@article {pmid41605825,
year = {2026},
author = {Rodriguez, AD and DuBose, JR and Rozga, A and Zimring, CM and Mynatt, ED and Clifford, GD and Vickers, KL and Goldstein, FC and Giannotto, EL and Thelin, J and Levey, AI},
title = {Rationale and design of a multidomain lifestyle program for mild cognitive impairment.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71068},
doi = {10.1002/alz.71068},
pmid = {41605825},
issn = {1552-5279},
support = {//The James M. Cox Foundation/ ; //Cox Enterprises, Inc./ ; },
mesh = {*Cognitive Dysfunction/therapy/psychology ; Humans ; *Life Style ; Quality of Life ; },
abstract = {The development of non-pharmacological treatment approaches is supported by evidence that addressing key modifiable risk factors may prevent or delay up to 45% of dementia cases. The Charlie and Harriet Shaffer Cognitive Empowerment Program (CEP) was developed to address current gaps in access to, and evidence for, interventions that reduce lifestyle risk factors and improve quality of life in individuals with mild cognitive impairment (MCI). Co-designed with patients and families, clinicians, researchers, and industry professionals, the CEP is situated in a conceptual framework that guides assessments and interventions/supports to holistically address the experience of living with MCI. CEP comprises four cores (Therapeutic Programs, Technology, Built Environment, and Innovation Accelerator) that map to the conceptual framework. We contend that our approach provides an opportunity to contribute to the evidence base for multidomain lifestyle programs and gain a deeper understanding of MCI and how individuals can be empowered to manage it. HIGHLIGHTS: The cognitive empowerment program (CEP) is a multidomain lifestyle program that was developed using a co-design process and a conceptual framework that holistically addresses the experience of living with mild cognitive impairment (MCI). CEP provides comprehensive assessment and intervention/support through four cores that map to the conceptual framework: therapeutic programs, technology, built environment and research innovation. CEP's unique approach provides an opportunity to build the evidence base for multidomain lifestyle interventions and to develop and refine lifestyle biomarkers that can be used for early detection of MCI, tracking of disease progression, and objective measurement of the impact of lifestyle interventions.},
}

*Cognitive Dysfunction/therapy/psychology
Humans
*Life Style
Quality of Life

@article {pmid41603883,
year = {2026},
author = {Burn, O and Molloy, K and Kanekiyo, M and Parker, C and Rothwell, S and Pan, JJ and Trueman, D and Ritchie, C},
title = {Estimating the long-term health outcomes of treatment with lecanemab in early Alzheimer's disease: a modelling study.},
journal = {Journal of medical economics},
volume = {29},
number = {1},
pages = {250-262},
doi = {10.1080/13696998.2025.2600875},
pmid = {41603883},
issn = {1941-837X},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Markov Chains ; Aged ; Male ; Female ; Severity of Illness Index ; Cognitive Dysfunction/drug therapy ; Aged, 80 and over ; Standard of Care ; Disease Progression ; Quality-Adjusted Life Years ; },
abstract = {AIMS: To assess the long-term effects of lecanemab plus standard of care (SoC) compared with SoC alone in a cohort of patients with early Alzheimer's disease (AD; mild cognitive impairment [MCI] due to AD, or mild AD dementia) using different modeling approaches and data from Clarity AD (NCT0388745538).

METHODS: A Markov model was employed using health states based on disease severity, long-term institutionalization, and death, with disease severity defined using the Clinical Dementia Rating - Sum of Boxes (CDR-SB) classification for MCI due to AD, and Mild, Moderate, and Severe AD. State transitions during the first 18 months of treatment were estimated using either patient count data (Approach 1) or multistate survival analysis (Approach 2). Transition probabilities beyond 18 months for the lifetime of the cohort were informed by longitudinal natural history data for the SoC arm with a hazard ratio for time-to-worsening health state applied to estimate outcomes in the lecanemab arm.

RESULTS: Over a lifetime horizon, the model predicted a delayed time to Mild, Moderate, and Severe AD for patients treated with lecanemab compared to SoC by 1.31, 1.85, and 2.04 years, respectively when using Approach 1. Patients treated with lecanemab experienced a survival benefit of 1.36 years, comprised of an additional 1.85 years in early AD and 0.49 years less in moderate and severe AD, compared to patients treated with SoC alone. The model also predicted that compared to SoC, lecanemab increased the time in community care and reduced time spent in institutional care. Results were similar when using Approach 2.

LIMITATIONS: Long-term disease progression was informed by constant annual transition probabilities derived from the published literature.

CONCLUSIONS: Patients treated with lecanemab experience delayed progression to Moderate and Severe AD, resulting in additional life-years (LYs) and reduced time in institutional care.},
}

Humans
*Alzheimer Disease/drug therapy
Markov Chains
Aged
Male
Female
Severity of Illness Index
Cognitive Dysfunction/drug therapy
Aged, 80 and over
Standard of Care
Disease Progression
Quality-Adjusted Life Years

@article {pmid41603392,
year = {2026},
author = {Prevot, E and Shand, C and , and Oxtoby, N},
title = {How reproducible are data-driven subtypes of Alzheimer's disease atrophy?.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251415019},
doi = {10.1177/13872877251415019},
pmid = {41603392},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) exhibits substantial clinical and biological heterogeneity, complicating efforts in treatment and intervention development. While new computational methods offer insights into AD subtyping and disease staging, the reproducibility of these subtypes across datasets remains understudied, particularly concerning the robustness of subtype definitions when validated on diverse databases.ObjectiveThis study evaluates the robustness of the AD progression subtypes identified by the Subtype and Stage Inference (SuStaIn) algorithm on a larger and more diverse cohort.MethodsWe extracted T1-weighted MRI data for 5444 subjects from ANMerge, OASIS, and ADNI datasets, forming four independent cohorts. Each cohort was analyzed with SuStaIn under two conditions: one using the full cohort, including cognitively normal controls, and another excluding controls to test subtype robustness.ResultsResults confirm the three primary atrophy subtypes identified in earlier studies: Typical, Cortical, and Subcortical, as well as the emergence of rare and atypical AD variants such as posterior cortical atrophy. Notably, each subtype displayed varying robustness to the inclusion of controls, with certain subtypes, like the Subcortical subtype, more influenced by cohort composition.ConclusionsThis investigation underscores SuStaIn's reliability for defining stable AD subtypes and suggests its utility in clinical stratification for trials and diagnosis. However, our findings also highlight the need for improved dataset ethnic and demographic diversity, particularly in terms of ethnic representation, to enhance generalizability and support broader clinical application.},
}

@article {pmid41603342,
year = {2026},
author = {Sha, L and Wu, M and Sun, S and Xie, Y and Liu, Y and Li, Z and Liu, R and Guo, W and Yan, S and Xu, B and Kang, L},
title = {Subcutaneous transplantation of mesenchymal stem cell spheroids ameliorates cognitive deficits in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418164},
doi = {10.1177/13872877261418164},
pmid = {41603342},
issn = {1875-8908},
abstract = {BackgroundMesenchymal stem cell (MSC)-based therapy has emerged as a promising alternative treatment for Alzheimer's disease (AD) but is limited by low cell survival rates and complex handling.ObjectiveThe present study explored the therapeutic potential of subcutaneous transplantation of MSC spheroids in a mouse AD model.MethodsWe prepared uniform size MSC spheroids with good stemness properties, and performed three consecutive subcutaneous treatments with MSC spheroids on early-stage AD APP/PS1 mice (6 months old), with each injection administered one month apart. Following treatment, behavioral experiments were conducted to evaluate learning and cognitive functions. Additionally, positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) were utilized to assess cerebral glucose metabolism and neuronal functional connectivity. Subsequently, brain tissue sections were prepared and stained to evaluate amyloid plaque deposition, levels of inflammation, and other pathological changes.ResultsAPP/PS1 mice treated with MSC spheroids demonstrated better performance in cognitive behavioral tests compared to the AD model group. Imaging studies showed that brain glucose metabolism was higher in the MSC spheroids-treated group than in the AD model group, with enhanced functional brain connectivity. Moreover, pathological analysis revealed that MSC spheroids treatment resulted in a reduced amyloid-β plaque burden and attenuated inflammatory phenotypes in AD mice. MSC spheroids also protected neurons from apoptosis and restored synaptic plasticity.ConclusionsOur study suggests that subcutaneous transplantation of MSC spheroids reduced key pathological changes in AD by improving brain glucose metabolism and alleviating inflammation.},
}

@article {pmid41603338,
year = {2026},
author = {Ho, BL and Liu, CF and Huang, YB and Huang, LC and Yang, YH},
title = {Treatment persistence with acetylcholinesterase inhibitors in Alzheimer's disease: Real-world evidence from a retrospective cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251415021},
doi = {10.1177/13872877251415021},
pmid = {41603338},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is the leading cause of dementia worldwide, yet long-term persistence with acetylcholinesterase inhibitors remains suboptimal in routine practice.ObjectiveTo compare real-world treatment persistence among patients with mild to moderate AD receiving oral donepezil, rivastigmine capsules, or transdermal rivastigmine patches, and to identify factors influencing discontinuation.MethodsIn this retrospective cohort study, 1062 patients aged ≥65 years with newly diagnosed AD were identified from a hospital registry between 2015 and 2019 and followed through 2021. Treatment persistence was evaluated by duration and 1-year continuation rates. Discontinuation was defined as a prescription gap exceeding 90 days. Multivariable Cox proportional hazards models were used to identify predictors of discontinuation.ResultsPatients receiving donepezil had significantly longer mean treatment duration (3.03 years) and higher 1-year continuation rates (66.2%) than those receiving rivastigmine capsules (1.81 years, 39.9%) or patches (1.43 years, 45.5%). Both rivastigmine formulations were independently associated with greater discontinuation risk (adjusted hazard ratio [aHR] 1.44 and 1.76, respectively; p < 0.001). Participation in a national dementia care program was the strongest protective factor, associated with a 69% lower discontinuation risk (aHR 0.31; p < 0.001). Higher baseline CASI scores, younger age, and milder cognitive impairment predicted greater persistence, whereas adverse events markedly increased discontinuation.ConclusionsDonepezil demonstrated superior real-world persistence compared with rivastigmine. Structured dementia care programs substantially enhanced treatment continuity, underscoring the importance of both pharmacologic choice and system-level support in sustaining long-term therapy in AD.},
}

@article {pmid41603335,
year = {2026},
author = {Byeon, JH and Lee, D and Shin, EJ and Park, EM and Yoon, EJ and Kim, H and Ham, H and Yeo, J and Yoo, H and Youn, JH and Kang, SH and Lee, JY},
title = {Validation of a web-based cognitive test for early detection of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261415925},
doi = {10.1177/13872877261415925},
pmid = {41603335},
issn = {1875-8908},
abstract = {BackgroundEarly detection of Alzheimer's disease (AD) is critical for effective disease management and treatment. Web-based assessment tools offer advantages by enabling broader accessibility and reducing reliance on specialized clinical infrastructure.ObjectiveThis study aimed to validate a self-administered, web-based cognitive assessment tool for AD screening.MethodsA total of 106 older adults aged 55 to 84 years were recruited and clinically classified as cognitively unimpaired (CU, n = 35), amnestic mild cognitive impairment (aMCI, n = 37), or AD (n = 34). Participants completed Cogscreen, a 10-min web-based cognitive test comprising verbal cued memory and digit symbol substitution tasks.ResultsBoth the verbal cued memory and digit symbol substitution tasks showed significant score differences among CU, aMCI, and AD (p < 0.001). The Cogscreen composite score yielded area under the curve (AUC) values of 0.876 for aMCI (cut-off = 0.64, sensitivity = 0.865, specificity = 0.657) and 0.994 for AD (cut-off = -0.59, sensitivity = 0.971, specificity = 0.971), and outperformed the Mini-Mental State Examination (MMSE) in diagnosing aMCI (AUC = 0.638, p = 0.001). The composite score significantly correlated with the Consortium to Establish a Registry for Alzheimer's Disease assessment packet total score (r = 0.765, p < 0.001) and MMSE score (r = 0.722, p < 0.001).ConclusionsCogscreen is a rapid, self-administered cognitive screening tool for detecting aMCI and AD. It outperforms the MMSE in identifying early cognitive decline and holds potential for detecting even subtler cognitive changes in the future.},
}

@article {pmid41602207,
year = {2025},
author = {Tarnanas, I and Seixas, A and Wyss, M and Vlamos, P and Çöltekin, A},
title = {Merging multimodal digital biomarkers into "Digital Neuro Fingerprints" for precision neurology in dementias: the promise of the right treatment for the right patient at the right time in the age of AI.},
journal = {Frontiers in digital health},
volume = {7},
number = {},
pages = {1727707},
pmid = {41602207},
issn = {2673-253X},
abstract = {Digital biomarkers are revolutionizing medicine in ways that were unimaginable a few years ago. Consequently, precision medicine approaches now realistically can promise personalization, i.e., the right treatments for the right patients at the right time, including earlier, targeted interventions which lead to a major paradigm shift in how medicine is practiced from reactive to preventive action. Although the scientific evidence is clear on the power of digital biomarkers, there is an unmet need for translating these findings into actionable insights in clinical practice. In this paper, we focus on Alzheimer's disease and related dementias (ADRD), and how digital biomarkers could empower clinical decision making in its preclinical stages. We argue that a new all-encompassing score is needed, akin to a BrainHealth Index linked to the established and validated risk stratifications frameworks and is directed at the prevention of ADRD. Specifically, we propose the new concept "Digital Neuro Fingerprint (DNF)", built with simultaneous collection of multimodal digital biomarkers (speech, gait, eye movements etc.) from smartphone based augmented reality or virtual reality while an individual is immersed in activities of daily living. Fusing the captured multimodal digital biomarkers, data is automatically analyzed with custom combinations of machine- and deep-learning approaches and enhanced with explainable artificial intelligence (XAI) and uncertainty quantifications. We argue that DNF is useful for capturing ADRD progression and should supersede the biomarkers that are invasive and expensive to obtain, offering a sensitive and highly specific score that measures meaningful aspects of health for the patients in high-frequency intervals.},
}

@article {pmid41602161,
year = {2025},
author = {Greco, D and Čočková, Z and Das, D and Mali, AS and Novotný, J and Olsen, MJ and Telenský, P},
title = {Small molecule FTO inhibitor MO-I-500 protects differentiated SH-SY5Y neuronal cells from oxidative stress.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1736173},
pmid = {41602161},
issn = {1662-5099},
abstract = {INTRODUCTION: Oxidative stress is a central driver of brain aging, impairing cellular function and increasing susceptibility to neurodegenerative diseases. Recent studies suggest that the RNA demethylase FTO regulates N6-methyladenosine (m6A) RNA modification, a key pathway in modulating oxidative stress in the brain. However, the precise mechanisms underlying FTO's role remain unclear. This study examines the neuroprotective potential of MO-I-500, a small-molecule FTO inhibitor, against oxidative stress induced by tert-butyl hydroperoxide (TBHP) in neuron-like SH-SY5Y cells differentiated with retinoic acid and BDNF (dSH-SY5Y).

METHODS: dSH-SY5Y cells were treated with MO-I-500 alone for 72 h or with TBHP alone for 24 h. Alternatively, cells were pretreated with 1 μM MO-I-500 for 48 h, followed by co-treatment with MO-I-500 and 25 or 50 μM TBHP for an additional 24 h, for a total treatment duration of 72 h. Cellular metabolism was assessed using a Seahorse XF MitoStress assay, and oxidative stress markers, including ROS and superoxide levels, were quantified with DCFDA and MitoSOX probes. ATP content was measured using a bioluminescence assay.

RESULTS: FTO inhibition by MO-I-500 induced a metabolic shift toward an energy-efficient state, enhancing cellular resilience to oxidative stress. Pretreatment significantly reduced TBHP-induced oxidative damage, lowering intracellular ROS levels and preserving ATP content.

CONCLUSION: Together with our previous findings demonstrating the protective effects of MO-I-500 in astrocytes and recent studies supporting the importance of astrocyte function in neurodegeneration, these results suggest a dual protective role of MO-I-500 in neurons and astrocytes. This dual action positions MO-I-500 as a promising therapeutic strategy to mitigate oxidative damage and reduce the risk of neurodegenerative diseases, including Alzheimer's disease.},
}

@article {pmid41601969,
year = {2025},
author = {Ntsapi, C and Weyers, M and Chinheya, R and Jim, T and Matsabisa, M},
title = {Exploring cannabinoid modulation on autophagy mechanisms in Alzheimer's disease: a review.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1748368},
pmid = {41601969},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of toxic protein aggregates in the brain, leading to brain cell death and cognitive impairment. Central to AD pathogenesis is the autophagy pathway, a crucial cellular self-digestion process. Cannabinoids, the fundamental phytochemical compounds derived from the Cannabis sativa plant, have been demonstrated to exhibit neuroprotective qualities when used as a treatment at microdoses. However, the impact of multi-cannabinoid treatments on autophagy induction and subsequent cell survival in AD in vitro models remains uncertain. This review seeks to explore the potential of a multi-cannabinoid treatment strategy in enhancing neuronal cell survival through autophagy activation within an AD in vitro model. The proposed approach involves a combination of cannabinoids in their potential to upregulate autophagy mechanisms, potentially supporting neuronal cell resilience. By unravelling the mechanistic link between autophagy, cannabinoid treatment, and neuronal viability, this review aims to elucidate how cannabinoids influence neuronal function and survival at a cellular and molecular level. By offering insights into the exploitation of the endocannabinoid system, this review contributes to the development of novel cannabinoid-based treatment avenues for AD. This pursuit aligns with the broader objective of addressing the debilitating effects of AD on the quality of life for those affected.},
}

@article {pmid41601601,
year = {2025},
author = {Yang, E and Al-Ghraiybah, NF and Alkhalifa, AE and Woodie, LN and Swinford, SP and King, J and Greene, MW and Kaddoumi, A},
title = {Dose-dependent evaluation of chronic oleocanthal on metabolic phenotypes and organ toxicity in 5xFAD mice.},
journal = {Pharmacological research. Natural products},
volume = {8},
number = {},
pages = {},
pmid = {41601601},
issn = {2950-1997},
abstract = {In Alzheimer's disease (AD), alterations in the basal metabolic rate (BMR) and energy expenditure, known as metabolic phenotyping, are present early in the disease, which progresses as the disease advances. The Mediterranean diet, including extra-virgin olive oil (EVOO), has been known to reduce AD risk. Oleocanthal (OC) is a major phenolic compound in EVOO. Previous research showed that OC reduced brain amyloid-β, tau hyperphosphorylation, neuroinflammation, and improved blood-brain barrier and memory functions in AD mouse models. In this work, we aimed to investigate the dose-dependent impact of chronic oral OC treatment on modulating metabolic phenotypes affected by AD and its toxicity in 5xFAD mice, an AD mouse model. 5xFAD mice were treated with OC for 3 months, starting at the ages of one (prevention mode, before the pathology hallmarks appear) and 6 months (treatment mode, after the pathology hallmarks appear). Findings demonstrated OC altered metabolic phenotypes in the 5-20 mg/kg dose range in both groups. Furthermore, OC proved not toxic except at 20 mg/kg, where hepatic toxicity is observed. In conclusion, these findings highlight the OC effect in rectifying metabolic phenotypes in AD. However, it limits the dose range in mice to 5 and 10 mg/kg despite exhibiting a favorable response in metabolic parameters due to observed hepatotoxicity with the 20 mg/kg.},
}

@article {pmid41601569,
year = {2025},
author = {Gan, Y and Sun, J and Yang, D and Fang, C and Zhou, Z and Yin, J},
title = {Exploration and validation of biomarkers for Alzheimer's disease based on GEO database.},
journal = {IBRO neuroscience reports},
volume = {19},
number = {},
pages = {1157-1165},
pmid = {41601569},
issn = {2667-2421},
abstract = {OBJECTIVES: The purpose of this study is to leverage bioinformatics techniques to identify differentially expressed genes in Alzheimer's disease (AD), explore potential biomarkers for its early diagnosis, and provide new insights for the early diagnosis and treatment of AD.

METHODS: Two Alzheimer's disease-associated datasets, GSE66351 and GSE153712, were obtained from the Gene Expression Omnibus (GEO) database. Differential methylation analysis was conducted on the raw data utilizing the R programming language. Key genes were discerned by integrating LASSO regression, Pearson correlation analysis, and protein-protein interaction network analysis (PPI). Furthermore, the functional roles of these genes were investigated via Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analyses. To assess their causal association with AD, a Mendelian randomization analysis was performed.

RESULTS: In two AD datasets, we identified a total of 387 overlapping differential methylation sites, which mapped to 297 genes. The GO enrichment analysis indicated that these genes are involved in a range of biological processes, such as signal transduction, cell cycle regulation, as well as the function of neuronal cell bodies and synapses. Furthermore, KEGG pathway analysis uncovered that these genes play crucial roles in the PI3K-Akt and TGF-beta signaling pathways. By utilizing a combination of LASSO, Pearson correlation analysis, and PPI network interaction analysis, we have identified five pivotal genes: EBF1, IGF1, EGR2, PRDM16, and RBL2. Finally, Mendelian randomization analysis demonstrated that the IVW analysis for cg00000029 (RBL2) yielded statistically significant results with an odds ratio (OR) of 1.201, and a 95 % confidence interval (CI) ranging from 1.089 to 1.325, corresponding to a p -value of 0.000249.

CONCLUSIONS: This study not only confirmed the known genes linked to AD but, more significantly, revealed the potential connection between the RBL2 gene and AD. Furthermore, it verified a causal link between RBL2 and the risk of AD onset. This finding suggests that the RBL2 gene could serve as a promising biomarker for the early diagnosis of AD, thereby offering novel avenues for future research and clinical interventions.},
}

@article {pmid41599763,
year = {2026},
author = {Md Roslan, AH and Tengku Muhazan Shah, TMH and Mohd Saffian, S and John, LJ and Che Ramli, MD and Nassir, CMNCM and Mahadi, MK and Hein, ZM},
title = {Neuroprotective Potential of SGLT2 Inhibitors in Animal Models of Alzheimer's Disease and Type 2 Diabetes Mellitus: A Systematic Review.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {1},
pages = {},
doi = {10.3390/ph19010166},
pmid = {41599763},
issn = {1424-8247},
support = {GUP-2024-100//National University of Malaysia/ ; },
abstract = {Background: Alzheimer's disease (AD) features progressive cognitive decline and amyloid-beta (Aβ) accumulation. Insulin resistance in type 2 diabetes mellitus (T2DM) is increasingly recognised as a mechanistic link between metabolic dysfunction and neurodegeneration. Although sodium-glucose cotransporter-2 inhibitors (SGLT2is) have established glycaemic and cardioprotective benefits, their neuroprotective role remains less well defined. Objectives: This systematic review examines animal studies on the neuroprotective effects of SGLT2i in T2DM and AD models. Methods: A literature search was conducted across the Web of Science, Scopus, and PubMed databases, covering January 2014 to November 2024. Heterogeneity was assessed with I[2], and data were pooled using fixed-effects models, reported as standardised mean differences with 95% confidence intervals. We focus on spatial memory performance as measured by the Morris Water Maze (MWM) test, including escape latency and time spent in the target quadrant, as the primary endpoints. The secondary endpoints of Aβ accumulation, oxidative stress, and inflammatory markers were also analysed and summarised. Results: Twelve studies met the inclusion criteria for this review. A meta-analysis showed that SGLT2i treatment significantly improved spatial memory by reducing the escape latency in both T2DM and AD models. In addition, SGLT2i yielded a significant improvement in spatial memory, as indicated by an increased target quadrant time for both T2DM and AD. Furthermore, SGLT2i reduced Aβ accumulation in the hippocampus and cortex, which met the secondary endpoint; the treatment also lessened oxidative stress and inflammatory markers in animal brains. Conclusions: Our findings indicate that SGLT2is confer consistent neuroprotective benefits in experimental T2DM and AD models.},
}

@article {pmid41599761,
year = {2026},
author = {Yang, L and Yin, Y and Liu, X and Guo, B},
title = {Aptamer-Based Delivery of Genes and Drugs Across the Blood-Brain Barrier.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {1},
pages = {},
doi = {10.3390/ph19010164},
pmid = {41599761},
issn = {1424-8247},
support = {1R01CA293945-01/NH/NIH HHS/United States ; RP260101//Cancer Prevention and Research Institute of Texas/ ; },
abstract = {The blood-brain barrier (BBB) restricts therapeutic delivery to the central nervous system (CNS), hindering the treatment of neurological disorders, such as Alzheimer's disease, Parkinson's disease, brain cancers, and stroke. Aptamers, short single-stranded DNA or RNA oligonucleotides that can fold into unique 3D shapes and bind to specific target molecules, offer high affinity and specificity, low immunogenicity, and promising BBB penetration via receptor-mediated transcytosis targeting receptors such as the transferrin receptor (TfR) and low-density lipoprotein receptor-related protein 1 (LRP1). This review examines aptamer design through the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) and its variants, mechanisms of BBB crossing, and applications in CNS disorders. Recent advances, including in silico optimization, in vivo SELEX, BBB chip-based MPS-SELEX, and nanoparticle-aptamer hybrids, have identified brain-penetrating aptamers and enhanced the brain delivery efficiency. This review highlights the potential of aptamers to transform CNS-targeted therapies.},
}

@article {pmid41599628,
year = {2025},
author = {Titze-de-Almeida, R and Oliveira Gomes, GM and Santos, TCD and Titze-de-Almeida, SS},
title = {C16-siRNAs in Focus: Development of ALN-APP, a Promising RNAi-Based Therapeutic for Alzheimer's Disease.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {1},
pages = {},
doi = {10.3390/ph19010026},
pmid = {41599628},
issn = {1424-8247},
abstract = {This review examines a small interfering RNA (siRNA) designed for intrathecal (IT) injection, which reduces the formation of amyloid beta precursor protein (APP), a critical factor in the pathology of Alzheimer's disease (AD). The siRNA, designated ALN-APP, incorporates a 16-carbon chain (C16-siRNA) to enhance its delivery to the central nervous system (CNS) while leveraging advancements in specificity and duration of action based on previously approved drugs by the Food and Drug Administration. The development of ALN-APP involved a comprehensive analysis of the optimal carbon chain length and its conjugation position to the siRNA. Preclinical studies conducted on male Sprague Dawley rats, mice, and non-human primates (NHPs) demonstrated the efficacy of ALN-APP. In rats, an IT injection of C16-siRNAs at a concentration of 30 mg/mL, delivering a dose of 0.9 mg, resulted in cranial distribution via cerebrospinal fluid and led to a 75% reduction in copper-zinc superoxide dismutase 1 (SOD1) mRNA levels. These effects were dose-dependent and persisted for three months across multiple brain regions. Furthermore, studies in NHPs indicated that soluble APP levels were reduced to below 25%, sustained for two months. In the cerebrovascular amyloid Nos2[-/-] (CVN) mouse model of AD, administration of 120 µg of siRNA via the intracerebroventricular route produced reductions in APP expression, with mRNA levels remaining suppressed for 60 days in the ventral cortex. Indeed, ALN-APP controlled neuropathology in 5xFAD mice by significantly reducing amyloid levels and brain neuroinflammation, with improved behaviors in the elevated plus maze. Following these promising results in animal models, ALN-APP advanced to a Phase 1 trial, designated ALN-APP-001, which assessed its safety and efficacy in 12 participants with early-onset Alzheimer's disease (EOAD). Initial findings revealed a 55% reduction in soluble APPα and a 69% reduction in APPβ by day 15. These exploratory findings require further validation with larger cohorts and proper statistical analysis. In a subsequent cohort of 36 patients, administration of the 75 mg dose via IT injection led to mean reductions of 61.3% in soluble APPα (sAPPα) and 73.5% in soluble APPβ (sAPPβ) after one month. These silencing effects persisted for six months and were associated with important decreases in Aβ42 and Aβ40 levels. These results highlight the potential of ALN-APPs to address Alzheimer's pathology while maintaining a favorable safety profile. Whether ALN-APP succeeds in further clinical trials, key challenges include ensuring accessibility and affordability due to treatment costs, the need for specialized intrathecal administration, and establishing infrastructure for large-scale production of siRNAs. In conclusion, advancements in ALN-APP represent a promising strategy to reduce beta-amyloid formation in AD, with substantial biomarker reductions suggesting potential disease-modifying effects. Continued development may pave the way for innovative treatments for neurodegenerative diseases.},
}

