluated the efficacy and safety of pioglitazone on cognitive outcomes in individuals with mild cognitive impairment or Alzheimer disease.

METHODS: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched through July 2025 for randomized controlled trials comparing pioglitazone with placebo in adults with mild Alzheimer disease or mild cognitive impairment. Cognitive outcomes included the Mini-Mental State Examination, the Wechsler Memory Scale-Revised, and the Alzheimer's Disease Assessment Scale-Cognitive subscale. Safety outcomes included adverse events, serious adverse events, treatment discontinuation, and peripheral edema. Random-effects meta-analyses were conducted using frequentist and Bayesian approaches.

RESULTS: Six randomized trials, including 3680 participants, were analyzed. Pioglitazone was not associated with differences in Mini-Mental State Examination or Wechsler Memory Scale-Revised scores compared with placebo. Alzheimer's Disease Assessment Scale-Cognitive subscale estimates modestly favored pioglitazone, although this finding was not consistent across other cognitive measures. Overall, adverse events and serious adverse events were similar between treatment groups. Treatment discontinuation occurred less frequently with pioglitazone. Peripheral edema was reported more frequently with pioglitazone, although estimates were based on a small number of events and wide CIs.

CONCLUSION: Pioglitazone was not associated with consistent differences in global cognitive outcomes in individuals with mild cognitive impairment or Alzheimer disease. Safety outcomes were broadly comparable to placebo, although peripheral edema occurred more frequently.},
}

@article {pmid42640625,
year = {2026},
author = {Kim, MH and Colantonio, LD and Glymour, MM and Hamad, R and Adler-Milstein, J and Kershaw, KN and Boscardin, J and Wang, Z and Oti, AS and Howard, VJ},
title = {Discordance Between Cognitive Impairment Status and Claims-Based ADRD Diagnosis: Temporal Patterns and Racial Differences in the REGARDS Cohort, 2006 to 2021.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
pmid = {42640625},
issn = {1546-4156},
abstract = {INTRODUCTION: Understanding the concordance between incident cognitive impairment status and the diagnosis of Alzheimer disease and related dementias (ADRD) is clinically important, as a diagnosis serves as the gateway for treatment, care planning, and supportive services.

METHODS: Using the REGARDS cohort (2006 to 2021) linked to Medicare claims, we examined the discordance between incident cognitive impairment and claims-based ADRD diagnoses. Directly standardized diagnosis rates were estimated by year, overall, and race, and stratified by cognitive impairment status. Logistic regression models were used to examine sociodemographic correlates of diagnosis.

RESULTS: The sample included 45,191 observations (23% Black) of 8368 participants. Among those with incident cognitive impairment, 30.8% received a claim-based diagnosis, and while 8.9% of those without incident cognitive impairment received a claim-based diagnosis. ADRD diagnosis rates remained stable, whereas rates among observations with incident cognitive impairment rose through the early 2010s, then plateaued and declined. The black race and education below the college level were associated with lower odds of diagnosis in this group; female sex was associated with higher odds. Among observations without cognitive impairment, older age and female sex were associated with higher odds; Midwest or West/Northeast residence and less than high school education were associated with lower odds.

DISCUSSION: Differences observed in the study may potentially represent underlying disparities in access to care and dementia diagnosis in clinical practice.},
}

@article {pmid42641545,
year = {2026},
author = {Gao, W and Hu, K and Yang, G and Pan, J and Xu, X and You, P and Li, K and Zhao, Y and Wang, X and Xu, Y},
title = {Puerarin alleviates memory deficits through the modulation of D‑serine-mediated N-methyl-D-aspartate receptor activity in presenilin 1/2 conditional double knockout mice.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {161},
number = {},
pages = {158727},
doi = {10.1016/j.phymed.2026.158727},
pmid = {42641545},
issn = {1618-095X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, the formation of amyloid-β plaques and neurofibrillary tangles, and synaptic dysfunction. Puerarin (PUE), an isoflavone C-glycoside extracted from Pueraria lobata, has demonstrated potential in attenuating AD-related cognitive decline; however, the mechanisms governing the effects of PUE remain incompletely understood.

PURPOSE: To investigate the mechanisms underlying PUE's anti-AD effects.

METHODS: Presenilin 1/2 conditional double knockout mice served as the AD model. Following one month of PUE administration, memory function was evaluated through behavioral testing, and hippocampal synaptic plasticity was assessed using electrophysiological recordings. D‑serine levels were quantified via ELISA. Additionally, Western blotting and qRT-PCR were employed to analyze the expression of glutamate receptor subunits and key enzymes involved in D‑serine metabolism. The mechanistic role of D‑serine was further validated through intrahippocampal D‑serine injections in mice and the application of a serine racemase (SR) inhibitor in N2a cells.

RESULTS: PUE administration reversed memory impairment and enhanced both hippocampal long-term potentiation and synaptic transmission by increasing the open probability of N-methyl-D-aspartate receptor (NMDAR) channels. Furthermore, PUE elevated D‑serine levels and upregulated the expression of SR. Notably, these therapeutic effects were replicated by exogenous D‑serine and abolished by treatment with an SR inhibitor.

CONCLUSION: These findings indicate that PUE alleviates cognitive deficits by promoting SR-mediated D‑serine biosynthesis and subsequently restoring NMDAR activity. Accordingly, PUE represents a viable therapeutic candidate for the prevention and management of AD.},
}

@article {pmid42633943,
year = {2026},
author = {Fujita, S and Fushimi, Y and Otsuka, Y and Murata, K and Buonincontri, G and Koerzdoerfer, G and Nittka, M and Fukunaga, I and Takabayashi, K and Hagiwara, A and Motoi, Y and Nakajima, M and Murakami, K and Shima, A and Kubota, M and Bilgic, B and Kamagata, K and Sawamoto, N and Abe, O and Nakamoto, Y and Aoki, S},
title = {Brain Amyloid Burden Mapping Using MR Fingerprinting Aided by Deep Learning.},
journal = {Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine},
volume = {25},
number = {4},
pages = {},
doi = {10.2463/mrms.mp.2026-0112},
pmid = {42633943},
issn = {1880-2206},
mesh = {Humans ; Positron-Emission Tomography ; *Deep Learning ; *Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/metabolism ; Prospective Studies ; *Amyloid beta-Peptides/metabolism ; Reproducibility of Results ; Female ; Male ; *Brain Mapping/methods ; Alzheimer Disease/diagnostic imaging ; },
abstract = {PURPOSE: To develop and externally validate a non-invasive framework for quantifying brain amyloid-β (Aβ) deposition using magnetic resonance fingerprinting (MRF) and neural network-based decoding, with positron emission tomography (PET) as the reference standard.

METHODS: This prospective multi-site study included 44 participants from 2 sites who had undergone, or were scheduled to undergo, Aβ PET within 1 year. MRF was performed on a 3T MR system using a 2D fast imaging with steady-state precession sequence with B1 correction, covering the whole brain in 9.5 min. PET images were co-registered to the MRF space, and regional amyloid load was calculated using an automated template-based pipeline. An inverse mapping function was implemented to convert MRF signals into amyloid burden maps. Repeatability, agreement with PET-based centiloid values, and associations with cognitive scores were evaluated.

RESULTS: The generated amyloid maps were visually similar to PET images. Test-retest analysis showed high repeatability, with a coefficient of variation of 1.8 ± 1.3% and an intraclass correlation coefficient of 0.84. In the external test set, MRF-based measurements correlated significantly with PET centiloid scores (Spearman's ρ = 0.589, P = 0.015) and Montreal Cognitive Assessment scores (ρ = -0.543, P = 0.020).

CONCLUSION: The proposed framework enables non-invasive Aβ mapping using a clinically feasible MRI protocol and may support repeated assessment for monitoring during anti-amyloid treatment.},
}

Humans
Positron-Emission Tomography
*Deep Learning
*Magnetic Resonance Imaging/methods
*Brain/diagnostic imaging/metabolism
Prospective Studies
*Amyloid beta-Peptides/metabolism
Reproducibility of Results
Female
Male
*Brain Mapping/methods
Alzheimer Disease/diagnostic imaging

@article {pmid42634203,
year = {2026},
author = {Khan, MS and Ashesh, AM and Mammen, MV and Alhusaini, A and Jawaid, T and Akhtar, MS and Orayj, K and Ansari, I and Kumar, D and Kumar, A},
title = {Targeting NMDA Receptor Pathways in Alzheimer's Disease, From Cellular Mechanisms to Treatment Strategies.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X474645260731070203},
pmid = {42634203},
issn = {1875-6190},
abstract = {The Alzheimer's Disease (AD) lacks effective disease-modifying therapy, even though amyloid-targeting immunotherapies have recently been applied clinically. N-methyl-D-Aspartate Receptors (NMDARs) play a central yet mechanistically complicated role in the pathophysiology of AD, where they are convergence points of amyloid-beta (Aβ) oligomer toxicity, tau-dependent excitotoxicity, and progressive synaptic failure. This critical review examines NMDAR dysfunction across the AD spectrum, with a focus on subunit-regulated signalling, subcellular localisation, and subsequent pathological cascades. The effects of Aβ oligomers on NMDAR activity involve multiple mechanisms that disrupt their function, including glutamate dysregulation mediated by GLT-1, redistribution of GluN2B to extrasynaptic areas, and inhibition of JAK2-CREB via activation of extrasynaptic receptors. Tau enhances excitotoxic injury throughdendritic mislocalization, and the tau-Fyn-GluN2B complex, which propels pro-death signalling by DAPK1. This conceptually important prevailing synaptic-extrasynaptic dichotomy is fiercely criticised here, given evidence that synaptic receptors containing GluN2A also mediate pathological signalling during sustained Aß exposure, and that tri-heteromeric receptor populations are problematic for subunit-selective targeting. Neuroinflammation, dysfunction of the blood-brain barrier, and excitotoxic amplification via GluN2C/D-enriched receptor pools in neurons, astrocytes, microglia, oligodendrocytes, and endothelial cells are underexplored therapeutic targets for neurodegenerative disease (non-neuronal NMDARs). Memantine is the only approved NMDAR-targeting agent for AD. Subunit-selective antagonists have not been translated into clinical use, and the positive allosteric modulator dalzanemdor (SAGE-718) did not pass its randomised Phase 2 trial in 2024. The most mechanistically justified approach is to advance subunit-selective, compartment-specific, or protein-complexdisrupting strategies. Although it is not established whether any single NMDAR-targeting intervention will suffice as a disease-modifying therapy, the convergence of molecular, genetic, and clinical evidence positions NMDAR dysfunction as a tractable , if therapeutically demanding , node in the AD pathogenic network, warranting continued, mechanism-informed drug discovery.},
}

@article {pmid42634340,
year = {2026},
author = {Cui, H and Li, Q and Yao, Y and Wang, X and Tian, S},
title = {Physicochemical Characterization and Biological Activity of Ethanol- Extracted Residue of Saussurea involucrata.},
journal = {Combinatorial chemistry & high throughput screening},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113862073470898260602093207},
pmid = {42634340},
issn = {1875-5402},
abstract = {INTRODUCTION: Saussurea involucrata's ethanol-extracted residue (ROSI), a byproduct of its oral liquid preparation, nevertheless holds significant therapeutic promise. To evaluate its potential as a treatment for neurodegenerative illnesses, this study investigates its physicochemical properties and biological activity.

