@article {pmid41501420,
year = {2026},
author = {Wang, XY and Zhou, WS and Gaur, U and Zhen, XC and Zheng, WH},
title = {Sigma-1 receptor positive allosteric modulator promotes neuronal survival and improves cognitive deficits in AD mice via sigma-1 receptor/ERK pathway.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {41501420},
issn = {1745-7254},
abstract = {The sigma-1 receptor is an important new therapeutic drug target for Alzheimer's disease (AD). Here, we reported that SOMCL-668, a novel selective and potent sigma-1 receptor allosteric modulator, is neuroprotective in AD both in vitro and in vivo. SOMCL-668 promoted PC12 cells against Aβ-induced intracellular reactive oxygen species (ROS) accumulation, mitochondrial membrane potential hyperpolarization and neuronal apoptosis. Similar results were obtained in SH-SY5Y and primary cortical culture neurons. The mechanistic study showed that SOMCL-668 stimulated the phosphorylation of ERK and CREB, while pharmacological inhibition or knockout of ERK via CRISPR-Cas9 attenuated its protective effects. Further studies with the sigma-1 receptor agonists/antagonists and knockout of sigma-1 receptor via CRISPR-Cas9 indicated that the sigma-1 receptor is essential for the effect of SOMCL-668. In 3xTg-AD mice, SOMCL-668 improved the learning and memory deficits, inhibited neuronal apoptosis and oxidative stress, reduced Aβ deposition and tau protein phosphorylation via ERK/CREB pathway. Moreover, pretreatment with sigma-1 receptor antagonist BD1047 blocked the effect of SOMCL-668. These results demonstrated that SOMCL-668 provides neuroprotection in AD and its effect is mediated by the sigma-1 receptor/ERK/CREB pathway. Our findings support that SOMCL-668 can be utilized as a potential drug for the prevention and treatment of Alzheimer's disease.},
}

@article {pmid41500848,
year = {2025},
author = {Prabha, PK and Jain, A and Dadoo, N and Charan, S and Medhi, B and Prakash, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105361},
doi = {10.1002/alz70856_105361},
pmid = {41500848},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics/diagnosis ; *Biomarkers/blood ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease ; Cholesterol/metabolism ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition marked by memory loss, cognitive decline, and eventually motor and behavioural dysfunction. Most AD drug trials have failed due to the lack of early intervention, which is crucial for treatment effectiveness. Though early diagnosis remains challenging owing to blood-brain barrier, blood-based biomarkers are being explored due to their non-invasive nature. Genes involved in cholesterol and lipid metabolism, such as APOE, APOJ, ABCA7, and SORL1, have also been observed to increase AD risk.

METHODS: Clinical studies of polymorphisms in cholesterol homeostasis pathway involving participants clinically diagnosed with Alzheimer's Disease of any form as per set criteria of diagnosis for AD were included after comprehensive search across PubMed, Embase, Scopus and Web of Science. Independent reviewers extracted data from the included studies which included information like general information, participants, study methods, polymorphisms studied, outcomes, results, conclusion, etc. Any discrepancies or doubts was resolved by a third reviewer.

RESULT: A total of 1870 studies were identified based on the designed search strategy, which reduced to 216 after removal of duplicates, with 45 studies considered suitable for the final meta-analyses. The risk of AD was significantly associated in random effect model for SNP rs3846662 (HMGCR; OR = 1.16, 95% CI = 0.99, 1.35, I[2] = 59%, p = 0.06), rs11136000 (CLU; OR = 1.15, 95% CI = 1.08, 1.22, I[2] = 0%, p = 0.83), rs754203 (CYP46A1; OR = 1.10, 95% CI = 0.92, 1.33, I[2] = 87%, p < 0.01), and rs3851179 (PICALM; OR = 1.18, 95% CI = 1.05, 1.33, I[2] = 77%, p < 0.01).

CONCLUSION: The selected SNPs were found to be significantly associated with the risk of AD, with risk alleles for rs3846662, rs11136000, rs754203, and rs3851179 being G, C, T, C alleles respectively with an OR of 1.16, 1.15, 1.10, and 1.18 respectively. Therefore, these can be considered to be AD biomarkers.},
}

Humans
*Alzheimer Disease/genetics/diagnosis
*Biomarkers/blood
Polymorphism, Single Nucleotide
Genetic Predisposition to Disease
Cholesterol/metabolism

@article {pmid41500650,
year = {2025},
author = {Tirambulo, CVG and Merlini, S and Paul, M and Lizarraga, C and Brinton, RD and Vitali, F},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105280},
doi = {10.1002/alz70856_105280},
pmid = {41500650},
issn = {1552-5279},
mesh = {Humans ; Female ; *Biomarkers/blood ; Male ; *Alzheimer Disease/blood/genetics/diagnosis ; Aged ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; Middle Aged ; Apolipoprotein E4/genetics ; Registries ; Risk Factors ; },
abstract = {BACKGROUND: Individuals in the early stages of Alzheimer's disease (AD) constitute a heterogeneous group, with diverse risk factor profiles such as chromosomal sex, apolipoprotein E (APOE) genotype, and comorbidities, evolving over distinct time courses. Within a prodromal phase that can extend for one to three decades, opportunities and challenges exist in identifying crucial tipping points in progression and opportunities for prevention.

METHOD: Our study aimed to identify subgroups within the 389 individuals at high-risk for AD (65.6±6.4 years old, 67.1% female, 38.8% APOE ε4 carriers) from the Wisconsin Registry for Alzheimer's Prevention data, 2001-2022. We analyzed prospectively collected data covering patient characteristics (age, sex, race, and APOE ε4 carrier status), medical history (history of diabetes, hypertension, and hyperlipidemia), plasma biomarkers (amyloid-β (Aβ) 40, Aβ42, Aβ40/42 ratio, phosphorylated tau (p-tau) 181, and p-tau 217), and blood laboratory parameters (insulin, glucose, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol). Employing classical clustering methodologies (CCMs, k-means (KMs), KMs with principal component analysis, hierarchical clustering (HC), and HC with dynamic time warping) to inform the unsupervised deep embedded clustering (DEC) algorithm, we evaluated cluster membership and assessed clinical validity. Variable contributions to the predicted cluster membership were assessed using SHapley Additive exPlanations values.

RESULT: Our DEC findings demonstrated promising results by identifying more distinct risk profile patterns for each cluster (n = 6) compared to CCMs (n = 2); achieving a more evenly distributed partitioning of participants into clusters with increased stability, measured by Jaccard and entropy scores; and validating the clinical recognizability based on laboratory values, plasma biomarkers, physician cognitive diagnoses, and Preclinical Alzheimer Cognitive Composite scores. Cluster characterization revealed participants in cluster 6 (n = 44) were most at-risk for AD, consisting of female APOE ε4 carriers with elevated p-tau levels. Conversely, cluster 4 (n = 57) was the least at-risk, youngest cluster, comprising females with fewer comorbid conditions and the lowest AD biomarker levels. Cluster 3 (n = 81) represented the control population.