@article {pmid41599308,
year = {2026},
author = {Ptak, A and Warchoł, M and Morańska, E and Laurain-Mattar, D and Spina, R and Dupire, F and Waligórski, P and Simlat, M},
title = {Amaryllidaceae Alkaloids and Phenolic Acids Identification in Leucojum aestivum L. Plant Cultures Exposed to Different Temperature Conditions.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {2},
pages = {},
doi = {10.3390/molecules31020258},
pmid = {41599308},
issn = {1420-3049},
support = {00078.DDD.6509.00124.2022.06//Agency for Restructuring and Modernization of Agriculture/ ; },
mesh = {*Amaryllidaceae Alkaloids/chemistry/metabolism ; Temperature ; *Hydroxybenzoates/metabolism/chemistry/analysis ; *Amaryllidaceae/chemistry/metabolism ; *Liliaceae/chemistry/metabolism ; },
abstract = {Amaryllidaceae alkaloids are of notable pharmacological relevance. For instance, galanthamine is used in the treatment of Alzheimer's disease, while other alkaloids (lycorine, crinine, etc.) derived from Amaryllidaceae plants are also of great interest because they exhibit antitumour, antiviral, antibacterial, antifungal, antimalarial, analgesic and cytotoxic properties. Phenolic acids comprise a group of natural bioactive substances that have commercial value in the cosmetic, food and medicinal industries due to their antioxidant, anticancer, anti-inflammatory and cardioprotective potential. In the present study, the effect of temperature (15, 20, 25 and 30 °C) on Amaryllidaceae alkaloid and phenolic acid biosynthesis in Leucojum aestivum in vitro plant cultures was investigated. The highest diversity of alkaloids (i.e., galanthamine, crinan-3-ol, demethylmaritidine, crinine, 11-hydroxyvitattine, lycorine, epiisohaemanthamine, chlidanthine) was noted in plants cultured at 30 °C. By contrast, ismine and tazettine were only present in plants cultured at 15 °C. Temperatures of 20 °C and 30 °C were found to stimulate galanthamine accumulation. The highest lycorine content was noted in plants grown at temperatures of 15 and 30 °C, and it was negatively correlated with the expression of the gene that encodes the cytochrome P450 96T (CYP96T) enzyme which catalyses a key step in the biosynthesis of different types of Amaryllidaceae alkaloids. This observation may reflect temperature-induced shifts in metabolic flux among different branches of Amaryllidaceae alkaloid biosynthesis. The observed stimulating effect of a 15 °C temperature on the chlorogenic, caffeic, p-coumaric, sinapic, ferulic and isoferulic acid content was in line with the highest expression of a gene that encodes the tyrosine decarboxylase (TYDC) enzyme, which is involved in plant stress response mechanisms. At 30 °C, however, the highest content of the caffeic, vanillic, p-coumaric and isoferulic acids was noted.},
}

*Amaryllidaceae Alkaloids/chemistry/metabolism
Temperature
*Hydroxybenzoates/metabolism/chemistry/analysis
*Amaryllidaceae/chemistry/metabolism
*Liliaceae/chemistry/metabolism

@article {pmid41599225,
year = {2026},
author = {Bernatoniene, J and Kopustinskiene, DM and Casale, R and Medoro, A and Davinelli, S and Saso, L and Petrikonis, K},
title = {Nrf2 Modulation by Natural Compounds in Aging, Neurodegeneration, and Neuropathic Pain.},
journal = {Pharmaceutics},
volume = {18},
number = {1},
pages = {},
doi = {10.3390/pharmaceutics18010118},
pmid = {41599225},
issn = {1999-4923},
support = {S-A-UEI-23-7//Research Council of Lithuania (LMTLT)/ ; },
abstract = {This review summarizes the role of nuclear factor erythroid 2-related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing vulnerability to diseases. In neurodegenerative disorders-including Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis-evidence indicates that impaired Nrf2 signaling contributes to oxidative damage, neuroinflammation, and mitochondrial dysfunction. Furthermore, in neuropathic pain, similar mechanisms are involved, and Nrf2 could play a role as a potential analgesic target because of its role in regulating cellular defense pathways. We also review natural Nrf2 modulators (e.g., flavonoids, other polyphenols, terpenoids, alkaloids), discussing their benefits alongside common translational limitations such as poor solubility, low oral bioavailability, rapid metabolism, and potential safety issues, including possible pro-oxidant effects and chemoresistance. We also outline future directions that should prioritize improving delivery systems, addressing NRF2/KEAP1 gene variations, evaluating combinations with standard therapies, exploring preventive applications, and defining dosing, treatment duration, and long-term safety. Overall, current evidence indicates that Nrf2 modulation is a practical, cross-cutting approach relevant to healthy aging and disease management.},
}

@article {pmid41599190,
year = {2026},
author = {El-Dakroury, WA and Salim, SA and Said, AR and Asaad, GF and Abdelhameed, MF and Shabana, ME and Ibrahim, MM and Abualmajd, SG and Mosaad, HH and Salama, AA and Asran, SE and Amer, ML and Doghish, AS and El-Tokhy, FS},
title = {Novel Repurposing of Empagliflozin-Loaded Buccal Composite (Chitosan/Silk Fibroin/Poly(lactic acid)) Nanofibers for Alzheimer's Disease Management via Modulation of Aβ-AGER-p-tau Pathway.},
journal = {Pharmaceutics},
volume = {18},
number = {1},
pages = {},
doi = {10.3390/pharmaceutics18010083},
pmid = {41599190},
issn = {1999-4923},
abstract = {Background/Objectives: Empagliflozin (EMPA) was repurposed for Alzheimer's disease (AD) treatment via buccal delivery, exploiting novel nanofibers (NFs) integrating chitosan (Cs), silk fibroin (Fb), and poly(lactic acid) (PLA). Methods: EMPA-loaded Cs/Fb/PLA NFs were electrospun in different formulations to optimize the formulation parameters. The optimized formulation was then investigated for its enhanced in vivo effect. Results: Optimized nanofiber diameters ranged from 459 ± 173 to 668 ± 148 nm, possessing bead-free morphology confirmed by SEM and satisfactory mechanical properties. EMPA was successfully well-dispersed in the polymer matrix as evidenced by FTIR, XRD, and drug content. The optimized NFs displayed a hydrophilic surface (contact angle < 90°), and biphasic drug release with sustained EMPA liberation (84.98% over 24 h). In vivo, buccal EMPA-Cs/Fb/PLA NFs in an AlCl3-induced AD rat model significantly reduced brain-amyloid-β, phosphorylated tau, IL-1β, and AGER expression by 2.88-, 2.64-, 2.87-, and 2.50-fold, respectively, compared to positive controls, and improved locomotor activity (1.86-fold) and cognitive performance (T-maze) (4.17-fold). Compared to pure EMPA, the nanofiber formulation achieved further reductions in amyloid-β (1.78-fold), p-tau (1.42-fold), IL-1β (1.89-fold), and AGER (1.38-fold), with efficacy comparable to memantine. Histopathological examination revealed preservation of the hippocampal neuronal structure. Conclusions: The findings suggest EMPA-loaded Cs/Fb/PLA NFs as a promising non-invasive, sustained-release buccal delivery platform for AD therapy, offering multimodal neuroprotection through modulation of the Aβ-AGER-p-tau axis.},
}

@article {pmid41599177,
year = {2026},
author = {Li, F and Wu, L and Feng, X and Li, Y and Fan, H},
title = {Extracellular Vesicles in Alzheimer's Disease: Dual Roles in Pathogenesis, Promising Avenues for Diagnosis and Therapy.},
journal = {Pharmaceutics},
volume = {18},
number = {1},
pages = {},
doi = {10.3390/pharmaceutics18010070},
pmid = {41599177},
issn = {1999-4923},
support = {LQ24H160003//Zhejiang Provincial Natural Science Foundation/ ; 2023KY299//Medical Scientific Research Foundation of Zhejiang Province/ ; 2024KY351//Medical Scientific Research Foundation of Zhejiang Province/ ; 2023J365//Ningbo Natural science foundation/ ; 2021A-012-G//Young Innovative Talent Project of Yongjiang Talent Introduction Programme of Ningbo Municipal Government/ ; 2023RC004//Bei'An Talent Programme of Jiangbei District of Ningbo/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tau tangles, chronic neuroinflammation, and synaptic loss, leading to cognitive decline. Extracellular vesicles (EVs)-lipid bilayer nanoparticles secreted by nearly all cell types-have emerged as critical mediators of intercellular communication, playing a complex dual role in both the pathogenesis and potential treatment of AD. This review generally delineates two opposite roles of EVs in pathogenesis and potential treatment of AD. On one hand, EVs derived from neurons, astrocytes, microglia and oligodendrocytes can propagate toxic proteins (Aβ, tau) and inflammatory signals, thereby accelerating disease progression. On the other hand, EVs-especially those from mesenchymal stem cells (MSCs)-exert neuroprotective effects by facilitating toxic protein clearance, modulating immune responses, preserving synaptic integrity, and alleviating oxidative stress. The cargo-carrying function of EVs gives them considerable diagnostic value. The associated cargos such as proteins and microRNAs (miRNAs) in the EVs may serve as minimally invasive biomarkers for early detection and monitoring of AD. Therapeutically, engineered EVs, including those incorporating CRISPR/Cas9-based genetic modification, are being developed as sophisticated delivery platforms for targeting core AD pathologies. Furthermore, this review highlights emerging technologies such as microfluidic chips and focused ultrasound (FUS), discussing their potential to enhance the translational prospects of EV-based early diagnostic and treatment for AD.},
}

@article {pmid41599176,
year = {2026},
author = {Santos, P and Sá Filho, AS and Aprigliano, V and Duarte, AG and Ribeiro, NA and Lombardo, KM and Fajemiroye, JO and Buchholz, AP and Vaz, VR and Chiappa, GR},
title = {Liraglutide and Exenatide in Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis of Cognitive Outcomes.},
journal = {Pharmaceutics},
volume = {18},
number = {1},
pages = {},
doi = {10.3390/pharmaceutics18010069},
pmid = {41599176},
issn = {1999-4923},
abstract = {Background/Objective: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) exhibit neuroprotective properties in preclinical models of Alzheimer's disease (AD), reducing amyloid accumulation, neuroinflammation, and insulin resistance within the brain. However, clinical evidence regarding their cognitive effects in AD and mild cognitive impairment (MCI) remains inconclusive. To evaluate the effects of GLP-1 RAs on cognitive outcomes in patients with AD or MCI due to AD. Methods: A systematic review was conducted according to PRISMA 2020 and registered in PROSPERO (CRD420251143171). Although the original registry was broad, the identification of a small set of homogeneous randomized controlled trials (RCTs) during screening, prior to data extraction, allowed for a random-effects meta-analysis of cognitive outcomes. RCTs enrolling adults with clinically or biomarker-confirmed AD or MCI were included. Interventions comprised liraglutide or exenatide compared with placebo. Standardized mean differences (SMD) in global cognitive scores were pooled using a random-effects model (restricted maximum likelihood [REML] estimator with Hartung-Knapp adjustment). Results: Three randomized trials (n = 278 participants; 51% women; mean age 68 ± 7 years) met inclusion criteria. Treatment duration ranged from 26 weeks to 18 months. Pooled analysis revealed no significant effect of GLP-1 RAs on global cognition compared with placebo -0.21 (95% CI -0.81 to 0.38; I[2] = 47%; τ[2] = 3.77). Sensitivity analyses restricted to liraglutide or studies ≥ 12 months yielded similar results. Conclusions: Current randomized evidence does not support cognitive improvement with GLP-1 RAs in AD or MCI.},
}

@article {pmid41598278,
year = {2026},
author = {Burgos-Puentes, S and Avendaño-Estrada, A and Sablón-Carrazana, M and Ramírez-Hernández, E and Granados-Juárez, A and Ramírez-Rodríguez, GB and Meraz-Ríos, M and Martínez-Coria, H and Ávila-Rodríguez, MA},
title = {Animal Models of Alzheimer's Disease Evaluated with [[11]C]Pittsburg Compound B.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {1},
pages = {},
doi = {10.3390/life16010123},
pmid = {41598278},
issn = {2075-1729},
support = {PRONACES 322512//CONAHCYT/ ; PAPPIT-IT201623//DGAPA-UNAM/ ; },
abstract = {Several animal models of Alzheimer's disease have been developed and tested for diagnostic and treatment purposes. [[11]C]PIB is the gold-standard radiotracer for the detection of Aβ plaque deposits, a hallmark of the disease. This study aimed to evaluate the in vivo detection of Aβ plaques using [[11]C]PIB microPET imaging across different animal models of Alzheimer's disease. The study included 3xTg-AD transgenic mice, TgF344-AD transgenic rats and Aβ injection-based rat model. The results showed an age-related increase in [[11]C]PIB uptake in 3xTg-AD mice, particularly in the midbrain and thalamus. In TgF344-AD rats, differences were also observed compared to WT controls, with the highest values observed in the hippocampus and cortex. In the injection-based model, inoculated rats showed greater uptake in the injection site than SHAM animals. Across all microPET studies, [[11]C]PIB uptake was consistently higher in females than in their male counterparts. These findings support the value of transgenic and Aβ injection-based models in preclinical research on Aβ plaque deposition and highlight the importance of considering species, model type, sex, and age in experimental design.},
}

@article {pmid41597254,
year = {2026},
author = {Brustovetsky, T and Khanna, R and Brustovetsky, N},
title = {Collapsin Response Mediator Protein 2 (CRMP2) Modulates Induction of the Mitochondrial Permeability Transition Pore in a Knock-In Mouse Model of Alzheimer's Disease.},
journal = {Cells},
volume = {15},
number = {2},
pages = {},
doi = {10.3390/cells15020179},
pmid = {41597254},
issn = {2073-4409},
support = {R01 NS098772/GF/NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics ; Disease Models, Animal ; Mitochondria/metabolism ; *Mitochondrial Permeability Transition Pore/metabolism ; Mice ; *Nerve Tissue Proteins/metabolism/genetics ; Phosphorylation ; *Intercellular Signaling Peptides and Proteins/metabolism ; Gene Knock-In Techniques ; Neurons/metabolism ; *Mitochondrial Membrane Transport Proteins/metabolism ; Mice, Transgenic ; Humans ; },
abstract = {Hyperphosphorylated collapsin response mediator protein 2 (CRMP2) is elevated in the cerebral cortex of an APP-SAA knock-in mouse model of Alzheimer's disease and binds the adenine nucleotide translocase (ANT) in a phosphorylation-dependent manner. We propose that, in Alzheimer's disease (AD) mitochondria, dissociation of hyperphosphorylated CRMP2 from ANT promotes opening of the permeability transition pore (PTP). We showed that purified ANT, when reconstituted into giant liposomes, forms large calcium-dependent channels resembling the PTP, which are effectively blocked by recombinant, unphosphorylated CRMP2. In synaptic mitochondria isolated from the cortices of APP-SAA knock-in mice and control B6J hAbeta mice, we observed an increased susceptibility to permeability transition pore (PTP) induction in AD mitochondria, accompanied by reduced viability of cultured cortical neurons. Pre-treatment of AD mice with the CRMP2-binding small molecule (S)-lacosamide ((S)-LCM), which prevents CRMP2 hyperphosphorylation and restores its interaction with ANT, attenuated PTP induction and improved neuronal viability. Interestingly, direct application of (S)-LCM to isolated mitochondria failed to suppress PTP induction, indicating that its protective effect requires upstream cellular mechanisms. These findings support a phosphorylation-dependent role for CRMP2 in regulating PTP induction in AD mitochondria and highlight (S)-LCM as a promising therapeutic candidate for mitigating mitochondrial dysfunction and enhancing neuronal viability in AD.},
}

Animals
*Alzheimer Disease/metabolism/pathology/genetics
Disease Models, Animal
Mitochondria/metabolism
*Mitochondrial Permeability Transition Pore/metabolism
Mice
*Nerve Tissue Proteins/metabolism/genetics
Phosphorylation
*Intercellular Signaling Peptides and Proteins/metabolism
Gene Knock-In Techniques
Neurons/metabolism
*Mitochondrial Membrane Transport Proteins/metabolism
Mice, Transgenic
Humans

@article {pmid41596702,
year = {2026},
author = {Shaikh, A and Ahmad, F and Murthy, J and Teoh, SL and Yahaya, MF},
title = {Early Molecular Biomarkers in an Amyloid-β-Induced Rat Model of Alzheimer's Disease: Effects of Kelulut Honey.},
journal = {International journal of molecular sciences},
volume = {27},
number = {2},
pages = {},
doi = {10.3390/ijms27021059},
pmid = {41596702},
issn = {1422-0067},
support = {GUP-2021-038//UKM Research University Grant/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/chemically induced/pathology/blood ; *Amyloid beta-Peptides/metabolism/toxicity ; *Biomarkers/metabolism/blood ; Rats ; Disease Models, Animal ; *Honey ; Chemokine CCL2/metabolism/blood ; Hippocampus/metabolism/pathology ; Male ; Peptide Fragments/metabolism ; tau Proteins/metabolism ; Superoxide Dismutase-1/metabolism/blood ; Phosphorylation ; Humans ; Transcription Factor RelA/metabolism ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide, characterized by progressive neurodegeneration and cognitive decline. Early diagnosis remains critical for enabling timely intervention. However, detecting the earliest pathological changes is challenging due to the limited availability of reliable biomarkers that reflect early disease pathology in experimental models. This study evaluated molecular markers associated with AD-related processes in a rat model inoculated with human amyloid β (Aβ)1-42 peptides. We assessed the levels of biomarkers: Aβ1-42, Aβ42, phosphorylated tau, monocyte chemoattractant protein-1 (MCP-1), nuclear factor kappa B (NF-κB p65) and superoxide dismutase 1 (SOD1) in hippocampal tissue and serum using enzyme-linked immunosorbent assay. A treatment group receiving Kelulut honey was included to evaluate biomarker responsiveness. Results showed significant elevation in hippocampal Aβ1-42 and phosphorylated tau in diseased rats, with changes in inflammatory markers MCP-1 and NF-κB p65, whereas no significant change was observed in oxidative stress marker SOD1. Serum levels of Aβ1-42 and MCP-1 did not differ significantly between groups, indicating limited peripheral sensitivity after a month of disease induction. These findings suggest that amyloid-, tau-, and inflammation-related markers in hippocampal tissue may be informative for early pathological changes in this acute model, while serum markers showed limited sensitivity.},
}

Animals
*Alzheimer Disease/metabolism/chemically induced/pathology/blood
*Amyloid beta-Peptides/metabolism/toxicity
*Biomarkers/metabolism/blood
Rats
Disease Models, Animal
*Honey
Chemokine CCL2/metabolism/blood
Hippocampus/metabolism/pathology
Male
Peptide Fragments/metabolism
tau Proteins/metabolism
Superoxide Dismutase-1/metabolism/blood
Phosphorylation
Humans
Transcription Factor RelA/metabolism

@article {pmid41596649,
year = {2026},
author = {Al-Ghraiybah, NF and Alkhalifa, AE and Itokazu, Y and Farr, TO and Perez, NC and Ali, H and Kaddoumi, A},
title = {Apolipoprotein E4 in Alzheimer's Disease: Role in Pathology, Lipid Metabolism, and Drug Treatment.},
journal = {International journal of molecular sciences},
volume = {27},
number = {2},
pages = {},
doi = {10.3390/ijms27021004},
pmid = {41596649},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology/genetics ; *Apolipoprotein E4/metabolism/genetics ; *Lipid Metabolism ; Animals ; Blood-Brain Barrier/metabolism/pathology ; },
abstract = {Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. Among the genetic risk factors linked to AD, the Apolipoprotein E4 (ApoE4) remains the strongest. It is well known that carrying the ApoE4 isoform is associated with advanced AD pathology, blood-brain barrier (BBB) disruption, and changes in lipid metabolism. In this review, we provide an overview of the role of centrally and peripherally produced ApoE in AD. After this introduction, we focus on new findings regarding ApoE4's effects on AD pathology and BBB function. We then discuss ApoE's role in lipid metabolism in AD, highlighting examples of lipid changes caused by carrying the ApoE4 isoform. Next, the review explores the implications of ApoE4 isoforms for current treatments-whether they involve anti-amyloid therapy or other pharmacological agents used for AD-emphasizing the importance of personalized medicine approaches for patients with this high-risk allele. This review aims to provide an updated overview of ApoE4's effects on AD pathology and treatment. By integrating recent discoveries, it underscores the critical need to consider ApoE4 status in both research and clinical settings to enhance therapeutic strategies and outcomes for individuals with AD.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy/pathology/genetics
*Apolipoprotein E4/metabolism/genetics
*Lipid Metabolism
Animals
Blood-Brain Barrier/metabolism/pathology

@article {pmid41596530,
year = {2026},
author = {Higgins, M and Wasef, V and Kwakowsky, A},
title = {FDA-Approved Passive Immunization Treatments Against Aβ in Alzheimer's Disease: Where Are We Now?.},
journal = {International journal of molecular sciences},
volume = {27},
number = {2},
pages = {},
doi = {10.3390/ijms27020883},
pmid = {41596530},
issn = {1422-0067},
mesh = {*Alzheimer Disease/therapy/immunology/metabolism ; Humans ; *Amyloid beta-Peptides/immunology/metabolism/antagonists & inhibitors ; *Immunization, Passive/methods ; United States ; Apolipoprotein E4/genetics ; Blood-Brain Barrier/metabolism ; United States Food and Drug Administration ; Animals ; Antibodies, Monoclonal/therapeutic use ; Biomarkers ; Antibodies, Monoclonal, Humanized ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by decreased amyloid-beta (Aβ) clearance, enhanced Aβ aggregation, an increased risk of amyloid-related imaging abnormalities (ARIA), and blood-brain barrier (BBB) dysfunction. The APOE4 allele, being the leading genetic risk factor for AD, contributes strongly to these symptoms. This review covers the relationship between APOE4 status and the efficacy of FDA-approved monoclonal antibody (mAb) therapies, namely aducanumab, lecanemab, and donanemab. Across several clinical trials, APOE4 carriers exhibited higher rates of ARIA-E and ARIA-H compared to non-carriers. While the therapies did often meet biomarker endpoints (i.e., reduced amyloid), benefits were only observed in early and mild AD, and cognitive benefits were often marginal. Going forward, experimental apoE4-targeted immunotherapies may ease the burden of APOE4-related pathology. The field is shifting towards a more integrated approach, focusing on earlier interventions, biomarker-driven precision treatment, and improved drug delivery systems, such as subcutaneous injections, receptor-mediated transport, and antibodies with enhanced BBB penetration. As it stands, high treatment costs, limited accessibility, and strict eligibility criteria all stand as barriers to treatment. By integrating the APOE4 genotype into treatment planning and focusing on disease-stage-specific approaches, a safer and more effective means of treating AD could be achieved.},
}

*Alzheimer Disease/therapy/immunology/metabolism
Humans
*Amyloid beta-Peptides/immunology/metabolism/antagonists & inhibitors
*Immunization, Passive/methods
United States
Apolipoprotein E4/genetics
Blood-Brain Barrier/metabolism
United States Food and Drug Administration
Animals
Antibodies, Monoclonal/therapeutic use
Biomarkers
Antibodies, Monoclonal, Humanized

@article {pmid41596255,
year = {2026},
author = {Wang, Z and Ba, S and Li, M and Wei, Y and Wang, Y and Mao, J and Xiang, Y and Qin, D and Zeng, C},
title = {Targeting the Gut Microbiota: Mechanistic Investigation of Polyphenol Modulation of the Gut-Brain Axis in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {2},
pages = {},
doi = {10.3390/ijms27020604},
pmid = {41596255},
issn = {1422-0067},
support = {82560898//National Natural Science Foundation of China/ ; 82060831//National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease/drug therapy/microbiology/metabolism ; Humans ; *Gastrointestinal Microbiome/drug effects ; *Polyphenols/pharmacology/therapeutic use ; *Brain/drug effects/metabolism ; Animals ; },
abstract = {Alzheimer's disease (AD) represents an increasingly severe global health challenge. Recently, the role of the gut-brain axis in AD pathogenesis has garnered significant attention. Dysbiosis of the gut microbiota can exacerbate core pathologies such as neuroinflammation, amyloid beta (Aβ) deposition, and tau hyperphosphorylation through neural, endocrine, and immune pathways. Polyphenolic compounds have emerged as a focal point in neuroprotective research owing to their pronounced anti-inflammatory and antioxidant properties. Notably, polyphenols exert effects not only by directly influencing the central nervous system (CNS) but also through indirectly modulating the composition and function of the gut microbiota, thereby impacting bidirectional gut-brain communication. This dual mechanism offers a potential avenue for their application in the prevention and treatment of AD. This review aims to compile recent research on the relationship between polyphenols and the gut microbiota. We assessed the literature from PubMed, Google Scholar, and Web of Science databases, published from the establishment of the database to 24 November 2025. The keywords used include "Polyphenols", "Gut-brain axis", "Gut microbiota", "Alzheimer's disease", "Epigallocatechin gallate", "Quercetin", "Curcumin", "Ferulic acid", "Resveratrol", "Anthocyanin", "Myricetin", "Chlorogenic acid", etc. This review discusses the various mechanisms by which polyphenols influence AD through modulating the gut microbiota. Polyphenols and gut microbiota exhibit critical bidirectional interactions. On one hand, the bioavailability and activity of polyphenols are highly dependent on metabolic conversion by gut microbiota. On the other hand, polyphenols selectively promote the proliferation of beneficial bacteria such as bifidobacteria and lactobacilli like prebiotics, while inhibiting the growth of pathogenic bacteria. This reshapes the intestinal microecology, enhances barrier function, and regulates beneficial metabolites. Utilizing a nanotechnology-based drug delivery system, the pharmacokinetic stability and brain targeting efficacy of polyphenols can be significantly enhanced, providing innovative opportunities for the targeted prevention and management of AD.},
}