MATERIALS AND METHODS: UV-Vis, IR spectroscopy, UHPLC-Q Exactive HFX systems, microscopy, powder characterisation, and thermogravimetric analysis were used to examine the physical and chemical characteristics of ROSI. Antioxidant activities and pancreatic lipase inhibition were assessed. Its therapeutic targets for neurodegenerative disorders were predicted by network pharmacology and molecular docking analyses.

RESULTS: ROSI demonstrated high organic acid content, a uniform porous structure, consistent particle size, and high thermal stability, meeting industrial flowability standards. While showing modest pancreatic lipase inhibition, it exhibited potent antioxidant activity. Pharmacomics analysis suggests ROSI may target multiple pathways involved in neurodegenerative diseases.

DISCUSSION: Despite its modest pancreatic lipase inhibitory effect, ROSI exhibits potent antioxidant activity and stable physicochemical properties suitable for industrial applications. Network pharmacology and molecular docking analyses reveal therapeutic potential for ROSI in neurodegenerative diseases such as Alzheimer's and Parkinson's. Consequently, ROSI serves as a natural antioxidant and a raw material for the development of functional foods and pharmaceuticals.

CONCLUSION: ROSI holds promise as an adjunctive treatment for neurodegenerative diseases, particularly for its antioxidant effects and industrial applicability. Further research should optimize its use in chronic disease management and explore its broader medicinal potential.},
}

@article {pmid42634351,
year = {2026},
author = {Patnaik, S and Patra, PK and Patra, CN and Panda, KC},
title = {Biomarkers, Diagnostics, and Emerging Therapies in Alzheimer's Disease: A Comprehensive Systematic Review (2015-2025).},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249427154260531181405},
pmid = {42634351},
issn = {1875-6166},
abstract = {INTRODUCTION: The underlying association between multiple risk factors like age, preexisting diseases, infections, traumatic brain injuries, and certain genetic factors makes the diagnosis and treatment a challenge in AD. Identification of biomarkers and proper diagnosis of AD could make its management easier. Advances in diagnostic techniques like Positron Emission Tomography (PET) imaging have greatly improved the ability to identify, detect early, monitor disease progression, and manage its therapy.

METHODS: The recent therapeutic advancements in treatments encompass immunotherapies aimed at amyloid-beta (Aβ) and tau proteins, novel drug delivery systems, non-pharmacological methodologies, and personalised medicine techniques, combination therapies, and non-invasive brain stimulation are important in the management of AD. Cholinesterase inhibitors, such as galantamine, rivastigmine, and donepezil, are used to enhance cognitive performance and reduce confusion. Moderate to severe AD, memantine, a N-methyl-D-aspartate receptor (NMDA) receptor antagonist, is prescribed. Researchers are looking into both active and passive vaccines to get antibodies to Aβ plaques, and monoclonal antibodies, such as Lecanemab and Donanemab, which are used to treat early-stage AD.

RESULTS: Ongoing research is focused on identifying new biomarkers and therapeutic targets, advancing gene therapy, and refining immunotherapeutic approaches for AD.

DISCUSSION: There is growing interest in comprehending the influence of lifestyle and environmental factors on the mitigation of AD risk. Ongoing research is essential to elucidate the complexity of AD pathophysiology and to create effective therapies.

CONCLUSION: This review highlights the critical need for future AD research to bridge identified gaps in early detection, focus on improving early diagnosis, developing more effective treatments, refining existing drugs and therapies, and understanding the underlying disease progression mechanisms.},
}

@article {pmid42634372,
year = {2026},
author = {Tong, Y and Hu, G and Liu, L and Zhang, Y and Jiang, N and Hou, Y and Zhang, M},
title = {Dynamic Entropic Mapping of Alzheimer's Neuropathology: Eyes-Open and Eyes-Closed EEG Biomarkers through Wavelet Entropy Analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050450560260119050625},
pmid = {42634372},
issn = {1875-5828},
abstract = {BACKGROUND: Alzheimer's Disease (AD) is characterized by amyloid-β plaques and tau tangles, while current diagnostic tools are often invasive and costly. Electroencephalography (EEG) offers a non-invasive alternative, with alpha rhythm abnormalities as key features. Impaired alpha reactivity during the transition from Eyes-Closed (EC) to Eyes-Open (EO) reflects early thalamocortical dysfunction.

OBJECTIVE: This study employs EO/EC wavelet entropy analysis to assess neurodynamic features across frequency bands, aiming to explore entropy-based EEG markers for early AD detection.

METHODS: This cross-sectional study enrolled 60 participants (30 AD and 30 controls). EEG was recorded during 60-second EC and Eyes-Open (EO) states using a 20-channel system. Continuous Wavelet Transform (CWT) and multiscale entropy were used to assess complexity differences across bands and regions between groups.

RESULTS: AD patients showed reduced alpha entropy differences between EC and EO states. Multiscale entropy difference (ΔEN α) analysis revealed weaker modulation in β-α and θ-δ bands compared with HC. Occipital ΔEN α correlated significantly with MMSE, with the strongest association in the alpha band (r = 0.9000, P < 0.001).

DISCUSSION: This study applies dual-state wavelet entropy analysis to reveal impaired neural reactivity in AD during eyes-open and eyes-closed transitions. The ΔEN α metric distinguishes AD from controls and correlates with cognitive decline, reflecting reduced neural flexibility and disrupted frequency-specific network dynamics.

CONCLUSION: This study shows that dual-state wavelet entropy analysis, especially ΔEN α, is a noninvasive tool for detecting neurodynamic abnormalities in AD. It reflects loss of state-dependent responsiveness and neural complexity, with potential for early screening and objective evaluation of treatment.},
}

@article {pmid42634511,
year = {2026},
author = {Mishra, R and Chauhan, N and Agrawal, KK},
title = {Current Targeted Nanoparticle Therapy for Alzheimer's Disease: Current Advances and Future Prospects.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026471444260724103751},
pmid = {42634511},
issn = {1875-5739},
abstract = {BACKGROUND: The effects of Alzheimer's disease (AD) on society are profound. The blood-brain barrier selectively permits the penetration of specific forms of molecules through the blood circulation into the CNS, which can restrict the effectiveness of medications supplied systemically. The therapeutic targets are located in the CNS. However, local administration channels to the CNS are rather intrusive, which can lead to patient discomfort and limit the feasibility of repeated treatments.

METHODOLOGY: This article has evaluated treatment methodologies for AD that use nanoparticles to target the brain and the pathological features of the illness. The material that is currently available has been categorized based on the aspect of AD that is discussed: targeted medication and neurodegeneration.

RESULT: The use of nanoparticles in the targeted delivery of medications intended to alleviate the symptoms of AD or halt the disease's progression has yielded positive results. Because of their multivalence, nanoparticles can target the treatment site, pass through the blood-brain barrier, and be functionalized with various targeting groups. Intravenous administration, rather than more intrusive techniques, has enhanced drug bioavailability in the CNS. Furthermore, the development of vaccinations and medication formulations for intranasal delivery has utilized nanoparticles.

DISCUSSION: This study focused on the advancement of AD treatment. Nanoparticles are designed to enhance drug bioavailability through intravenous and intranasal routes for quicker brain access with fewer side effects. Nanoparticles also aid in targeting disease features like amyloid- beta plaques and tau tangles. While results in animal models are positive, transitioning to human clinical trials requires a more profound understanding of AD mechanisms and biomarker identification.

CONCLUSION: Research employing animal models suggests that targeted nanoparticles can enhance the effectiveness of AD treatments. A deeper understanding of AD mechanisms will lead to more successful targeted nanoparticle applications.},
}

@article {pmid42634550,
year = {2026},
author = {Du, Y and Li, J and Han, F and Li, J and Lin, H and Ge, F},
title = {Safety Comparison of Acetylcholinesterase Inhibitors Using FAERS Spontaneous-Reporting Data: Drug-Specific Reporting Signals and Time-to-Onset Dynamics.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050497124260720115932},
pmid = {42634550},
issn = {1875-5828},
abstract = {INTRODUCTION/OBJECTIVE: Acetylcholinesterase Inhibitors (AChEIs) are widely used for symptomatic treatment of Alzheimer's disease, but their post-marketing reporting profiles may differ. This study compared FAERS disproportional reporting signals and Time-To-Onset (TTO) patterns for donepezil, galantamine, and rivastigmine.

METHODS: FAERS reports from Q1 2004 to Q2 2025 were analyzed. Reports listing donepezil, galantamine, or rivastigmine as the primary suspect drug were retained. Unique case-drug-Preferred Term (PT) triplets were constructed after case-level and drug-event-level de-duplication. Positive signals were defined conservatively by the intersection of ROR, PRR, BCPNN, and MGPS/EBGM criteria. TTO was evaluated using cumulative onset-distribution curves, Weibull models, and Accelerated Failure-Time (AFT) models.

RESULTS: The analysis included 9,474 donepezil reports, 3,042 galantamine reports, and 14,666 rivastigmine reports. The four-method intersection identified 286 positive PT reporting signals for donepezil, 143 for galantamine, and 259 for rivastigmine. Donepezil showed prominent cardiac reporting signals, including sinus bradycardia (ROR = 49.0) and electrocardiogram QT prolongation (ROR = 16.75). Rivastigmine showed application-site signals, including application-site erythema (ROR = 21.36) and application-site pruritus (ROR = 18.07). Galantamine showed signals including bradycardia (ROR = 15.37), fall (ROR = 3.44), and decreased appetite (ROR = 3.57). Median TTOs were 38, 44, and 64 days for donepezil, galantamine, and rivastigmine, respectively. Rivastigmine showed a later reported onset than donepezil in the AFT model (TR = 1.08; p = 0.008).

DISCUSSION: The findings suggest shared cholinergic reporting patterns and drug-specific signal profiles. Because FAERS lacks exposure denominators, these results indicate disproportional reporting rather than incidence, causality, or comparative clinical risk.