CONCLUSION: Going forward, these outcomes will enable a robust pipeline for integrating electronic medical record data, empowering diverse patient characterization, and better identify those at risk to implement personalized preventative treatment within heterogeneous populations at risk for AD.},
}

Humans
Female
*Biomarkers/blood
Male
*Alzheimer Disease/blood/genetics/diagnosis
Aged
Amyloid beta-Peptides/blood
tau Proteins/blood
Middle Aged
Apolipoprotein E4/genetics
Registries
Risk Factors

@article {pmid41499862,
year = {2025},
author = {Nadais, A and Castro, C and Martins, I and Trigo, D and Nunes, C and Henriques, AG and de Lourdes Pereira, M and da Cruz E Silva, OAB},
title = {Nanoparticle-mediated Zn delivery impacts neural protein phosphatase activity.},
journal = {Biomaterials advances},
volume = {182},
number = {},
pages = {214675},
doi = {10.1016/j.bioadv.2025.214675},
pmid = {41499862},
issn = {2772-9508},
abstract = {In recent years, the use of nanoparticles (NPs) in diagnosis and treatment of different disorders has been a matter of intensive research. Due to their physical and chemical properties, zinc oxide nanoparticles (ZnO NP) have been explored in a range of biological applications, including cancer and neurological diseases. Regarding the latter, while some studies report protective effects of ZnO NP in cultured cells and animal models, others indicate that these NPs have a harmful impact on the brain, such as promoting oxidative stress and cell death. Previous results from our group have suggested beneficial effects for zinc (Zn) cations in both modulating protein aggregation and on Alzheimer's disease (AD) pathology. In this context, the effect of encapsulated Zn as a nanoparticle on protein aggregation and its influence on protein phosphorylation events associated with AD were explored. The results herein presented show that ZnO NP contributed to a decrease in protein aggregation in neuronal cells. However, these NPs were also found to decrease PP1 and PP2A activity, potentially contributing to increased phosphorylation of tau and APP, which are AD pathology hallmarks. In conclusion, while the use of NPs as a Zn delivery system may offer benefits by reducing aggregate formation, they also appear to induce undesired molecular changes, like those observed in AD. Therefore, a holistic approach should be incorporated as we move forward in this research line, as their effects on distinct cellular processes may be dual edged.},
}

@article {pmid41499797,
year = {2025},
author = {Grigoli, MM and Pachane, BC and Fuzer, AM and de Oliveira, SD and Targas, ABA and Alexandre-Silva, V and Selistre-de-Araujo, HS and Manzine, PR and Cominetti, MR},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105542},
doi = {10.1002/alz70856_105542},
pmid = {41499797},
issn = {1552-5279},
mesh = {Humans ; Tretinoin/pharmacology ; Cell Line, Tumor ; *Cell Differentiation/drug effects/physiology ; Laminin/pharmacology ; Biomarkers/metabolism ; *Neurons/drug effects/metabolism ; Acetylcholinesterase/metabolism ; Neuroblastoma/pathology ; Tubulin/metabolism ; Neurites ; Extracellular Matrix/metabolism ; },
abstract = {BACKGROUND: The SH-SY5Y neuroblastoma cell line is a valuable in vitro model for studying neuronal differentiation and neurodegenerative diseases like Alzheimer's disease (AD). Traditional differentiation protocols mainly use retinoic acid (RA); however, they lack extracellular matrix (ECM) components that are critical for mechanotransduction and cellular adhesion, which limits their physiological relevance. Laminins, a key ECM glycoprotein, play an essential role in neurite outgrowth and synaptic formation, indicating their potential to enhance neuronal differentiation.

METHOD: SH-SY5Y cells were cultured in DMEM/F12 supplemented with fetal bovine serum (FBS) and essential additives. Differentiation was induced using RA (10 µM and 25 µM) and a laminin-rich ECM (LrECM). Plates were pre-coated with Matrigel® (a laminin-rich ECM) before seeding the cells. Differentiation efficiency was monitored over 10 days through light microscopy, immunofluorescence for neuronal markers (NeuN and β3-tubulin), and acetylcholinesterase (AChE) activity assays. Western blotting assessed β3-tubulin expression, and neurite lengths were quantified using FIJI software.

RESULT: The combined RA and LrECM treatment significantly enhanced SH-SY5Y differentiation when compared to RA alone. Neuronal morphology, marked by extensive neurite outgrowth, became evident as early as day 4 and was sustained for up to 10 days. Immunofluorescence confirmed increased NeuN expression, showing a shift from cytoplasmic to perinuclear localization over time. β3-tubulin levels remained consistently high in LrECM-treated cells, unlike those treated with RA alone, which demonstrated a decline after day 7. Enhanced cholinergic differentiation was indicated by elevated AChE activity, particularly at 25 µM RA, although higher RA concentrations were unable to sustain neuronal characteristics and raised concerns about cytotoxicity.

CONCLUSION: The incorporation of LrECM into SH-SY5Y differentiation protocols significantly enhances neuronal differentiation and maintains neuron-like characteristics, providing a more physiologically relevant in vitro model for studying AD and other neurodegenerative diseases. This approach enables cost-effective, rapid differentiation and more accurately mimics the brain microenvironment, establishing a strong platform for neurobiological research and therapeutic screening.},
}

Humans
Tretinoin/pharmacology
Cell Line, Tumor
*Cell Differentiation/drug effects/physiology
Laminin/pharmacology
Biomarkers/metabolism
*Neurons/drug effects/metabolism
Acetylcholinesterase/metabolism
Neuroblastoma/pathology
Tubulin/metabolism
Neurites
Extracellular Matrix/metabolism

@article {pmid41499417,
year = {2025},
author = {Young, AL and Wijeratne, PA and Aksman, LM and Binette, AP and Strandberg, O and Oxtoby, NP and Altmann, A and Alexander, DC and Stomrud, E and Palmqvist, S and Mattsson-Carlgren, N and Vogel, JW and Hansson, O},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104804},
doi = {10.1002/alz70856_104804},
pmid = {41499417},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/metabolism/cerebrospinal fluid ; Positron-Emission Tomography ; *Alzheimer Disease/diagnostic imaging/metabolism/cerebrospinal fluid/pathology ; Male ; Female ; *Biomarkers/cerebrospinal fluid/metabolism ; Aged ; Disease Progression ; *Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; Sweden ; *Brain/diagnostic imaging/metabolism ; Middle Aged ; *Amyloid/metabolism ; },
abstract = {BACKGROUND: Amyloid and tau accumulation in Alzheimer's disease is known to be dynamic, with expected rates of accumulation varying depending on disease stage. Establishing the precise timeline of amyloid and tau accumulation and quantifying their dynamic progression is important for identifying an optimal intervention window and predicting treatment response.

METHOD: 960 individuals were selected from the Swedish BioFINDER-2 study with at least two tau-PET scans (Table 1; follow-ups were at 1 year (N = 66), 2 years (N = 924), 4 years (N = 335); 6 years (N = 60)). Two intersecting data subsets were selected: 773 individuals having at least two amyloid-PET scans for estimating amyloid duration, and 434 CSF-amyloid-positive individuals for comparison with timelines across the whole population. Regional tau-PET SUVR abnormality was computed in five established data-driven regions using mixture modelling. A novel explicit-duration version of the temporal event-based model (T-EBM) was used to determine the order and timeline of global amyloid-PET and regional tau-PET abnormality. The explicit duration approach accounts for censoring of an individual's first and last visit and handles arbitrary time intervals.