*Alzheimer Disease/drug therapy/microbiology/metabolism
Humans
*Gastrointestinal Microbiome/drug effects
*Polyphenols/pharmacology/therapeutic use
*Brain/drug effects/metabolism
Animals

@article {pmid41595595,
year = {2025},
author = {Beretti, F and Malenchini, M and Gatti, M and Maraldi, T},
title = {Oxidative Stress as a Central Mechanistic Bridge Between Alzheimer's and Vascular Pathologies in Mixed Dementia: Emerging Evidence and Therapeutic Perspectives.},
journal = {Biomedicines},
volume = {14},
number = {1},
pages = {},
doi = {10.3390/biomedicines14010059},
pmid = {41595595},
issn = {2227-9059},
abstract = {Mixed dementia (MD), characterized by overlapping features of Alzheimer's disease (AD) and vascular dementia (VaD), represents the most prevalent form of late-life cognitive decline. Increasing evidence identifies oxidative stress as a unifying molecular mechanism driving both neurodegenerative and vascular pathologies in MD. Reactive oxygen species (ROS) contribute to amyloid-β aggregation, tau hyperphosphorylation, endothelial dysfunction, and blood-brain barrier disruption, creating a self-perpetuating cycle of neuronal and vascular injury. Mechanistic models demonstrate how chronic hypoperfusion and mitochondrial dysfunction exacerbate ROS generation and neuroinflammation, while impaired Nrf2-mediated antioxidant defense further amplifies damage. Therapeutically, classical antioxidants show inconsistent efficacy, shifting focus toward mitochondrial protection, Nrf2 activation, and lifestyle-based oxidative load reduction. Therefore, we sought to outline therapeutic approaches capable of broadly targeting these mechanisms, through focused narrative analysis of recent studies employing delivery systems for antioxidant proteins and/or redox-regulating miRNAs. In particular, experimental interventions using mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) demonstrate neuroprotective and anti-inflammatory effects via the Nrf2 pathway, suggesting promising avenues for multimodal treatment. Integrating oxidative, vascular, and neurodegenerative paradigms is essential for advancing diagnostic precision and developing targeted interventions capable of addressing the complex pathophysiology of mixed dementia.},
}

@article {pmid41595571,
year = {2025},
author = {Lee, MS and Son, SJ and Kim, J and Go, S and Hong, CH and Roh, HW and Chang, J},
title = {Exploratory Analysis of Autophagy-Lysosomal Pathway Proteins in Dermal Fibroblasts as Potential Peripheral Biomarkers for Alzheimer's Disease: A Pilot Study.},
journal = {Biomedicines},
volume = {14},
number = {1},
pages = {},
doi = {10.3390/biomedicines14010034},
pmid = {41595571},
issn = {2227-9059},
support = {RS-2024-00338983//National Research Foundation of Korea/ ; RS-2019-NR040055//National Research Foundation of Korea/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is characterized by accumulation of abnormal intracellular substances and autophagy-lysosomal pathway (ALP) dysfunction. While current diagnostic methods rely on cerebrospinal fluid biomarkers and neuroimaging, minimally invasive peripheral biomarkers are needed. Dermal fibroblasts could serve as accessible reporters of AD-related molecular changes. This exploratory pilot study investigated whether ALP-associated proteins in patient-derived fibroblasts could serve as potential peripheral biomarkers for AD diagnosis. Methods: We analyzed dermal fibroblasts from 9 AD patients (amyloid Positron emission tomography (PET)-positive) and 9 age-matched controls (amyloid PET-negative). Comprehensive immunoblot analysis assessed expression profiles of 16 AD- and ALP-associated proteins. Autophagic flux and lysosomal function were evaluated using bafilomycin A1 treatment and LysoTracker staining. Diagnostic performance was assessed through receiver operating characteristic (ROC) curve analysis and multivariable logistic regression. Results: AD fibroblasts showed significantly reduced Beta-site APP cleaving enzyme 1 (BACE1) (p = 0.022) and elevated Tax1-binding protein 1 (TAX1BP1) (p = 0.035) expression. BCL2-associated athanogene proteins 2 (BAG2) and OPTN demonstrated consistent directional changes across patients. Preliminary ROC analysis showed promising performance for protein combinations, with BAG2 + OPTN achieving Area under the curve (AUC) = 0.963 (sensitivity 77.8%, specificity 88.9%). Integration with Apolipoprotein E4 (APOE4) status further enhanced diagnostic accuracy (APOE4 + BACE1: AUC = 0.914). Notably, baseline autophagic flux and lysosomal acidification were preserved, suggesting pathway-specific rather than systemic ALP dysfunction. Conclusions: This exploratory study provides preliminary evidence that dermal fibroblast-derived ALP proteins show disease-associated alterations in AD and may represent potential peripheral biomarkers. However, given the small sample size (n = 18) and lack of independent validation, these findings require confirmation in larger multi-center cohorts before clinical translation.},
}

@article {pmid41594924,
year = {2026},
author = {Bao, Y and Miao, G and He, N and Bao, X and Shi, Z and Hu, C and Liu, X and Wang, B and Sun, C},
title = {Melatonin as a Guardian of Mitochondria: Mechanisms and Therapeutic Potential in Neurodegenerative Diseases.},
journal = {Biology},
volume = {15},
number = {2},
pages = {},
doi = {10.3390/biology15020189},
pmid = {41594924},
issn = {2079-7737},
abstract = {Mitochondrial dysfunction is a key early pathological process in neurodegenerative diseases (NDs), leading to oxidative stress, impaired energy metabolism, and neuronal apoptosis prior to the onset of clinical symptoms. Although mitochondria represent important therapeutic targets, effective interventions targeting mitochondrial function remain limited. This review summarizes current evidence regarding the mechanisms by which melatonin protects mitochondria and evaluates its therapeutic relevance, with a primary focus on Alzheimer's disease, Parkinson's disease, and Huntington's disease-the major protagonists of NDs-while briefly covering other NDs such as amyotrophic lateral sclerosis, multiple sclerosis, and prion diseases. Melatonin selectively accumulates in neuronal mitochondria and exerts neuroprotection through multiple pathways: (1) direct scavenging of reactive oxygen species (ROS); (2) transcriptional activation of antioxidant defenses via the SIRT3 and Nrf2 pathways; (3) regulation of mitochondrial dynamics through DRP1 and OPA1; and (4) promotion of PINK1- and Parkin-mediated mitophagy. Additionally, melatonin exhibits context-dependent pleiotropy: under conditions of mild mitochondrial stress, it restores mitochondrial homeostasis; under conditions of severe mitochondrial damage, it promotes pro-survival autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby conferring stage-specific therapeutic advantages. Overall, melatonin offers a sophisticated mitochondria-targeting strategy for the treatment of NDs. However, successful clinical translation requires clarification of receptor-dependent signaling pathways, development of standardized dosing strategies, and validation in large-scale randomized controlled trials.},
}

@article {pmid41594819,
year = {2026},
author = {Motoi, Y and Sanjo, N},
title = {Switching from Oral Cholinesterase Inhibitors to a Transdermal Donepezil Patch Attenuated Gastrointestinal Symptoms and Allowed Treatment Continuation in Three Patients with Alzheimer's Disease in Clinical Settings.},
journal = {Brain sciences},
volume = {16},
number = {1},
pages = {},
doi = {10.3390/brainsci16010098},
pmid = {41594819},
issn = {2076-3425},
abstract = {Background: Cholinesterase inhibitors (ChEIs) are commonly prescribed for the treatment of Alzheimer's disease (AD) and achieve long-term benefits for cognition and survival in real-world settings. However, the discontinuation rate is high due to their side effects, with gastrointestinal (GI) symptoms hampering long-term prescriptions. The risk of side effects associated with rivastigmine was previously shown to be lower with transdermal delivery than with oral capsules; however, this has yet to be examined in detail for donepezil, the most widely used ChEI. The daily application of a donepezil transdermal patch was officially approved in Japan in 2023. The incidence of side effects was lower with the donepezil transdermal patch than with oral donepezil in healthy volunteers, but has not yet been assessed in clinical settings. Results: We herein report three AD patients in two different memory clinics who developed GI symptoms with oral ChEIs that were attenuated by switching to the donepezil transdermal patch. Conclusions: The donepezil transdermal patch may improve tolerability and adherence in patients who develop gastrointestinal adverse effects with oral donepezil.},
}

@article {pmid41594643,
year = {2026},
author = {Pawar, Y and Kopranovic, A and C S, R and Meyer-Almes, FJ},
title = {Epigenetic Dysregulation in Neurodegeneration: The Role of Histone Deacetylases and Emerging Inhibitor Strategies.},
journal = {Biomolecules},
volume = {16},
number = {1},
pages = {},
doi = {10.3390/biom16010103},
pmid = {41594643},
issn = {2218-273X},
support = {none//Darmstadt University of Applied Sciences/ ; },
mesh = {Humans ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use/chemistry ; *Histone Deacetylases/metabolism/genetics ; *Epigenesis, Genetic/drug effects ; *Neurodegenerative Diseases/genetics/drug therapy/metabolism ; Animals ; },
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are characterized by complex pathologies with progressive neurodegeneration, protein misfolding, oxidative stress, and persistent inflammation. Recent findings indicate the pivotal involvement of epigenetic disruption, particularly aberrant histone deacetylase (HDAC) activity, in disease initiation and progression. In the current review, we systematically discuss the mechanistic function of HDACs across all classes (I, IIa, IIb, III, and IV) in neurodegenerative disease mechanisms, such as their involvement in the modulation of gene expression, mitochondrial function, proteostasis, and neuronal survival. We discuss the therapeutic potential, as well as limitations, of HDAC inhibitors (HDACis), such as pan-inhibitors and isoenzyme-selective inhibitors, and new multi-target-directed ligands with HDAC inhibition combined with acetylcholinesterase modulation, PDE modulation, MAO-B inhibition, or NMDAR modulation. Particular emphasis is placed on the development of HDAC6-selective inhibitors with enhanced brain permeability and reduced toxicity, which have shown promising preclinical efficacy in ameliorating hallmark pathologies of AD, PD, and HD. In addition, s-triazine-based scaffolds have recently emerged as promising chemotypes in HDAC inhibitor design, offering favorable pharmacokinetic profiles, metabolic stability, and the potential for dual-target modulation relevant to neurodegeneration. The review also explores the future of HDAC-targeted therapies, including PROTAC degraders, dual-inhibitor scaffolds, and sustainable, BBB-penetrant molecules. Collectively, this review underscores the importance of HDAC modulation as a multifaceted strategy in the treatment of neurodegenerative diseases and highlights the need for continued innovation in epigenetic drug design.},
}

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

@article {pmid41594629,
year = {2026},
author = {Zedde, M and Losa, M and Grisafi, E and Lucia, DD and Gandoglia, I and Del Sette, M and Pardini, M and Roccatagliata, L and Pascarella, R and Piazza, F},
title = {Spontaneous and Drug-Induced Amyloid-Related Imaging Abnormalities: Overlaps, Divergences, and Clinical Implications Across a Continuum Between Alzheimer's Disease and Cerebral Amyloid Angiopathy.},
journal = {Biomolecules},
volume = {16},
number = {1},
pages = {},
doi = {10.3390/biom16010089},
pmid = {41594629},
issn = {2218-273X},
mesh = {Humans ; *Cerebral Amyloid Angiopathy/diagnostic imaging/metabolism/pathology ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology ; *Amyloid/metabolism ; },
abstract = {BACKGROUND: Amyloid-related imaging abnormalities (ARIA) have gained significance in the context of anti-amyloid therapies (AATs), exhibiting clinical and radiological manifestations that overlap with Cerebral Amyloid Angiopathy-related inflammation (CAA-ri). This review aims to elucidate the similarities and differences between spontaneous (sARIA) and drug-induced ARIA (dARIA).

METHODS: We conducted a narrative review comparing sARIA and dARIA, focusing on their underlying mechanisms, clinical presentations, and implications for diagnosis and treatment.

RESULTS: Both sARIA and dARIA are characterized by similar pathophysiological mechanisms involving amyloid deposits and neuroinflammation. Notably, ARIA can manifest as ARIA-E (edema) or ARIA-H (hemorrhage), with varying incidence rates in clinical trials. The review highlights that while sARIA occurs independently from treatment, dARIA is associated with AAT and can lead to significant symptomatic presentations.

CONCLUSIONS: Understanding the continuum between sARIA and dARIA is crucial for improving diagnostic criteria, risk stratification, and therapeutic approaches. The proposed unified framework emphasizes the need for consensus in managing these conditions and advancing future research in amyloid-related diseases.},
}

Humans
*Cerebral Amyloid Angiopathy/diagnostic imaging/metabolism/pathology
*Alzheimer Disease/diagnostic imaging/metabolism/pathology
*Amyloid/metabolism

@article {pmid41593839,
year = {2026},
author = {Grese, Z and Naidu, A and Silverglate, BD and Grossberg, GT},
title = {The impact of the ketogenic diet on Alzheimer's disease progression.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/14737175.2026.2621502},
pmid = {41593839},
issn = {1744-8360},
abstract = {INTRODUCTION: The ketogenic diet as a potential treatment for Alzheimer's disease (AD) has been investigated in several controlled trials. This topic is significant because of the limited nature of current interventions for AD, and the increasing recognition that lifestyle interventions may be important for reducing the risk of AD. The ketogenic diet is one of the few lifestyle interventions that has the potential to be beneficial after diagnosis.

AREAS COVERED: In this narrative review, the authors discuss the biological plausibility of how a ketogenic diet may improve amyloid burden and reduce neuroinflammation by providing an alternative energy source. They review relevant meta-analyses, systematic reviews, and controlled trials to investigate this diet in people diagnosed with AD. To this end, the authors used PubMed to search for appropriate systematic reviews and human trials, and closely examined the bibliographies of these papers to find trials potentially missed in their initial search.

EXPERT OPINION: More research is needed before a ketogenic diet could be broadly recommended in patients diagnosed with AD. However, to the extent a treatment effect has been demonstrated, it is comparable to some pharmaceutical interventions in AD. Challenges that remain include demonstrating improvement in quality of life, improving adherence, and standardizing ketogenic therapies.},
}

@article {pmid41593813,
year = {2026},
author = {Beusink, M and de Rijke, TJ and Schaaij-Visser, TBM and Berkhout, M and Kroon, L and Smeitink, M and van der Landen, SM and Kaijser, KKM and Saaltink, DJ and van der Rhee, E and Rebers, S and de Boer, C and Rhodius-Meester, HFM and van der Flier, WM and Visser, LNC},
title = {Evaluation and lessons learned regarding Public Involvement: a panel advising on an Alzheimer's disease and related dementia cohort study.},
journal = {Research involvement and engagement},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40900-026-00844-1},
pmid = {41593813},
issn = {2056-7529},
support = {ZonMw projectnumber 10510022110004//the Memorabel Dementia Fellowship 2021/ ; },
}

@article {pmid41593242,
year = {2026},
author = {Hobson, R and Levy, SHS and Singal, CMS and Flaherty, D and Xiao, H and Ciener, B and Reddy, H and Zabinyakov, N and Kim, CY and Teich, AF and Shneider, NA and Bradshaw, EM and Elyaman, W},
title = {Clonal CD8[+] T cells populate the leptomeninges and coordinate with immune cells in human degenerative brain diseases.},
journal = {Nature immunology},
volume = {},
number = {},
pages = {},
pmid = {41593242},
issn = {1529-2916},
support = {PF-IMP-870699//Parkinson's Foundation (Parkinson's Foundation, Inc.)/ ; },
abstract = {Meningeal immune cells monitor the central nervous system (CNS) and influence neuroinflammation in mice, but the human leptomeningeal immune landscape and the changes that occur in this immunological niche in neurodegeneration remain underexplored. Here we performed single-cell RNA and T cell receptor (TCR) sequencing of 99,625 high-quality immune cells from 57 leptomeninges and brain samples from donors with Alzheimer's disease (AD), amyotrophic lateral sclerosis and Parkinson's disease and found that although the leptomeninges are home to highly clonally expanded CD8 tissue-resident memory (TRM) T cells, the maximal level of clonal expansion was decreased in AD in comparison to non-neurodegenerative controls. Intra-patient paired tissue analysis further revealed that brain and leptomeningeal TCR repertoires share significant similarities, but tissue-specific clones emerge in AD. Finally, in AD, the degree of CD8 TRM clonal expansion was positively correlated with microglial TGFB2, suggesting that brain and leptomeningeal immune cells coordinate their activities in AD. In addition to identifying key inflammatory dynamics in the human degenerating CNS, this study establishes a foundational resource for future studies that could inform treatment for AD and other neuroinflammatory diseases.},
}

@article {pmid41593034,
year = {2026},
author = {Fulop, T and Cohen, AA and Frost, EH and Lévesque, S and Khalil, A and Rodrigues, S and Desroches, M and Alami, M and Berrougui, H and Ramassamy, C and Hirokawa, K and Witkowski, JM and Laurent, B},
title = {Unmasking the hidden catalyst: How infections trigger Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251415571},
doi = {10.1177/13872877251415571},
pmid = {41593034},
issn = {1875-8908},
abstract = {For years, the understanding of Alzheimer's disease (AD) has been shaped by the amyloid hypothesis, which suggests that pathological markers like amyloid-β (Aβ) and phosphorylated tau are the primary drivers of the disease. This hypothesis has guided the development of major treatment strategies, including monoclonal antibodies targeting Aβ. However, most of these treatments have failed to produce clinically significant results, highlighting the urgent need for a new therapeutic approach. It is now evident that AD is a complex, multifactorial disease that develops over decades, ultimately leading to Aβ and tau accumulation. Therefore, addressing the underlying causes of these depositions is crucial. One well-supported yet underrecognized theory is the infection hypothesis, which links infections to AD pathology. Despite substantial scientific evidence, this perspective has faced significant resistance. In this review, we describe how chronic infections contribute to AD by triggering neuroinflammation and Aβ accumulation. We also explore the barriers to accepting the infection hypothesis and the steps necessary for its integration into drug development and early-stage treatment strategies. Persisting with an amyloid-centric approach will only exacerbate the societal burden. Embracing the infection hypothesis could transform AD research, diagnosis, and treatment, bringing new hope to millions.},
}

@article {pmid41592930,
year = {2026},
author = {Fu, Z and Yang, Y and Chung, MK and Cheng, F},
title = {Artificial Intelligence to Guide Repurposing of Drugs.},
journal = {Annual review of medicine},
volume = {77},
number = {1},
pages = {381-398},
doi = {10.1146/annurev-med-050224-122802},
pmid = {41592930},
issn = {1545-326X},
mesh = {*Drug Repositioning/methods ; Humans ; *Artificial Intelligence ; Machine Learning ; Precision Medicine ; },
abstract = {With the pharmacokinetics, dosing, safety, and manufacturing of approved or investigational drugs already well-characterized, drug repurposing and repositioning offer emerging strategies to rapidly develop effective treatments for various challenging diseases. However, the growing mass of genetic and multiomics data has not been effectively explored by the drug repurposing community due to a lack of accurate approaches. This review aims to be an authoritative, critical, and accessible review and discussion of general interest to the drug repurposing community concerning the use of artificial intelligence (AI) and machine learning (ML) tools. Emerging questions include what is achievable with AI in this domain and what its impact will be, what AI and ML embrace, and how we, as geneticists, pharmacologists, and computational scientists, can contribute to the discovery of new, inexpensive, and affordable repurposable medicines. The fast growth of genetics and multiomics data (genomics, transcriptomics, proteomics, metabolomics, and radiomics) and electronic health records in diverse populations contributes to answering questions, including how to rapidly identify effective repurposable medicines, what a clinically meaningful effect size in trials is, and what the potential implications for precision medicine are. This review discusses AI and ML for drug repurposing in the context of genetics, multiomics, real-world data collection, and crowdsourcing of knowledge. We conclude by considering questions on how AI and ML methodologies can unite the diverse aspects of translational medicine for emerging treatment development in human-challenging diseases.},
}

*Drug Repositioning/methods
Humans
*Artificial Intelligence
Machine Learning
Precision Medicine

@article {pmid41592521,
year = {2026},
author = {Wang, J and Su, O and Meng, Z and Lu, L and Qi, Y and Zhang, Z and Li, Z and Dong, X and Lian, H and Mu, Y},
title = {Layered double hydroxide-induced modulation of oxidative stress in disease therapy.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {195},
number = {},
pages = {119063},
doi = {10.1016/j.biopha.2026.119063},
pmid = {41592521},
issn = {1950-6007},
abstract = {Oxidative stress plays a crucial role in the development of various diseases, including diabetes, cardiovascular diseases, cancer, and rheumatic disorders. It disrupts the redox balance and initiates a series of pathological changes. As two-dimensional inorganic solids with an open structure and anion-exchange properties, layered double hydroxides (LDHs) offer significant advantages in the biomedical field, such as drug carriers, antioxidant catalysts. This article outlines application of LDHs in the treatment of cancer, rheumatic diseases, bone disorders, diabetes, Alzheimer's disease, and other conditions. More importantly, this paper elaborates on the challenges faced by the application of LDHs, including the biological activity to be explored, the performance to be optimized, and their in vivo functions and molecular mechanisms to be clarified. The solution strategies have also been discussed, which pointed out the direction for promoting the clinical transformation and application of LDHs in the future.},
}

@article {pmid41592400,
year = {2026},
author = {Gönüllü, S and Aydın, Ş and Çelik, H and Çelik, O and Küçükler, S and Topal, A and Akay, R and Yıldız, MO and Alım, B and Çulha, MH and Özdemir, S},
title = {In vitro investigation of miR-206-3p-loaded extracellular vesicles as modulators of Aβ-induced neurodegeneration.},
journal = {Biochemical and biophysical research communications},
volume = {802},
number = {},
pages = {153306},
doi = {10.1016/j.bbrc.2026.153306},
pmid = {41592400},
issn = {1090-2104},
abstract = {In this study, we investigated the therapeutic potential of miR-206-3p delivered via small extracellular vesicles (sEVs) in an in vitro Alzheimer's disease model using SH-SY5Y human neuroblastoma cells treated with amyloid beta (Aβ). The sEV-miR-206-3p complexes were successfully loaded with miR-206-3p (∼0.001 copies per particle) without disrupting vesicle integrity or inducing cytotoxicity at the optimized concentration of 5 μg/mL. Aβ treatment significantly increased oxidative stress markers (ROS, MDA, LDH) and decreased antioxidant enzyme activity (SOD), while GPX1 showed an opposite trend. Furthermore, Aβ elevated proinflammatory gene expression (ICAM1, TNF-α) and reduced neuroprotective BDNF levels, induced mitochondrial dysfunction (increased Cyt-c, PINK1, DNM1L; decreased TFAM), impaired synaptic proteins (CPLX2, ROR1), and promoted tau phosphorylation and Aβ accumulation. Treatment with sEV-miR-206-3p effectively mitigated these alterations, reducing oxidative stress, suppressing neuroinflammatory responses, restoring mitochondrial function and synaptic protein levels, and attenuating tau and Aβ pathology. These findings demonstrate that miR-206-3p-loaded sEVs protect neuroblastoma cells from Aβ-induced neurodegenerative processes, highlighting their potential as a novel drug delivery system for neuroprotection.},
}

@article {pmid41591746,
year = {2026},
author = {Cummings, JL and Chumki, SR and Chang, D and Zhang, Z and Brubaker, M and Hefting, N and Such, P and Wang, D and Grossberg, GT},
title = {Efficacy of Brexpiprazole in Participants with Agitation Associated with Dementia Due to Alzheimer's Disease: Pooled Analysis of Randomized Controlled Trials.},
journal = {Clinical drug investigation},
volume = {},
number = {},
pages = {},
pmid = {41591746},
issn = {1179-1918},
abstract = {OBJECTIVE: This analysis aimed to evaluate the efficacy of brexpiprazole 2 or 3 mg/day for the treatment of agitation associated with dementia due to Alzheimer's disease, on the basis of pooled clinical trial data.

METHODS: Data were pooled from two similarly designed, phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled trials of fixed-dose brexpiprazole in participants in care facilities or community-based settings who had agitation associated with dementia due to Alzheimer's disease. Efficacy outcomes included Cohen-Mansfield Agitation Inventory (CMAI) total score (which measures the frequency of 29 different agitation symptoms), Clinical Global Impression-Severity of illness (CGI-S) score, CMAI factor scores (aggressive behaviors, physically nonaggressive behaviors, and verbally agitated behaviors), and response rates. A sensitivity analysis included a third trial with flexible dosing.

RESULTS: In total, 621 participants were randomized (brexpiprazole, 368; placebo, 253), and completion rates were 320/368 (87.0%) and 225/253 (88.9%), respectively. Mean (SD) baseline CMAI total scores were: brexpiprazole 76.9 (17.2) points and placebo 75.5 (18.0) points. Over 12 weeks, CMAI total scores improved by least squares mean (SE) - 22.8 (0.8) points for brexpiprazole and - 18.3 (1.0) points for placebo, with a least squares mean difference between treatment arms of - 4.50 points (95% CI - 6.90 to - 2.10; p < 0.001; Cohen's d 0.30). CGI-S, CMAI factor, and response analyses also showed greater improvement with brexpiprazole versus placebo. The sensitivity analysis was supportive.

CONCLUSIONS: Brexpiprazole 2 or 3 mg/day reduced agitation symptoms compared with placebo over 12 weeks in this large, pooled sample of participants with dementia due to Alzheimer's disease.

STUDY REGISTRATION: ClinicalTrials.gov identifiers: NCT01862640, NCT03548584, and NCT01922258.},
}

@article {pmid41591137,
year = {2025},
author = {Khalid, MZ and Iqbal, N and Ali, B and Rahman, JSU and Iqbal, S and Almudaimeegh, L and Hamd, ZY and Gareeballah, A},
title = {Detection and Classification of Alzheimer's Disease Using Deep and Machine Learning.},
journal = {Tomography (Ann Arbor, Mich.)},
volume = {12},
number = {1},
pages = {},
doi = {10.3390/tomography12010004},
pmid = {41591137},
issn = {2379-139X},
support = {RSP 25850//Princess Nourah bint Abdulrahman University/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/classification/diagnosis ; *Magnetic Resonance Imaging/methods ; *Deep Learning ; Male ; Aged ; Female ; *Machine Learning ; Brain/diagnostic imaging/pathology ; Support Vector Machine ; Aged, 80 and over ; Image Interpretation, Computer-Assisted/methods ; },
abstract = {BACKGROUND/OBJECTIVES: Alzheimer's disease is the leading cause of dementia, marked by progressive cognitive decline and a severe socioeconomic burden. Early and accurate diagnosis is crucial to enhancing patient outcomes, yet traditional clinical and imaging assessments are often limited in sensitivity, particularly at early stages. This study presents a dual-modal framework that integrates symptom-based clinical data with magnetic resonance imaging (MRI) using machine learning (ML) and deep learning (DL) models, enhanced by explainable AI (XAI).