CONCLUSION: Donepezil, galantamine, and rivastigmine showed distinct FAERS reporting profiles and early post-initiation TTO patterns. These findings are hypothesis-generating and require confirmation in independent pharmacovigilance or clinical datasets.},
}

@article {pmid42634764,
year = {2025},
author = {Kordi, MR and Kooshan, AR and Jafari-Hokmabadi, SP and Gaeini, AA and Zobeydi, AM},
title = {Combating cognitive decline in a rat model of Alzheimer's disease: The role of high-intensity interval training and cannabidiol administration in modulating microRNA-124, BACE1, and nestin.},
journal = {Current journal of neurology},
volume = {24},
number = {3},
pages = {219-228},
pmid = {42634764},
issn = {2717-011X},
abstract = {Background: The global prevalence of Alzheimer's disease (AD) has emerged as a paramount concern due to the aging population. The current research examines the effects of six-week high-intensity interval training (HIIT), with and without cannabidiol (CBD) supplementation, on cognitive decline, micro ribonucleic acid (miRNA)-124 expression levels, and the protein expression of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and nestin in the hippocampus of rats with amyloid beta (Aβ)-induced AD. Methods: 30 male Wistar rats were randomly divided into six groups: control (CNT), sham, Alzheimer (AD), Alzheimer + HIIT (H-AD), Alzheimer + CBD (C-AD), and Alzheimer + HIIT + CBD (CH-AD). Following the hippocampal injection of Aβ1-42, the HIIT protocol and CBD supplementation [20 mg/kg/day, per os (P.O.)] were initiated and conducted over six weeks. After the last intervention, the hippocampus tissues were collected to assess miRNA-124 expression levels and the protein expression of BACE1 and nestin. Results: HIIT alone and in combination with CBD treatment significantly improved cognitive impairment induced by AD. Moreover, both treatments significantly reduced BACE1 protein expression and increased nestin protein expression in AD rats. However, despite decreased miRNA-124 expression levels in the AD group in comparison with the CNT group, HIIT and CBD administration did not alter miRNA-124 expression levels in other groups. Conclusion: The findings can contribute to a higher understanding of the beneficial effects of HIIT combined with CBD administration in mitigating AD-induced cognitive impairment by reducing BACE1 protein expression and increasing nestin protein expression.},
}

@article {pmid42627738,
year = {2026},
author = {Chang, Y and Kim, HJ and Kim, Y and Park, A and Nam, S and Banerjee, DR and Hasenour, CM and Young, JD and Brooks, GA and Wolfe, RR and Kim, IY},
title = {Exogenous lactate ameliorates Aβ-induced energy deficit and neurotoxicity with increased mitochondrial TCA cycle carbon flux in SH-SY5Y cells.},
journal = {American journal of physiology. Cell physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpcell.00268.2026},
pmid = {42627738},
issn = {1522-1563},
support = {2021R1A2C3005801//National Research Foundation of Korea (NRF)/ ; GCU-202106260001//Gachon University/ ; //Myocare Inc/ ; },
abstract = {A growing body of evidence has demonstrated the existence of metabolic dysfunction in neurodegenerative diseases, including Alzheimer's disease (AD), suggesting that deprivation of energy substrates impairs cellular dynamics. As the glucose utilization declines in AD patients, the need for alternative energy sources becomes crucial to sustain neuronal activities and prevent cell death induced by neurotoxic proteins, such as amyloid beta (A(?)) aggregates. In this context, lactate has been investigated as a potential alternative brain energy substrate in several studies, yet its impact on neuronal cells under A(?)-induced toxicity remains unclear. We confirmed significant suppression of energy production-related biological pathways by analyzing brain transcriptomic data of AD patients. In subsequent in vitro studies, exogenous lactate treatment ameliorated neuron-like cell death caused by A(?) aggregates. Using a [13]C stable isotope tracer, we verified cellular lactate uptake and its incorporation into TCA cycle in neurons under the neurotoxic condition. [13]C metabolic flux analysis further supported these findings by revealing that lactate treatment restored Aβ-suppressed mitochondrial TCA cycle fluxes. These metabolic improvements were accompanied by increased expression of mitochondrial proteins. These findings support lactate shuttling as a mechanism for supplying lactate-derived carbon to mitochondrial energy metabolism, which may improve neuronal resilience under Aβ-induced metabolic stress.},
}

@article {pmid42628381,
year = {2026},
author = {Quan, YS and Liu, JY and Liu, H and Sun, YX and Wang, YL and Liu, Z and Quan, ZS and Shen, QK},
title = {Design synthesis and evaluation of usnic acid derivatives as multi-target drugs for Alzheimer's disease.},
journal = {Bioorganic chemistry},
volume = {181},
number = {},
pages = {110398},
doi = {10.1016/j.bioorg.2026.110398},
pmid = {42628381},
issn = {1090-2120},
abstract = {The pathogenesis of AD is complex, and existing clinical drugs only alleviate symptoms and are difficult to block the course of the disease. Although UA has neuroprotective activities such as antioxidant and anti-inflammatory properties, its anti-AD activity is severely restricted by drug defects such as a single target and insufficient blood-brain barrier permeability. Therefore, this study takes UA as the lead compound, designs and synthesizes 38 UA derivatives, systematically evaluates their anti-AD biological activity, and aims to screen for multifunctional anti AD lead compounds. Among them, the lead compound S12 exhibited exceptional activity, with an EC50 value of 1.24 μM representing a 17.9-fold improvement in potency relative to the parent compound. Furthermore, WB assays were conducted to elucidate the underlying mechanism of action of this compound. The results revealed that compound S12 exerts anti-AD activity through the synergistic modulation of multiple signaling pathways: it inhibits activation of the MAPK and NF-κB pathways, as well as aberrant phosphorylation of tau protein; concurrently, it downregulates BACE1 expression to reduce Aβ production, and suppresses activation of the Bax/Bcl-2 pathway thereby inhibiting caspase-1 activation and ultimately confers neuroprotective, anti-AD effects. The apparent permeability coefficient of compound S12 across an in vitro (BBB) model was determined to be 7.66 × 10[-6] cm/s, confirming its ability to effectively cross the BBB. Further pharmacological evaluation demonstrated that S12 exerted a potent ameliorative effect on learning and memory deficits in an AD mouse model. In vivo toxicity assessment, no gross or histopathological abnormalities were observed in the major organs, including the heart, liver, spleen, and kidneys. Moreover, S12 significantly attenuated neuronal pathological injury in the hippocampus of Aβ-induced AD model mice, underscoring its robust neuroprotective activity. In conclusion, compound S12 demonstrates robust efficacy in ameliorating learning and memory deficits, enhancing blood-brain barrier permeability, and exerting anti-AD activity. Accordingly, it represents a highly promising multifunctional therapeutic candidate for the treatment of AD.},
}

@article {pmid42630070,
year = {2026},
author = {Alsharayri, S and Knox, S and Cutty, M and Mollalo, A},
title = {Dual eligibility and neuropsychiatric symptoms and treatment disparities among Medicare Part D beneficiaries with Alzheimer's disease and related dementias.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261478140},
doi = {10.1177/13872877261478140},
pmid = {42630070},
issn = {1875-8908},
abstract = {BackgroundNeuropsychiatric symptoms (NPS) are common and clinically consequential in Alzheimer's disease and related dementias (ADRD), yet their recognition and treatment may vary across socioeconomic groups. Dual-eligible Medicare-Medicaid beneficiaries represent a vulnerable population, but differences in NPS documentation and management remain unclear.ObjectiveTo examine whether dual eligibility is associated with differences in (1) documented NPS and (2) prescription fills among Medicare beneficiaries with ADRD who received home health (HH) care.MethodsWe conducted a cross-sectional study of 167,484 Medicare Part D beneficiaries with ADRD who received HH care and were identified using the Chronic Conditions Warehouse flag. Dual eligibility was the primary exposure. NPS were identified using diagnosis codes from medical claims. Prescription fills for NPS-related medications were identified using Medicare Part D prescription drug event data (≥2 prescription fills for anxiety-related medications and antidepressants). Logistic regression models estimated associations of dual eligibility with NPS documentation and prescription fills, adjusting for demographic characteristics, original Medicare entitlement, and comorbidity burden.ResultsDual-eligible beneficiaries comprised 30.7% of the cohort. Documented confusion and anxiety were the most prevalent symptoms. Dual-eligible beneficiaries had a higher prevalence of confusion (83.5% versus 82.0%) and anxiety (57.0% versus 53.2%) compared with Medicare-only beneficiaries. After adjustment, dual eligibility was associated with higher odds of documented confusion (aOR 1.18, 95% CI 1.14-1.22) and anxiety (aOR 1.19, 95% CI 1.15-1.22). Dual eligibility was also associated with slightly higher odds of anxiety-related prescription fills (aOR 1.21, 95% CI 1.17-1.26), whereas antidepressant prescription fills did not differ (aOR 1.00, 95% CI 0.95-1.05).ConclusionsDual eligibility was associated with modest differences in NPS documentation and prescription fills, suggesting differences in recognition and management of NPS among beneficiaries with ADRD.},
}

@article {pmid42630294,
year = {2026},
author = {Shafi, S and Ansari, GA},
title = {Developing artificial intelligence-based techniques for brain MRI image segmentation.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1894751},
pmid = {42630294},
issn = {1662-4548},
abstract = {INTRODUCTION: Brain MRI image segmentation is essential for the accurate diagnosis and treatment of neurological disorders, including brain tumors, Alzheimer's disease, and multiple sclerosis. Artificial intelligence (AI), particularly deep learning, has emerged as an effective approach for improving the precision and efficiency of medical image segmentation while reducing manual effort.

METHODS: This study utilized a publicly available Kaggle brain MRI dataset containing labeled images for supervised learning. A Convolutional Neural Network (CNN)-based framework was developed for automatic brain MRI segmentation. The methodology incorporated preprocessing techniques, including noise removal, normalization, and data augmentation, to improve image quality and model performance. The proposed model was evaluated using Accuracy, Dice Score, and Intersection over Union (IoU).

RESULTS: Experimental results demonstrated that the proposed AI-based segmentation framework achieved high segmentation accuracy and effectively distinguished normal brain tissue from abnormal regions. The model outperformed conventional image-processing methods by providing improved segmentation precision, reducing manual intervention, and enhancing the reliability of medical image analysis.

DISCUSSION: The findings demonstrate the potential of AI-based deep learning techniques for automated brain MRI segmentation in clinical applications. The proposed framework can support clinicians by improving diagnostic accuracy and reducing processing time. Future work will focus on implementing more advanced deep learning architectures and expanding the dataset to further improve segmentation performance and clinical applicability.},
}

@article {pmid42631247,
year = {2026},
author = {Chen, X and Boey, J and Wei, K and Ding, C and Malagón, P and Hong, JP and Zhou, Z},
title = {The Use of Dynamic Neck Lymphaticovenous Anastomosis in the Adjunctive Treatment of Alzheimer's Disease: A Retrospective Case Series.},
journal = {Archives of plastic surgery},
volume = {53},
number = {4},
pages = {352-360},
pmid = {42631247},
issn = {2234-6163},
abstract = {BACKGROUND: Lymphovenous anastomosis (LVA) has recently emerged as a potential method for the symptomatic management of Alzheimer's disease (AD). Building on this, we conceptualize the "dynamic neck lymphovenous anastomosis" (DN-LVA) to illustrate the versatility of our technique. DN-LVA utilizes a vein graft that traverses through the sternocleidomastoid muscle to facilitate the drainage of lymphatic fluid from the deep cervical lymphatic vessels to the external jugular vein.