RESULT: The T-EBM inferred that tau accumulates in a Braak-like pattern (Figure 1a), estimating an average timeline of global amyloid and regional tau accumulation (Figure 1b) of around 20 years. Progression from stage 1 (amyloid) to stage 2 (entorhinal tau) was estimated to take 8 years on average, from stage 2 to stage 3 (temporal lobe tau) 5.5 years, and 2-3 years between each subsequent stage. The timeline was consistent in amyloid-positive individuals (most amyloid-negative individuals were stage 0 and did not influence the timeline). Figure 1c shows the number of individuals progressing between stages at follow-up. Individuals who progressed in stage (progressors) were older, had more advanced symptoms (diagnosis), more APOE4 alleles, worse MMSE scores, and were more frequently amyloid-positive compared to non-progressors (Table 2).

CONCLUSION: Amyloid accumulates slowly, after which tau spreads from the entorhinal cortex to the temporal lobe, initially at a slower pace before accelerating to a faster rate across the cortex. This data indicates that slower rates of accumulation would be expected at earlier stages. Work is ongoing validating these timelines in additional datasets.},
}

Humans
*tau Proteins/metabolism/cerebrospinal fluid
Positron-Emission Tomography
*Alzheimer Disease/diagnostic imaging/metabolism/cerebrospinal fluid/pathology
Male
Female
*Biomarkers/cerebrospinal fluid/metabolism
Aged
Disease Progression
*Amyloid beta-Peptides/metabolism/cerebrospinal fluid
Sweden
*Brain/diagnostic imaging/metabolism
Middle Aged
*Amyloid/metabolism

@article {pmid41499318,
year = {2026},
author = {Melrose, J},
title = {Roles for Electrochemical Proton Gradients in Mitochondrial Energy Production and Neurosensory Processes in Health and Disease.},
journal = {Developmental neurobiology},
volume = {86},
number = {1},
pages = {e70006},
doi = {10.1002/dneu.70006},
pmid = {41499318},
issn = {1932-846X},
support = {//Melrose Personal Research Fund/ ; },
mesh = {Humans ; Animals ; *Mitochondria/metabolism ; *Energy Metabolism/physiology ; *Protons ; *Proton-Motive Force/physiology ; *Nervous System Diseases/metabolism ; Oxidative Stress/physiology ; },
abstract = {This study reviews the roles of proton electrochemical gradients in ubiquitous mitochondrial energy production systems in cellular activation and functions in neurosensory signaling. Proton electrochemical gradients crucially shaped the evolution of life. The emergence of the proton-motive force in mitochondria was fundamental in energy production and central to the function of eukaryotic cells. Dysfunctional mitochondria, however, result in impaired formation of proton gradients and a wide spectrum of diseases. This is particularly prominent in tissues with high energetic demands, such as muscle and nervous tissues. Oxidant stress generated by dysfunctional proton conductance in the brain results in Alzheimer's and Parkinson's disease, muscular sclerosis, amyotrophic sclerosis, and Huntington's disease. In these disorders, oxidative stress, protein misfolding, and neuroinflammation lead to dysfunctional neuronal activity, neuronal damage, and death. Advancements in nanozyme-engineered synthetic enzymes offer a promising innovative approach to the treatment of these disorders. Nanozymes target proton conductance and the oxidant species they generate, scavenging oxygen free radicals and restoring redox balance, and offer neuronal protection and functional recovery of brain tissues. Neural injury and associated neurological diseases affect almost 1 billion people globally, so there is a clear need to develop effective methods that stimulate neural repair and regeneration. Glycosaminoglycans with proton capture and transport properties regulate intercellular signaling processes, synaptic functions, and cellular communication. Electroconductive hydrogels are showing impressive results in neural repair and regeneration. Glycosaminoglycans, particularly keratan sulfate, show useful electroconductive proton capture and transport properties, suggesting they may be worth evaluation in such procedures.},
}

Humans
Animals
*Mitochondria/metabolism
*Energy Metabolism/physiology
*Protons
*Proton-Motive Force/physiology
*Nervous System Diseases/metabolism
Oxidative Stress/physiology

@article {pmid41499301,
year = {2026},
author = {Mohasel-Roodi, M and Nozari, M and Shamsara, A and Basiri, M and Mirzaie, V and Baghalishahi, M},
title = {Effects of Dexmedetomidine on the Behavioral Outcomes in Streptozotocin-Induced Alzheimer's Disease Rats.},
journal = {Brain and behavior},
volume = {16},
number = {1},
pages = {e71196},
doi = {10.1002/brb3.71196},
pmid = {41499301},
issn = {2162-3279},
support = {402000357//Kerman Neuroscience Research Center, Kerman University of Medical Sciences/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced ; *Dexmedetomidine/pharmacology/administration & dosage ; Streptozocin/pharmacology ; Rats, Wistar ; Male ; Rats ; *Behavior, Animal/drug effects ; Anxiety/drug therapy ; Maze Learning/drug effects ; Disease Models, Animal ; Neuroprotective Agents/pharmacology ; *Adrenergic alpha-2 Receptor Agonists/pharmacology ; Cognitive Dysfunction/drug therapy ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive and prevalent neurodegenerative disorder characterized by progressive cognitive decline and memory impairment. Intracerebroventricular (ICV) administration of streptozotocin (STZ) in rodents recapitulates key features of sporadic AD, including brain insulin resistance and oxidative stress. Dexmedetomidine (Dex), a highly selective α2-adrenergic receptor agonist, has demonstrated neuroprotective and anti-inflammatory properties, suggesting its potential utility as a therapeutic approach for AD.

METHODS: Seventy adult male Wistar rats were randomly allocated to seven experimental groups: Control, Sham, STZ, Sham + Dex (25 µg/kg), and STZ + Dex (25, 50, 100 µg/kg). Cognitive performance and anxiety-like behaviors were evaluated using the open-field test (OFT), elevated plus maze (EPM), Y-maze test, and Morris water maze (MWM).

RESULTS: In the Y-maze, STZ-treated rats exhibited significant reductions in spontaneous alternation behavior (p = 0.002), which were significantly reversed by Dex (25 µg/kg, p = 0.002). In the MWM, the STZ administration resulted in prolonged escape latencies and increased path lengths compared with Control animals (p < 0.05). Treatment with Dex (25 µg/kg) significantly improved spatial learning and memory retention (p < 0.05). No significant differences were observed in locomotor activity and anxiety-related behaviors in the OFT or EPM.