METHODS: Four ML classifiers-K-Nearest Neighbors (KNN), Support Vector Machine (SVM), Decision Tree (DT), and Random Forest (RF)-were trained on demographic and clinical features. For stage-wise classification, five DL models-CNN, EfficientNetB3, DenseNet-121, ResNet-50, and MobileNetV2-were applied to MRI scans. Interpretability was incorporated through SHAP and Grad-CAM visualizations.

RESULTS: Random Forest achieves the highest accuracy of 97% on clinical data, while CNN achieves the best overall performance of 94% in MRI-based staging. SHAP and Grad-CAM were used to find clinically relevant characteristics and brain areas, including hippocampal atrophy and ventricular enlargement.

CONCLUSIONS: Integrating clinical and imaging data and interpretable AI improves the accuracy and reliability of AD staging. The proposed model offers a valid and clear diagnostic route, which can assist clinicians in making timely diagnoses and adjusting individual treatment.},
}

Humans
*Alzheimer Disease/diagnostic imaging/classification/diagnosis
*Magnetic Resonance Imaging/methods
*Deep Learning
Male
Aged
Female
*Machine Learning
Brain/diagnostic imaging/pathology
Support Vector Machine
Aged, 80 and over
Image Interpretation, Computer-Assisted/methods

@article {pmid41591092,
year = {2026},
author = {Angelopoulou, E and Papageorgiou, S and Papatriantafyllou, J},
title = {Reframing Dementia Prevention Strategies Aligned with the WHO Global Action Plan: A Structured Narrative Review Focusing on Mild Behavioral Impairment.},
journal = {Neurology international},
volume = {18},
number = {1},
pages = {},
doi = {10.3390/neurolint18010018},
pmid = {41591092},
issn = {2035-8385},
abstract = {Background/Objectives: Dementia represents a growing public health challenge. The WHO Global Action Plan on the Public Health Response to Dementia emphasizes early detection, risk reduction, and innovation as key priorities. Mild Behavioral Impairment (MBI), defined as the emergence of persistent neuropsychiatric symptoms in older individuals, represents a potential marker of early neurodegeneration and possible window for early intervention. This review explores the role of MBI in dementia prevention, mapping current evidence within the WHO Global Action Plan framework. Methods: A comprehensive search was performed in PubMed, Scopus, and the official WHO website, during 1 September 2025-10 November 2025, without time restrictions. Eligible sources included original clinical studies, reviews, and policy documents addressing MBI, dementia prevention, and public health. Data were thematically synthesized according to the seven objectives of WHO: (1) dementia as a public health priority, (2) dementia awareness and friendliness, (3) dementia risk reduction, (4) dementia diagnosis, treatment, care and support, (5) support for dementia carers, (6) information systems for dementia, and (7) dementia research and innovation. Results: Accumulating evidence indicates that MBI assessment can capture early behavioral manifestations of neurodegenerative and other forms of dementia, correlating with fluid, neuroimaging and genetic biomarkers. Integrating MBI screening through the easy-to-administer MBI Checklist (MBI-C) into clinical and community-based care, including telemedicine pathways and research, may enhance early identification and personalized interventions, enrich the pool for clinical trials, and facilitate research in biomarker and therapy. MBI-related research further supports its integration in remote digital monitoring and population-based prevention. Conclusions: Embedding MBI-informed screening and interventions into national dementia strategies aligns with WHO objectives for early, equitable and scalable prevention and brain health.},
}

@article {pmid41590318,
year = {2026},
author = {Rajkumar, M and Tian, F and Javed, B and Prajapati, BG and Deepak, P and Girigoswami, K and Karmegam, N},
title = {Smart Biosensing Nanomaterials for Alzheimer's Disease: Advances in Design and Drug Delivery Strategies to Overcome the Blood-Brain Barrier.},
journal = {Biosensors},
volume = {16},
number = {1},
pages = {},
doi = {10.3390/bios16010066},
pmid = {41590318},
issn = {2079-6374},
mesh = {*Alzheimer Disease/drug therapy ; *Blood-Brain Barrier ; Humans ; *Drug Delivery Systems ; *Biosensing Techniques ; *Nanostructures/chemistry ; Animals ; Nanoparticles ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by persistent memory impairment and complex molecular and cellular pathological changes in the brain. Current treatments, including acetylcholinesterase inhibitors and memantine, only help with symptoms for a short time and do not stop the disease from getting worse. This is mainly because these drugs do not reach the brain well and are quickly removed from the body. The blood-brain barrier (BBB) restricts the entry of most drugs into the central nervous system; therefore, new methods of drug delivery are needed. Nanotechnology-based drug delivery systems (NTDDS) are widely studied as a potential approach to address existing therapeutic limitations. Smart biosensing nanoparticles composed of polymers, lipids, and metals can be engineered to enhance drug stability, improve drug availability, and target specific brain regions. These smart nanoparticles can cross the BBB via receptor-mediated transcytosis and other transport routes, making them a promising option for treating AD. Additionally, multifunctional nanocarriers enable controlled drug release and offer theranostic capabilities, supporting real-time tracking of AD treatment responses to facilitate more precise and personalized interventions. Despite these advantages, challenges related to long-term safety, manufacturing scalability, and regulatory approval remain. This review discusses current AD therapies, drug-delivery strategies, recent advances in nanoparticle platforms, and prospects for translating nanomedicine into effective, disease-modifying treatments for AD.},
}

*Alzheimer Disease/drug therapy
*Blood-Brain Barrier
Humans
*Drug Delivery Systems
*Biosensing Techniques
*Nanostructures/chemistry
Animals
Nanoparticles

@article {pmid41589495,
year = {2026},
author = {Dewangan, A and Nandy, SK and Das, AK and Sharma, A and Sharma, L},
title = {Enzymatic Biomarkers for Early Diagnosis of Alzheimer's Disease: Uncovering Key Targets and Mechanisms.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273418918251112112429},
pmid = {41589495},
issn = {1996-3181},
abstract = {Alzheimer's Disease (AD) is a neuronal illness that disrupts behavior, cognitive, and functional abilities. The development of AD is progressive, continuous, and irreversible, from preclinical illness to mild cognitive or even behavioral disturbance to dementia (a medical brain condition) triggered by AD. Worldwide accepted hypotheses of AD are called the amyloid-cascade and hyperphosphorylated tau-cascade hypotheses, and enzymes are implicated in the pathophysiology of AD directly or indirectly. There is an implication of enzymes in the pathophysiology of AD. Enzymes include proteases (e.g., neprilysin), kinases (e.g., glycogen synthase kinase-3), cholinergic enzymes (e.g., acetylcholinesterase), metalloproteinases (e.g., matrix metalloproteinases), and oxidative stress-related enzymes (e.g., superoxide dismutase). However, during abnormal or early Alzheimer's Disease (AD) conditions, the activity and expression of these enzymes are altered in biological samples such as blood, urine, and cerebrospinal fluid (CSF) in patients with early AD when examined. These alterations in enzyme activity in early AD demonstrate the potential of these enzymes as biomarkers. Early detection of AD in its early stages is crucial for effective control and treatment of the disease. Existing diagnostic techniques rely mainly on neuroimaging and medical evaluation. Through this technique, we can only diagnose the advanced or late stage of AD. Therefore, there is a crucial need to establish valid biomarkers that might assist in the early detection of AD. Enzymatic targets have come to light as a promising alternative for the development of selective and sensitive diagnostic assays. This review aims to investigate the potential of enzymes as an enzymatic target for early AD diagnosis, emphasizing their diagnostic use and fundamental mechanisms. Here, we summarize the role or implication of 25 enzymes in the pathophysiology of AD in the early stage.},
}

@article {pmid41589493,
year = {2026},
author = {Almawashee, HS and Khalaj-Kondori, M and Hosseinpour Feizi, MA and Safaralizadeh, R},
title = {Correlation of miR-214, miR-204, miR-25, miR-15a Expression with IL-33 and Malondialdehyde in Blood Samples from Patients with Alzheimer's Disease.},
journal = {MicroRNA (Shariqah, United Arab Emirates)},
volume = {},
number = {},
pages = {},
doi = {10.2174/0122115366411857251025004952},
pmid = {41589493},
issn = {2211-5374},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a late-onset neurodegenerative disease that affects older people. Deregulations of miRNAs play essential roles in AD pathogenesis; as a re-sult, they might be potential biomarkers for AD development, diagnosis, and treatment. This case-control study aimed to assess the expression of miR-214, miR-204, miR-15a, miR-25, and inves-tigate their correlations with the expression of IL-33, plasma level of Malondialdehyde (MDA), and Mini-Mental State Examination (MMSE) score of the AD patients.

METHODS: Blood samples were obtained from 125 participants, including 75 AD patients and 50 healthy controls. Plasma MDA level was assessed using the ZellBio ELISA kit. Total RNA was extracted from blood lymphocytes using RiboExTM (GeneAll), and expression levels of miRNAs and IL-33 were evaluated by qRT-PCR.

RESULTS: Results showed that miR-15a and miR-25, and IL-33 were downregulated in the pa-tients' group, but miR-214 and miR-204 were upregulated. Besides, the plasma level of MDA was significantly higher in the AD patients. A statistically significant negative correlation was observed between miR-15a and IL-33 expression. The MDA level showed a negative correlation with MMSE and a positive correlation with IL-33. Correlations between the miRNAs and MDA or MMSE scores were all non-significant. However, ROC curve analysis revealed that expres-sions of the studied miRNAs, IL-33, and the plasma level of MDA effectively differentiate AD patients from healthy controls.

DISCUSSION: Results showed that expression levels of miR-214, miR-204, miR-25, miR-15a, and IL-33 and MDA plasma levels are deregulated in AD patients, highlighting their potential relation with AD pathogenesis.

CONCLUSION: Expression levels of the studied miRNAs and IL33, and plasma level of MDA might be considered as potential biomarkers for AD development and diagnosis.},
}

@article {pmid41589492,
year = {2026},
author = {Liu, A and Li, J and Gao, W and Li, X and Song, J and Xing, L and Li, H},
title = {Research Progress on Targeted Inhibition of Ferroptosis and Alzheimer's Disease Treatment.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575411431251125115235},
pmid = {41589492},
issn = {1875-5607},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the formation of senile plaques and neurofibrillary fiber tangles. Studies have shown that increased regional iron loading in the brain, dysregulation of iron homeostasis in the body, oxidative stress, and protein and lipid oxidation are all involved in the pathogenesis of AD. Ferroptosis, an irondependent, lipid peroxidation-driven form of regulated cell death, is increasingly implicated in the pathological process of AD, and some new compounds targeting ferroptosis demonstrate therapeutic efficacy in both cellular and animal models of AD. Therefore, this article systematically summarizes recent advances in the role of ferroptosis in AD pathogenesis and highlights progress in targeting ferroptosis for AD treatment, providing insights for future therapeutic and preventive strategies.},
}

@article {pmid41588889,
year = {2026},
author = {Thakur, A and Chowdhury, KR and Kumar, A and Sharma, VV and Bhatia, R},
title = {Targeting Non-coding RNAs in Neurodegeneration: Advances in Therapeutic RNA Modalities and Next-Gen Delivery Technologies.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050421604251108045622},
pmid = {41588889},
issn = {1875-5828},
abstract = {Non-coding RNA (ncRNA)-based therapies represent an emerging and transformative approach in the treatment of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)/Motor Neuron Disease (MND). This review explored the potential for targeting microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, reinforced by promising results from clinical trials demonstrating their capacity to modulate disease pathways. The incorporation of cutting-edge computational methodologies, including RNA structure prediction and gene regulatory network analysis, has been at the forefront in enhancing the efficacy of ncRNA-based treatments. Moreover, chemical methods have improved RNA molecules' stability, accuracy, and directed delivery, enhancing their therapeutic effects. Moreover, cutting-edge RNA editing technologies like Clustered Regularly Interspaced Short Palindromic Repeats/CRISPRassociated protein 13 (CRISPR/Cas13) are advancing our ability to directly manipulate ncRNA expression, offering a powerful avenue for addressing the molecular origins of neurodegeneration. Despite these advances, challenges persist, particularly in ensuring the specificity, delivery efficiency, and long-term efficacy of these treatments. Nanotechnology provides innovative solutions to these obstacles, facilitating more efficient and precise RNA delivery, especially to neuronal tissue. In conclusion, ncRNA-based therapies, while still in nascent stages, represent a hopeful frontier in the fight against NDs. With ongoing research and technological advancements, these therapies could not only halt disease progression but also redefine the future of ND treatment, offering new avenues for patients' care and clinical success.},
}

@article {pmid41588888,
year = {2026},
author = {Sahu, A and Khileshwari, and Patle, K and Jain, P and Ajazuddin, },
title = {Advances in Nose-to-Brain Delivery Systems for Effective Alzheimer's Disease Management.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050395356251106100427},
pmid = {41588888},
issn = {1875-5828},
abstract = {Neurodegenerative diseases comprise a heterogeneous group of disorders characterized by the progressive structural and functional deterioration of neurons in the central nervous system. Among them, Alzheimer's disease is the most prevalent worldwide. Despite their distinct clinical manifestations, many neurodegenerative disorders share convergent pathophysiological mechanisms such as protein misfolding and aggregation, oxidative stress, mitochondrial dysfunction, and neuroinflammation, which ultimately drive neuronal loss. These processes lead to profound impairments in cognitive performance, motor coordination, and overall functional capacity, making such diseases exceptionally difficult to diagnose early and manage effectively. Traditional treatment approaches administered orally or parenterally face limitations, including high hepatic metabolism, poor penetration across the blood-brain barrier (BBB), and systemic side effects. This review highlights the potential of the nose-to-brain (N2B) delivery system as an emerging and promising therapeutic strategy. N2B delivery utilizes the olfactory and trigeminal nerve pathways in the nasal cavity to rapidly and precisely deliver drugs to the central nervous system without crossing the blood-brain barrier. Because the system is non-invasive, it offers high bioavailability, reduced systemic exposure, and improved patient compliance. The use of lipid nanocarriers, nanoparticles, dendrimers, and nanogels to enhance the stability of drugs, facilitating efficient targeting and controlled release, is a crucial factor in optimizing N2B drug delivery systems. Various attributes influence drug transport, which are physiological, physicochemical and formulation-dependent characteristics. The main challenges faced by the N2B delivery system are enzymatic degradation and mucociliary clearance. Emerging technologies, such as AI, 3D Printing, and personalized medicine, all hold promise for future inventions in this area. Preclinical and clinical trials demonstrate the efficacy of delivering N2B in treating neurodegenerative diseases; however, its full potential remains to be seen due to regulatory, safety, and scalability concerns. Hence, this review emphasizes the research required to pursue interdisciplinary collaboration and unlock the full potential of N2B delivery, as well as a new approach to transforming neurodegenerative conditions.},
}

@article {pmid41588887,
year = {2026},
author = {Edelbach, B and Huang, L and Boling, W},
title = {Vagus Nerve Stimulation in the Management of Neurodegenerative Diseases: A Systematic Review of Advances in Animal Research and Clinical Applications.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050373772251103053036},
pmid = {41588887},
issn = {1875-5828},
abstract = {INTRODUCTION: Vagus Nerve Stimulation (VNS) has been approved by the FDA as a treatment for epilepsy, depression, post-ischemic stroke rehabilitation, and migraine in patients. It is emerging as a potential treatment for neurodegenerative diseases. Herein, we summarize the research on VNS and its application in common neurodegenerative diseases.

METHODS: A literature search was completed in PubMed, ScienceDirect, and Google Scholar using the terms: "neurodegeneration," "neuromodulation," "Vagus Nerve Stimulation," "Parkinson's Disease (PD)," "Alzheimer's Disease (AD)," "dementia," "neuroinflammation," and "cognitive dysfunction." Animal and clinical studies using VNS as a primary intervention in neurodegenerative diseases were included.

RESULTS: The studies of VNS application in Parkinson's and Alzheimer's models were reviewed. In animal studies, VNS was associated with increased locomotion and balance, as well as reduced cognitive impairments. The underlying neuroprotective mechanisms included: increased dopaminergic neurons, reduced α-synuclein concentration in the brain, preservation of the nigrostriatal dopaminergic pathway, increased α7nAChR expression, reduced apoptotic markers, reduced neuroinflammation, and significant reductions in microglial and astrocytic densities. In clinical studies with small patient populations of PD or AD/mild cognitive impairment, VNS was associated with improved gait parameters and enhanced performance in memory-based tasks.

DISCUSSION: Vagus Nerve Stimulation (VNS) shows neuroprotective and anti-inflammatory effects in animal models of Alzheimer's and Parkinson's disease, but clinical results remain inconsistent due to variability in treatment duration, outcome measures, and reliance on subjective assessments. Emerging physiologic biomarkers such as VSEP, EEG, and magnetoencephalography may provide more objective measures of therapeutic response.

CONCLUSIONS: The systematic review highlights the potential of VNS as a therapeutic approach for managing neurodegenerative diseases. The efficacy of VNS in animal models of Parkinson's and Alzheimer's diseases involves both neuroprotection and anti-neuroinflammation, while additional protective mechanisms require further exploration.},
}

@article {pmid41588609,
year = {2026},
author = {Zhou, S and Hassan, H and Guo, J and Xu, Y and Zhang, P and Yuan, L and Zhou, T and Chen, R},
title = {From gut to brain: formulation and transporter-guided approaches to maximise rutin central nervous system delivery.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-27},
doi = {10.1080/1028415X.2026.2617363},
pmid = {41588609},
issn = {1476-8305},
abstract = {Neurological disorders, including Alzheimer's and Parkinson's disease, are characterised by high morbidity and disability, representing a major global health challenge. A central obstacle in their treatment is the blood-brain barrier, a highly selective interface that limits drug delivery to the central nervous system. Rutin, a naturally occurring flavonoid, exhibits potent antioxidant, anti-inflammatory, and neuroprotective activities, yet its clinical utility remains constrained by poor solubility, low oral bioavailability, and restricted blood-brain barrier permeability. Recent advances in drug delivery and formulation science offer promising solutions. Nanoparticle encapsulation, peptide conjugation, intranasal delivery, and co-administration with absorption enhancers have been shown to improve rutin's solubility, metabolic stability, and central nervous system penetration in preclinical models. Mechanistic studies further reveal that rutin can modulate efflux transporters, regulate tight-junction proteins, and influence microglial activity and cellular metabolism, collectively contributing to enhanced neuroprotection. Experimental evidence highlights its potential to mitigate key neurodegenerative processes, particularly in Alzheimer's disease. This review synthesises current knowledge on rutin's pharmacological effects, limitations in bioavailability, and innovative strategies to improve blood-brain barrier penetration. By integrating mechanistic insights with advances in delivery technologies, this review underscores rutin's translational potential. Priority next steps include optimising delivery systems, establishing long-term safety, and conducting well-designed clinical trials to define efficacy and dosing.},
}

@article {pmid41588589,
year = {2026},
author = {Justin, S and Ali, SA and Masood, M and Abbasi, SW and Farhat, SM and Shakeel, R and Khalid, A and Mahboob, A and Zafar, S and Zahid, S and Ahmed, T},
title = {Evaluation of the Combined Therapeutic Potential of Turmeric and Donepezil on the Cholinergic System in a Mouse Model of AD-like Pathology.},
journal = {Current drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113894501433829251216060839},
pmid = {41588589},
issn = {1873-5592},
abstract = {INTRODUCTION: The multifactorial pathogenesis of Alzheimer's Disease (AD) makes effective prevention and treatment challenging. Integrative medicine presents a promising approach by complementing conventional treatments with neuroprotective nutraceuticals. This study investigates the individual and combinatorial effects of turmeric, a neuroprotective herb, and donepezil, an acetylcholinesterase (AChE) inhibitor, on cognitive functions in a scopolamine-induced amnesic mouse model.

METHODS: Molecular interactions of curcuminoids and donepezil with AChE were analyzed using AutoDock Vina and AMBER22. In animal model studies, amnesia was induced in BALB/c mice via subcutaneous injections of scopolamine (1mg/kg/day) for a duration of 25 days. From the 11th day onwards, the turmeric rhizome powder (20mg/kg/day) and donepezil (0.5mg/kg/day) were orally administered as monotherapies or in combination. Cognitive functions were assessed through behavior tests.

RESULTS: Molecular docking and dynamics simulations revealed that curcuminoids (curcumin, bisdemethoxycurcumin, and desmethoxycurcumin) inhibited AChE more effectively than donepezil. Animal studies demonstrated significant enhancements in spatial, reference, recognition, and contextual fear memories, with both turmeric and donepezil monotherapies, and their combination therapy. No significant differences were observed between monotherapies, and no additive effect was evident in the combination therapy.

DISCUSSION: Co-administration of turmeric and donepezil did not yield a significant additive effect on cognitive improvement in scopolamine-induced amnesic mice. Turmeric monotherapy showed cognitive improvements comparable to those of donepezil monotherapy, highlighting its potential as a candidate therapy for donepezil-resistant AD.

CONCLUSION: Turmeric monotherapy improved cognitive performance similarly to donepezil monotherapy in scopolamine-induced amnesic mice. These preliminary findings require further research, including dose optimization and clinical trials, to establish their clinical relevance.},
}

@article {pmid41588303,
year = {2026},
author = {Zuo, CT and Lu, JY},
title = {[AI-driven PET-MRI multimodal fusion: paradigm shift and clinical translation challenges in precision diagnosis and treatment of neurodegenerative diseases].},
journal = {Zhonghua yi xue za zhi},
volume = {106},
number = {4},
pages = {289-293},
doi = {10.3760/cma.j.cn112137-20250730-01894},
pmid = {41588303},
issn = {0376-2491},
support = {82394434, 82272039, 82021002//National Natural Science Foundation of China/ ; 2022ZD0211606//Science and Technology Innovation 2030-Major Project/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/therapy/diagnostic imaging ; *Magnetic Resonance Imaging ; *Positron-Emission Tomography ; *Multimodal Imaging ; Precision Medicine ; *Artificial Intelligence ; },
abstract = {Individualized precision diagnosis and treatment of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, etc.) faces challenges due to overlapping early symptoms and clinical/pathological heterogeneity. PET-MRI multimodal imaging, integrating in vivo molecular pathological information from PET with brain structural/functional information revealed by MRI, has become a crucial cornerstone for precision diagnosis and treatment of neurodegenerative diseases. However, its clinical translation is limited by practical bottlenecks, such as complexities in data integration, and uneven distribution of resources. AI, with its unique strengths in multimodal data fusion, automated quantitative analysis, and cross-modal image synthesis, is gradually reshaping the paradigm of diagnostic and therapeutic landscape of neurodegenerative diseases. This article systematically explores the pivotal role of AI in PET-MRI, covering its contributions to improving diagnostic objectivity, deciphering disease heterogeneity, enabling stratified care pathways. It also critically addresses the multiple challenges hindering the clinical implementation of AI and proposes that future efforts should focus on the development of interpretable AI models, the construction of embedded clinical systems, and the exploitation of inclusive technological solutions to promote the deep integration of AI and PET-MRI, ultimately driving the transformation of neurodegenerative diseases towards a precision medicine paradigm of early prevention, early diagnosis, and early treatment.},
}

Humans
*Neurodegenerative Diseases/diagnosis/therapy/diagnostic imaging
*Magnetic Resonance Imaging
*Positron-Emission Tomography
*Multimodal Imaging
Precision Medicine
*Artificial Intelligence

@article {pmid41588024,
year = {2026},
author = {Khodaei, F and Namavar, MR and Soutodeh, N and Hadipour, A and Asadi, F and Khoshnoud, MJ and Rashedinia, M},
title = {Mitochondrial protective effects of ellagic acid in a rat model of sporadic Alzheimer's disease induced by STZ.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {3498},
pmid = {41588024},
issn = {2045-2322},
support = {9958//Shiraz University of Medical Sciences/ ; },
mesh = {Animals ; *Ellagic Acid/pharmacology ; *Alzheimer Disease/chemically induced/drug therapy/metabolism/pathology ; *Mitochondria/drug effects/metabolism ; Streptozocin/toxicity ; Rats ; Disease Models, Animal ; Oxidative Stress/drug effects ; Male ; *Neuroprotective Agents/pharmacology ; Hippocampus/drug effects/metabolism/pathology ; Maze Learning/drug effects ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder primarily affecting the elderly, characterized by mitochondrial dysfunction. Mitochondria play a dual role in AD, serving both as the main source of reactive oxygen species (ROS) generation and as a major target of oxidative damage. This study aimed to investigate the protective mechanisms of ellagic acid (EA) a natural dietary polyphenol on mitochondrial function in an intracerebroventricular (ICV) streptozotocin (STZ)-injected rat model of AD. Rats were randomly assigned to six groups: Control, Sham, STZ (1.5 mg/kg on days 1 and 3), STZ + EA 5 mg/kg, STZ + EA 50 mg/kg, and STZ + EA 100 mg/kg. On day 14, behavioral tests (Shuttle box and Step-down), histopathological evaluations, oxidative stress markers, and mitochondrial indices were assessed in brain tissue. Treatment with EA (100 mg/kg) significantly improved spatial memory, as evidenced by increased latency time in the Morris water maze test (p < 0.001). Furthermore, EA treatment mitigated hippocampal neurodegeneration, increasing neuronal density in the CA1 subfield (p < 0.001) and restoring total hippocampal volume (p < 0.01). At the biochemical level, EA markedly reduced oxidative stress levels (p < 0.001) and enhanced mitochondrial function, restoring cortical ATP levels (p < 0.001) and cytochrome c oxidase activity (p < 0.01) compared to the STZ- group. In conclusion, these findings suggest that EA may have therapeutic potential in mitigating mitochondrial dysfunction and oxidative stress in AD, offering a promising approach for addressing neurodegeneration and energy deficits associated with the disease.},
}

Animals
*Ellagic Acid/pharmacology
*Alzheimer Disease/chemically induced/drug therapy/metabolism/pathology
*Mitochondria/drug effects/metabolism
Streptozocin/toxicity
Rats
Disease Models, Animal
Oxidative Stress/drug effects
Male
*Neuroprotective Agents/pharmacology
Hippocampus/drug effects/metabolism/pathology
Maze Learning/drug effects