METHODS: This study presents a retrospective analysis of patients who underwent DN-LVA between November 2024 and January 2025. The clinical outcome was evaluated through positron emission tomography/computed tomography (PET/CT) imaging and cognitive assessment tools, which included Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Neuropsychiatric Inventory (NPI), and Clinical Dementia Rating (CDR). The vein graft was harvested from the lower limb.

RESULTS: Five subjects were recruited into this study. Postoperative PET/CT scans revealed up to a 6.9% increase in glucose metabolism in patient 3, a decrease of 12.3% in amyloid deposits, and a 4.7% reduction in tau deposits in patient 5 and patient 4, respectively. Clinically, MMSE and MoCA scores were improved by 1.8 and 1.4, respectively. NPI scores decreased by 5.8 across five overall, and the CDR remained unchanged in all subjects. All grafts demonstrated vessel patency, and no postoperative complications were observed.

CONCLUSION: DN-LVA appears to be a safe, minimally invasive procedure with potential cognitive and metabolic benefits in AD. Further studies with larger cohorts and longer follow-up are warranted to confirm these preliminary findings.},
}

@article {pmid42631306,
year = {2026},
author = {de Oliveira, GLDS and Bertollo, AG},
title = {Non-pharmacological strategies for the management of Alzheimer's disease.},
journal = {Dementia & neuropsychologia},
volume = {20},
number = {},
pages = {e20250290},
pmid = {42631306},
issn = {1980-5764},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disease affecting various cognitive domains, requiring a holistic and integrated therapeutic approach. The treatment of AD goes beyond pharmacological interventions, also necessitating non-pharmacological therapies that can act synergistically, both with each other and with emerging pharmacological treatments, including new anti-amyloid therapies. These therapies aim to improve patients' quality of life and alleviate behavioral symptoms, such as agitation and depression, and delay disease progression. Current clinical and meta-analytic evidence suggests that these approaches can be effectively integrated with conventional treatment, offering a valuable alternative to enhance patients' overall well-being. However, further research is needed to deepen the understanding of the ideal combination of the new anti-amyloid therapies, to address the limitations of current evidence, and to robustly establish their effectiveness in the clinical context of AD, aiming to generate a broader and more lasting impact on disease treatment. This narrative review aims to synthesize the evidence on diverse non-pharmacological therapies for managing AD and discuss their practical implications for clinical care.},
}

@article {pmid42631411,
year = {2026},
author = {Elwakil, BH and Helal, AM and El-Khatib, M and Abdelnaser, A and Darwish, AA and Shehata, NS and Akl, SH and Moneer, EA and Bakr, BA and El Wakil, A},
title = {Multilayered Silica-Core/Chitosan-Coated Nanostructures Co-Delivering Tamoxifen and Quercetin Mitigate LPS-Associated Neurodegenerative and Alzheimer's Disease-Like Alterations.},
journal = {Journal of biomedical materials research. Part B, Applied biomaterials},
volume = {114},
number = {8},
pages = {e70150},
doi = {10.1002/jbm.b.70150},
pmid = {42631411},
issn = {1552-4981},
support = {PUP-24-8//Pharos University in Alexandria/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology/chemically induced ; *Chitosan/chemistry/pharmacology ; *Quercetin/pharmacology/chemistry/pharmacokinetics ; *Lipopolysaccharides/toxicity ; *Silicon Dioxide/chemistry/pharmacology ; *Tamoxifen/pharmacology/chemistry/pharmacokinetics ; Rats ; Mice ; Male ; },
abstract = {Cholinergic dysfunction, oxidative stress, neuroinflammation, and proteinopathies are among the major hallmarks of Alzheimer's disease (AD). This study aimed to develop and evaluate the therapeutic potential of multilayered silica-based/chitosan-coated nanoparticles (Si@CsNPs) co-loaded with quercetin (QUR) and tamoxifen (TAM) in an LPS-induced neuroinflammatory murine model exhibiting AD-like neuropathological alterations associated with bacterial endotoxin exposure. Molecular docking and target prediction analyses suggested that TAM may exert partial cholinesterase inhibitory activity and potentially interact with muscarinic receptor- and epidermal growth factor receptor (EGFR)-associated pathways, which are implicated in neuroinflammation and oxidative stress regulation. The resulting silica-based/chitosan-coated nanoparticles (Si@CsNPs) co-loaded with QUR and TAM (QUR/TAM-Si@CsNPs) were spherical in shape, exhibited a core-shell architecture, and demonstrated high loading efficiencies for QUR (93.1% ± 2.56) and TAM (84.27 ± 3.66), with a mean particle diameter of approximately 135 nm as determined by TEM. Behavioral assessment using Morris Water Maze revealed that lipopolysaccharide (LPS) administration impaired spatial learning and memory in rats; these effects were significantly ameliorated by QUR/TAM-Si@CsNPs treatment, to a greater extent than Si@CsNPs loaded individually with QUR or TAM. Biochemical, apoptotic, and histopathological analyses further demonstrated that treatment with QUR/TAM-Si@CsNPs normalized acetylcholinesterase activity, Tau protein level, β-amyloid accumulation, pro-inflammatory mediators, and apoptotic indices while preserving hippocampal architecture. Collectively, these findings demonstrate that QUR/TAM-Si@CsNPs exert combined anti-inflammatory and neuroprotective effects, highlighting their promise as a multifunctional nanotherapeutic strategy against LPS-associated neurodegenerative and AD-like neuropathological alterations.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology/chemically induced
*Chitosan/chemistry/pharmacology
*Quercetin/pharmacology/chemistry/pharmacokinetics
*Lipopolysaccharides/toxicity
*Silicon Dioxide/chemistry/pharmacology
*Tamoxifen/pharmacology/chemistry/pharmacokinetics
Rats
Mice
Male

@article {pmid42631497,
year = {2026},
author = {Gopal, RK and Pathoor, NN and Ganesh, PS},
title = {Eubiosis and dysbiosis in periodontitis-related systemic diseases.},
journal = {Journal of periodontology},
volume = {},
number = {},
pages = {},
doi = {10.1002/jper.70188},
pmid = {42631497},
issn = {1943-3670},
abstract = {BACKGROUND: This narrative review examines the eubiosis-dysbiosis spectrum in periodontitis and its systemic implications. Evidence is drawn from the literature through 2026; as a narrative review, some selection bias cannot be excluded. Periodontitis, affecting 10%-15% of adults globally, drives systemic health disorders through microbial dysbiosis.

OBJECTIVES: This narrative review examines microbial ecological shifts in periodontitis and their implications for cardiovascular disease (CVD), diabetes mellitus (T2D), neurodegenerative disorders, rheumatoid arthritis (RA), and other systemic conditions.

METHODS: We have synthesized the current evidence on oral microbiome transitions from eubiosis to dysbiosis, focusing on mechanistic pathways linking periodontal disease to systemic health outcomes.

RESULTS: Periodontal dysbiosis may influence systemic health through mechanisms including bacteremia, chronic inflammation, molecular mimicry, and microbiome axis interactions. Individuals with periodontitis show 1.5 to 2-fold increased cardiovascular risk, bidirectional relationships with diabetes (HbA1c reductions of 0.3%-0.5% following periodontal treatment), and associations with Alzheimer's disease, rheumatoid arthritis, and inflammatory bowel disease. Key pathogens including Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Fusobacterium nucleatum have been proposed as keystone species capable of remodeling microbial communities and potentially contributing to systemic effects.

CONCLUSIONS: Understanding the eubiosis-dysbiosis spectrum provides crucial insights into oral-systemic health connections and offers therapeutic targets for managing both periodontal and systemic diseases. Integrated medical-dental care approaches, precision medicine strategies, and microbiome-based therapeutics represent promising future directions.},
}

@article {pmid42631776,
year = {2026},
author = {Dineshbhai, TK and Rafaliya, D and Singh, A and Maheshwari, S and Lalan, M and Chakraborthy, GS},
title = {Emerging diagnostic biomarkers and therapeutic targets in Alzheimer's disease.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42631776},
issn = {1568-5608},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease and is the most common cause of dementia in the world. Cognitive decline, memory problems, behavioral disturbances, and, finally, loss of functional independence characterize it. AD has risen and continues to increase globally, especially among aging people. A team of researchers at the University of Alberta says that we need faster, better diagnosis and treatment of AD. It elaborates on the progressive understanding of AD pathophysiology, biomarkers, emergent targets, and the latest delivery solution. The paper covers and discusses various disease-causing mechanisms like plaque formation, tau hyperphosphorylation, etc., which causes AD. Research is also being undertaken on the role of genetic and epigenetic factors in the pathogenesis and evolution of diseases, including but not limited to APOE polymorphisms, DNA methylation, modifications of histones, and non-coding RNAs. Researchers have discovered biomarkers relevant to AD, particularly those found in CSF and blood. The biomarkers include Aβ42, phosphorylated tau, neurofilament light chain, GFAP, and TREM2. Other biomarkers include salivary, urinary, neuroimaging, and digital. Next come the therapeutic strategies targeting amyloid aggregation, tau pathology, and other types of dysfunctions. Recent developments in monoclonal antibodies, kinase inhibitors, anti-inflammatory agents, neurotrophic agents, and antioxidant therapies are stressed. Moreover, nanotechnology-based and targeted delivery systems being developed for drugs include, but are not limited to, liposomes, polymeric nanoparticles, dendrimers, nanoemulsions, and intranasal formulations to enhance blood-brain barrier permeability. A combination of biomarker-guided diagnostics with mechanism-based therapies might enable precision medicine approaches and improve clinical outcomes in AD.},
}

@article {pmid42632150,
year = {2026},
author = {Chenxi, D and Miaomiao, W and Jiahui, F and Hongming, Z and Lu, G and Lihua, W and Ying, Z and Xiaoqing, C and Jing, Z and Yanhong, S},
title = {Technological evolution of hyperthermia: From traditional moxibustion to nanomaterial-mediated platforms for inflammatory diseases.},
journal = {Journal of thermal biology},
volume = {140},
number = {},
pages = {104557},
doi = {10.1016/j.jtherbio.2026.104557},
pmid = {42632150},
issn = {0306-4565},
abstract = {Hyperthermia, a physical therapeutic modality with unique advantages in treating inflammatory diseases, has evolved rapidly from empirical practice to precision medicine. Technologically, it has expanded from whole-body hyperthermia and traditional moxibustion to localized approaches, including photothermal, magnetothermal, ultrasound, and implantable platforms. Traditional moxibustion acts through heat and near-infrared radiation, while nanomaterials and smart devices now enable precise control over temperature, spatial targeting, and treatment duration. these modalities converge on conserved mechanisms: TRPV channel activation, HSF1-HSP70 induction, and immune modulation, which collectively alleviate inflammation and promote tissue repair in inflammatory bowel disease, osteoarthritis, and Alzheimer's disease. This review summarizes technological evolution, mechanistic insights and therapeutic applications, thereby providing a framework for developing precision hyperthermia strategies and multifunctional platforms for inflammatory diseases.},
}

@article {pmid42632510,
year = {2026},
author = {Yi, F and Ma, J and Zhao, R and Xie, Q and Lu, S and Zhang, K and Zhong, Z and OuYang, H and Qin, Y and Xu, M and Xue, Q and Wang, X and Wei, W and Liu, Y},
title = {Zonisamide improves cognitive impairment and psychiatric symptoms related with SAPAP3 in mouse models of Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {1033},
number = {},
pages = {179279},
doi = {10.1016/j.ejphar.2026.179279},
pmid = {42632510},
issn = {1879-0712},
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by pathological changes in Aβ&Tau, cognitive impairment, and may also manifest psychiatric symptoms. Zonisamide (ZNS) has been demonstrated its improvement of cognitive dysfunction in T2DM mice in our previous study. However, the efficacy and mechanism of ZNS in treating AD remain unclear.