CONCLUSIONS: These findings indicate that Dex at 25 µg/kg attenuates STZ-induced cognitive deficits, likely through neuroprotective and anti-inflammatory mechanisms. The results highlight Dex as a promising candidate for AD therapy, though further research is required to elucidate its underlying molecular pathways. The study supports the potential repurposing of Dex for neurodegenerative disorders.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced
*Dexmedetomidine/pharmacology/administration & dosage
Streptozocin/pharmacology
Rats, Wistar
Male
Rats
*Behavior, Animal/drug effects
Anxiety/drug therapy
Maze Learning/drug effects
Disease Models, Animal
Neuroprotective Agents/pharmacology
*Adrenergic alpha-2 Receptor Agonists/pharmacology
Cognitive Dysfunction/drug therapy

@article {pmid41498900,
year = {2026},
author = {Lin, ZY and Cai, LL and Lin, JX and Zheng, GY},
title = {Tiaobu Xinshen Recipe Improves Cognitive Deficits by Alleviating Synaptic Ultrastructure Degradation and Reducing Amyloid β in Transgenic Mice of Alzheimer's Disease.},
journal = {Chinese journal of integrative medicine},
volume = {},
number = {},
pages = {},
pmid = {41498900},
issn = {1993-0402},
abstract = {OBJECTIVE: To investigate the effect of Tiaobu Xinshen Recipe (TXR) on cognitive function of 5xFAD transgenic mice and explore the potential mechanisms.

METHODS: Six-month-old male wild-type (WT) mice and 5xFAD transgenic mice were randomly divided into vehicle (0.9% NaCl), TXR (granules, 4.18 g/kg) and donepezil (0.625 mg/kg) groups using a random number table, respectively, which were given intragastric administration once a day for 60 d. Spatial learning and memory performance was tested with modified Morris water maze (MMWM) test. Synaptic ultrastructure in the hippocampal CA1 region was observed by transmission electron microscopy. The levels of amyloid β (Aβ), the major amyloid precursor protein (APP)-cleaving enzymes and Aβ-degrading enzymes including β-secretase, α-secretase, neprilysin (NEP) and insulin-degrading enzyme (IDE), were detected by immunohistochemistry staining and Western blot, respectively.

RESULTS: In MMWM test, when compared with the 5xFAD-vehicle group, 5xFAD-TXR group demonstrated a significantly shorter escape latency to the platform and increased number of platform crossings and time spent in target quadrant (P<0.05 or P<0.01). The ultrastructure of synapse in the hippocampal CA1 region of mice in the 5xFAD-TXR group was significantly changed, including increased numbers of mitochondria and synaptic vesicles, intact synaptic membrane, and thickened postsynaptic density. The Aβ load was markedly decreased in the cerebral cortex and hippocampus CA1 subregion of TXR-treated 5xFAD mice (P<0.05). TXR treatment decreased APP levels and increased IDE expression in brains of 5xFAD mice (P<0.01). However, TXR treatment had no effect on α- and β-secretase, and NEP in 5xFAD mice (P>0.05).

CONCLUSION: TXR improves cognitive dysfunction in 5xFAD mice by alleviating synaptic ultrastructure degradation and reducing Aβ.},
}

@article {pmid41498751,
year = {2025},
author = {Biel, D and Steward, A and Dewenter, A and Dehsarvi, A and Zhu, Z and Roemer-Cassiano, S and Frontzkowski, L and Hirsch, F and Brendel, M and Franzmeier, N},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104771},
doi = {10.1002/alz70856_104771},
pmid = {41498751},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; *tau Proteins/blood ; Aged ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; Longitudinal Studies ; *Cognitive Dysfunction/diagnostic imaging ; Amyloid beta-Peptides ; Aged, 80 and over ; Brain/pathology/diagnostic imaging ; },
abstract = {BACKGROUND: With the approval of anti-amyloid therapies in Alzheimer's disease (AD), surrogate biomarkers are urgently needed to monitor treatment effects that translate into clinical benefits. Candidate biomarkers, including amyloid-PET, tau-PET, plasma phosphorylated tau (p-tau), and MRI-assessed atrophy, capture core pathophysiological changes in AD. While cross-sectional biomarker assessments are critical for diagnosis and staging, biomarker change rates may better reflect disease dynamics, making them more suitable for monitoring treatment efficacy. Therefore, we determined which biomarker most effectively tracks cognitive changes in AD, identifying those best suited for efficient monitoring of disease-modifying treatments.

METHOD: We leveraged ADNI (N = 108) and A4 (N = 151) participants with longitudinal AD biomarker data (global amyloid-PET, temporal meta tau-PET, plasma p-tau217, MRI-assessed cortical thickness in the AD signature region) together with cognitive assessments (ADNI: MMSE, ADAS13, CDR-SB; A4: MMSE, PACC). Linear mixed models were used to calculate change rates for biomarkers and cognition. To test whether biomarker changes track cognitive decline, linear models were applied, to test biomarker change rates as a predictor of cognitive change rates. Standardized beta values from bootstrapped linear models were extracted to compare the strengths of correlations between biomarkers and cognitive decline. For non-parametric comparisons, 95% confidence intervals (CIs) of standardized beta values were compared. Models were controlled for age, sex, education, and baseline cognition, with ADNI models additionally adjusted for clinical status.

RESULT: In both cohorts, changes in temporal tau-PET, plasma p-tau217, and MRI-assessed cortical thickness were associated with cognitive decline (ADNI: Figure 1; A4: Figure 2). Amyloid-PET changes showed no significant association with cognitive changes (ADNI: Figure 1A+F+K; A4: Figure 2A+F). Bootstrapping confirmed that tau-PET, plasma p-tau217, and cortical thickness track cognitive decline, but not amyloid-PET (ADNI: Figure 1E+J+O; A4: Figure 2E+J). Overlapping CIs for tau-PET and plasma p-tau217 indicated comparable predictive accuracy.

CONCLUSION: Our findings demonstrate that tau-PET and plasma p-tau217 are robust biomarkers for monitoring cognitive changes, with plasma p-tau217 offering a cost-effective, scalable alternative for clinical use. Changes in amyloid-PET do not reliably reflect cognitive decline, limiting its utility as a treatment monitoring tool. Although cortical thickness correlates with cognitive changes, its application is limited by pseudoatrophy and volume loss induced by anti-amyloid antibody treatments.},
}

Humans
*Biomarkers/blood
Male
Female
*Alzheimer Disease/diagnostic imaging/pathology/metabolism
*tau Proteins/blood
Aged
Magnetic Resonance Imaging
Positron-Emission Tomography
Longitudinal Studies
*Cognitive Dysfunction/diagnostic imaging
Amyloid beta-Peptides
Aged, 80 and over
Brain/pathology/diagnostic imaging

@article {pmid41498704,
year = {2025},
author = {Bathe, T and Salomasova, S and Lalia, M and Kunze, LH and Palumbo, G and Oos, R and Joseph, E and Brendel, M},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104796},
doi = {10.1002/alz70856_104796},
pmid = {41498704},
issn = {1552-5279},
mesh = {Animals ; *Biomarkers/cerebrospinal fluid/metabolism ; Mice ; Mice, Transgenic ; Disease Models, Animal ; *Alzheimer Disease/drug therapy ; Positron-Emission Tomography ; tau Proteins/metabolism ; Humans ; Brain/metabolism/pathology/diagnostic imaging/drug effects ; *Tauopathies/drug therapy ; Microglia/metabolism ; },
abstract = {BACKGROUND: The prevalence of neurodegenerative diseases (ND), including Alzheimer's disease (AD) and non-AD tauopathies, is projected to rise significantly by 2050 due to an aging global population. Chronic neuroinflammation, driven by glial activation in response to protein pathologies, is a major contributor to disease progression. Targeting glial dysfunction through immunomodulatory therapies offers a promising approach to mitigate the effects of tauopathies and other ND.