@article {pmid41585699,
year = {2026},
author = {Ferreira, LAP and Caruso, L and Nadur, NF and Franco, DP and Sousa, GLS and Lacerda, RB and Kümmerle, AE},
title = {Imidazo[1,2‑a]pyridines in Medicinal Chemistry: Recent Advances in Synthesis and Biological Activities.},
journal = {ACS omega},
volume = {11},
number = {2},
pages = {2348-2383},
pmid = {41585699},
issn = {2470-1343},
abstract = {Imidazo-[1,2-a]-pyridines are widely recognized scaffolds present in several marketed drugs, including the anxiolytics alpidem, saripidem, necopidem, and zolpidem, which are some of the most prescribed medications for insomnia. In this review, we analyze publication trends, which reveal exponential growth in research involving this scaffold. We highlight recent synthetic strategies (2017-2025) for the preparation of imidazo-[1,2-a]-pyridine derivatives, such as condensation, multicomponent and tandem reactions, intramolecular cyclizations, and oxidative couplings under green conditions. In addition, we discuss innovative Medicinal Chemistry studies exploring their applications in the treatment of cancer, Alzheimer's disease, tuberculosis, and neglected tropical diseases. Significant advances have been made in identifying derivatives with potent activity against specific biological targets, including kinases, tubulin, HDACs, the cytochrome bc1 complex of Mycobacterium tuberculosis, and key enzymes involved in the pathogenesis of Alzheimer's disease, such as cholinesterases and secretases. Altogether, this review consolidates the vast therapeutic potential of the imidazo-[1,2-a]-pyridine core, emphasizing its synthetic versatility and broad spectrum of biological activities, which firmly establish it as a privileged scaffold for drug discovery.},
}

@article {pmid41585467,
year = {2026},
author = {Yue, J and Wang, X and Ringman, J and Shi, Y},
title = {Graphical modeling of cortical tau pathology topography for its subtyping in Alzheimer's disease.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
pmid = {41585467},
issn = {2837-6056},
abstract = {Hyperphosphorylated tau tangles are essential hallmarks of Alzheimer's disease (AD) and their propagation across brain regions was often considered to follow the classic Braak stages. Recent post-mortem and in vivo tau positron emission tomography (PET) studies, however, revealed the frequent presence of tau pathology heterogeneity. Clustering or event-based methods were proposed previously for the subtyping to tau pathology in AD, but they often lack robustness to varying distributions of disease severity across cohorts. To robustly discover and model tau pathology subtypes in AD, we propose in this work a novel graphical modeling framework that can disentangle the phenotypical differences of tau PET imaging due to disease heterogeneity from the spatiotemporal variations of disease stages. First, we propose a novel Reeb graph representation at the individual level to characterize the topographic patterns of salient tau pathology on cortical surfaces. Next, we use only cross-sectional tau PET data to develop a graphical model at the population level to encode the inter-subject spatiotemporal relationships, which enables us to robustly derive subtypes based on the topographic patterns of tau pathology and hence achieve increased generalization power to new samples with distinct tau pathology severity from the training data. Using synthetic and large-scale tau PET imaging data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) studies, we compare with the state-of-the-art SuStaIn method and demonstrate the improved generalization performance of the proposed method. In addition, we validate both methods on a cohort of autosomal dominant Alzheimer's disease (ADAD) patients with known tau pathology patterns to show that our method has more robust performance in testing data with large deviations from training data. Furthermore, for preclinical patients of the A4 cohort, we demonstrate more significant differences in clinical cognitive measures can be observed across subtypes discovered by our method.},
}

@article {pmid41585268,
year = {2025},
author = {Srivastav, J and Sharma, S},
title = {Viral and non-viral cellular therapies for neurodegeneration.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1718669},
pmid = {41585268},
issn = {2296-858X},
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive loss of neurons and still lack curative treatment options. In this review, we describe current and developing therapeutic strategies that include viral vector-based gene delivery, antisense oligonucleotide (ASO) and RNA interference methods, stem cell transplantation, and genome editing technologies. Adeno-associated viruses (AAVs) and lentiviruses have been used for gene delivery in preclinical and clinical studies, while ASOs are under development to reduce expression of pathogenic proteins such as tau, α-synuclein, and mutant huntingtin. Cellular therapies, including mesenchymal stem cell (MSC)-based paracrine support and transplantation of neurons derived from induced pluripotent stem cells (iPSCs), are being evaluated, particularly in PD and AD. We also discuss important gene targets such as APOE4, GBA1, SCNA, and MAPT, and how treatment strategies may differ between monogenic and polygenic forms of these disorders. Lastly, we highlight recent efforts focused on genes like TREM2, PINK1, and progranulin, and examine their role in the future development of gene- and cell-based interventions.},
}

@article {pmid41585084,
year = {2025},
author = {Matsuzaka, Y and Iyoda, M},
title = {Applications, image analysis, and interpretation of computer vision in medical imaging.},
journal = {Frontiers in radiology},
volume = {5},
number = {},
pages = {1733003},
pmid = {41585084},
issn = {2673-8740},
abstract = {This review summarizes the current advances, applications, and research prospects of computer vision in advancing medical imaging. Computer vision in healthcare has revolutionized medical practice by increasing diagnostic accuracy, improving patient care, and increasing operational efficiency. Likewise, deep learning algorithms have advanced medical image analysis, significantly improved healthcare outcomes and transforming diagnostic processes. Specifically, convolutional neural networks are crucial for modern medical image segmentation, enabling the accurate, efficient analysis of various imaging modalities and helping enhance computer-aided diagnosis and treatment planning. Computer vision algorithms have demonstrated remarkable capabilities in detecting various diseases. Artificial intelligence (AI) systems can identify lung nodules in chest computed tomography scans at a sensitivity comparable to that of experienced radiologists. Computer vision can analyze brain scans to detect problems such as aneurysms and tumors or areas affected by diseases such as Alzheimer's. In summary, computer vision in medical imaging is significantly improving diagnostic accuracy, efficiency, and patient outcomes across a range of medical specialties.},
}

@article {pmid41584821,
year = {2026},
author = {Ali, F and Babour, A and Asiry, O and Alghamdi, W and Masmoudi, A and Rajkhan, NW},
title = {Advancing neurological disease treatment: a computational approach for fibroblast growth factor detection.},
journal = {Biomedical engineering letters},
volume = {16},
number = {1},
pages = {167-176},
pmid = {41584821},
issn = {2093-985X},
abstract = {Fibroblast Growth Factor plays a crucial role in neurological health, contributing to neuron protection, injury recovery, and angiogenesis. It is also significantly involved in the onset and progression of neurodegenerative disorders such as Huntington's, Alzheimer's, Parkinson's disease, and stroke, making FGF a vital target for therapeutic interventions. Despite its importance, no computational tool has been developed to predict FGF proteins. In this study, we present the first novel deep learning-based computational approach designed for the prediction of FGF proteins. We constructed two novel, high-quality datasets curated from the UniProt database for training and evaluation. Sequences were transformed into numerical representations using three complementary feature encoding methods including Dipeptide Composition, Dipeptide Deviation from Expected Mean, and Grouped Amino Acid Composition. These features capture both local and global sequence information. Multiple deep learning models were explored, including Convolutional Neural Network, Bidirectional Long Short-Term Memory, Generative Adversarial Network, and Gated Recurrent Unit. Among these, our proposed Convolutional Neural Network-based model outperformed all others, achieving an accuracy of 83.50%, sensitivity of 84.30%, specificity of 82.67%, F1 score of 83.42%, and a Matthews Correlation Coefficient of 0.671. The proposed approach has the potential to advance therapeutic discovery by enabling accurate identification of Fibroblast Growth Factor and improving our understanding of their role in neurological health and disease.},
}

@article {pmid41583320,
year = {2025},
author = {Miura, K},
title = {Hematuria as a Diagnostic Clue to Non-cirrhotic Hyperammonemia Due to Corynebacterium urealyticum Urinary Tract Infection: A Case Report.},
journal = {Cureus},
volume = {17},
number = {12},
pages = {e100082},
pmid = {41583320},
issn = {2168-8184},
abstract = {Hyperammonemia is an important cause of altered mental status in older adults; however, non-cirrhotic hyperammonemia in the absence of underlying liver dysfunction is easily overlooked. Hyperammonemia secondary to urinary tract infection (UTI) caused by urease-producing bacteria is relatively rare, and reliable clinical clues for early diagnosis have not been fully established. We report the case of a 95-year-old woman with Alzheimer's disease residing in a nursing facility. She had macroscopic hematuria for two days without any change in consciousness. On the day of admission, she was found unresponsive at breakfast and was transported to the emergency department with impaired consciousness. On arrival, she had renal dysfunction and marked hyperammonemia (168 µg/dL) but normal liver function tests. Her urine was alkaline, turbid, and purulent with gross hematuria, and her mental status improved rapidly after bladder catheterization and fluid resuscitation. Urine culture yielded Corynebacterium urealyticum, and she was diagnosed with non-cirrhotic hyperammonemia secondary to a UTI caused by this urease-producing organism. Including the present case, a review of 33 English- and Japanese-language reports identified gross hematuria in 15 cases, microscopic hematuria alone in 11, and no hematuria in seven; thus, 78.8% of patients demonstrated some degree of hematuria. These findings suggest that, in older patients with preserved liver function who present with impaired consciousness, the presence of hematuria is an important clue to hyperammonemia secondary to a UTI due to urease-producing bacteria. When hematuria is observed, clinicians should consider this entity in the differential diagnosis and promptly assess urine pH, urinary retention, and indwelling urinary catheters to identify ammonia-producing sources and perform timely drainage to prevent delays in diagnosis and treatment.},
}

@article {pmid41583006,
year = {2025},
author = {Eyamu, J and Ku, B and Kim, K and Lee, KH and Kim, JU},
title = {Aperiodic EEG signatures: unveiling the interplay between APOE ε4 and mild cognitive impairment subtypes.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1675330},
pmid = {41583006},
issn = {1663-4365},
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a cognitive decline syndrome in the elderly, often a precursor to dementia. It is a heterogeneous condition that can signal degenerative disorders like Alzheimer's or non-degenerative conditions such as vascular issues, depression, or poorly managed diabetes. Early detection of MCI is crucial for timely intervention, and differentiating its phenotypes helps in understanding its causes, progression, and treatment. EEG, which records brain electrical activity, consists of rhythmic and arrhythmic components. Examining these inherently overlapping EEG components calls for quantification, ensuring that an appropriate physiological mechanism is attributed to a given neural response. This study explores the interaction between APOE ε4 (APOE4) and cognitive impairment on non-oscillatory EEG activity.

METHODS: We examined aperiodic EEG activity using a parameterized spectral estimation approach in a sample comprising 751, 142, and 279 cognitively normal (CN), non-amnestic (naMCI), and amnestic (aMCI) MCI patients, respectively. The 5-min EEG was recorded using a prefrontal two-channel EEG device in a resting state, eyes closed. Cognitive decline was assessed using the Seoul Neuropsychological Screening Battery (SNSB) and the Mini-Mental State Examination (MMSE). The analyses were performed using various statistical methods, including independent t-tests and generalized linear models (GLM) with an identity link function. These analyses investigated the main and interaction effects of the APOE4 status and participants' cognitive states.

RESULTS: We found interactions between APOE4 and cognitive states in the aperiodic EEG exponent and the spectral power ratio (SPR). Distinct patterns were observed in the exponent, offset, and SPR between APOE4 non-carriers and carriers across the CN, naMCI, and aMCI. Among the APOE4 carriers, the aMCI individuals exhibited heightened aperiodic activity and a reduced SPR than the naMCI. Furthermore, the CN had a lower SPR compared to the naMCI. However, no differences in the aperiodic component and SPR were observed in the APOE4 non-carriers across the cognitive states.

DISCUSSION: The higher aperiodic component and a reduced SPR observed in aMCI relative to naMCI in APOE4 carriers may indicate an interplay between genetic predisposition, neuropathological changes, and cognitive decline. These aperiodic components, combined with APOE4 status, represent promising neurophysiological markers that may help identify individuals at elevated risk for cognitive decline or progression toward AD.},
}

@article {pmid41582996,
year = {2025},
author = {Deng, Y and Yin, H and Lu, Z and Lan, H and Liu, W and Zuo, C and Pan, N and Tian, X and Gong, Q},
title = {LRP1 at the crossroads of Aβ clearance and therapeutic targeting in Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1669405},
pmid = {41582996},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD), characterized by progressive cognitive decline, memory impairment and behavioral disturbances, is the most common form of dementia, and no disease-modifying treatments are available to halt or slow its progression. Amyloid-beta (Aβ) is suggested to play a pivotal role in the pathogenesis of AD, and enhancing the clearance of Aβ from the brain has emerged as a major research direction. As the primary receptor for Aβ clearance at the blood-brain barrier (BBB), low-density lipoprotein receptor-related protein 1 (LRP1) plays a crucial role in regulating Aβ transport and metabolism. Understanding the mechanisms through which LRP1 functions, as well as the factors that influence its activity is essential for enhancing Aβ clearance from the brain and developing targeted therapeutic strategies for Alzheimer's disease. In this review, we introduce the transport of Aβ across the BBB, followed by a discussion of the basic structure and function of LRP1 and its role in AD progression. Then, we summarize factors affecting LRP1 function and current advances in LRP1-targeted therapies. Finally, we explore the potential of LRP1 as a therapeutic target for AD. So, LRP1 may be a central modulator of Aβ dynamics and a clinically actionable target for treatment of Alzheimer's disease.},
}

@article {pmid41437270,
year = {2025},
author = {Hu, WT and Butts, B and Misiura, M and Verble, DD and Swatson, E and Park, C and Watson, J and Hammerschlag, BL and Nayyar, A and Korrapati, N and Trotti, LM and Benameur, K and Scorr, LM and Zetterberg, H and Mielke, MM and Wharton, W},
title = {CSF estrogens' relationships to neuroinflammatory markers and brain networks in middle-aged and older black and white women.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {31},
pmid = {41437270},
issn = {1742-2094},
support = {AG066203/AG/NIA NIH HHS/United States ; AG054046/AG/NIA NIH HHS/United States ; AG066203/AG/NIA NIH HHS/United States ; AG054046/AG/NIA NIH HHS/United States ; },
abstract = {UNLABELLED: Neuroprotective properties of estrogen have poorly translated to reduced neurodegeneration in clinical trials of systemic estrogen replacement therapy. To more directly assess biological processes associated with brain estrogen (estrone, estradiol) levels, we recruited 81 women (42 non-white) and 28 men (13 non-white) for cerebrospinal fluid (CSF) hormone, targeted proteomic, and volumetric brain analysis. In the mostly post-menopausal women, we found CSF estrogen levels to only modestly correlate with their corresponding plasma levels, and were additionally influenced by body mass index or age. CSF estrone was also correlated with a marker of Alzheimer’s disease (AD) neuropathologic change (CSF Aβ42/Aβ40), but this was not the case for the more biologically active CSF estradiol. Aptamer-based proteomic analysis of 1,075 CSF markers for inflammation, proteolysis, signaling, and DNA/RNA regulation revealed CSF estrogen levels to associate with alternative complement pathway proteins, and shifts observed in AD (apoE, RAGE). Parallel MRI analysis correlated higher CSF estrogen with smaller volumes of the brain somatosensory and posterior-medial networks without influence from cognition or neurodegeneration. Analysis using plasma estrogens only partially reproduced CSF estrogens’ biochemical correlates but provided inconclusive relationships with brain volume correlates. These findings highlight the association between CSF levels of the more biologically active estradiol and CSF inflammatory pathways involving AD risk genes as potential mechanisms linking hormone status to AD risks, and suggest caution in using CSF estrone or plasma estrogens when interpreting treatment or preventive studies.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03657-3.},
}

@article {pmid41582466,
year = {2026},
author = {Kim, H and Lee, KH and Han, C and Patkar, AA and Masand, PS and Bahk, WM and Pae, CU},
title = {Brexpiprazole for the Treatment of Agitation Associated with Dementia due to Alzheimer's Disease: Clinical Perspectives.},
journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology},
volume = {24},
number = {1},
pages = {15-29},
doi = {10.9758/cpn.24.1252},
pmid = {41582466},
issn = {1738-1088},
abstract = {Dementia is a neuropsychiatric disorder that primarily affects the elderly, leading to a widespread decline in cognitive function and significant impairment of occupational, social, and personal functioning. In addition to cognitive deficits, dementia is frequently comorbid with behavioral and psychological symptoms of dementia (BPSD), such as agitation. When present, these secondary symptoms can exacerbate the clinical course of the disease, reduced treatment responsiveness, increased rates of admission to long-term care facilities, extended hospitalization, higher risk of personal injury and a substantial socioeconomic burden. Given these consequences, early management of BPSD-particularly agitation-is critical to mitigating these risks. Although antipsychotics are commonly prescribed to manage agitation, risperidone remains the only agent approved by regulatory authorities for this indication. Recently, however, brexpiprazole, a medication with a pharmacological profile distinct from that of risperidone, received U.S. FDA approval (on May 11, 2023) for the treatment of agitation associated with Alzheimer's disease. Agitation is among the most prevalent BPSD manifestations, with symptoms ranging from verbal to physical aggression. Given its recent approval and unique pharmacodynamic properties, brexpiprazole may have strong potential as a therapeutic option for this population. This paper aims to review the pharmacological mechanisms, clinical evidence, and future perspectives of brexpiprazole as a novel therapeutic option for managing agitation in patients with Alzheimer's disease.},
}

@article {pmid41581519,
year = {2026},
author = {Vossel, K and Johnson, EL and Cretin, B and Matsumoto, R},
title = {Epileptic activity in Alzheimer's disease: emerging insights and therapeutic implications.},
journal = {The Lancet. Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1016/S1474-4422(25)00425-9},
pmid = {41581519},
issn = {1474-4465},
abstract = {An estimated 60% of patients with Alzheimer's disease develop epilepsy or subclinical epileptiform activity over the course of the disease. New-onset seizures in cognitively healthy adults also increase the risk of developing dementia. Epileptic activity, including both seizures and subclinical epileptiform discharges, can hasten the onset of Alzheimer's disease and accelerate cognitive decline. Studies are investigating whether antiseizure medications could improve cognitive outcomes, particularly in patients with Alzheimer's disease with epileptic activity. Detection of epileptic activity in people with Alzheimer's disease requires high clinical vigilance and neurophysiological monitoring. Evaluation and treatment of late-onset epilepsy or Alzheimer's disease-associated epileptic activity should be informed by clinical advances. Epilepsy management is especially important in patients receiving anti-amyloid monoclonal antibodies, which can increase seizure risk. Recent insights support the concept of an epileptic subtype of Alzheimer's disease, position epileptic activity as a modifiable risk factor in Alzheimer's disease, highlight innovations for earlier identification of epileptic activity, and provide evidence supporting the need for early detection and targeted treatment across the stages of Alzheimer's disease.},
}

@article {pmid41580393,
year = {2026},
author = {Feiten, AF and Dahm, K and Schlepckow, K and van Lengerich, B and Suh, JH and Reifschneider, A and Wefers, B and Bartos, LM and Wind-Mark, K and de Weerd, L and Ulas, T and De-Domenico, E and Grundschöttel, P and Paulusch, S and Tast, B and Honda, T and Müller, SA and Becker, M and Khalin, I and Ricci, A and Liesz, A and Brunner, B and Krenner, C and Buschmann, K and Nuscher, B and Spieth, L and Junker, N and Berghoff, SA and Davis, SS and Neher, JJ and Wurst, W and Plesnila, N and Lewcock, JW and Simons, M and Lichtenthaler, SF and Di Paolo, G and Brendel, M and Capell, A and Monroe, KM and Schultze, JL and Haass, C},
title = {TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-68706-8},
pmid = {41580393},
issn = {2041-1723},
support = {HA1737/16-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; },
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and loss-of-function coding variants are major risk factors for late onset Alzheimer's disease (LOAD). To better understand the molecular and functional changes associated with TREM2 signalling in microglia, we generated a TREM2 reporter mouse. In APP transgenic animals, bulk RNA-sequencing of isolated microglia sorted based on reporter expression highlighted TREM2 level-related changes in major immunometabolic pathways, and enrichment of genes in oxidative phosphorylation and cholesterol metabolism in microglia with increased TREM2 expression. Metabolic and lipidomic profiling of sorted microglia showed that, independent of Aβ pathology, TREM2 expression correlated with signatures consistent with increased cellular redox, energetics, and cholesterol homoeostasis. In accordance, metabolic activity correlated with phagocytic capacity. Finally, we performed chronic treatment with a TREM2 agonist antibody and identified a window of TREM2 expression where microglia are most responsive, thereby informing clinical applications of TREM2 agonists.},
}

@article {pmid41579987,
year = {2026},
author = {Jeon, YN and Baek, JS},
title = {TPGS-coated zein nanoparticles encapsulating Haematococcus pluvialis extract for Alzheimer's disease: An in vitro evaluation towards brain-targeted delivery.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {150378},
doi = {10.1016/j.ijbiomac.2026.150378},
pmid = {41579987},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) aggregation and limited treatment efficacy due to the restrictive nature of the blood-brain barrier (BBB). To address this, we developed d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS)-coated Zein nanoparticles (Hp-Zein-TPGS NPs) encapsulating Haematococcus pluvialis (Hp) extract as a brain-targeted drug delivery system. Hp-Zein-TPGS NPs exhibited high physical stability over 14 days, sustained astaxanthin release, and potent antioxidant activity. The NPs also demonstrated excellent biocompatibility, showing minimal cytotoxicity in both bEnd.3 and SH-SY5Y cells, along with enhanced cellular uptake in vitro. Based on the reported effects of TPGS on P-glycoprotein (P-gp) inhibition and membrane fluidity, a delivery strategy was designed to facilitate BBB transport. In an in vitro BBB model, Hp-Zein-TPGS NPs exhibited increased transport, and Rhodamine 123 (Rh123) accumulation analysis indicated properties associated with the regulation of P-gp mediated efflux. In addition, Thioflavin T (ThT) fluorescence and morphological analyses confirmed that Hp-Zein-TPGS NPs effectively inhibited Aβ1-42 aggregation and fibril formation, while WST and Annexin V-FITC/PI assays demonstrated that Hp-Zein-TPGS NPs significantly attenuated Aβ1-42-induced neuronal toxicity, indicating their neuroprotective effects. Taken together, these findings suggest that Hp-Zein-TPGS NPs possess favorable stability, biocompatibility, BBB transport potential, and neuroprotective effects, highlighting their promise as a nanocarrier system for brain-targeted therapeutic delivery in AD.},
}

@article {pmid41579901,
year = {2026},
author = {Tariot, PN and Lopera, FS and Ríos-Romenets, S and Sink, KM and Giraldo-Chica, M and Acosta-Baena, N and Villegas, G and Espinosa, A and Castaño, ML and Muñoz, C and Ospina, P and Bocanegra, Y and Tirado, V and Henao, E and Cardona, E and Luna, E and Lopez, H and Sánchez, G and Collazos, MM and Alvarez, S and Aguillón, D and Hu, N and Clayton, D and Bittner, T and Schneider, A and Dolton, M and Poon, V and Nguyen, J and Thomas, RG and Schneider, LS and Chen, K and Su, Y and Alexander, RC and Quiroz, YT and Cai, Y and Xu, YR and Ostaszewski, B and Selkoe, DJ and Ashton, NJ and Denkinger, MN and Jakimovich, LJ and Doody, RS and Langbaum, JB and Reiman, EM},
title = {Safety and efficacy of crenezumab in cognitively unimpaired carriers of the PSEN1[Glu280Ala] mutation at risk for autosomal-dominant Alzheimer's disease in Colombia (API ADAD Colombia Trial): a phase 2, randomised, double-blind, placebo-controlled trial.},
journal = {The Lancet. Neurology},
volume = {25},
number = {2},
pages = {147-159},
doi = {10.1016/S1474-4422(25)00426-0},
pmid = {41579901},
issn = {1474-4465},
mesh = {Humans ; *Alzheimer Disease/genetics/drug therapy ; Double-Blind Method ; Male ; *Presenilin-1/genetics ; Female ; Middle Aged ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; Colombia ; Adult ; Mutation/genetics ; Heterozygote ; Treatment Outcome ; },
abstract = {BACKGROUND: To have maximal benefit, Alzheimer's disease-modifying treatments might need to be started before the onset of clinical symptoms. Mutations of the PSEN1 gene are inherited as fully penetrant, autosomal-dominant traits, which almost always result in the clinical onset of Alzheimer's disease before the age of 65 years. We aimed to evaluate the efficacy, including possible delayed emergence of cognitive impairment, and safety of crenezumab, an anti-amyloid monoclonal antibody, in cognitively unimpaired carriers of the PSEN1[Glu280Ala] mutation at high imminent risk of developing symptoms due to Alzheimer's disease.

METHODS: This 5-8-year common-close, double-blind, placebo-controlled, single-centre trial screened kindred members aged 30-60 years from the main health-care site in Medellín, Colombia. Participants who were cognitively unimpaired and carried the PSEN1[Glu280Ala] autosomal-dominant mutation were randomly assigned 1:1 to receive placebo or subcutaneous crenezumab (investigators and participants were masked to treatment allocation), with an initial 300 mg dose every 2 weeks that increased to 720 mg every 2 weeks, and a later optional increase to 60 mg/kg intravenously every 4 weeks. Randomisation was stratified by age, education, APOE ɛ4 carrier status, and baseline Clinical Dementia Rating. Mutation non-carriers received placebo and were included in a 1:2 ratio of non-carriers to carriers to maintain genotype masking and include a genetic kindred control. Dual primary outcomes were the annualised rates of change in the Alzheimer's Prevention Initiative (API) preclinical autosomal-dominant Alzheimer's disease (ADAD) composite test total score and Free and Cued Selective Reminding Test-Cueing Index (FCSRT-CI) assessed in randomised participants who received at least one dose of the study drug, according to treatment assignment. Primary endpoints were assessed with a random coefficient regression model with a missing-at-random assumption adjusting for randomisation factors. Safety endpoints for mutation carriers were assessed in randomised participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT01998841) and is completed.

FINDINGS: 619 Colombian API registrants were prescreened, 315 were assessed for eligibility, and 252 were enrolled (crenezumab-carrier, n=85; placebo-carrier, n=84; placebo-non-carrier, n=83; 160 [63%] women and 92 [37%] men) between Dec 20, 2013, and Feb 27, 2017. 237 (94%) completed the trial, with final data collection on March 22, 2022. The annualised rate of change in the API ADAD composite was -1·10 (SE 0·29) in the crenezumab group and -1·43 (0·29) in the placebo group (between-group difference 0·33 [95% CI -0·48 to 1·13]; p=0·43). The annualised rate of change in FCSRT-CI was -0·03 (0·00) in the crenezumab group and -0·04 (0·00) in the placebo group (between-group difference 0·01 [0·00 to 0·02]; p=0·16). All participants had at least one adverse event; serious adverse events occurred in 23 (27%) of 84 in the crenezumab group and 21 (25%) of 84 in the placebo group. No fatalities occurred.

INTERPRETATION: Crenezumab therapy administered for 5-8 years did not result in significant benefits on our primary clinical outcomes in cognitively unimpaired participants predisposed to developing ADAD dementia; secondary and exploratory outcomes also showed no significant effect on removal of amyloid plaques or other clinical or biomarker outcomes. Together with the results of other anti-amyloid β trials, robust fibrillar amyloid removal appears necessary for clinical efficacy in people with elevated brain amyloid. This study will further inform the biomarker, cognitive, and clinical trajectory of preclinical ADAD, the risk of clinical progression in amyloid-positive and amyloid-negative mutation carriers, and the size and design of future secondary and primary prevention trials.