AIM: We aims to investigate the therapeutic efficacy of ZNS for AD and its potential molecular mechanisms.

METHODS: Three-month-old 5xFAD mice were treated with ZNS (20 mg/kg, i.p.) for 12-week. The behavioral test assesses cognitive function and psychiatric symptoms. Aβ-PET/CT, immunofluorescence, and Thioflavine-S staining assessed the levels of Aβ plaques. Proteomics and Western blot analyses evaluated synapse-associated proteins, amyloid precursor protein (APP) related proteins and phosphorylated tau.

RESULTS: We discovered for the first time that ZNS significantly improved spatial learning and memory, and also alleviated psychiatric symptoms in 5xFAD. Besides, ZNS increased PSD95, SYP, BDNF, and SAP90/PSD-95-related protein 3 (SAPAP3), which plays a crucial role in compulsive-like behaviors. Importantly, siRNA-mediated knockdown of SAPAP3 in N2A/APP cells inhibited the regulatory effect of ZNS on PSD95 and NMDAR2A (NR2A). In addition, ZNS treatment reduced Aβ deposition in the brain. It also downregulated APP, p-APP (Thr668), BACE1, and PS1, and attenuated tau phosphorylation at Ser396 by inhibiting its upstream kinase ERK1/2 activity.

CONCLUSION: ZNS exerts neuroprotective effects in 5xFAD mice and improves AD-related cognitive impairment and AD-like lesions, which establishes ZNS as a promising therapeutic avenue for AD and its associated psychiatric symptoms.},
}

@article {pmid42633398,
year = {2027},
author = {Chen, H and Si, Y and Cheng, Q and Yu, Q and Cui, Z and Yu, S and Zhao, X and Jin, Y and Wang, Y and Li, M and Lu, Z},
title = {Therapeutic potential and underlying mechanisms of engineered young plasma-derived exosomes in Alzheimer's disease.},
journal = {Bioactive materials},
volume = {67},
number = {},
pages = {497-523},
pmid = {42633398},
issn = {2452-199X},
abstract = {Exosomes (EXOs) derived from the plasma of young individuals are believed to have the potential to ameliorate aging-related memory deficits. However, their specific roles and mechanisms in Alzheimer's disease (AD) therapy have not yet been systematically investigated. In this study, the rabies virus glycoprotein-targeting peptide (RVG-29) was conjugated to the surface of young plasma-derived EXOs to construct RVG-engineered EXOs (RVG-EXOs), and their therapeutic potential and underlying mechanisms in AD models were systematically evaluated. In 3×Tg AD model mice, exogenous administration of young plasma-derived EXOs and their engineered product (RVG-EXOs) revealed that RVG-EXOs could more efficiently enter brain tissue and target neurons, significantly reduce Aβ plaque and phosphorylated Tau (P-Tau) pathological deposition, restore synaptic structure, promote neuronal survival, and improve cognitive behavior. Mechanistic studies demonstrated that RVG-EXOs inhibited RPTOR expression, thereby activating the autophagy pathway and promoting the clearance of pathological proteins. Both in vitro and in vivo experiments confirmed that overexpression of RPTOR significantly suppressed the therapeutic effects of RVG-EXOs. single-cell transcriptomic profiling further revealed that RVG-EXOs not only increased neuronal proportion and modulated excitatory/inhibitory neuronal balance but also reshaped the microglial landscape by reducing deleterious disease-associated while increasing homeostatic surveillant microglia. In summary, this study not only reveals for the first time the potential value of young plasma-derived EXOs in AD treatment but also, through RVG engineering strategies and the elucidation of the RPTOR-autophagy mechanism, provides new insights for targeted therapy of neurodegenerative diseases.},
}

@article {pmid42627571,
year = {2026},
author = {Wang, Q and Wei, Y and Shen, C and Kang, W and Wang, L},
title = {CT1812 Attenuates Surgery-Induced Cognitive Impairment and Modulates TMEM97- and PGRMC1-Associated Hippocampal Stress Responses in Aged Mice.},
journal = {Neurochemical research},
volume = {51},
number = {5},
pages = {},
pmid = {42627571},
issn = {1573-6903},
support = {82201549//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Membrane Proteins/metabolism ; *Hippocampus/drug effects/metabolism ; Male ; Mice, Inbred C57BL ; Mice ; *Aging/drug effects/metabolism ; *Cognitive Dysfunction/metabolism/drug therapy/etiology ; *Postoperative Cognitive Complications/metabolism/drug therapy ; Receptors, Progesterone ; },
abstract = {Postoperative neurocognitive disorders (PND) are common complications in older surgical patients, but druggable mechanisms linking surgical trauma to hippocampal synaptic and cognitive vulnerability remain poorly defined. The σ-2 receptor (σ-2R), encoded by transmembrane protein 97 (TMEM97), and progesterone receptor membrane component 1 (PGRMC1) intersect membrane lipid biology and synaptic stress signaling; CT1812, a pharmacological σ-2R complex modulator, has shown target engagement in early Alzheimer's disease trials, but whether this pathway participates in postoperative hippocampal injury is unknown. This study examined whether surgery-induced hippocampal stress in aged mice is associated with TMEM97 and PGRMC1 signaling and whether early CT1812 treatment can attenuate this response. Young adult (2-3 months) and aged (18-20 months) male C57BL/6J mice underwent sham operation or laparotomy; aged mice were further treated with vehicle or CT1812 (3 mg/kg, intravenous injection, days 0-3). Hippocampal molecular changes were assessed by western blotting and immunofluorescence on day 3, and behavior was evaluated by open field test (OFT) and Morris water maze (MWM) on days 6-10. Laparotomy increased hippocampal TMEM97 and PGRMC1 expression and induced anxiety-like and spatial-memory deficits preferentially in aged mice, without evidence that locomotor impairment explained the behavioral phenotype. TMEM97 and PGRMC1 were detected in neuronal nuclei (NeuN)-positive neurons, ionized calcium-binding adapter molecule 1 (Iba-1)-positive microglia, and glial fibrillary acidic protein (GFAP)-positive astrocytes in hippocampal cornu ammonis 1 (CA1), supporting multicellular pathway involvement. In aged surgical mice, CT1812 significantly reduced upregulation of TMEM97 and PGRMC1, improved OFT center-zone occupancy and MWM performance, and restored the synaptic markers postsynaptic density protein 95 (PSD95) and synaptophysin. CT1812 also normalized lipid-handling proteins, including apolipoprotein E (ApoE), ATP-binding cassette transporter A1 (ABCA1), cholesterol 24-hydroxylase (CYP46A1), and low-density lipoprotein receptor (LDLR), and reduced perilipin 2 (PLIN2) accumulation in neurons and microglia. In parallel, CT1812 attenuated a selective endoplasmic reticulum (ER) stress response involving binding immunoglobulin protein (BIP) and protein kinase R-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2α (eIF2α) signaling in hippocampal neurons, and suppressed microglial nuclear factor κB (NF-κB)/NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammatory activation, whereas C/EBP homologous protein (CHOP) was not significantly changed. These findings support a model in which postoperative injury in the aged hippocampus engages a lipid-proteostatic and inflammatory stress program associated with TMEM97 and PGRMC1, and suggest that CT1812 attenuates cognitive vulnerability by restraining this coupled response.},
}

Animals
*Membrane Proteins/metabolism
*Hippocampus/drug effects/metabolism
Male
Mice, Inbred C57BL
Mice
*Aging/drug effects/metabolism
*Cognitive Dysfunction/metabolism/drug therapy/etiology
*Postoperative Cognitive Complications/metabolism/drug therapy
Receptors, Progesterone

@article {pmid42627656,
year = {2026},
author = {Meiselbach, MK and Xu, J and Brown, T and Polsky, D},
title = {Medicare Advantage Beneficiary Enrollment Decisions Following New Complex Conditions.},
journal = {JAMA health forum},
volume = {7},
number = {8},
pages = {e262843},
pmid = {42627656},
issn = {2689-0186},
mesh = {Humans ; *Medicare Part C/statistics & numerical data ; United States ; Female ; Male ; Aged ; Chronic Disease/epidemiology ; Aged, 80 and over ; Cohort Studies ; Insurance, Medigap/statistics & numerical data ; },
abstract = {IMPORTANCE: Prior research has demonstrated higher rates of disenrollment from Medicare Advantage (MA) among people with greater health care needs. Yet, less is known about how disenrollment responds to changes in medical complexity, whether disenrollment varies by the degree of complexity, and how these patterns differ by state Medigap protections and MA plan characteristics.

OBJECTIVE: To examine changes in MA plan disenrollment following the development of new complex medical conditions and assess heterogeneity by number of conditions, state Medigap policy, and plan characteristics.

This cohort study used Medicare enrollment and claims data from 2016 to 2021. The study population included beneficiaries continuously enrolled in MA in 2016 without complex medical conditions from 2016 through 2018. A treatment group developed a new complex condition in 2019; a comparison group did not develop a complex condition through 2021. Data were analyzed from December 1, 2025, to March 1, 2026.

EXPOSURE: Development of 1 or more new complex medical conditions in 2019, including acute myocardial infarction, Alzheimer disease and related dementia, atrial fibrillation, chronic kidney disease, chronic obstructive pulmonary disease, depression, congestive heart failure, or stroke.

MAIN OUTCOMES AND MEASURES: Annual disenrollment from the prior year MA plan, which included disenrollment to traditional Medicare (TM) or switching to another plan within MA. Difference-in-differences models with beneficiary and year fixed effects were estimated and converted to differences in percentage points.