METHOD: PS19 mice receive chronic treatment with GV1001 over 5 months. Serial neuroimaging techniques, including PET scans targeting tau protein, microglial activation, and astrocytic responses, are employed to assess treatment effects in vivo (Figure 1). Postmortem validation is performed using immunohistochemistry and biochemical methods, comparing treated mice to placebo and non-transgenic controls.

RESULT: The research scope is to monitor the efficacy of GV1001 in a transgenic tau mouse model (PS19) with an early-intervention biomarker study using molecular biology and neuroimaging techniques including TSPO (microglia) PET, deprenyl (astroglia) PET, tau PET (perfusion and retention) and CSF markers of inflammation (e.g. sTREM2) and neurodegeneration (NfL). Preliminary findings, expected to be presented at the conference, will provide insights into the drug's ability to modulate glial activity, restore homeostasis, and reduce tau pathology.

CONCLUSION: This study highlights the potential of monitoring immunomodulatory strategies to address the complex interplay between chronic neuroinflammation and protein aggregation in ND. If successful, these findings could inform the development of novel therapeutic approaches for AD and related disorders, bridging the gap between preclinical research and clinical application.},
}

Animals
*Biomarkers/cerebrospinal fluid/metabolism
Mice
Mice, Transgenic
Disease Models, Animal
*Alzheimer Disease/drug therapy
Positron-Emission Tomography
tau Proteins/metabolism
Humans
Brain/metabolism/pathology/diagnostic imaging/drug effects
*Tauopathies/drug therapy
Microglia/metabolism

@article {pmid41498508,
year = {2025},
author = {Doecke, JD and Chenna, A and Lo, M and Badal, Y and Yee, B and Martone, RL and Petropoulos, C and Fowler, CJ and Laws, SM and Rainey-Smith, SR and Martins, RN and Rowe, CC and Masters, CL and Winslow, JW},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104702},
doi = {10.1002/alz70856_104702},
pmid = {41498508},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Amyloid beta-Peptides/blood/metabolism ; Male ; Female ; *Cognitive Dysfunction/blood/diagnostic imaging/diagnosis ; Aged ; *Alzheimer Disease/blood/diagnostic imaging/diagnosis ; *tau Proteins/blood ; Peptide Fragments/blood ; Cohort Studies ; Positron-Emission Tomography ; Aged, 80 and over ; Australia ; Middle Aged ; },
abstract = {BACKGROUND: With the increasing number of countries approving disease-modifying therapies (DMTs) for patients with either Mild Cognitive Impairment (MCI) or mild Alzheimer's disease (AD), it is vitally important to streamline treatment assessment processes. Blood-based biomarkers (BBMs) have been suggested as rivals to cerebrospinal fluid (CSF) biomarkers in their accuracy to detect neocortical Amyloid-Beta (Aβ). However, there is little consensus on potential thresholds and resulting confirmatory test performance for international use in target populations.

METHOD: Two separate sub-cohorts-the AD continuum cohort (ADCC) [cognitively impaired + unimpaired; N = 197] and the intention to treat cohort (ITTC) [cognitively impaired; N = 200]-from the Australian Imaging Biomarkers and Lifestyle (AIBL) study of aging, were designed to test the accuracy and potential cut-offs of leading BBM Lumipulse assays from Fujirebio (pTau217 and Aβ42/40) to detect PET-Aβ (centiloid ≥25; amyloid prevalence ∼63%).

RESULT: Using the pTau217/Aβ42 ratio significantly improved the area under the curve (AUC) over pTau217 alone to detect PET-Aβ positivity in both the ADCC and ITTC (Figure 1A, ADCC p = 0.01; Figure 1B: ITTC p = 0.009). The Youden's Index cut-off for pTau217 was higher in the ITTC compared to the ADCC (0.25 pg/mL vs. 0.179 pg/mL). The highest accuracy observed for either single BBMs, the ratio of BBMs, or the linear combination of BBMs that included age, gender, and APOE ε4 was 93-95% in the ADCC (linear combination of pTau217, Aβ42/40, age, gender, and APOE ε4; pTau217/Aβ42 ratio) and 95-97% in the ITTC (linear combination; pTau217/Aβ42 ratio). The lowest number of participants in the intermediate zone using dual cut-offs at 95% sensitivity and specificity was 9% and 14% for the pTau217/Aβ42 ratio in the ADCC and ITTC (92-93% accuracy), and 0% for the linear combination (pTau217, Aβ42/40, age, gender, and APOE ε4) in the ITTC (95% accuracy).

CONCLUSION: The general performance of the Lumipulse assays was similar across both the ADCC and ITTC, indicating strong repeatability independent of clinical stage. Focusing on only participants eligible for DMTs increased sensitivity and improved accuracy for the Aβ-containing pTau217/Aβ42 ratio and linear combination of markers, and resulted in small numbers of unclassified participants by the test.},
}

Humans
*Biomarkers/blood
*Amyloid beta-Peptides/blood/metabolism
Male
Female
*Cognitive Dysfunction/blood/diagnostic imaging/diagnosis
Aged
*Alzheimer Disease/blood/diagnostic imaging/diagnosis
*tau Proteins/blood
Peptide Fragments/blood
Cohort Studies
Positron-Emission Tomography
Aged, 80 and over
Australia
Middle Aged

@article {pmid41498480,
year = {2026},
author = {Goodall, LS and Lennon, MJ and Sachdev, PS and Gorelick, PB and Kovacic, JC and Samaras, K},
title = {Current and Emerging Therapeutic Approaches for Vascular Cognitive Impairment and Dementia.},
journal = {Journal of the American College of Cardiology},
volume = {87},
number = {1},
pages = {77-100},
doi = {10.1016/j.jacc.2025.09.1502},
pmid = {41498480},
issn = {1558-3597},
mesh = {Humans ; *Dementia, Vascular/therapy/prevention & control ; *Cognitive Dysfunction/therapy ; },
abstract = {Cardiovascular risk factors contribute to the majority of dementia cases, with about 20% directly attributable to vascular cognitive impairment and dementia (VCID). VCID treatment developments have been slow compared with Alzheimer's disease (AD), which now has several FDA-approved symptom- and disease-modifying agents. In the second part of this JACC Seminar Series, advances and new perspectives on the management and prevention of VCID are reviewed. There is reasonable evidence that cognitive enhancers (donepezil, galantamine, and memantine) modestly improve cognition in vascular dementia (VaD), the most severe form of VCID, especially if there is associated AD pathology. Antidepressants may benefit those with depression and stroke, but they have poor efficacy in those with depression and VaD alone. Behavioral, social, and environmental interventions are first-line therapies for managing VCID-associated agitation and psychosis. Second-line antipsychotics have not been trialed in those with VaD alone, but are beneficial where AD and VaD co-exist, with risperidone and quetiapine effective in reducing psychosis and agitation. Primary prevention of VCID includes identifying and managing cardiometabolic risk factors along with manifestations of covert cerebrovascular disease. Both primary and secondary VCID prevention involve management of cardiovascular risks, specifically hypertension, diabetes mellitus, smoking, atrial fibrillation, obesity, and sedentariness. Management of vascular risk factors may moderately reduce the risk of incident cognitive impairment. Novel interventions currently being evaluated in clinical trials are discussed. The discovery and utilization of VCID and AD biomarkers will enhance the specificity and effectiveness of interventions such that a precision-medicine approach to disease-specific medical therapy may be taken.},
}