FUNDING: US National Institute on Aging (NIA), Banner Alzheimer's Institute, Genentech, F Hoffmann-La Roche.},
}

Humans
*Alzheimer Disease/genetics/drug therapy
Double-Blind Method
Male
*Presenilin-1/genetics
Female
Middle Aged
*Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects
Colombia
Adult
Mutation/genetics
Heterozygote
Treatment Outcome

@article {pmid41576501,
year = {2026},
author = {Jayaswamy, PK and Ambrish, T and Sangamesh, VC and Kabekkodu, SP and Kellarai, A and Shetty, J and Shetty, P},
title = {EGFR-Annexin A2 signaling-mediated tauopathy in amyloid-β and aluminum chloride-induced Alzheimer's disease and its modulation by the HDAC inhibitor butyrate.},
journal = {Ecotoxicology and environmental safety},
volume = {310},
number = {},
pages = {119775},
doi = {10.1016/j.ecoenv.2026.119775},
pmid = {41576501},
issn = {1090-2414},
abstract = {Alzheimer's disease (AD) is typified by amyloid-β (Aβ) accumulation and tauopathy, culminating in synaptic destabilization, dendritic atrophy, and widespread neurodegeneration. Epidermal growth factor receptor (EGFR), prominently expressed during neurodevelopment, is largely quiescent in adulthood but undergoes pathological reactivation in AD, with its mechanistic contribution remaining elusive. Here, we delineate the EGFR-Annexin A2 (AnxA2) signaling nexus as a pivotal mediator of tau hyperphosphorylation in Aβ1-42-challenged SH-SY5Y and PC12 neuronal cultures and in aluminum chloride (AlCl3)/D-galactose (D-gal)-induced AD rat models. In vitro, Aβ1-42 orchestrated synergistic EGFR-AnxA2 activation, triggering site-specific tau phosphorylation (Thr231/Ser396), synaptic protein depletion, apoptotic cascades, neuroinflammatory signaling, and plasminogen activator inhibitor-1 (PAI-1)-driven fibrinolytic deficits. In vivo, AlCl3/D-gal rats displayed hippocampal EGFR-AnxA2 upregulation, region-specific tauopathy, cognitive impairments in Open Field and Novel Object Recognition paradigms, oxidative perturbations, and elevated TNF-α. Butyrate intervention abrogated EGFR-AnxA2 hyperactivity, attenuated tau pathology, restored PAI-1/tissue plasminogen activator homeostasis, and mitigated oxidative stress and neuroinflammation. Moreover, butyrate preserved synaptic and dendritic architecture, modulated apoptotic effectors by upregulating Bcl-2 and suppressing Bad, and enhanced neuronal viability. In vivo pre-and post-treatment paradigms improved behavioral and molecular outcomes, with prophylactic administration exhibiting superior efficacy. Collectively, these findings establish EGFR-AnxA2 as a central driver of tauopathy and identify prophylactic butyrate as a mechanistically grounded, diet-derived neuroprotective strategy capable of attenuating tau hyperphosphorylation, synaptic loss, and neuroinflammation in AD.},
}

@article {pmid41575675,
year = {2026},
author = {Kopalli, SR and Wankhede, N and Rahangdale, SR and Sammeta, S and Aglawe, M and Koppula, S and Taksande, B and Upaganlawar, A and Umekar, M and Kale, M},
title = {Age-driven dysbiosis: gut microbiota in the pathogenesis and treatment of aging disorders.},
journal = {Biogerontology},
volume = {27},
number = {1},
pages = {42},
pmid = {41575675},
issn = {1573-6768},
mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Dysbiosis/therapy/microbiology ; *Aging/physiology ; Animals ; Probiotics/therapeutic use ; },
abstract = {Aging, a complex physiological and molecular process, has undergone significant changes, of which gut microbiome composition has surfaced as an important key in the maintenance of neurological health. Recent studies have revealed the significant impact of age-related gut dysbiosis in the induction of neuroinflammation, metabolic syndrome, disruptions in gut-brain axis, and age-related neurological decline. Although significant studies have revealed the impact of the microbiome-gut-brain axis in individual neurological diseases, an aging-focused holistic synthesis has not yet been adequately developed. This review provides a critical assessment of the involvement of age-related dysbiosis of gut microbiota in the development and progression of neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and cognitive aging of the elderly, and to focus on age-related microbial patterns and mechanisms of dysbiosis related to neurological aging, including inflammation and immune system dysregulation, metabolic changes, oxidative stress, barrier dysfunction, and gut-brain communication through enteroendocrine, enteric neural, and vagal mechanisms, and to emphasize disease-specific and common microbial patterns of dysbiosis and beneficial and harmful microbial roles in aging diseases. This review assesses some of the latest promising therapies aimed at the microbiota, such as probiotics, prebiotics, dietary therapies, fecal microbiota transplantation, as well as pharmacological therapies, and critically discusses their limitations in terms of interindividual variability and their generalisation and applicability. Focusing on mechanistic, comparative, and translation aspects, this review offers a comprehensive approach to neurological aging due to gut microbiota and identifies gaps for future precision microbiome-based interventions.},
}

Humans
*Gastrointestinal Microbiome/physiology
*Dysbiosis/therapy/microbiology
*Aging/physiology
Animals
Probiotics/therapeutic use

@article {pmid41575410,
year = {2026},
author = {Neth, BJ and Graff-Radford, J and Cogswell, PM and Johnson, DR and Botha, H and McCarter, SJ and Jones, DT and Conkins, MM and Hardin, DB and Spence, JJ and Rhegness, CL and Allen, LA and Coburn, RP and Pounders, JD and Burkett, BJ and Pillai, JJ and Day, GS and Graff-Radford, NR and Lachner, C and Messina, SA and Jain, MK and Stricker, NH and Machulda, MM and Fields, JA and Boots, EA and Aduen, PA and Barnard, LR and Remold, MA and Anderlik, AM and Asleson, KM and Martin, LL and Klaassen, JA and Larsen, JJ and Algeciras-Schimnich, A and Bornhorst, JA and Rumilla, AM and Jack, CR and Boeve, BF and Knopman, DS and Petersen, RC and Ramanan, VK},
title = {Establishing an Alzheimer Disease Therapeutics Clinic: Experience From a Year of Evaluations.},
journal = {Mayo Clinic proceedings},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.mayocp.2025.09.019},
pmid = {41575410},
issn = {1942-5546},
abstract = {OBJECTIVE: To describe the establishment and initial experience of a multidisciplinary Alzheimer disease treatment clinic (ADTC), focusing on the evaluation of eligibility for novel disease-modifying therapies, as well as the treatment and monitoring of qualifying patients.

PATIENTS AND METHODS: We completed a retrospective review of cases seen through the Mayo Clinic ADTC between October 2, 2023, and December 31, 2024. Typical evaluations occurred over 4 to 5 days and included multimodal testing, office visits, and a weekly case conference modeled on tumor board meetings.

RESULTS: Patients evaluated in the ADTC (N=232) ranged from 52 to 85 years of age (mean age, 71.2 years). Most patients had mild cognitive impairment (128 of 232 [55%]) or mild dementia (72 of 232 [31%]) syndromes. Overall, 121 patients (52%) were judged eligible for antiamyloid therapy. Eligibility rates were higher among internal (from our institution) referrals compared with external referrals (63% [146 of 232] vs 37% [86 of 232). Reasons for treatment ineligibility were typically multiple but commonly included magnetic resonance imaging features, too severe cognitive/functional impairment, and general health conditions believed likely to increase therapeutic risks. In some cases, the ADTC evaluation uniquely identified treatment risk factors, such as cerebral amyloid angiopathy, that had not been previously discussed with patients. Through shared decision making, approximately 30% of eligible patients (25 of 81) ultimately deferred antiamyloid therapy. In addition, approximately 10% of patients evaluated in the ADTC were amyloid-negative by positron emission tomography, suggesting non-Alzheimer disease diagnoses for their presentations.

CONCLUSION: The ADTC facilitated systematic implementation of antiamyloid therapies for early Alzheimer disease and provided a scalable foundation for integrating future approved treatment options.},
}

@article {pmid41574617,
year = {2026},
author = {Sharma, P and Goyal, R},
title = {Mitigation of Circadian Disruption-Induced Amyloid Pathology, Neuroinflammation, and Cognitive Disability in C57BL/6J Mice Using Estradiol.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00650},
pmid = {41574617},
issn = {1948-7193},
abstract = {Circadian rhythms (CRs) are intrinsic 24 h cycles that regulate critical physiological processes, including sleep-wake behavior, hormonal signaling, and cognition. Disruption of CRs, often caused by chronic aberrant light exposure, has been linked to neurodegenerative diseases such as Alzheimer's disease (AD), through altered expression of core clock genes and neurotransmitter imbalances. Estrogen is a known neuromodulator that influences both circadian timing and cognitive function, yet the mechanistic interplay between estrogen and circadian dysregulation in neurodegeneration remains underexplored. In this study, we investigated whether estradiol could mitigate neuropathological and circadian disturbances induced by chronic, constant light (LL) exposure in female C57BL/6J mice. Mice were exposed to LL for 6 or 10 weeks (LL6, LL10) to model progressive CR disruption. LL10 significantly delayed locomotor rhythms (p < 0.0001), elevated hippocampal amyloid-β (Aβ) levels (p = 0.0018), and reduced SCN GABA and glutamate levels (p < 0.01), compared to LL6 and light-dark (LD) controls. Both LL6 and LL10 also showed decreased hippocampal nitric oxide and glutathione levels (p < 0.05), indicating oxidative stress. Estradiol treatment (1.5 or 3 μg/kg) restored activity rhythms, reduced Aβ accumulation (p = 0.0019), and normalized SCN neurotransmitter levels (GABA; p = 0.0046; glutamate: p = 0.0003). These effects were abrogated by tamoxifen, suggesting estrogen receptor-mediated signaling. Histological analysis further showed that estradiol attenuated hippocampal inflammation and neuronal damage in LL10-exposed animals. These results demonstrate that estrogen protects against circadian disruption-induced neuropathology and supports its potential as a therapeutic agent in mitigating cognitive decline via ER-dependent pathways.},
}

@article {pmid41573517,
year = {2025},
author = {Ham, HJ and Park, SS and Lee, YS and Kim, TH and Son, DJ and Kim, JH and Lim, KH and Park, H and Lee, HJ and Yun, J and Han, SB and Choi, MK and Hong, JT},
title = {CHI3L1 monoclonal antibody therapy mitigates cognitive impairment by inhibiting neuroinflammation through ERK and NF-κB pathway in Tg2576 mice.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1728279},
pmid = {41573517},
issn = {1662-5099},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is neurodegenerative disorder characterized by chronic inflammation in the brain. Chitinase-3-like 1 (CHI3L1), a secreted glycoprotein that is upregulated in a variety of diseases with chronic inflammation, represents a promising target for AD. Here, we studied the inhibitory effect of a novel CHI3L1 monoclonal antibody (H1) on memory impairment and neuroinflammation in Tg2576 transgenic mice.

METHODS AND RESULTS: H1 was shown to cross the blood-brain barrier selectively, as confirmed by fluorescence imaging. Tg2576 mice were administered H1 (2 mg/kg, i.v., weekly for 1 month), and cognitive functions were assessed through behavioral tests. H1 treatment alleviated memory impairment and reduced amyloid deposition and neuroinflammation both in Tg2576 mice and Aβ-induced BV-2 microglial cells. Mechanistically, H1 inhibited the ERK and NF-κB signaling pathways and suppressed M1 microglial marker expression. Global proteomic analysis and gene expression profiling in BV-2 cells and Tg2576 mouse brains revealed a strong association between CHI3L1 and HAX1 expression. H1 therapy significantly reduced HAX1 levels in both in vivo and in vitro models. Moreover, HAX1 induction by Aβ or CHI3L1 was blocked by an NF-κB inhibitor.

DISCUSSION: These findings suggest that CHI3L1 monoclonal antibody therapy may attenuate cognitive decline in AD by modulating neuroinflamma.},
}

@article {pmid41573383,
year = {2025},
author = {Liu, B and Chen, C and Cai, P and Zhang, J and Yang, L and Chen, X and Ma, X and Jiang, X and Zhang, A and Song, L and Jiang, L},
title = {The alterations in brain network functional gradients and dynamic functional connectivity in Alzheimer's disease: a resting-state fMRI study.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1716076},
pmid = {41573383},
issn = {1663-4365},
abstract = {BACKGROUND AND PURPOSE: Alzheimer's disease (AD), the most common form of dementia worldwide, is characterized by progressive cognitive decline. Extensive evidence from dynamic functional connectivity (dFC) studies has demonstrated unstable functional states, reduced network flexibility, and impaired transitions between large-scale neurocognitive networks across the AD continuum. However, how these temporal abnormalities are embedded within the hierarchical spatial organization of brain networks, as captured by functional gradients (FG), and whether combined FG-dFC metrics can provide mechanistically interpretable and potentially sensitive imaging biomarkers, remain to be elucidated.

METHODS: This study enrolled 46 AD patients who were diagnosed according to the Amyloid/Tau/Neurodegeneration (ATN) biological diagnostic framework and 37 age- and sex-matched healthy controls (HC). All participants underwent resting-state fMRI. Functional gradients were derived using connectivity similarity matrices and diffusion embedding (aligned and standardized), while dFC was estimated with a sliding window approach and clustered into four recurrent states. Group differences were assessed with two-sample t-tests with Gaussian Random Field (GRF) correction. Correlation analyses included ATN biomarkers and cognitive scores. A linear support vector machine (SVM) with leave-one-out cross-validation evaluated classification performance based on significant FG features.

RESULTS: Compared to the healthy controls, AD patients exhibited widespread FG alterations between regions of the Default Mode Network (DMN) and the Sensorimotor Network (SMN). In the first gradient DMN, the left precuneus showed reduced gradient scores, whereas the right medial superior frontal gyrus and bilateral angular gyri were increased. In the first gradient of the SMN, the right supplementary motor area increased while bilateral superior temporal gyri decreased. Second-gradient reductions were confined to two regions: the left postcentral gyrus (SMN) and left middle occipital gyrus (visual network, VIS). The right medial superior frontal gyrus first-gradient score correlated negatively with T-Tau (r = -0.50, P = 0.006) and age (r = -0.36, P = 0.02); the right angular gyrus correlated negatively with age (r = -0.29, P = 0.04); the left precuneus correlated positively with age (r = 0.38, P = 0.009). dFC revealed four recurrent states (27.59, 17.67, 28.27, 26.47% of total occurrences). Relative to HC, AD showed higher FT and MDT in states 1-2 and lower scores in state 3, with NT unchanged, alongside state-dependent bidirectional connectivity changes (fronto-insular-sensorimotor increases; DMN-temporal and visuo-auditory decreases). The SVM achieved an AUC of 0.776, sensitivity 78.26%, specificity 67.57%, and accuracy 73.49%, with the right superior temporal gyrus within SMN first-gradient contributing most.

CONCLUSION: AD is characterized by macro-scale hierarchical disorganization centered on the principal functional gradient, accompanied by reduced cross-state flexibility and state-dependent connectivity abnormalities. The combined functional gradient-dynamic functional connectivity (FG-dFC) analysis provides complementary spatiotemporal insights and reveals imaging features associated with T-Tau levels and age, offering new perspectives on the neuropathological mechanisms of AD and potential imaging biomarkers. Moreover, these network topology and dynamic connectivity metrics may prove useful for monitoring disease progression, evaluating treatment effects, and stratifying patients in future clinical and interventional studies.},
}

@article {pmid41573059,
year = {2025},
author = {Ayla, S and Saygi, HI and Sahin, M and Ciftkaya, E and Kilic, A and Pence, S and Bahadori, F and Dolanbay, EG and Elibol, B},
title = {Urtica dioica can regulate autophagy pathway in the rat hippocampal tissue after STZ-induced neurodegeneration.},
journal = {Northern clinics of Istanbul},
volume = {12},
number = {5},
pages = {531-539},
pmid = {41573059},
issn = {2536-4553},
abstract = {OBJECTIVE: Autophagy plays a crucial role in neuroprotection by helping to clear toxic substances, like misfolded proteins. In neurodegeneration, autophagy is impaired leading to the accumulation of harmful proteins that disrupt neuronal function, promote inflammation, and contribute to the degeneration of brain cells. Therefore, because of its anti-inflammatory and anti-oxidative actions, the effects of Urtica dioica (UD) on the proteins of autophagy signaling pathways was studied in the hippocampus of rats with streptozotocin-(STZ) induced neurodegeneration.

METHODS: Neurodegeneration model of rats was induced by intracerebroventricular injection of STZ (3 mg/kg) to observe both cognitive deficits and autophagic dysfunction. Then, the rats in the treatment group were consumed UD at the dose of 50 mg/kg/day for 4 weeks. At the end of 4 weeks, passive avoidance test was applied for cognitive functions and hippocampal tissue of rats were investigated to determine the changes in the proteins related to autophagy by western blotting and immunofluoresecence.

RESULTS: UD treatment slightly attenuated the STZ-induced memory deficiencies in the rats. In addition, an increase in the autophagy was noted by increasing the expression of Beclin, ATG5, and LC3β proteins in the STZ-UD group compared to the STZ group.

CONCLUSION: In summary, UD may be a candidate molecule as a therapeutic strategy to protect neurons in neurodegeneration through increasing autophagy to reduce toxic protein accumulation.},
}

@article {pmid41572310,
year = {2026},
author = {Kashem, M and Haldenby, O and Ahmad, JF and Muhammad, AA and Mostert, CM and Ali, S},
title = {Are diagnostic technologies for alzheimer's disease and dementia cost-effective? A systematic review of economic evaluations.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01933-1},
pmid = {41572310},
issn = {1758-9193},
abstract = {BACKGROUND: Alzheimer's disease (AD) and dementia pose a significant clinical and economic burden globally. Early diagnosis and intervention can potentially delay disease progression. Current diagnostic guidelines recommend considering imaging and biomarker analysis in conjunction with clinical evaluation. Given limited healthcare resources, evidence on the cost-effectiveness of diagnostic technologies is critical to guide allocation of resources.

OBJECTIVE: To systematically review the economic evaluation studies of neuroimaging, biomarkers, and other diagnostic or screening strategies for diagnosing and/or tracking the progression of AD or dementia.

METHODS: A comprehensive search was conducted across Medline, Embase, PsycINFO, CINAHL and EconLit, and to identify relevant studies, with no restrictions on country, language, or publication period. Quality of the studies was evaluated using the Consensus on Health Economic Criteria-Extended (CHEC-Extended) checklist.

RESULTS: Out of 6,804 records, 21 studies met the eligibility criteria. These included evaluations of neuroimaging technologies such as Positron Emission Tomography, Single Photon Emission Computed Tomography, Computed Tomography, and Magnetic Resonance Imaging (n = 10), cerebrospinal fluid and blood biomarkers (n = 7), and alternative diagnostic strategies including screening programs, machine learning-based models, and multidisciplinary care approaches (n = 4). Among the studies evaluating imaging technologies, most (n = 6) did not find them to be cost-effective. In contrast, CSF and blood biomarker studies found these technologies to be cost-effective, with some variability in results. Methodological quality score ranged between 15% and 95%, indicating a mix of low- to high-quality studies. Due to heterogeneity in study designs and reported outcomes, direct comparisons were not feasible.

CONCLUSIONS: While many studies were of high quality, heterogeneity in study objectives, design, and outcomes restricted evidence synthesis. Future research should ensure methodological consistency, transparent cost reporting, and integration of new treatment frameworks to improve the policy relevance and reliability of economic evidence for AD diagnostics.},
}

@article {pmid41571954,
year = {2026},
author = {Ahn, NH and Hong, SC and Hong, CR and Lee, EH and Lee, JH and Choi, SB and Jung, J and Kim, Y and Kim, JS and Park, K and Kim, YK and Kim, Y and Yang, SH},
title = {Fucoxanthin Extracted from the Microalgae Phaeodactylum tricornutum Ameliorates Alzheimer's Pathologies with the Reduction of Aβ-Induced NLRP3 Inflammasome Activation in APP/PS1 Mice.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {385},
pmid = {41571954},
issn = {1559-1182},
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Xanthophylls/pharmacology/therapeutic use/isolation & purification ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; *Inflammasomes/metabolism ; Mice ; *Microalgae/chemistry ; Microglia/drug effects/metabolism ; Mice, Inbred C57BL ; Astrocytes/drug effects/metabolism/pathology ; tau Proteins/metabolism ; *Presenilin-1/metabolism ; Male ; *Amyloid beta-Protein Precursor/metabolism ; Brain/pathology/drug effects/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, one of the most common types of dementia, accompanying severe learning and memory dysfunctions. In AD brains, the misfolded aggregation and deposits of amyloid-β (Aβ) and tau are frequently observed before the cognitive symptom onset; thus, trials for alleviation of these lesions are considered commensurate strategies with AD treatment. Additionally, increasing evidence suggests that misfolded and aggregated proteins induce the activation of microglia and astrocytes by the release of the inflammatory mediators via the activation of the inflammatory signaling cascade, which consequently contributes to AD pathogenesis. Here, we investigated the therapeutic potential of fucoxanthin, a compound derived from the microalgae Phaeodactylum tricornutum, in mitigating AD pathologies. Fucoxanthin was shown to inhibit the aggregation of Aβ and tau, converting their aggregates to monomeric forms. In the brain of APP/PS1 transgenic mice, fucoxanthin administration significantly reduced the levels of Aβ plaques and hyperphosphorylated tau and further ameliorated cognitive impairments by inhibiting the activation of microglia and astrocytes. Notably, fucoxanthin effectively regulated Aβ-induced NLRP3 inflammasome activation in astrocytes, reducing neuroinflammation associated with AD. Thus, our findings showing the multifaceted therapeutic mode of action of fucoxanthin against AD provide that fucoxanthin would have promising roles in the strategies of AD treatment.},
}

Animals
*Alzheimer Disease/drug therapy/pathology/metabolism
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Xanthophylls/pharmacology/therapeutic use/isolation & purification
*Amyloid beta-Peptides/metabolism
Mice, Transgenic
*Inflammasomes/metabolism
Mice
*Microalgae/chemistry
Microglia/drug effects/metabolism
Mice, Inbred C57BL
Astrocytes/drug effects/metabolism/pathology
tau Proteins/metabolism
*Presenilin-1/metabolism
Male
*Amyloid beta-Protein Precursor/metabolism
Brain/pathology/drug effects/metabolism

@article {pmid41571775,
year = {2026},
author = {Sathish, R and Muthukumar, R and Kumaran, KM and Murugan, SP},
title = {Intelligent decision-making systems for early detection of alzheimer's disease using wearable technologies and deep learning.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-36895-3},
pmid = {41571775},
issn = {2045-2322},
abstract = {Intelligent decision-making systems using wearable electronics and deep learning (DL) might identify Alzheimer's disease (AD) early for treatment. These technologies can continually monitor vital signs and behavioral characteristics to identify early cognitive deterioration in patients. Clinical examinations, neuroimaging, and cognitive testing are the main ways to identify Alzheimer's, but they are difficult, expensive, and frequently miss the illness early on. Such approaches lack the sensitivity and real-time monitoring essential for early intervention. Through wearable technology and sophisticated DL approaches, Early Detection using Deep Learning Algorithm (ED-DLA) tackles these constraints. In real time, wearable sensors capture data on heart rate, sleep habits, and physical activity. DL algorithms evaluate this data to identify early Alzheimer's. Continuous and non-invasive monitoring improves detection sensitivity and accuracy. To evaluate sequential wearable device data, the suggested technique uses an RNN-based image classification model. Temporal patterns are essential for understanding AD development, and the RNN does so well. The slight changes in cognitive and physical activities may indicate early-stage dementia. The suggested AD diagnosis and management system improves early detection accuracy and real-time monitoring, making it more dependable and scalable.},
}

@article {pmid41571077,
year = {2026},
author = {Abdel-Aal, RA and Meligy, FY and Kamel, G and Ashry, IEM},
title = {Cognitive Enhancing Effect of Canagliflozin in Aluminum-Induced Rat Model of Alzheimer's-Like Disease: Cross Talk Between Amyloid-Β and BDNF/GSK-3β Signaling.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178581},
doi = {10.1016/j.ejphar.2026.178581},
pmid = {41571077},
issn = {1879-0712},
abstract = {The strong relationship between Alzheimer's Disease (AD) and diabetes mellitus (DM) is described by the term "type 3 diabetes". Canagliflozin (CAN), a sodium-glucose co-transporter 2 inhibitor (SGLT2i), is an antidiabetic agent under investigation as a potential new treatment for AD due to its acetylcholinesterase (AChE) inhibitory properties. We aimed to examine the effect of CAN on the efficacy of the anti-acetylcholinesterase, rivastigmine (RIV), against aluminum chloride (AlCl3)-induced AD rat model. The efficacy of CAN, RIV, and CAN plus RIV against abnormal behavioral, biochemical, and histological changes in AlCl3-induced AD in rats was examined. Three weeks of treatment with CAN partially reversed the AlCl3-induced behavioral dysfunction, along with significantly elevated levels of brain-derived neurotrophic factor (BDNF) and decreased levels of AChE, glycogen synthase kinase-3β (GSK3β), amyloid beta (Aβ) deposits, and inducible nitric oxide synthase (iNOS) expression. Histological examination revealed that CAN administration significantly increased RIV's efficacy by protecting neurons in rats' hippocampal tissues from AlCl3-induced damage. Interestingly, the RIV+CAN combination exhibited a more pronounced inhibitory effect on Aβ plaque formation, iNOS activity, and neurodegeneration compared to either RIV or CAN alone. However, this combination did not show any additive benefits for behavior, AChE activity, BDNF, or GSK3β concentrations compared with RIV alone. Our research indicates that CAN has potential benefits for AD, as evidenced by improvements in cognitive abilities, cholinergic activity, and neurogenesis in rats with AD. This is attributed to the upregulation of BDNF/GSK3β signaling, reduced neuroinflammation, and Aβ deposition.},
}

@article {pmid41570950,
year = {2026},
author = {Guo, J and Shi, C and Yu, C and Wang, Y and He, M},
title = {Protein S-Sulfhydration: Mechanisms and Therapeutic Implications in Alzheimer's Disease and Parkinson's Disease.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2026.01.033},
pmid = {41570950},
issn = {1873-4596},
abstract = {BACKGROUND: Alzheimer's disease (AD), Parkinson's disease (PD) and other neurodegenerative diseases have complex pathogenic mechanisms. Traditional theories (e.g., free radical damage/oxidative stress, inflammatory responses) have laid a foundation for understanding these pathological processes. However, single mechanisms cannot fully explain their complexity. In recent years, post-translational modifications (PTMs)-especially redox-related types such as S-sulfhydration-have emerged as key complementary regulators of nervous system homeostasis and disease progression. It is mediated by the endogenous gas signaling molecule hydrogen sulfide (H2S) and has unique regulatory effects.

AIM OF REVIEW: This review systematically summarizes the molecular mechanisms and therapeutic targets of S-sulfhydration in AD and PD. It discusses the potential of S-sulfhydration in disease intervention and treatment. It also looks into H2S-based therapeutic strategies and their clinical application prospects. This review aims to provide a theoretical basis for understanding the role of PTMs in neurological diseases.