RESULTS: The analytic sample included 1 054 926 beneficiaries, including 219 942 (mean [SD] age, 75.3 [6.3] years; 54.6% female) who developed new complex conditions in 2019 and 834 984 (mean [SD] age, 73.8 [5.6] years; 56.7% female) who did not develop a new complex condition in 2019. Developing any new complex condition was associated with an increase of 3.3 (95% CI, 3.1-3.5) percentage points (pp) in MA disenrollment, including an increase of 2.8 (95% CI, 2.7-2.9) pp in disenrollment to TM. The number of new complex conditions was associated with increased disenrollment, from 1.4 (95% CI, 1.3-1.6) pp for 1 condition to 12.8 (95% CI, 11.6-13.9) pp for 4 or more conditions. Disenrollment to TM was 1.5 (95% CI, 0.9-2.1) pp higher among beneficiaries residing in states with Medigap guaranteed issue and community rating protections.

CONCLUSIONS AND RELEVANCE: In this study, development of new complex medical conditions was associated with higher MA disenrollment, particularly to TM and in states with Medigap protections, and the magnitude increased with medical complexity. These findings highlight how changes in health status and state policy may shape Medicare coverage decisions.},
}

Humans
*Medicare Part C/statistics & numerical data
United States
Female
Male
Aged
Chronic Disease/epidemiology
Aged, 80 and over
Cohort Studies
Insurance, Medigap/statistics & numerical data

@article {pmid42622822,
year = {2026},
author = {Zhang, H and Lai, J and Wang, T and Li, T and Liu, S and Sun, DL and Chen, W and Kuang, W and Li, X and Zhang, M and Liao, Z and Xiang, X and Tuerxun, M and Zhang, X and Zhang, N and Xiao, S and Jessen, F and Yu, E and Yu, X and Wang, H},
title = {Adaptation and feasibility of the International Registry for Alzheimer's Disease and Other Dementias real-world datasets in old-age mental healthcare practice in China.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261478137},
doi = {10.1177/13872877261478137},
pmid = {42622822},
issn = {1875-8908},
abstract = {BackgroundAnti-amyloid disease-modifying therapies (DMTs) for early Alzheimer's disease (AD) are entering routine care, increasing the need for harmonized, registry-ready real-world data. The International Registry for Alzheimer's Disease and Other Dementias (InRAD) proposed a minimum dataset (MDS) and extended dataset (EDS), but their applicability to psychiatry-led old age mental healthcare practices in China is uncertain.ObjectiveTo adapt the InRAD dataset for real-world AD DMT practice across multiple psychiatry institutions in China and assess the feasibility of routine data capture for the proposed MDS/EDS.MethodsWe conducted a modified Delphi consensus study and a multicenter feasibility survey. Forty-nine experts classified domains/items into the MDS or EDS using predefined agreement thresholds. Thirty-five DMT-initiating mental healthcare teams reported the routine availability of the proposed data elements.ResultsHighly consistent with InRAD, ten domains were included in the China-adapted MDS/EDS, covering patient profiles and lifestyle, diagnostic work-up and biomarkers, treatment, outcomes, safety, treatment-monitoring examinations, and registry discontinuation. However, item prioritization reflected local practice, emphasizing diagnostic traceability, functional and neuropsychiatric outcomes, caregiver burden, and structured safety capture. Feasibility results revealed that many MDS elements were collected, but the consensus-defined MDS exceeded what is currently captured in a standardized, analysis-ready format; most EDS items were moderately feasible, while WHO-5 (patient version) and DAT-scan were least feasible.ConclusionsAn InRAD-aligned dataset is broadly acceptable for psychiatry-led AD DMT practices in China, but implementation gaps remain. A phased registry approach with standardized definitions and workflow-supported capture may improve the completeness and comparability of real-world DMT evidence.},
}

@article {pmid42622974,
year = {2026},
author = {Talebi, A and Nabili, S and Alaei, M and Koohsarian, P and Doostmohammadi, A and Dadashpour, M},
title = {Exosome-derived biomarkers as non-invasive tools in stroke, Parkinson's disease, and Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42622974},
issn = {1573-7365},
mesh = {Humans ; *Exosomes/metabolism ; Biomarkers/metabolism ; *Alzheimer Disease/metabolism/diagnosis ; *Parkinson Disease/metabolism/diagnosis ; *Stroke/metabolism/diagnosis ; Animals ; MicroRNAs/metabolism ; },
abstract = {Neurological disorders, including stroke, Parkinson's disease (PD), and Alzheimer's disease (AD), are among the most prevalent and debilitating neuropathological conditions, affecting over 50 million people globally. Effective prevention and treatment strategies require a comprehensive understanding of reliable and disease-specific biomarkers. Such insights can enhance diagnostic precision, enable early detection, and support the development of targeted therapeutic approaches. In this review, we focus on exosome-derived proteins and small non-coding RNAs as promising non-invasive biomarkers for stroke, PD, and AD, given the accessibility and stability of exosomes in biological fluids. Furthermore, we examine their potential diagnostic and therapeutic relevance, emphasizing their functional roles, specificity, and sensitivity. Finally, we discuss current limitations, emerging challenges, and future research directions to guide the advancement of exosome-based biomarker discovery and clinical translation in neurological disorders. However, we emphasize that the comparative effectiveness of exosomal microRNAs (miRNAs) versus protein biomarkers requires direct validation in future head‑to‑head cohort studies.},
}

Humans
*Exosomes/metabolism
Biomarkers/metabolism
*Alzheimer Disease/metabolism/diagnosis
*Parkinson Disease/metabolism/diagnosis
*Stroke/metabolism/diagnosis
Animals
MicroRNAs/metabolism

@article {pmid42623143,
year = {2026},
author = {Chen, Y and Ge, L and Lazarovici, P and Zheng, W},
title = {Artemisinin Attenuates Aβ1-42 Aggregation via the CaMK IV/PKA-CREB-Ace-H4 Cascade in Neuronal Cultures and 3xTg-AD Models.},
journal = {The American journal of Chinese medicine},
volume = {},
number = {},
pages = {1-23},
doi = {10.1142/S0192415X26500667},
pmid = {42623143},
issn = {1793-6853},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disease with a rising global prevalence, is characterized by amyloid-β (Aβ) aggregation, tau hyperphosphorylation, inflammation, oxidative damage, and neuronal apoptosis. Studies have increasingly recognized epigenetic modifications as key regulators in the development of AD. Epigenetic modifications, particularly histone acetylation, are increasingly recognized as critical regulators of cell survival and AD pathogenesis. Although artemisinin (ART) exhibits potent anti-oxidative, anti-inflammatory, and neuroprotective properties, its impact on histone acetylation in AD remains uncharacterized. This study investigated whether ART regulates histone acetylation to confer neuroprotection and rescue behavioral deficits in Alzheimer's disease models. Using SH-SY5Y cells, primary neurons, and 3xTg-AD mice, we found that ART restores histone acetylation homeostasis by enhancing histone H4 acetylation. Mechanistically, this effect is driven by the activation of the CaMK IV/PKA-CREB signaling cascade. Treatment with ART reduced ROS, improved mitochondrial function, decreased Aβ1-42 deposition, and suppressed neuronal apoptosis. However, these beneficial effects were abolished by PKA or CaMK IV inhibitors. Consequently, ART treatment significantly reduced reactive oxygen species (ROS) generation, restored mitochondrial function, decreased Aβ1-42 deposition, suppressed neuronal apoptosis, and alleviated AD-like neuropathology and cognitive deficits. Crucially, the neuroprotective and epigenetic benefits of ART were entirely abolished by pharmacological inhibitors of PKA or CaMK IV. This study is the first to demonstrate that artemisinin ameliorates AD pathology and behavioral impairments via the CaMK IV/PKA-CREB-Ace-H4 axis, establishing ART as a promising therapeutic candidate for epigenetic intervention in AD.},
}

@article {pmid42623762,
year = {2026},
author = {Wang, X and Liu, Y and Liu, J and Wang, R and Zheng, J and Deng, Z and Song, K and Zhang, D and Wang, C and Zhu, K and Zhang, J and Wu, C and Hou, G and de Vries, EFJ and Wang, Y},
title = {Translational imaging evidence for rapid reversal of amyloid and myelin pathology following deep cervical lymphatic-venous anastomosis in Alzheimer's disease.},
journal = {Nuclear medicine and biology},
volume = {160-161},
number = {},
pages = {109675},
doi = {10.1016/j.nucmedbio.2026.109675},
pmid = {42623762},
issn = {1872-9614},
abstract = {BACKGROUND: Recently, microsurgical restoration of extracranial lymphatic outflow through lymphatic-venous anastomosis (LVA) has been explored as a potential, albeit controversial, therapeutic strategy to enhance glymphatic clearance in Alzheimer's disease (AD); however, its impact on AD-related neuropathology has not yet been quantitatively or longitudinally evaluated. In this study, we performed translational PET imaging to determine whether restoring extracranial lymphatic outflow can rapidly and reversibly modulate cerebral glucose metabolism, myelin integrity, and amyloid burden in relation to cognitive improvement.

METHODS: A cervical lymphatic obstruction model was established in rats, followed by longitudinal [[18]F]FDG-PET and [[11]C]MeDAS-PET to assess cerebral glucose metabolism and myelin integrity before and after LVA, with imaging findings further validated by immunohistochemistry. A cohort of eight AD patients underwent LVA and received [[11]C]PIB and [[11]C]MeDAS PET imaging at baseline and follow-up. The imaging results were correlated with cognitive performance.

RESULTS: In Sprague-Dawley rats, cervical lymphatic obstruction led to significantly elevated cerebral glucose metabolism and reduced myelin integrity, both of which were largely restored to near-normal levels following LVA treatment, as further validated by immunohistochemical analyses. Similarly, in AD patients, LVA produced a 36.0 ± 2.1% decrease in cortical amyloid burden on [[11]C]PIB-PET (p < 0.001) and a 59.8 ± 29.0% increase in [[11]C]MeDAS uptake (p = 0.005). Subsequent correlation with MMSE scores demonstrated that short-term cognitive improvement was associated with greater myelin restoration and greater amyloid reduction.

CONCLUSION: These preliminary findings provide initial evidence that restoration of extracranial lymphatic outflow may modulate core neuropathological processes in AD, justifying further investigation in larger cohorts with appropriate control groups and randomized controlled designs to validate and extend these observations.