Humans
*Dementia, Vascular/therapy/prevention & control
*Cognitive Dysfunction/therapy

@article {pmid41498479,
year = {2026},
author = {Sachdev, PS and Bentvelzen, AC and Gustafson, D and Hansra, GK and Hosoki, S and Jiang, J and Lennon, MJ and Moro, MA and Saks, DG and Samaras, K and Kovacic, JC and Kalaria, R},
title = {Vascular Cognitive Impairment and Dementia: Clinical Features, Neuropathology, and Biomarkers.},
journal = {Journal of the American College of Cardiology},
volume = {87},
number = {1},
pages = {52-76},
doi = {10.1016/j.jacc.2025.11.008},
pmid = {41498479},
issn = {1558-3597},
mesh = {Humans ; Biomarkers/metabolism ; *Dementia, Vascular/diagnosis/pathology ; *Cognitive Dysfunction/diagnosis/etiology ; Risk Factors ; *Brain/pathology ; },
abstract = {Vascular cognitive impairment and dementia (VCID), ie, cognitive impairment secondary to cerebrovascular disease (CeVD), is the second most common form of dementia after Alzheimer's disease (AD), accounting for 15% to 20% of all cases. CeVD, in fact, contributes to dementia alongside other neuropathologies in up to 75% of dementia cases. CeVD and AD not only frequently co-occur in the brain, but they may also interact, and some VCID risk factors (midlife hypertension and diabetes) also increase AD risk. Because CeVD and cardiovascular disease share risk factors and pathophysiology, the cardiovascular clinician is likely to encounter both in the clinic. Moreover, common cardiac disorders, such as atrial fibrillation, heart failure, acute coronary syndrome, and valvular disease, increase VCID risk. There have been recent developments in the diagnostic criteria for VCID, with advances in risk biomarkers, treatment, and prevention of cognitive impairment and dementia. The diagnosis of VCID is a 2-step process, with the initial identification of a cognitive syndrome followed by the establishment of a predominantly vascular etiology, guided by clinical history and examination and substantiated by neuroimaging, preferably magnetic resonance imaging. Clinical presentations include an acute onset, a stepwise decline, a fluctuating course if caused by multiple strokes, or a gradual slow progression if attributable to cerebral small vessel disease. Cognitive deficits can be found in several domains, such as information-processing speed, attention, executive function, and emotional lability, sometimes referred to as the subcortical syndrome, often seen in the early stages of VCID without cortical infarcts. The diagnosis is supported by the identification of large and small infarcts, lacunes, white matter hyperintensities, dilated perivascular spaces and cerebral microbleeds using magnetic resonance imaging. This part 1 of a 2-part JACC review series describes the clinical features, pathophysiology, and biomarkers of VCID for cardiovascular clinicians who have a critical role in its early identification, management, and prevention in their patients.},
}

Humans
Biomarkers/metabolism
*Dementia, Vascular/diagnosis/pathology
*Cognitive Dysfunction/diagnosis/etiology
Risk Factors
*Brain/pathology

@article {pmid41498388,
year = {2025},
author = {Chiotis, K and Blazhenets, G and Eloyan, A and Maiti, P and Zhang, J and Touroutoglou, A and Kirby, K and Hammers, DB and Carrillo, MC and Dickerson, BC and Apostolova, LG and Rabinovici, GD and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104661},
doi = {10.1002/alz70856_104661},
pmid = {41498388},
issn = {1552-5279},
mesh = {Humans ; Male ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; Female ; *tau Proteins/metabolism ; Biomarkers/metabolism ; *Amyloid beta-Peptides/metabolism ; Positron-Emission Tomography ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Longitudinal Studies ; Aged ; Cognitive Dysfunction/drug therapy/diagnostic imaging ; Middle Aged ; Brain/diagnostic imaging/metabolism ; },
abstract = {BACKGROUND: In clinical trials, monoclonal antibodies targeting Aβ pathology have shown strong target engagement, resulting in rapid Aβ clearance and a deceleration in rate of clinical decline. Now that these treatments are approved and implemented in clinical practice, we could assess their effects in observational studies involving these patients.

METHOD: We analyzed data from 20 participants with early-onset Alzheimer's disease (EOAD) in the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort, treated with Aducanumab (n = 4), Lecanemab (n = 15), or both (one transitioning from Aducanumab to Lecanemab). All participants had MCI or mild dementia at baseline, longitudinal Aβ and tau PET, as well as cognitive assessments, with at least one observation before and after treatment initiation. We applied piecewise regression with a knot at the treatment start, to evaluate changes in Aβ and tau PET burden and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. We compared the trajectories of treated participants with an untreated group (i.e., treated-untreated comparison) from LEADS, matched for age, sex, APOE ε4 genotype, pretreatment Aβ and tau PET load, CDR-SB, and follow-up duration, using a 1:3 matching design.

RESULT: The median treatment duration was 8 months (IQR=5-10). In the piecewise regression model, the treated group showed significant decreases in Aβ burden post-treatment (Δ=-52 Centiloids/yr, p <0.001) with widespread neocortical involvement (Figure 1). However, no significant inflection in tau burden (Δ=0 SUVR/yr, p = 0.58) or CDR-SB (Δ=0.3 units/yr, p = 0.57) trajectories was observed. In the treated-untreated comparison, the treated group showed a trend toward slower increases in CDR-SB scores post-treatment (ΔT=-1.8, p = 0.07) compared to the untreated group (Figure 2). Aβ levels significantly decreased in the treated group compared to the untreated group (ΔΤ=-8.5, p <0.001). No significant differences in tau trajectories were observed between groups (ΔT=0.4, p = 0.68), with both showing increases in cortical regions of interest.

CONCLUSION: We observed excellent target engagement, with piecewise regression models showing rates of Aβ clearance comparable to those seen in Phase 3 trials. The study was underpowered to detect cognitive benefits, which are limited over a short follow-up interval. These findings underscore the utility of observational studies with biomarker data in evaluating treatment efficacy, offering insights that complement traditional randomized trials.},
}

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

@article {pmid41496378,
year = {2025},
author = {Zhao, Y and Lu, H and Jiang, X},
title = {Advance in neuroprotective effects of proanthocyanidins (PCs): Structure, absorption, bioactivities, mechanism, and perspectives.},
journal = {Pharmacological research},
volume = {223},
number = {},
pages = {108082},
doi = {10.1016/j.phrs.2025.108082},
pmid = {41496378},
issn = {1096-1186},
abstract = {With the global population growing and aging, along with increasing environmental, metabolic, and lifestyle-related risk factors, the worldwide incidence of stroke, Alzheimer's disease (AD) and other dementias, meningitis, and other neurological disorders-along with associated mortality-has risen significantly. Proanthocyanidins (PCs), which are oligomers and polymers of flavan-3-ols, are widely distributed across the plant kingdom, including in grape seeds, cinnamon, apples, cranberries, lotus seeds, and pine bark. They represent the second most abundant class of polyphenols in nature, after lignin. A substantial body of preclinical evidence indicates that PCs exert significant neuroprotective effects through multiple mechanisms. This review provides a systematic overview of the sources, structural characteristics, and bioavailability of PCs, with a focus on their pharmacological mechanisms in nervous system disease. Specifically, it examines their roles in regulating oxidative stress, neuroinflammation, protein homeostasis, apoptosis, autophagy, and key signaling pathways, including Nrf2/HO-1, CREB/BDNF, PI3K/Akt, MAPK, and NF-κB. Furthermore, this review systematically summarized the distinct structural forms of PCs, including monomers, dimers, trimers, and polymers, and explores their structure-activity relationships (SARs) in modulating the gut-brain axis. Additionally, recent advances in PCS-based nano-delivery systems and clinical studies related to neurological disorders are summarized. Growing evidence indicates that microbial metabolism in the gut serves as a key mechanism underlying their neuroprotective effects. Finally, the potential applications of PCs as promising dietary supplements or therapeutic agents for the prevention and treatment of nervous system diseases are discussed, along with existing challenges and future perspectives.},
}