This review summarizes clearly: in AD and PD, S-sulfhydration interacts with protein modifications like phosphorylation, S-nitrosylation and succinylation. It regulates key pathogenic proteins such as Tau, Aβ and Parkin. It also takes part in regulating energy metabolism, resisting oxidative stress and inhibiting inflammatory responses. These effects influence neuronal survival and functional homeostasis. This indicates that S-sulfhydration plays an important regulatory role in AD and PD progression. It is part of the complex network of pathological mechanisms. Its modification mechanisms and interaction pathways offer promising complementary molecular targets and intervention strategies for treating AD, PD, and other potential neurodegenerative diseases.},
}

@article {pmid41570699,
year = {2026},
author = {Razzaq, R and Ahmed, T and Butt, AM and Jabeen, Z and Khalid, A and Shahid, I and Alzahrani, AR and Rehman, S},
title = {Betanin-encapsulated nanoparticles mitigate neurotoxicity against AlCl3-induced Alzheimer's disease via modulation of AChE/TNF-α/IL-1β expression.},
journal = {Biochemical and biophysical research communications},
volume = {801},
number = {},
pages = {153293},
doi = {10.1016/j.bbrc.2026.153293},
pmid = {41570699},
issn = {1090-2104},
abstract = {Alzheimer's disease (AD), the most common health problem, is significantly characterized by oxidative stress, neuroinflammation, and cholinergic dysfunction, provoking growing interest in natural antioxidants with improved bioavailability. This study is intended to evaluate the neuroprotective impact and the probable mechanism of betanin and formulated betanin-encapsulated nanoparticles (ChBetNPs) in an AlCl3 and D-galactose-induced rat model Alzheimer's-like neurotoxicity. The rats were treated daily with AlCl3 and D-galactose for 21 days to induce neurotoxicity, followed by two weeks of treatment with low and high doses of betanin and ChBetNPs. After treatment, cognitive performance, oxidative stress markers, acetylcholinesterase (AChE) activity, and hippocampal inflammatory gene expression were assessed. Both low and high doses of ChBetNPs (40 mg/kg/day and 80 mg/kg/day respectively) significantly improved learning and memory performance in AlCl3 + D-galactose-treated rats. Treatment with ChBetNPs also markedly restored antioxidant defenses, as evidenced by increased activities of CAT (∗∗P < 0.01), elevated reduced GSH, and reduced levels of the lipid peroxidation marker MDA. The higher dose of ChBetNPs produced a pronounced protective effect on cholinergic function, reflected by a robust reduction in brain AChE activity (∗∗∗∗P < 0.0001). In addition, both free betanin and ChBetNPs at low and high doses significantly (∗∗P < 0.01) downregulated the hippocampal mRNA expression of AChE, α-synuclein, TNF-α, and IL-1β in hippocampal region of brain as compared with untreated group, indicating attenuation of neuroinflammatory and protein-aggregation-related pathways. In summary, our findings demonstrate that ChBetNPs enhanced learning, memory, and cholinergic neurotransmission, likely by mitigating oxidative stress and the associated NF-κB-mediated inflammatory responses.},
}

@article {pmid41570392,
year = {2026},
author = {Wischik, CM and Stefanacci, R and Bentham, P and Gauthier, S and Zetterberg, H and Wilcock, GK and Froelich, L and Burns, A and MacSweeney, E and Ballard, C and Yu, JT and Choon, TS and Asvatourian, V and Muehlemann, N and Priel, J and Kook, K and Sullivan, T and Downie, D and Miller, S and Pringle, C and Storey, JMD and Baddeley, T and Harrington, CR and Penny, LK and Arastoo, M and Staff, R and Sandu, AL and Shiells, H and Lo, S and Nazlee, N and Evans, E and Hull, C and Schelter, BO},
title = {Clinical, imaging and blood biomarker outcomes in a Phase 3 clinical trial of tau aggregation inhibitor hydromethylthionine mesylate in mild cognitive impairment and mild to moderate dementia due to Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {3},
pages = {100480},
doi = {10.1016/j.tjpad.2026.100480},
pmid = {41570392},
issn = {2426-0266},
abstract = {BACKGROUND: Hydromethylthionine mesylate (HMTM) targets tau pathology and has tau-independent symptomatic activity.

OBJECTIVES: To evaluate the safety and efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer's disease (AD).

SETTING: 82 centres in Canada, European Union, United Kingdom and United States of America.

PARTICIPANTS: A total of 598 amyloid β-PET positive participants were included; 44% (263) met clinical criteria for MCI due to Alzheimer's disease and 56% (335) were diagnosed with mild to moderate dementia due to AD.

INTERVENTION: HMTM 16 mg/day and 8 mg/day were compared with methylthioninium chloride (MTC) 4 mg twice weekly, intended as an inactive urinary colourant to preserve blinding with respect to possible urinary discolouration caused by HMTM.

MEASUREMENTS: HMTM and MTC were compared on cognitive and functional endpoints for the first 52 weeks followed by all receiving HMTM 16 mg/day to 104 weeks in a modified delayed-start trial design. Biomarker outcomes included change in plasma levels of neurofilament light chain (NfL), pTau217 and MRI measures of grey matter atrophy.

RESULTS: It was not possible to demonstrate significant differences on the co-primary clinical endpoints (ADAS-cog11 and ADCS-ADL23) at 52 weeks due to symptomatic activity in the control arm. In participants with MCI, statistically significant differences in cognitive decline (ADAS-cog13) emerged at 78 weeks (p = 0·0291) and 104 weeks (p = 0·0308) between early- and delayed-start HMTM 16 mg/day in analyses specified prior to the 24-month database lock. Statistically significant cognitive improvement over baseline score was sustained for 78 weeks in the early start MCI group, with no significant cognitive or functional decline to 104 weeks. There was a significant reduction in progression of neurodegeneration measured by NfL change (p = 0·0291) at 52 weeks in the whole population, consistent with significant reductions in progression of grey matter atrophy at 52 and 104 weeks, and a reduction in progression of tau pathology (pTau217, p = 0·0165) in MCI. Headache (1·5%) and diarrhoea (1·2%) were the most frequent adverse effects.

CONCLUSIONS: Although HMTM 16 mg/day arrested progression of neurodegeneration and reduced grey matter atrophy at 52 weeks, symptomatic activity in the control arm precluded separation of treatment arms at 52 weeks on primary clinical endpoints. In participants with MCI, significant clinical separation was seen only at 78 and 104 weeks. This effect has been confirmed in a further study. HMTM was well tolerated and has the potential to offer an accessible oral treatment option with a benign safety profile which could be delivered with minimal patient/physician burden.},
}

@article {pmid41569280,
year = {2026},
author = {Huynh, ALH and Wang, S and Lee, K and Amadoru, S and Wrigley, S and Zisis, G and Ernstrom, K and Raman, R and Aisen, P and Sperling, RA and Masters, CL and Ward, D and Yates, PA},
title = {Prevalence of frailty and its association with cognition in preclinical Alzheimer's disease: a cross-sectional analysis of baseline data from the A4 study.},
journal = {Age and ageing},
volume = {55},
number = {1},
pages = {},
doi = {10.1093/ageing/afaf378},
pmid = {41569280},
issn = {1468-2834},
mesh = {Humans ; Aged ; Female ; Cross-Sectional Studies ; Male ; *Alzheimer Disease/epidemiology/diagnosis/psychology ; *Frailty/epidemiology/diagnosis/psychology ; Prevalence ; *Cognition ; Amyloid beta-Peptides/metabolism ; Aged, 80 and over ; *Frail Elderly ; Geriatric Assessment ; Risk Factors ; Prodromal Symptoms ; },
abstract = {BACKGROUND: The prevalence and role of frailty in preclinical Alzheimer's disease (AD) is unclear.

METHODS: Cross-sectional analyses of pre-randomization data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) study were analysed to derive two models of a frailty index (FI)-full [FI-Full] and cognitive variables removed [FI-CVR]. The prevalence of frailty (FI > 0.25) according to amyloid status (Aβ+/-), and the association of frailty and cognition (determined by the Preclinical Alzheimer Cognitive Composite (PACC) score) and whether frailty moderates the relationship between amyloid status and cognition was assessed, adjusting for age, sex and education.

RESULTS: Four thousand four hundred eighty-six participants were included (mean age 71.3 ± 4.7 years, 30% participants Aβ+, 59% female). The prevalence of frailty in preclinical AD was 22% (or 44% when cognitive variables were removed from the FI). Using either FI model, in adjusted analyses, Aβ+ participants were more likely to be frail compared to Aβ- [FI-Full-Odds ratio (OR) 1.43 95% confidence interval (CI) 1.20-1.71, P < .001; FI-CVR-OR 1.21 95% CI 1.05-1.40, P < .008]. Frail participants had lower PACC scores compared to non-frail participants, on average (FI-Full-PACC score -0.58 95% CI -0.76 to -0.40, P < .001; FI-CVR-PACC score -0.26 95% CI -0.40 to -0.12, P < .001). Frailty did not influence the relationship between Aβ status and cognition.

CONCLUSIONS: In a cohort screened for a preclinical AD trial, elevated Aβ levels were associated with frailty and frailty was associated with reduced cognitive performance independent of elevated Aβ levels. These associations, and whether or not frailty is associated with longitudinal cognitive decline independent of Aβ status, warrant further study.},
}

Humans
Aged
Female
Cross-Sectional Studies
Male
*Alzheimer Disease/epidemiology/diagnosis/psychology
*Frailty/epidemiology/diagnosis/psychology
Prevalence
*Cognition
Amyloid beta-Peptides/metabolism
Aged, 80 and over
*Frail Elderly
Geriatric Assessment
Risk Factors
Prodromal Symptoms

@article {pmid41569242,
year = {2026},
author = {Zuliani, G and Boscolo Bragadin, F and Romagnoli, T and Polastri, M and Cervellati, C and Dario, FDP and Brombo, G and Zuin, M},
title = {Long-Term Effect of Acetylcholinesterase Inhibitors on Behavioral and Psychological Symptoms of Dementia.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {1},
pages = {e70195},
doi = {10.1002/gps.70195},
pmid = {41569242},
issn = {1099-1166},
mesh = {Humans ; *Cholinesterase Inhibitors/therapeutic use ; Aged ; Male ; Female ; *Dementia/drug therapy/psychology ; Aged, 80 and over ; Severity of Illness Index ; Behavioral Symptoms/drug therapy ; },
abstract = {OBJECTIVE: Behavioral and psychological symptoms of dementia (BPSD) are critical aspects of the clinical presentation of dementia. There is no universally accepted approach for the managment of BPSD, currently based first on a non-pharmacological and subsequently on a pharmacological approach. We explored the potential effect of long-term treatment with acetylcholinesterase inhibitors (AChEI) on BPSD severity over time.

METHODS: The initial sample included 4032 older patients with mild-moderate dementia (Alzhemier's disease - AD, Lewy body dementia - LBD, or vascular dementias - VaD) from the National Alzheimer's Coordinating Center Uniform Data Set (NACC UDS). After propensity score matching, a cohort of 1408 patients (704 treated with AChEI = AChEI+ and 704 not treated = AChEI-) was generated. The mean age was 73.2 years (females: 50.4%). The mean follow-up duration was 4.3 ± 1.6 years (range: 2.2-8.3 years). Patients were evaluated at baseline, T1 (2 years), T2 (4 years), T3 (6.2 years), and T4 (8.1 years). BPSD severity was assessed by Neuropsychiatric Inventory (NPI-Q).

RESULTS: The baseline mean NPI-Q severity score was 1.33. At T4, the score increased to 1.41 in AChEI- patients (+6% from baseline), while it decreased to 1.26 in AChEI+ (-6%) (all p < 0.01 from T1 to T4). As regards the NPI-Q sub-items, six of them (hallucinations, agitation/aggression, depression/dysphoria, anxiety, disinhibition and irritability/lability) exhibited significant differences over time (all p < 0.01) in favor of the AChEI + group (stabilization or improvement). Similar trends were observed when LOAD, LBD and VaD were considered separately. In contrast, for five domains (delusions, elation/euphoria, motor disturbances, night-time behaviors, and appetite/eating changes) no differences were observed.

CONCLUSIONS: Our study supports the potential role for AChEI in BPSD management, demonstrating a trend toward symptoms stabilization or improvement in patients with mild-moderate dementia. Although the effects were not uniform across all NPI-Q domains, and the limitations of the study, our results reinforces the relevance of AChEI in the comprehensive treatment of dementia.},
}

Humans
*Cholinesterase Inhibitors/therapeutic use
Aged
Male
Female
*Dementia/drug therapy/psychology
Aged, 80 and over
Severity of Illness Index
Behavioral Symptoms/drug therapy

@article {pmid41568736,
year = {2025},
author = {Liu, W and Li, Y and Qin, W and Wang, X and Li, W and Li, Y and , and Jia, J},
title = {The impact of cholinesterase inhibitors on cognitive trajectories in mild cognitive impairment patients based on amyloid beta status.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {5},
pages = {e70193},
doi = {10.1002/alz.70193},
pmid = {41568736},
issn = {1552-5279},
support = {CX23YZ15//Chinese Institutes for Medical Research/ ; U20A20354//Key Project of the National Natural Science Foundation of China/ ; 81530036//Key Project of the National Natural Science Foundation of China/ ; 7244355//Beijing Municipal Natural Science Foundation/ ; 31627803//National Key Scientific Instrument and Equipment Development Project/ ; No.2021ZD0201802//STI2030-Major Projects/ ; Z201100005520016//Beijing Brain Initiative from Beijing Municipal Science & Technology Commission/ ; Z201100005520017//Beijing Brain Initiative from Beijing Municipal Science & Technology Commission/ ; 82401404//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Cognitive Dysfunction/drug therapy/metabolism ; Male ; Female ; Disease Progression ; *Cholinesterase Inhibitors/therapeutic use/adverse effects ; *Amyloid beta-Peptides/metabolism ; Aged ; *Alzheimer Disease ; Aged, 80 and over ; *Cognition/drug effects ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: This study examines whether cholinesterase inhibitors (ChEIs) influence the progression to Alzheimer's disease (AD) dementia and cognitive trajectories in amnestic mild cognitive impairment (MCI) patients, considering their amyloid beta (Aβ) status.

METHODS: Kaplan-Meier and time-varying Cox models evaluated ChEI use and different Aβ status on MCI-to-AD progression. Linear mixed-effects models assessed cognitive trajectories. Locally estimated scatterplot smoothing regression analyzed cognitive changes before and after ChEI initiation.

RESULTS: Among 558 amnestic MCI participants (168 ChEI users), ChEI users exhibited higher risk of progression to AD dementia (hazard ratio = 1.77, 95% confidence interval: 1.15 to 2.73, p = 0.001). Both ChEI use and Aβ burden independently accelerated MCI progression and cognitive decline. Cognitive trajectories demonstrated decline before ChEI initiation and continued to decline after treatment began.

DISCUSSION: The association between ChEI treatment and accelerated progression to AD dementia and cognitive decline, independent of Aβ status, emphasized the need to reconsider optimal timing for ChEI initiation in MCI.

HIGHLIGHTS: ChEI use in MCI was associated with increased risk of progression to AD dementia. ChEI use in MCI was associated with accelerated longitudinal cognitive decline. Cognitive decline persisted after ChEI initiation rather than reversing. ChEI effects on MCI progression to AD dementia were independent of Aβ status.},
}

Humans
*Cognitive Dysfunction/drug therapy/metabolism
Male
Female
Disease Progression
*Cholinesterase Inhibitors/therapeutic use/adverse effects
*Amyloid beta-Peptides/metabolism
Aged
*Alzheimer Disease
Aged, 80 and over
*Cognition/drug effects
Neuropsychological Tests

@article {pmid41568664,
year = {2026},
author = {Jootar, T and Hongeng, S and Chiangjong, W},
title = {Engineering nanobodies for drug delivery systems in Alzheimer's disease.},
journal = {Artificial cells, nanomedicine, and biotechnology},
volume = {54},
number = {1},
pages = {104-118},
doi = {10.1080/21691401.2026.2617707},
pmid = {41568664},
issn = {2169-141X},
mesh = {*Alzheimer Disease/drug therapy/metabolism/immunology/pathology ; *Single-Domain Antibodies/therapeutic use/chemistry/immunology ; Humans ; Animals ; *Drug Delivery Systems ; *Protein Engineering ; Blood-Brain Barrier/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) remains a major global health challenge, with current therapies offering only symptomatic relief. A significant constraint in the development of effective treatments is the blood-brain barrier (BBB), as it greatly limits the access of therapeutic drugs targeting amyloid-β (Aβ) aggregation, tau hyperphosphorylation and neuroinflammation. Nanobodies, single-domain antibody fragments derived from camelids, have emerged as versatile tools with unique properties such as small size, high stability and the ability to penetrate the BBB. Engineered formats allow for specific targeting of Aβ and tau, receptor-mediated transcytosis, and conjugation with therapeutic or diagnostic substances. Preclinical studies show that nanobody-based strategies can reduce pathological burden, attenuate neuroinflammation and improve cognitive outcomes in AD models. Manufacturing scale-up, long-term safety and regulatory validation are among the remaining challenges, yet nanobody engineering represents a viable path to disease-modifying medicines. Innovative approaches, including artificial intelligence-driven design, i.e. 4-1BB agonist nanobodies, and clustered regularly interspaced short palindromic repeat-facilitated diversification of nanobody libraries - such as targeted complementarity-determining region 3 mutagenesis followed by functional screening against disease-relevant tau or Aβ conformers - alongside half-life extension strategies, are commencing to surmount these obstacles and enhance the potential of nanobody platforms to develop into clinically viable disease-modifying therapies.},
}

*Alzheimer Disease/drug therapy/metabolism/immunology/pathology
*Single-Domain Antibodies/therapeutic use/chemistry/immunology
Humans
Animals
*Drug Delivery Systems
*Protein Engineering
Blood-Brain Barrier/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid41567052,
year = {2026},
author = {Tziakouri, A and Loser, V and Vicino, A and Baumgartner, T and Di Liberto, G and Pantazou, V and Bernard-Valnet, R and Theaudin, M and Pot, C and Castro-Jimenez, M and Hübsch, CA and Bally, J and Strambo, D and Hirt, L and Caranzano, L and Rouaud, O and Allali, G and Salvioni, P and Sokolov, AA and Pignat, JM and Ryvlin, P and Perrenoud, MP and Rossetti, AO and Novy, J and Beuchat, I and Du Pasquier, R and Michel, P},
title = {[Neurology : what's new in 2025].},
journal = {Revue medicale suisse},
volume = {22},
number = {946},
pages = {161-164},
doi = {10.53738/REVMED.2026.22.946.48114},
pmid = {41567052},
issn = {1660-9379},
mesh = {Humans ; *Neurology/trends ; Female ; Pregnancy ; *Nervous System Diseases/therapy/diagnosis ; Multiple Sclerosis/therapy/drug therapy ; },
abstract = {In 2025, several major advances have marked the field of neurology. Anti-FcRN and anti-C5 antibodies have confirmed their long-term efficacy in the treatment of myasthenia gravis. Bruton tyrosine kinase inhibitors have expanded the therapeutic arsenal for multiple sclerosis. An antibody targeting α-synuclein appears to slow motor decline in early-stage Parkinson's disease. The efficacy of late thrombolysis in strokes with radiological mismatch has been confirmed. A blood biomarker facilitates early detection of Alzheimer's disease, and Swiss guidelines specify the modality for the use of anti-amyloid therapies in this disease. Finally, in pregnant women with epilepsy, the recommended dose of folic acid has been reduced.},
}

Humans
*Neurology/trends
Female
Pregnancy
*Nervous System Diseases/therapy/diagnosis
Multiple Sclerosis/therapy/drug therapy

@article {pmid41566034,
year = {2026},
author = {Peng, Y and Wang, SS and Lai, KD and Ye, JR and He, WB and Yan, X and Zhang, Z and Chu, SF and Chen, NH},
title = {Protopanaxatriol restores cognitive function in okadaic acid-treated mice via direct inhibition of pathological CDK5 activity.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {41566034},
issn = {1745-7254},
abstract = {Alzheimer's disease (AD), a prevalent neurodegenerative dementia, presents therapeutic challenges due to safety concerns about amyloid-targeting strategies. Traditional Chinese medicine (TCM) may offer alternative avenues for exploration. Ginsenoside Rg1, a key bioactive component of ginseng, has shown neuroprotective potential in okadaic acid (OKA)-induced rat model, its limited brain bioavailability suggests that its metabolite protopanaxatriol (Ppt) may exert these effects. In this study, we investigated the therapeutic effects of Ppt on OKA-induced mice model and the underlying mechanisms. Cultured hippocampal neurons were treated with OKA (0.5 nM) with or without Ppt co-treatment for 24 h. We showed that Ppt (1.25-40 nM) exerted dose-dependent neuroprotection against OKA-induced cytotoxicity, with the maximal protection observed at 10 nM. The suppressed tau aggregation by Ppt was confirmed using a Venus-tau bimolecular fluorescence complementation (BiFC) system. Molecular dynamics simulations and microscale thermophoresis (MST) revealed that Ppt bound to the catalytic domain of CDK5 at Cys83, destabilizing the CDK5/p25 complex. Co-immunoprecipitation (Co-IP) assays with CDK5 mutants (S159T, C83A, F80A and D86A) validated this interaction. In vivo mice were treated with Ppt (10 mg/kg, i.g.) for 25 days. On D8 and D9, the mice were bilaterally microinjected with OKA into the cerebral ventricles. We showed that Ppt administration improved spatial memory deficits in Novel Object Recognition and Barnes Maze tests; these effects were abolished in mice expressing a lentivirus-mediated CDK5[C83A] mutant. Hippocampal transcriptomic profiling in OKA-challenged mice following Ppt intervention revealed that Ppt modulated Drp1-mediated mitochondrial fission/fusion dynamics, mitigating OKA-induced mitochondrial homeostasis disruption. Collectively, these results demonstrate that Ppt attenuates tau pathology by selectively targeting CDK5 at Cys83, thereby reducing pathological kinase activity, rebalancing mitochondrial function, and improving cognitive outcomes in an OKA-induced mice neurodegeneration model. The study underscores the therapeutic potential of Ppt in AD treatment and supports CDK5 modulation as a strategic approach for addressing tau-related neurodegeneration.},
}

@article {pmid41565079,
year = {2026},
author = {Doshi, PP and Desale, SH and Khutale, AA and Sabarathinam, S and Suresh, S},
title = {Evaluating Senescence-Targeted Approaches in Alzheimer's Disease: What We Know and What Lies Ahead.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103029},
doi = {10.1016/j.arr.2026.103029},
pmid = {41565079},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease, which represents the most prevalent dementia worldwide. Although amyloid-β (Aβ) and tau pathology have been the classic focus of treatment, accumulating evidence indicates that ageing-associated cellular senescence plays a central role in AD pathogenesis. Senescent neurons, astrocytes, microglia and endothelial cells accumulate in the ageing and Alzheimer's brain and adopt a senescence-associated secretory phenotype characterized by sustained release of pro-inflammatory and neurotoxic factors. This chronic inflammatory milieu promotes neurodegeneration, disrupts the synaptic activity and is involved in cognitive deficit. Senolytics, which selectively eliminate senescent cells, have demonstrated benefit in multiple preclinical models of AD, including decreased neuroinflammation, improvement in neuronal function and cognitive performance. Several senolytic agents, such as dasatinib, quercetin, fisetin and navitoclax, hit anti-apoptotic modalities that support the survival of senescent cells. Early-phase human studies suggest the feasibility of senescence-targeted interventions and indicate that senescence-associated molecular changes may compromise blood-brain barrier integrity. Consistently, preclinical studies demonstrate partial restoration of barrier function following senolytic therapy; however, clinical translation remains limited and at an early stage. Major challenges include the identification of senolytic agents with effective central nervous system penetration, the determination of optimal dosing regimens and treatment schedules, generation of robust long-term safety profile in human population, and the development of predictive biomarkers to guide patient selection and clinical study design. As senolytics and senomorphic strategies continue to evolve, they hold promise as complementary approaches to existing anti-amyloid and anti-tau therapies by offering a multi-mechanistic approach toward AD modification. This review synthesizes current evidence on cellular senescence in AD, outlines the mechanistic rationale for senescence-targeted therapies, summarizes available clinical data, while providing future directions for integrating senolytics into AD management.},
}

@article {pmid41565030,
year = {2026},
author = {Zhang, X and Ding, W and Guo, C and Chen, X and Chen, B},
title = {Choline serves as the primary active compound of anti-aging tablets and targets PTGS2 to alleviate neuronal damage in Alzheimer's disease by modulating ferroptosis and apoptosis in nerve cells.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116040},
doi = {10.1016/j.bbr.2026.116040},
pmid = {41565030},
issn = {1872-7549},
abstract = {BACKGROUND: Alzheimer's disease (AD), a neurodegenerative disorder characterized by progressive cognitive impairment, involves pathological mechanisms including β-amyloid protein deposition, hyperphosphorylation of Tau proteins, and neuronal damage mediated by ferroptosis. As a traditional Chinese medicine, anti-aging tablets have potential neuroprotective effects, but their active ingredients and mechanisms have not been fully elucidated.

METHODS: We screened active ingredients and AD-related targets in anti-aging tablets using liquid chromatography-mass spectrometry combined with network pharmacology analysis. A protein-protein interaction network was established, and GO/KEGG enrichment analyses were performed. The binding of choline to PTGS2 was verified through molecular thermal shift assay. qPCR was utilized to detect PTGS2 expression. An AD model was constructed, with cellular injury levels evaluated through CCK-8, LDH assays, and WB detection by examining the expression of apoptosis-related biomarkers. The expression of ferroptosis-related proteins (FSP1, SLC7A11, GPX4) was examined through Western blot analysis. MDA and GSH/GSSG analyses determined lipid peroxidation and antioxidant capacity. DCFH-DA detected ROS levels.

RESULTS: The combined use of UPLC-MS/MS with network pharmacology led to the identification and characterization of choline as the key active ingredient in anti-aging tablets. PTGS2 was determined as its primary target. The direct binding of choline to PTGS2 was verified through molecular thermal shift assay. In vitro experiments revealed that choline significantly repressed cell damage in the AD model, as indicated by enhanced cell viability, reduced release of LDH, lowered levels of reactive oxygen species (ROS), and downregulated expression of caspase-3 and Bax. Additional studies uncovered that overexpression of PTGS2 exacerbated ferroptosis-related parameters (upregulation of MDA, decrease in GSH/GSSG ratio, downregulation of FSP1, SLC7A11, and GPX4 expression), whereas Fer-1 treatment reversed these changes.