TRIAL REGISTRATION: The study was registered on the Chinese Clinical Trial website on April 21, 2025 (Registration No. ChiCTR2500101149).},
}

@article {pmid42624382,
year = {2026},
author = {Yenkoyan, K and Davtyan, T and Torosyan, H and Galstian, S and Chavushyan, V},
title = {Bone marrow remodeling and brain-bone marrow crosstalk in Alzheimer's disease-like neurodegeneration.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106968},
doi = {10.1016/j.bbi.2026.106968},
pmid = {42624382},
issn = {1090-2139},
abstract = {Alzheimer's disease (AD) is increasingly recognized as a systemic disorder involving not only central neurodegeneration but also alterations in peripheral immune regulation and systemic homeostasis. Among these, the bone marrow represents a critical yet underexplored interface between the brain and systemic homeostasis. In the present study, we investigated whether AD-like neurodegeneration induces functional and structural remodeling of the bone marrow and whether these changes can be modulated through central neural stimulation and treatment with embryonic proteoglycans (PEG). An AD-like model was induced in adult male rats by intracerebroventricular administration of aggregated amyloid-β (Aβ1-42). Bone marrow alterations were assessed using ELISA for insulin-like growth factor-1 (IGF-1) and nerve growth factor (NGF), Western blot analysis of c-Fos and NF-κB, high-performance liquid chromatography for GABA determination, flow cytometry of hematopoietic and niche-associated cell populations, and morphological evaluation using hematoxylin and eosin and Giemsa staining. Additional modulation was performed by sequential electrostimulation of the hypothalamic supraoptic and paraventricular nuclei and by administration of embryonic proteins. Amyloid exposure significantly increased bone marrow IGF-1 levels, c-Fos expression, and NF-κB activation, accompanied by marked remodeling of marrow architecture characterized by reduced adiposity, increased hematopoietic cellularity, megakaryocytic abnormalities, and altered expression of progenitor-, neuronal-, and apoptosis-associated markers. Flow cytometry revealed shifts in specific CD3[+]CD3[+] T-cell subpopulations and increased apoptotic signaling, indicating dynamic reorganization of the hematopoietic niche. Hypothalamic stimulation and PEG treatment partially normalized these alterations, reducing inflammatory activation and restoring trophic and cellular balance. These findings demonstrate that AD-like neurodegeneration is associated with coordinated bone marrow remodeling and support the existence of a functional brain-bone marrow axis. The reversibility of these changes suggests that the bone marrow represents a biologically active and therapeutically accessible component of systemic responses to neurodegeneration, with potential relevance for future Alzheimer's disease interventions.},
}

@article {pmid42624557,
year = {2026},
author = {Halder, D and Prajapati, D and Banerjee, T and Biswas, S and Ghosh, B},
title = {Epigenetic modulators as therapeutics for neurodegenerative disorders/Alzheimer's disease.},
journal = {Methods in enzymology},
volume = {733},
number = {},
pages = {163-222},
doi = {10.1016/bs.mie.2026.06.010},
pmid = {42624557},
issn = {1557-7988},
mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics/metabolism ; *Epigenesis, Genetic/drug effects ; Animals ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; DNA Methylation/drug effects ; *Neurodegenerative Diseases/drug therapy/genetics ; Histone Deacetylases/metabolism ; },
abstract = {Epigenetic dysregulation is recognized as a primary contributor to the pathogenesis of neurodegenerative disorders, especially Alzheimer`s disease (AD). Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA regulation, govern gene expression without altering the DNA sequence, which plays a crucial role in neuronal development, synaptic plasticity, and memory formation. In AD, abnormal epigenetic alterations disrupt neuronal homeostasis, promote Aβ aggregation, tau hyperphosphorylation, and neuroinflammation, which leads to cognitive impairment. This chapter explores the assays performed and their processes using epigenetic modulators, along with their therapeutic potential in neurodegenerative diseases, especially AD. HDAC inhibitors, DNMT inhibitors, and emerging approaches, such as PROTACs for selective degradation of epigenetic enzymes, were discussed in the context of neurocognitive disorders. Preclinical and clinical evidence suggest that targeting specific HDAC isoforms (HDAC3, HDAC6, etc) can restore synaptic plasticity and improve cognitive function. This chapter further discusses recent advances, challenges in drug specificity, BBB permeability, and off-target epigenetic effects, which remain barriers to clinical translation. Case studies highlighting successful epigenetic interventions in AD models were presented to demonstrate therapeutic feasibility. Overall, epigenetic modulators present a promising therapeutic approach for neurodegeneration, and continued research integrating various assays like DNA methylation analysis, histone modification analysis, non-coding RNA analysis, neuroinflammation analysis, and functional and behavioral assays in AD models is significant in harnessing the full potential for AD treatment.},
}

Humans
*Alzheimer Disease/drug therapy/genetics/metabolism
*Epigenesis, Genetic/drug effects
Animals
*Histone Deacetylase Inhibitors/pharmacology/therapeutic use
DNA Methylation/drug effects
*Neurodegenerative Diseases/drug therapy/genetics
Histone Deacetylases/metabolism

@article {pmid42625393,
year = {2026},
author = {Okafor, NI and Abdelgader, A and Abobaker, M and Choonara, YE},
title = {A Review of the Therapeutic Potential of Stem Cell-Derived Nanocarriers to Treat Neurological Disorders.},
journal = {ChemistryOpen},
volume = {15},
number = {9},
pages = {e202500425},
pmid = {42625393},
issn = {2191-1363},
support = {//National Research Foundation (NRF) of South Africa/ ; },
mesh = {Humans ; *Nervous System Diseases/therapy/drug therapy ; Animals ; *Stem Cells/cytology/metabolism ; *Nanoparticles/chemistry ; Blood-Brain Barrier/metabolism ; *Drug Carriers/chemistry ; Stem Cell Transplantation ; },
abstract = {Neurological disorders (NDs) are characterized by substantial loss of specific neurons, with Alzheimer's and Parkinson's diseases being the most frequent NDs and nearly 99% of all "foreign substances" are prohibited from entering the brain by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (CFB). These barriers, while crucial for brain protection, pose significant challenges for drug delivery, as they restrict the entry of many therapeutic agents into the brain, and this represents the primary manifestation of the absence of pathogenesis-targeting therapeutics. With significant success across multiple cell transplantation research efforts, stem cell therapy has been utilized for decades to treat neurological disorders. They work by replacing injured or lost cells directly, releasing proliferation and neurotrophic factors through autocrine and paracrine actions, suppressing neurological inflammation, and activation of endogenous brain progenitor cells. Nanocarriers derived from stem cells represent an innovative and promising therapeutic strategy for combating neurological diseases, combining faculties of regeneration of stem cells with the precision of nanotechnology. These nanocarriers possess natural biocompatibility and can efficiently cross the BBB to transport the therapeutic agents directly to affected neural tissues, thereby promoting enhanced treatment efficacy while reducing off-target effects. However, key challenges remain in large-scale production, standardization, and long-term safety. Thus, this review has examined the potential applications of stem cell extracellular vesicle (EV)-nanocarriers, mainly exosomes and recent development in the treatment of neurological diseases.},
}

Humans
*Nervous System Diseases/therapy/drug therapy
Animals
*Stem Cells/cytology/metabolism
*Nanoparticles/chemistry
Blood-Brain Barrier/metabolism
*Drug Carriers/chemistry
Stem Cell Transplantation

@article {pmid42626026,
year = {2026},
author = {Mehta, V and Singh, D and Kelman, J and Nimma, S and Lutz, H and Schnee, A and Weisman, D and Rosenbloom, MH},
title = {Real-world determinants of time to initiation of anti-amyloid treatments: comparative data from private and academic practice settings.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70436},
pmid = {42626026},
issn = {2352-8729},
abstract = {INTRODUCTION: Earlier anti-amyloid therapy (AAT) initiation results in improved clinical outcomes in Alzheimer's disease (AD). We sought to identify demographic, clinical, and disease-related factors impacting door-to-treatment times (DTTs).

METHODS: A retrospective review of AAT data was conducted at private and academic neurological practices.

RESULTS: A total of 329 patients (53.2% from private versus 46.8% academic practices), mean age 73.5 ± 7.2 (55.3% female), with most being non-Hispanic White were treated with lecanemab (81.2%) or donanemab (18.2%). DTTs were significantly reduced (p < 0.05) in both practices when diagnosis was confirmed with blood-based biomarkers (BBBs) as well as with greater clinic experience dosing AATs. DTT increased in patients with non-Medicare insurance and was not impacted by diagnosis, referral source, apolipoprotein E genotype status, or clinic distance.

DISCUSSION: Patients with private insurance may experience greater delay in DTT, whereas BBBs may reduce DTT relative to traditional confirmatory biomarkers. DTT improves with clinic experience.},
}

@article {pmid42627514,
year = {2026},
author = {Cao, Q and Shen, M and Liu, Y and Li, C and Liu, L and Zhou, J and Yue, R and Niu, D and Ren, Y and Pan, L and Yao, J and Zhang, G},
title = {The role of microglia glucose metabolism reprogramming in Alzheimer's disease treatment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261478594},
doi = {10.1177/13872877261478594},
pmid = {42627514},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment, and there remains a lack of effective treatments capable of reversing or significantly slowing disease progression. Accumulating evidence indicates that the immune function of microglia, the resident immune cells of the central nervous system, is a critical factor in regulating AD pathogenesis. Emerging research in immunometabolism further reveals that glucose metabolic reprogramming serves as a central driver of microglial phenotypic and functional differentiation. This review systematically outlines the fundamental characteristics of microglial glucose metabolism and focuses on how the dynamic metabolic reprogramming it undergoes during AD progression regulates microglial immune behavior and inflammatory responses. Building on this, we further summarize key regulatory targets within the "metabolism-immune axis" and corresponding pharmacological intervention strategies. Finally, this article discusses current challenges and future research directions in the field of microglial immunometabolism. This review aims to provide a theoretical foundation for AD intervention strategies targeting the "metabolism-immune axis" and to offer insights for the development of novel disease-modifying therapeutics.},
}

@article {pmid42619761,
year = {2026},
author = {Copeland, MH and Youngstrom, DE and Konrad, KS and Diering, GH and Letsinger, AC and Aksu, LR and Yakel, JL and Cushman, JD},
title = {Diphenhydramine Disrupts Sleep Architecture in 5XFAD Alzheimer's Disease Model and Wild-Type Mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.22.739929},
pmid = {42619761},
issn = {2692-8205},
abstract = {Sleep disruption is common in Alzheimer's disease (AD). Diphenhydramine (DPH), a first-generation antihistamine with anticholinergic properties, is widely used as an over-the-counter sleep aid. We tested whether chronic DPH treatment alters sleep architecture in 5XFAD and wild-type mice. Female 5XFAD (n=16) and wild-type (WT) littermates (n=14) were implanted with wireless telemetry recording devices to measure electroencephalography (EEG), electromyography (EMG), temperature, and activity continuously. After a 24h baseline recording at 5 months of age, mice received oral DPH (10 mg/kg) or vehicle at ZT0 for one month. After this chronic treatment, sleep was recorded continuously for 48h during ongoing dosing. Sleep was scored as rapid eye movement (REM), non-rapid eye movement (NREM) 1, NREM2, or wake. A survival curve analysis was used to investigate the microarchitecture of sleep phases after chronic diphenhydramine treatment. At baseline, 5XFAD mice had more time in NREM1 than WT controls and had shorter REM and NREM2 bouts. Chronic DPH treatment fragmented NREM2 in both genotypes, reducing long NREM2 bouts. DPH increased total duration of NREM1 and REM during the active phase, which is analogous to daytime drowsiness in humans. DPH did not rescue 5XFAD sleep deficits; instead, DPH treatment exacerbated NREM2 fragmentation. Overall, chronic DPH use degrades sleep quality and increases fragmentation in both WT and AD-model mice, which questions the use of sedating anticholinergics as sleep aids, especially in AD.},
}

@article {pmid42620159,
year = {2026},
author = {Wander, PL and Doherty, L and Pan, Q and Carmichael, O and Turner, R and Kuo, S and Munshi, M and Wallia, A and Noble, JM and Shah, VO and Nadkarni, NK and Mudaliar, S and Dabelea, D and Temprosa, M and Knowler, WC and Nathan, DM and Luchsinger, JA and , },
title = {Randomized metformin and cognitive outcomes in the Diabetes Prevention Program Outcomes Study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.05.26359234},
pmid = {42620159},
abstract = {IMPORTANCE: Metformin may influence risk of dementia, with prior conflicting observations of protection or harm.