@article {pmid41496364,
year = {2026},
author = {Facchinetti, R and Valenza, M and Ciarla, C and Steardo, L and Serviddio, G and Palombelli, G and Verkhratsky, A and Steardo, L and Canese, R and Cassano, T and Scuderi, C},
title = {Ultramicronized palmitoylethanolamide restores astrocyte-neuron metabolic coupling and Klotho/FGF21 signaling in a triple-transgenic mouse model of Alzheimer's disease.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {195},
number = {},
pages = {118965},
doi = {10.1016/j.biopha.2025.118965},
pmid = {41496364},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD), a multifactorial neurodegenerative disorder, is characterized by metabolic deficiency, neuroinflammation, and synaptic impairment. Astrocyte-neuron metabolic coupling regulates cerebral energy homeostasis through key metabolites such as lactate, glutamate, and taurine. We investigated the therapeutic potential of ultramicronized-palmitoylethanolamide (um-PEA) in restoring the homeostasis of these metabolites in the triple transgenic (3 ×Tg-AD) mouse model of AD. Using in vivo magnetic resonance imaging and spectroscopy (MRI/MRS) combined with Western blot, we evaluated the effects of chronic um-PEA treatment on lactate-glutamate dynamics and taurine metabolism in the frontal cortex and hippocampus of 6- and 12 month-old mice. Our findings demonstrate that 3 ×Tg-AD mice exhibit lactate accumulation, glutamine/glutamate imbalance, and taurine depletion, alongside reduced expression of metabolic processes regulators such as FGF21, Klotho, and insulin receptor. Treatment with um-PEA successfully restored these metabolic changes by: (i) rebalancing lactate-glutamate metabolism, (ii) increasing taurine synthesis and transport, (iii) upregulating FGF21, Klotho, and insulin receptor expression, and (iv) modulating the metalloproteases ADAM10 and ADAM17, which regulate Klotho processing. These results identify um-PEA as a promising metabolic modulator capable of mitigating AD-related neurodegenerative processes. By targeting astrocyte-neuron metabolism and enhancing both FGF21 and Klotho pathways, um-PEA holds significant potential as an adjunctive therapeutic strategy for AD.},
}

@article {pmid41496361,
year = {2026},
author = {Huzián, O and Nagy, LI and Hackler, L and Knapp, L and Kocsis, ÁK and Szöts, I and Tamás, G and Puskás, LG and Molnár, G},
title = {Novel drug candidate binds to delta subunit containing GABAA receptors and improves spatial memory.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {195},
number = {},
pages = {118970},
doi = {10.1016/j.biopha.2026.118970},
pmid = {41496361},
issn = {1950-6007},
abstract = {The hydroxyquinoline derivative Q134R is a promising drug candidate for the treatment of Alzheimer's disease with cytoprotective and cognition-enhancing properties. Radioligand binding assays showed that Q134R reduced [[35]S]TBPS binding, consistent with modulation of the picrotoxin site or conformational states that regulate TBPS accessibility. Electrophysiological recordings in mouse brain slices revealed that Q134R significantly increased tonic inhibitory currents in cortical neurogliaform and dentate gyrus granule cells, both known to express delta subunit-containing GABAA receptors. This effect was abolished in mice deficient in the GABAA delta subunit confirming the delta subunit dependency of Q134R's action. Furthermore, in a scopolamine-induced amnesia model, Q134R treatment significantly improved spatial memory performance in wild-type mice, but not in mice lacking in the delta subunit. These results suggest that Q134R enhances tonic inhibition through delta subunit-containing GABAA receptors, which may contribute to the modulation of memory processes and serve as a protective mechanism in early-stage neurodegenerations. These receptor-mediated effects likely contribute to its broader therapeutic efficacy and may complement its previously reported interactions with signaling pathways such as NFAT and HIF-1.},
}

@article {pmid40511807,
year = {2025},
author = {Dodiya, R and Sharma, P and Israni, D and Kamal, MA and Greig, NH},
title = {Zebrafish-Based Parkinson's Disease Models: Unveiling Genetic Mechanisms and Therapeutic Pathways.},
journal = {CNS & neurological disorders drug targets},
volume = {24},
number = {12},
pages = {900-920},
pmid = {40511807},
issn = {1996-3181},
support = {AG000311//NHG: Intramural Research Program, National Institute on Aging, NIH, USA/ ; },
mesh = {Animals ; *Zebrafish/genetics ; *Parkinson Disease/genetics/therapy ; *Disease Models, Animal ; Humans ; },
abstract = {The zebrafish (Danio rerio) is widely utilised as a live vertebrate model in research on neurological development and nervous system diseases. This species exhibits various distinctive attributes that render it well-suited for investigating neurological disorders such as Parkinson's disease (PD). Zebrafish and humans have a genetic similarity of around 70%, and approximately 84% of the genes associated with human diseases have zebrafish equivalents. The genetic similarities and presence of neurotransmitters like dopamine allow scientists to study PD genes and proteins. Zebrafish are often challenged with neurotoxins to induce Parkinsonian symptoms, allowing researchers to evaluate attendant biochemical pathways. Zebrafish can also repair damaged organs, increasing their potential value in PD research. Because of their regenerative capacity and genetic resemblance to humans, these species can be used to study dopamine neurodegeneration and prospective PD treatments. In addition to PD, zebrafish are helpful models for studying Huntington's disease, Alzheimer's disease, epilepsy, depression, schizophrenia, and anxiety disorders. This article emphasizes significant findings of relevance to PD using the zebrafish model, describing its challenges and benefits. The investigation of key genes, protein pathways, and neurotoxins provides the opportunity to facilitate understanding of the role of dopamine neurotransmitters in PD and expedite the development of potentially promising therapeutic strategies.},
}

Animals
*Zebrafish/genetics
*Parkinson Disease/genetics/therapy
*Disease Models, Animal
Humans