CONCLUSION: This study revealed that choline targets PTGS2 to depress ferroptosis, thus alleviating AD-related neuronal injury. This study provides a theoretical basis for the pharmacodynamic effects of anti-aging tablets as well as new therapeutic strategies for AD.},
}

@article {pmid41564814,
year = {2026},
author = {Harris, K and Shyer, M and Wang, D and He, E and Cattani, M and Zhang, C and Farrell, CM and Jiang, X and Kim, Y and Schulz, PE},
title = {The influence of bapineuzumab and semagacestat on rapid progressors: A retrospective cohort study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {3},
pages = {100483},
doi = {10.1016/j.tjpad.2026.100483},
pmid = {41564814},
issn = {2426-0266},
abstract = {BACKGROUND: A subset of Alzheimer's disease patients progresses much more rapidly than average. These rapid progressors exhibit accelerated cognitive and functional decline. Potential differences in Alzheimer's biomarkers for rapid progressors and their responses to disease-modifying treatments remain poorly understood, with previous clinical trials and studies producing limited biomarker data and inconsistent results.

OBJECTIVES: Examine differences in rapid progressor versus non-rapid progressor outcomes in two AD treatment trials (bapineuzumab and semagacestat) and investigate cognitive and biomarker progression in the placebo groups.

DESIGN: Retrospective cohort study.

SETTING: Four randomized, double-blind, phase 3 clinical trials from the Center for Global Clinical Research Data (Semagacestat) and the Yale University Open Data Access Project (Bapineuzumab).

PARTICIPANTS: 4,902 patients (2,355 in bapineuzumab trials, 2,647 in semagacestat trials). Rapid progressors were operationally defined as the 10% of patients with the largest changes in cognitive scores from baseline to trial end.

INTERVENTION: Bapineuzumab (monoclonal antibody) and Semagacestat (γ-secretase inhibitor).

MEASUREMENTS: Cognitive assessments (CDR-SB, MMSE, ADAS-Cog, ADCS-ADL) and biological markers (CSF and plasma levels, MRI, FDG PET Scan, and Amyloid PET Scan) at baseline and endpoint.

RESULTS: Rapid progressors showed distinct baseline characteristics in both the bapineuzumab and semagacestat trials: younger age (61.27 vs 63.14 years, p=0.008; and, 72.64 v. 73.64 years, p=0.046), a higher proportion of APOE4 carriers (87.6% vs 41.4%, p<0.001; and, 85.2% vs 49.3%, p = 0.022), and greater cognitive impairment across all measures (p<0.001). Both progression groups demonstrated improvement in specific biomarkers with treatment, though with different patterns. With bapineuzumab according to Conditional Average Treatment Effect analysis, rapid progressors showed biomarker improvement in amyloid CSF, p-Tau CSF, and amyloid PET scan, while non-rapid progressors demonstrated biomarker improvements in p-Tau CSF, amyloid PET, and MRI. With semagacestat, rapid progressors showed improvements in amyloid CSF and plasma while non-rapid progressors showed improvements in amyloid CSF, FDG PET, and MRI.

CONCLUSIONS: This study provides crucial insights for clinical practice and trial design. The distinct response patterns between progression groups suggest that early identification and balancing of RPs between groups could improve clinical trial efficiency. The findings support the development of personalized treatment approaches for rapid progressors, who have aggressive disease progression. These results may significantly modify clinical trial design and patient care in Alzheimer's disease.},
}

@article {pmid41564595,
year = {2026},
author = {Muzurović, E and Katsiki, N and Volčanšek, Š and Plescia, F and Rizzo, M and Mantzoros, CS},
title = {Emerging incretin- and multi-agonist-based treatments - the continued refinement and continuous expansion of a potent therapeutic armamentarium for cardio-kidney-liver-metabolic diseases and beyond.},
journal = {Metabolism: clinical and experimental},
volume = {177},
number = {},
pages = {156494},
doi = {10.1016/j.metabol.2026.156494},
pmid = {41564595},
issn = {1532-8600},
abstract = {While the use of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) has achieved a central position in our therapeutic armamentarium, new and innovative incretin- and multi-agonist-based treatment strategies hold further promise as potential game-changers for obesity and cardio-kidney-liver-metabolic diseases. Molecular pathways of GLP-1, glucose-dependent insulinotropic polypeptide (GIP), amylin, glucagon and peptide YY have been consistently involved in improved outcomes associated with obesity and related disorders. Single, dual, and even triple drug combinations are being researched throughout all phases of clinical trials. The similarities in GLP-1, GIP, and glucagon peptide sequences enable the development of unimolecular multi-receptor activating agonists and/or antagonists. Furthermore, subcutaneously administered peptides are being supplemented with oral analogs currently in development. Both well-designed clinical trials and real-world evidence are fuelling the development of incretin and multi-agonist-based therapies, thereby holding the promise to deliver an increasing double-digit percent weight loss in addition to addressing many obesity-related comorbidities and complications. It is increasingly evident that early initiation of incretin-based therapy across a broad spectrum of cardio-kidney-metabolic disorders improves body weight, dysglycemia, and cardiovascular risk factor management and consequently is expected to reduce cardio-kidney-liver-metabolic and vascular morbidity and mortality and soon most probably those from obesity-related malignancies, Alzheimer's, and other neurocognitive diseases. This review explores new incretin- and multi-agonist-based therapies undergoing clinical trials for chronic weight management, type 2 diabetes mellitus with its complications, chronic kidney disease, metabolic dysfunction-associated steatotic liver disease and obstructive sleep apnea; it also highlights areas of uncertainty regarding the potency, safety, tolerability, and sustainability of incretin-based approaches for obesity and cardio-kidney-liver-metabolic disorders and finally, we discuss future directions.},
}

@article {pmid41564288,
year = {2026},
author = {Chen, ZH and Li, R and Jiang, YH and He, JK and Yan, SS and Zong, GH and Yi, ZX and Ren, XY and Jia, BH},
title = {Predictive Model of Acupuncture Adherence in Alzheimer Disease: Secondary Analysis of Randomized Controlled Trials.},
journal = {JMIR aging},
volume = {9},
number = {},
pages = {e82787},
doi = {10.2196/82787},
pmid = {41564288},
issn = {2561-7605},
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Male ; Aged ; Female ; *Acupuncture Therapy/statistics & numerical data ; Middle Aged ; Aged, 80 and over ; Randomized Controlled Trials as Topic ; China ; },
abstract = {BACKGROUND: The therapeutic efficacy of acupuncture in treating Alzheimer disease (AD) largely depends on consistent treatment adherence. Therefore, identifying key factors influencing adherence and developing targeted interventions are crucial for enhancing clinical outcomes.

OBJECTIVE: This study aims to develop and validate a predictive model for identifying patients with AD who are likely to maintain good adherence to acupuncture treatment.

METHODS: This secondary analysis included 108 patients with probable AD, aged 50 to 85 years, from 2 independent randomized controlled trials conducted at Guang'anmen Hospital, China Academy of Chinese Medical Sciences. Of all, 66 patients were assigned to the development cohort and 42 to the external validation cohort. Acupuncture adherence was defined as the proportion of completed sessions relative to scheduled sessions, with good adherence defined as ≥80% completion. Baseline data included demographic, clinical, cognitive, functional, psychological, and caregiving variables. Multivariable logistic regression with backward stepwise selection was used to identify significant predictors, and a nomogram was constructed based on the final model. Model performance was assessed using receiver operating characteristic curves, calibration plots, and decision curve analysis, with external validation performed by receiver operating characteristic analysis. Sensitivity analysis was performed using alternative adherence thresholds of 70% and 90%.

RESULTS: A higher number of treatments during the first month was associated with a significant increase in the odds of good adherence (odds ratio [OR] 3.06, 95% CI 1.68-7.01; P=.002), while longer disease duration (OR 0.97, 95% CI 0.94-1.00; P=.049) and receiving care from a part-time caregiver (OR 0.19, 95% CI 0.04-0.72; P=.022) were associated with lower odds of adherence. Sensitivity analyses further supported the stability and reliability of the model.

CONCLUSIONS: This study is the first to develop and validate a predictive model for acupuncture adherence in patients with AD. In clinical research, it can facilitate participant stratification and help identify individuals who may need additional adherence support, thereby reducing bias and enhancing trial quality. In clinical practice, the nomogram enables proactive adherence management by prospectively identifying high-risk patients and guiding targeted strategies to improve adherence and optimize therapeutic outcomes.},
}

Humans
*Alzheimer Disease/therapy/psychology
Male
Aged
Female
*Acupuncture Therapy/statistics & numerical data
Middle Aged
Aged, 80 and over
Randomized Controlled Trials as Topic
China

@article {pmid41563682,
year = {2026},
author = {Paul, R and Firdous, SM},
title = {Unraveling the molecular mechanisms of aluminium chloride-induced Alzheimer's disease.},
journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine},
volume = {},
number = {},
pages = {},
pmid = {41563682},
issn = {1572-8773},
abstract = {The most prevalent neurodegenerative illness is Alzheimer's disease (AD). Aluminium chloride (AlCl3) is a heavy metals that produces several neurodegenerative diseases, commonly AD. AlCl3 easily goes through the blood-brain barrier and reaches to brain. In this study, we reviewed literature, highlighting the various molecular mechanisms targeting AlCl3-induced neurodegenerative disorders like AD in numerous in vivo and in vitro models. AlCl3 can cause conformational changes in the beta-sheet of amyloid beta (Aβ) peptide that lead to the aggregation of Aβ in the brain's neuronal cells. AlCl3 can also decrease the expression of protein phosphatase 2A (PP2A), which is essential for evading tau aggregation and neurofibrillary tangles (NFTs) formation. It can increase acetylcholinesterase (AChE) levels in the brain, which can produce cognitive impairment. AlCl3 also produces calcium (Ca[2+]) and iron dyshomeostasis in neuronal cells. It activates various inflammatory mediators such as interleukin-6 (IL-6), interleukin-1β (IL-1β), plasminogen activator inhibitor-1 (PAI-1), and tumour necrosis factor-α (TNF-α). In addition, AlCl3 can increase the production of reactive oxygen species (ROS), which induce telomere degradation, may initiate telomere dysfunction that can initiate neuroinflammation, and induce cellular senescence. AlCl3 may increase the expression of glycogen synthase kinase-3 beta (GSK3β), which produces various cognitive impairments, leading to AD. Various therapeutic techniques like chelation, antioxidant, and drug therapy are used to treat AD, but a better-targeted approach and a deeper understanding of the molecular basis of Alzheimer's due to AlCl3 intoxication are crucial. AlCl3-induced neurotoxicity involves mitochondrial disruption, oxidative stress, neuroinflammation, and DNA impairment, necessitating further research for treatment against aluminium (Al)-induced AD. AlCl3 can cause neurodegenerative diseases like AD, but understanding its molecular mechanisms is challenging due to its interaction with biological systems.},
}

@article {pmid41563466,
year = {2026},
author = {Ueffing, M and Lange, C and Schlunck, G and Wolf, J},
title = {[Liquid biopsy proteomics in ophthalmology : A clinical and scientific perspective].},
journal = {Die Ophthalmologie},
volume = {},
number = {},
pages = {},
pmid = {41563466},
issn = {2731-7218},
abstract = {BACKGROUND: For many patients with age-related macular degeneration, diabetic retinopathy and other partially monogenetic retinal diseases as well as for tumors of the eye that are relatively rare but are usually associated with profound consequences for affected patients, there is still no effective treatment available. Metastatic melanoma, for example, remains poorly predictable with respect to disease progression, response to treatment and outcome. This illustrates the urgent need for a deeper molecular understanding of the disease with the goal to develop novel therapeutic strategies. Liquid biopsies of the aqueous humor represent a promising possibility for molecular analyses in the eyes of patients.

OBJECTIVE: A clinical and scientific perspective with respect to potential fields of applications of liquid biopsy proteomics in ophthalmology is presented.

MATERIAL AND METHODS: A systematic literature search was carried out in PubMed and the personal experiences of the authors are presented.

RESULTS AND CONCLUSION: Aqueous humor proteomics offer a plethora of potential applications in ophthalmology and could become a key factor in personalized ophthalmology. Potential areas of application include the selection of treatment based on the activated biological signalling pathways, the selection of patients for clinical trials as well as the diagnostics, prognosis estimation and monitoring of the response to treatment. In addition, it can be a valuable component of multimodal diagnostics and enable insights into neurodegenerative diseases, such as Alzheimer's or Parkinson's disease.},
}

@article {pmid41562905,
year = {2025},
author = {Fedotcheva, TA and Shimanovsky, NL},
title = {Current State of the Neurotrophin-Based Pharmaceutics in the Treatment of Neurodegenerative Diseases and Neuroinflammation.},
journal = {Medical sciences (Basel, Switzerland)},
volume = {14},
number = {1},
pages = {},
doi = {10.3390/medsci14010015},
pmid = {41562905},
issn = {2076-3271},
support = {124020900031-0//Ministry of Health of the Russian Federation/ ; },
mesh = {Humans ; *Nerve Growth Factors/therapeutic use ; *Neurodegenerative Diseases/drug therapy ; *Neuroinflammatory Diseases/drug therapy ; Animals ; },
abstract = {BACKGROUND: The regulation of the synthesis of the nerve growth factor and other neurotrophins is one of the dynamically developing areas of pharmacotherapy of neurological and mental disorders. Despite a large number of studies of various ligands of neurotrophin receptors, only a few have reached clinical application and only for ocular diseases. The aim of this narrative review was to systematize the main progress on neurotrophin-based pharmaceutics; to perform a comparative critical analysis of various therapeutic strategies, elucidate the underlying causes of clinical trial failures, and identify the most promising avenues for future development.

METHODS: The literature search was conducted in PubMed, Google Scholar, Medline, and EBSCO, and the ClinicalTrials.gov database was used to track current clinical studies, along with the official websites of pharmaceutical companies. The search covered original studies published up to October 2025, with inclusion restricted to articles published in English. Articles describing specific pharmacological compounds that had reached the clinical trial stage were selected. Foundational biological research was referenced to contextually explain the mechanisms of action of the drugs and their therapeutic implications.

RESULTS: Recombinant neurotrophins and synthetic molecules, the agonists and antagonists of their receptors, and cell-based gene therapy are promising means for the prevention and rehabilitation of ischemic conditions, as well as the treatment of neuropathic pain and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Some of these have undergone clinical trials, yet only neurotrophins for ocular diseases have been implemented in clinical practice: recombinant NGF-cenegermin and recombinant CNTF-Revakinagene taroretcel. The success of these eye drugs is likely attributable to their local administration, improved bioavailability, and low ocular immunoresistance.

CONCLUSIONS: The study identified limitations and future prospects for neurotrophin-based pharmaceuticals. For future clinical trials, attention should be paid to the pharmacogenetic profiles of the patients and the evaluation of the inflammatory status of the disease. Novel plasma biomarkers of the effectiveness are needed as well as TSPO-PET imaging. Drug delivery systems remain insufficient; therefore, efforts should focus on inducing endogenous neurotrophin production and developing highly selective agonists and antagonists of neurotrophin receptors. It is crucial to establish a favorable premorbid background before neurotrophin therapy to minimize immunoresistance.},
}

Humans
*Nerve Growth Factors/therapeutic use
*Neurodegenerative Diseases/drug therapy
*Neuroinflammatory Diseases/drug therapy
Animals

@article {pmid41562838,
year = {2026},
author = {Wozniczka, CM and Weaver, DF},
title = {β-Alanine Is an Unexploited Neurotransmitter in the Pathogenesis and Treatment of Alzheimer's Disease.},
journal = {NeuroSci},
volume = {7},
number = {1},
pages = {},
doi = {10.3390/neurosci7010013},
pmid = {41562838},
issn = {2673-4087},
support = {KF-2023-1//Krembli Foundation/ ; ASC-2024//Alzheimer's Society Canada/ ; },
abstract = {Alzheimer's disease (AD) remains an unmet medical challenge, as there are no effective therapies that alter the disease's progression. While approaches have targeted molecules like acetylcholine (ACh) and glutamate, these strategies have provided only limited benefits and do not address the complex molecular mechanisms underlying AD development. This review suggests that β-alanine (3-aminopropanoic acid) is an underexplored neurotransmitter that could serve as a potential AD drug target. Existing evidence indicates that β-alanine modulates GABAergic and glutamatergic neurotransmission, thereby affecting neuronal hyperexcitability. Additionally, studies suggest that β-alanine has antioxidant effects, reducing oxidative stress caused by reactive oxygen species (ROS). We propose that β-alanine might bind to Aβ/tau proteins, possibly targeting the six-amino acid sequences EVHHQK/DDKKAK, which are involved in protein aggregation. β-Alanine may also influence the release of pro-inflammatory cytokines from microglia, potentially reducing neuroinflammation. We also hypothesize that β-alanine may help regulate metal dyshomeostasis, which leads to ROS production. Taurine, structurally like β-alanine, appears to influence comparable mechanisms. Although structural similarity doesn't ensure therapeutic effectiveness, this evidence supports considering β-alanine as a treatment for AD. Furthermore, β-alanine and its analogues face challenges, including crossing the blood-brain barrier (BBB) and optimizing structure-activity relationships (SAR). This review includes articles through September 2025, sourced from four databases.},
}

@article {pmid41561733,
year = {2026},
author = {Curd, BC and Zubrick, C and Brown, CJC and Sorweid, MK and Dehoney, SB and Anzai, Y and Minoshima, S and Parks, AL and Frost, NA},
title = {Real-world experience with lecanemab therapy for Alzheimer's disease in the Intermountain West.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70251},
pmid = {41561733},
issn = {2352-8729},
abstract = {INTRODUCTION: Lecanemab is a monoclonal antibody targeting amyloid plaques that has been approved for the treatment of early symptomatic Alzheimer's disease. Here, we report on the clinical history and outcomes of the first 70 patients at the University of Utah to receive amyloid-removal therapy.

METHODS: This is a retrospective analysis of patients treated with lecanemab over a 26-month period. We extracted patient data from charts and analyzed demographics, health history, and clinical details with outcomes on lecanemab treatment.

RESULTS: In total, we observed 14 cases (20%) of amyloid-related imaging abnormalities (ARIAs), which was significantly associated with apolipoprotein E ε4 homozygosity. Zero cases of ARIAs were symptomatic, and there was no association between distance from clinic and adverse effects.

DISCUSSION: Our study examined the safety and tolerability of centrally managed lecanemab administration across a widely distributed region and suggests that use of distributed infusion sites increases access to disease-modifying treatment without significant increase in risk.

HIGHLIGHTS: Lecanemab therapy can be safely administered to patients across a broadly distributed area through a single clinical center.In our first 70 treated patients, 14 developed amyloid-related imaging abnormalities (ARIAs)-a rate of 20%, which is consistent with clinical trials of lecanemab.No patients experienced symptomatic ARIAs.ARIA incidence was significantly associated with apolipoprotein E genotype, but not other demographic factors, comorbid conditions, or baseline clinical details.},
}

@article {pmid41560836,
year = {2026},
author = {Zhang, Y and Yin, C and Tian, Y and Li, X and Wang, H and Han, S and Chen, H and Hou, H},
title = {Intranasal delivery of Odorranalectin-modified lipid nanoparticles for multi-targeted therapy of Alzheimer's disease.},
journal = {Materials today. Bio},
volume = {36},
number = {},
pages = {102764},
pmid = {41560836},
issn = {2590-0064},
abstract = {Oxidative stress, neuroinflammation, and β-amyloid (Aβ) deposition act synergistically to drive Alzheimer's disease (AD) progression. Effective treatment, therefore, requires multi-targeted strategies capable of addressing these interconnected pathological mechanisms. Here, an Odorranalectin (OL)-conjugated lipid nanoparticle (siB/QU@L-OL) was engineered for efficient intranasal delivery of β-site APP cleaving enzyme 1 (BACE1) siRNA (siB) and quercetin (QU). siB/QU@L-OL prepared via microfluidics exhibited uniform size distribution, high encapsulation efficiency, and robust stability. Following intranasal administration, OL surface modification enabled binding to L-fucose residues expressed on the olfactory epithelium, reducing mucociliary clearance and facilitating brain transport. In vitro, siB silenced BACE1 expression and inhibited Aβ generation, while QU alleviated Aβ-induced oxidative stress and neuroinflammation, thereby suppressing neuronal apoptosis. In APP/PS1 mice, siB/QU@L-OL restored Aβ homeostasis and redox balance, attenuated neuroinflammation and neuronal loss, and consequently improved cognitive performance. Collectively, this brain-targeted nanoplatform demonstrates strong potential for synergistic intervention in AD.},
}

@article {pmid41560713,
year = {2026},
author = {Barnwal, M and Baksh, S and Ismail, Z and Shade, DM and Moghekar, A and Ho, SG and Rosenberg, PB and Porsteinsson, AP and Lyketsos, CG and , },
title = {Blood biomarkers for Alzheimer's disease are correlated with measures of agitation and cognition in a randomized trial assessing the effects of escitalopram on agitation.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {1},
pages = {e70203},
pmid = {41560713},
issn = {2352-8737},
abstract = {INTRODUCTION: Escitalopram for Agitation in Alzheimer's Disease (S-CitAD) is a National Institutes of Health-funded randomized controlled trial that randomized 173 participants with clinically diagnosed Alzheimer's disease (AD) and agitation to escitalopram or placebo for 12 weeks, assessing efficacy and safety. There was no advantage for escitalopram in treating agitation, potentially attributed to including participants at various stages of AD brain pathology, reflected in levels of blood biomarkers. Here, we (1) estimated the fraction of participants meeting blood biomarker criteria for AD pathology, (2) examined associations between baseline blood biomarkers and agitation severity or cognitive functioning, and (3) evaluated whether baseline blood biomarkers predicted treatment response.

METHODS: Eighty-two randomized participants provided blood for biomarker measurement prior to randomization. Plasma amyloid beta (Aβ)42, Aβ40, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau (p-tau)217 were measured using standard methods. We examined associations of baseline blood biomarkers and clinical measures at baseline and follow-up with (1) agitation severity (Neuropsychiatric Inventory Clinical Rating of the agitation and aggression domains [NPI-C-A+A]), (2) cognitive status (Mini-Mental State Examination [MMSE]), and (3) escitalopram treatment.

RESULTS: Seventy-seven out of 82 (94%) scored above threshold for p-tau217, supporting the clinical diagnosis of AD. Baseline higher p-tau217 predicted higher NPI-C-A+A scores at weeks 6 (beta = 3.26, p < 0.001) and 12 (beta = 2.86, p = 0.01) after randomization. Baseline higher levels of GFAP (beta = -0.02, p = 0.0002) and p-tau217 (beta = -2.68, p = 0.003) were associated with lower baseline MMSE scores. After adjusting for treatment, higher baseline p-tau217 was associated with greater odds of worsening NPI-C-A+A scores at weeks 6 (odds ratio [OR] = 2.79, p = 0.02) and 12 (OR = 2.55, p = 0.02).

DISCUSSION: In this clinical trial cohort, elevated plasma p-tau217 confirmed AD pathology in 94% of participants and forecast greater agitation severity and worse cognitive functioning, underscoring its practical value for stratifying and monitoring patients in neuropsychiatric intervention studies.

HIGHLIGHTS: We examined whether Alzheimer's disease (AD) blood biomarkers predicted severity of agitation and cognitive impairment and/or treatment response in the 12-week Escitalopram for Agitation in Alzheimer's Disease (S-CitAD) randomized controlled trial.Blood phosphorylated tau (p-tau)217 confirmed the presence of significant AD brain amyloid pathology in 94% of these clinically diagnosed participants.Independent of treatment assignment, higher baseline p-tau217 predicted lower baseline and future Mini-Mental State Examination (MMSE) scores and worse agitation overtime.Independent of treatment assignment, higher baseline levels of glial fibrillary acidic protein were associated with lower baseline and follow-up MMSE scores.},
}

@article {pmid41560694,
year = {2026},
author = {Wan, Z and Feng, X and Chou, J and Zhou, X and Ma, T and Zhang, T},
title = {Sex- and brain region-specific gene expression in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251413797},
doi = {10.1177/13872877251413797},
pmid = {41560694},
issn = {1875-8908},
abstract = {BackgroundWomen with Alzheimer's disease (AD) have higher prevalence and more severe dementia syndrome than men with AD, and the brain regions are also affected differently. However, the underlying mechanisms are poorly understood.ObjectiveTo characterize the sex-dependent and region-specific gene expression in AD brain.MethodsA previously published large scale bulk tissue gene expression dataset from postmortem brain samples across 19 cortical regions of normal control and individuals diagnosed with dementia and neuropathology of AD was used for differential gene expression analysis. Functional enrichment analysis was used to identify enriched biological functions or pathways related to selected genes. Protein expression level of a selected gene was validated by western blot.ResultsWe identified 113 dysregulated genes in 11 AD brain regions (9 in men, 7 in women, and 5 shared between men and women). Notably, more dysregulated genes were found in women AD brain (77 genes) than in men (49 genes), and 13 dysregulated genes across these 11 brain regions were shared between women and men. Functional analysis further revealed the distinctive enrichment in categories of cellular component, biological process, and/or molecular function in these dysregulated genes. GPR34 gene expression was upregulated in the men AD brain across three different regions and a significant elevation of GPR34 protein level was confirmed in men AD brain.ConclusionsThese findings provide insight into sex- and brain region-specific gene expression dysregulation, which may indicate novel mechanisms underlying AD pathogenesis and will facilitate the development of personalized diagnosis and treatment strategies for AD.},
}

@article {pmid41560693,
year = {2026},
author = {Custodio, B and Montesinos, R and Bayona, W and Rojas Benites, MJ and Camargo, I and Ibañez, M and Huilca, J and Noriega de la Colina, A and Matias-Guiu, JA and Custodio, N},
title = {Perceptions of Peruvian neurologists toward the implementation of anti-amyloid drugs for early Alzheimer's disease in the departments of neurology.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251410959},
doi = {10.1177/13872877251410959},
pmid = {41560693},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disease affecting millions globally, with particular severity in low- and middle-income countries due to barriers in timely diagnosis and treatment. To date, two monoclonal anti-amyloids have shown positive results in phase III clinical trials. However, their administration is complex, requiring specialized infrastructure, highly trained professionals, and regular follow-ups, posing major challenges for healthcare systems.ObjectiveThis study explores Peruvian neurologists' perceptions of changes needed to implement monoclonal antibodies in line with clinical guidelines.MethodsA cross-sectional study was conducted in Peru using the key informant (KI) methodology. KI were neurologists from multiple regions across the country. A comprehensive list of tertiary-level hospitals (public healthcare system, social security, and police and armed forces) was compiled, and at least one neurologist from each institution was contacted. The instrument used was adapted from a study conducted in Spain, which included questions focusing on changes in diagnosis, patient care, diagnostic and therapeutic techniques, public and family impact, neurology resources, and dementia research. Data analysis was employed using Stata18, using descriptive statistics and frequency distributions.ResultsTwenty-eight neurologists completed the survey. There was consensus on the significant impact monoclonal antibodies would have on neurology services. Over 85% agreed that more neurologists and nurses would be needed. Additionally, 93% supported using brief diagnostic scales in primary care and increasing follow-up visit frequency.ConclusionsThe introduction of monoclonal antibodies for AD in Peru requires modifications to healthcare institutions, highlighting the urgent need for strategic healthcare planning.},
}