OBJECTIVE: To determine the association of randomization to metformin vs. placebo or intensive lifestyle intervention (ILS) in the Diabetes Prevention Program (DPP) with cognitive outcomes (cognitive impairment syndromes and trajectories of cognitive test performance) during the DPP Outcomes Study (DPPOS).

Prospective long-term follow-up of DPP/DPPOS participants at 27 U.S. centers among adults who were at high risk for type 2 diabetes (T2D) at baseline.

EXPOSURES: Randomization to metformin, placebo, or ILS (1996-1999) for 3.2 years followed by open-label metformin in the original randomized metformin group until 2021.

MAIN OUTCOMES & MEASURES: Cognitive impairment syndromes were adjudicated in 2022- 2024 in 1,483 participants (median age 74 [IQR 68, 80]) using the National Alzheimer's Coordinating Center Uniform Dataset version 3. Cognitive performance in executive and memory domains was ascertained with repeated cognitive tests between 2009 and 2024. Multinomial logistic regression and mixed-effects models were fit to examine associations of randomization to metformin with cognitive outcomes.

RESULTS: Total metformin exposure (mean ± SD) was 15.5 ±7.7 years/person in the metformin group. Persons in the placebo and ILS groups received out-of-study metformin usually after developing diabetes with mean metformin total exposure of 4.5 ±5.1 and 3.8 ±4.8 years/person in the placebo and ILS groups, respectively. Overall, the frequency distributions of the cognitive syndromes did not differ significantly by treatment group; however, randomization to metformin was associated with a 60% (OR 0.40 [95%CI 0.17, 0.97]) and 62% (OR 0.38 [95%CI 0.16, 0.89]) lower odds of dementia compared with placebo and ILS, respectively, after adjustment for demographics, education, income, and APOE-ε4 genotype. Randomization to metformin was also associated with significantly better memory performance over time (β=0.58; 95%CI: 0.09, 1.1; p=0.02; Cohen's d=0.1).

CONCLUSIONS AND RELEVANCE: Long-term metformin treatment is associated with a reduced risk of dementia and better memory performance among persons with pre-diabetes or T2D. Estimates were imprecise due to a limited number of dementia cases. Longer follow-up with more dementia cases is needed to confirm our findings.

KEY POINTS: Question: Is chronic metformin treatment related to the risk of dementia and cognitive impairment?Findings: Randomization to metformin in the Diabetes Prevention Program was associated with a lower risk of dementia in the Diabetes Prevention Program Outcomes Study compared with the randomization to placebo or randomization to intensive lifestyle intervention, but the overall distribution of cognitive impairment syndromes did not differ significantly by treatment group. Randomization to metformin was also related to modestly better longitudinal performance in a memory test.Meaning: Chronic metformin treatment may decrease the risk of dementia.},
}

@article {pmid42620184,
year = {2026},
author = {Falahati, M and Ramezannejad, E and Vaez-Gharamaleki, Y and Radnia, P and Shahba, S and Rasoulian, P and Rezaei, S and Dasmeh, N and Bemanalizadeh, M},
title = {Determining the metabolic profile measured using ultra-high pressure liquid chromatography associated with Beta Amyloid burden in the brain in individuals with mild cognitive impairment.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10065374/v1},
pmid = {42620184},
issn = {2693-5015},
abstract = {As the world's population ages, Alzheimer's disease (AD), a progressive neurodegenerative disorder, is becoming more common. The current diagnoses for AD are not precise enough to identify the disorder when it is possible to cure. An early indicator of Alzheimer's is the assessment of beta-amyloid by positron emission tomography (PET) score, a substantial decrease in the brain's metabolomics. Furthermore, Metabolomics can be detected by UPLC (ultra-high pressure liquid chromatography). This study investigates the link between metabolic profiles and beta-amyloid load in AD in order to shed light on possible biomarkers for disease progression. The data from 59 people who have been diagnosed with moderate cognitive impairment (MCI) is extracted from the Alzheimer's Disease Neuroimaging Initiative (ADNI). This study uses ultra-high-performance liquid chromatography (UPLC) to investigate the correlation between baseline metabolic data and changes in amyloid PET scores. Seven metabolites, including DOPA, Methionine Sulfoxide (Met.SO), Tryptophan Betaine, choline, leucine, valine, and FA (18:2), seem to have a substantial connection with amyloid PET scores. These can be used as early indications of AD progression, especially Met.SO is particularly relevant when considering time interaction. Understanding the metabolic alterations associated with amyloid load can pave the way for future research incorporating metabolites into a therapeutic treatment that can be identified as crucial to the illness's progression.},
}

@article {pmid42620424,
year = {2026},
author = {McGill, CJ and Christensen, A and Namvari, S and Thorwald, MA and Anson, H and Vermulst, M and Finch, CE and Benayoun, BA and Pike, CJ},
title = {17α-Estradiol Confers Limited Protection Against APOE4 Phenotypes in Middle-Aged Female Mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.06.743074},
pmid = {42620424},
issn = {2692-8205},
abstract = {Longevity-promoting interventions represent a promising strategy to mitigate brain aging and reduce Alzheimer's disease (AD) risk. The NIA Interventions Testing Program identified the weak estrogen 17α-estradiol (17αE2) as a compound that extends healthspan and lifespan in mice, with effects observed primarily in males. Our recent work demonstrated that 17αE2 healthspan benefits were modulated by human apolipoprotein E (APOE) genotype such that aging phenotypes were improved more strongly in middle-aged male mice with targeted-replacement of the AD-associated APOE4 allele compared to APOE3 , the risk neutral and most common APOE allele. Here, we tested whether APOE -dependent, AD-relevant benefits of 17αE2 observed in males extend to females. Specifically, we treated 12-month-old APOE3 and APOE4 targeted-replacement female mice for 6 months with chow containing 0 or 14.4ppm 17αE2. We find that relative to APOE3 , APOE4 genotype largely exhibits more robust systemic phenotypes associated with aging, including increased adiposity, impaired glucose tolerance, and reduced energy expenditure. Further, we observe that treatment with 17αE2 yields modest improvements in some outcomes, including decreased adiposity and increased lean mass, glucose tolerance, and energy expenditure, though significant benefits are found only in APOE4 females. In the CNS, we observed mixed effects of APOE genotype on behavioral performance and indices of brain aging, with APOE4 females performing worse in the Barnes Maze and having higher levels of the AD-related peptide soluble β-amyloid, but no APOE genotype differences in cortical lipid raft oxidative damage. In contrast to its systemic effects, 17αE2 did not significantly improve neural outcomes in APOE3 or APOE4 females. These findings address the impact of biological sex on established protective effects of a longevity-promoting intervention against APOE4 phenotypes, which have significant relevance to the prevention of age-related conditions including metabolic dysfunction, cognitive impairment and vulnerability to AD.},
}

@article {pmid42621237,
year = {2026},
author = {Xue, WY and Li, X and Li, WT and Qin, BZ and Wang, CZ and Liu, T and Wang, M},
title = {Post-marketing safety signals and report-level ARIA-E stratification for lecanemab and donanemab: an integrated FAERS and WHO-VigiAccess pharmacovigilance study.},
journal = {Therapeutic advances in drug safety},
volume = {17},
number = {},
pages = {20420986261473013},
pmid = {42621237},
issn = {2042-0986},
abstract = {BACKGROUND: Anti-β-amyloid monoclonal antibodies provide a disease-modifying treatment approach for Alzheimer's disease, but post-marketing safety concerns remain, particularly amyloid-related imaging abnormalities (ARIA). Real-world studies have mainly described adverse event spectra and disproportionality signals, whereas report-level amyloid-related imaging abnormalities with edema or effusion (ARIA-E) risk stratification remains less well characterized.

OBJECTIVES: To compare post-marketing adverse event profiles of lecanemab (LEC) and donanemab (DON), identify report-level factors associated with ARIA-E, and develop a machine learning model for ARIA-E risk stratification.

DESIGN: Retrospective pharmacovigilance study using spontaneous reporting databases.

METHODS: Adverse event reports for lecanemab and donanemab were analyzed using the Food and Drug Administration Adverse Event Reporting System (FAERS) and WHO-VigiAccess. FAERS disproportionality analyses were performed at the Preferred Term and System Organ Class levels using frequency-based and Bayesian methods. Time-to-onset and serious-outcome patterns were further explored. Multivariable logistic regression was used to examine factors associated with report-level ARIA-E. An extreme gradient boosting (XGBoost) model was developed using temporally split FAERS datasets with nested cross-validation and temporal external validation.

RESULTS: FAERS included 2961 lecanemab and 1542 donanemab primary suspect reports; WHO-VigiAccess included 2525 lecanemab- and 1450 donanemab-related reports. Across databases, adverse event profiles were dominated by neurological events, with ARIA-related events representing the central safety signals. Serious outcomes clustered mainly in the early treatment period and attenuated over time. In complete-case regression, no overall difference in ARIA-E reporting odds was observed between donanemab and lecanemab, whereas a significant donanemab-by-body weight interaction was identified. The XGBoost model showed modest discrimination, with area under the receiver operating characteristic curve values of 0.677 in internal validation and 0.630 in temporal external validation. Calibration was suboptimal, and decision curve analysis suggested limited net benefit mainly within low-threshold ranges.

CONCLUSION: ARIA-related and other neurological events remain the principal post-marketing safety concern for lecanemab and donanemab. The XGBoost model may support report-level risk prioritization, particularly during early treatment, but should not be used as a diagnostic substitute or a source of precise individualized risk estimates.},
}