@article {pmid41495612,
year = {2025},
author = {Yang, G and Zhu, D and Zhang, K},
title = {Nose-brain axis: A bridge from the nasal cavity to the central nervous system.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01770},
pmid = {41495612},
issn = {1673-5374},
abstract = {The nose-brain axis is a direct pathway linking the nasal cavity to the central nervous system. Odors, as well as exogenous substances such as pathogens, inflammatory mediators, and drugs, can enter the cranial cavity through pathways including the olfactory nerve, trigeminal nerve, and humoral routes, thereby enabling signal transmission and material exchange from the peripheral nasal cavity to the central nervous system. In recent years, advances in multimodal visualization technologies have made it possible to dynamically monitor the nose-brain axis from the molecular level to the tissue level, providing important means for revealing its functional characteristics and pathological changes. Owing to the existence of the nose-brain axis, nasal inflammation can, through neuro-immune interactions, activate central microglia and astrocytes and induce neuroinflammation, thus promoting the onset and progression of central nervous system diseases. In addition, the nose-brain axis offers a unique route for the treatment of central nervous system disorders. Intranasal drug delivery can bypass the blood-brain barrier, act directly on the central nervous system, increase intracranial drug bioavailability, and produce rapid effects, providing new ideas for treating cross-system diseases. This review systematically summarizes the anatomical pathways of the nose-brain axis, visualization monitoring technologies, and mechanisms by which nasal inflammation affects the central nervous system. It also reviews advances in intranasal drug delivery for emotional disorders, migraine, Parkinson's disease, and Alzheimer's disease, aiming to provide new strategies for studying the mechanisms by which nasal inflammation influences the central nervous system and for cross-system targeted therapy.},
}

@article {pmid41495456,
year = {2026},
author = {Chen, Z and Bi, S and Shan, Y and Wang, F and Wang, Y and Qi, Z and Wang, T and Li, X and Li, S and Xiao, H and Wang, S and Cui, B and Qi, Z and Han, Y and Yan, S and Lu, J and , },
title = {MRI-to-PET synthesis via deep learning for amyloid-β quantification in Alzheimer's disease.},
journal = {European radiology},
volume = {},
number = {},
pages = {},
pmid = {41495456},
issn = {1432-1084},
support = {82102010//National Natural Science Foundation of China/ ; 82394434//National Natural Science Foundation of China/ ; },
abstract = {OBJECTIVES: Amyloid-β (Aβ) PET is crucial for diagnosing and monitoring Alzheimer's disease (AD), but its high cost and radiation exposure limit its use. Deep learning techniques make it possible to generate PET from structured MRI data. In this study, we built a deep learning model to generate 3D synthetic Aβ PET images from structural MRI.

MATERIALS AND METHODS: The generative adversarial network with share parameters (ShareGAN) model was trained and tested with 1009 Aβ PET and paired MRI images from the Alzheimer's Disease Neuroimaging Initiative database and three tertiary hospitals in China. The 3D synthetic model operates on the whole volume rather than 2D image slices, realistically reproducing minor discrepancies between neighboring image planes. ShareGAN-based PET images were evaluated using quantitative metrics and visual assessment. Pearson correlation coefficient and Bland-Altman analyses were used to assess the correlation and concordance between synthetic and real PETs.

RESULTS: 3D Synthetic PET images showed high similarity and correlation with real Aβ PET in external testing sets 1 and 2 in terms of structural similarity index measure (0.898, 0.899), peak signal-to-noise ratio (34.690, 34.725), mean absolute error (0.031, 0.031), and standardized uptake value ratio (R = 0.758, 0.828). The diagnostic accuracy of PET positive or negative status in external testing sets 1 and 2 was 88.5% and 89.4%, respectively.

CONCLUSION: MRI-based 3D synthetic Aβ PET images can serve as a safe and cost-effective tool for Aβ status visualization, providing PET-eligible patients with Aβ PET-like imaging analysis to guide subsequent real Aβ PET scans.

KEY POINTS: Question Amyloid-β (Aβ) PET limitations (high cost, radiation, limited access) hinder early Alzheimer's disease (AD) detection. Clinical practice urgently requires a suitable supplementary method for Aβ pathology assessment. Findings AI-synthesized 3D Synthetic Aβ PET from structural MRI demonstrated strong consistency with real PET and effectively triaged high-risk patients for confirmatory scans. Clinical relevance This non-invasive, cost-effective method holds the promise of enabling wider Aβ pathology screening, reduces unnecessary PET scans, and supports early intervention in resource-limited settings, while preserving diagnostic rigor for treatment decisions.},
}

@article {pmid41494605,
year = {2026},
author = {Viqueira, L and Navarro, E and Negredo, P and Bernal, JA and Rodríguez-Franco, MI and ElenaTortosa, and López, MG},
title = {Long-term NRF2-driven microglial repopulation mitigates microgliosis, neuronal loss and cognitive deficits in tauopathy.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106253},
doi = {10.1016/j.bbi.2026.106253},
pmid = {41494605},
issn = {1090-2139},
abstract = {Tauopathies, including Alzheimer's disease, feature chronic microglial reactivity that drives neuroinflammation and disease progression. Pharmacological microglial depletion and subsequent repopulation using colony stimulating factor 1 receptor inhibitors have emerged as a potential therapeutic strategy to reprogram dysfunctional microglia. Despite promising short-term results, the long-term efficacy and pharmacological modulation of repopulated microglia remain poorly understood. Here, we investigated the long-term effects of microglial repopulation alone and in combination with the activation of the cytoprotective nuclear factor erythroid 2 p45-related factor 2 (NRF2) in an in vivo AAV-hTau[P301L] induced model. Integrating different behavioural, immunohistological and transcriptomic analysis, we evaluated cognitive function, tau pathology, neuronal survival and glial reactivity. We found that, whereas microglial repopulation alone did not significantly affect disease progression, NRF2-driven microglial replenishment sustained cognitive function, prevented hippocampal neuronal loss and restored microglial phenotype. Transcriptomic analyses further revealed that the combined treatment modulated tau- associated mitochondrial gene expression changes. These results highlight the importance of shaping the fate of self-renewed microglia and propose NRF2-mediated microglial repopulation as a potential pharmacological strategy for the treatment of tauopathies.},
}

@article {pmid41493713,
year = {2026},
author = {Hoveizi, E and Doraghi, K and Rostami, E},
title = {Fabrication and Characterization of Resveratrol-Loaded Solid Lipid Nanoparticles: Evaluation of Neuroprotective, Neurobehavioral, and Molecular Outcomes.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {346},
pmid = {41493713},
issn = {1559-1182},
support = {SCU.SB1403.12464//Shahid Chamran University of Ahvaz/ ; },
mesh = {*Resveratrol/pharmacology/administration & dosage/chemistry ; Animals ; *Nanoparticles/chemistry/ultrastructure ; *Neuroprotective Agents/pharmacology/administration & dosage/chemistry ; Male ; Rats ; Oxidative Stress/drug effects ; *Lipids/chemistry ; Antioxidants/pharmacology ; Neural Stem Cells/drug effects/metabolism ; *Behavior, Animal/drug effects ; Rats, Sprague-Dawley ; Interleukin-1beta/metabolism ; Memory/drug effects ; },
abstract = {Neurodegenerative processes involve oxidative stress, inflammation, and disrupted signaling, which contribute to cognitive decline. Resveratrol offers neuroprotection but suffers from poor solubility and bioavailability. Solid lipid nanoparticles (SLNs) can improve solubility, stability, and neural targeting, thereby enhancing efficacy. This study investigates whether SLN/resveratrol treatment modulates neuroprotective targets (HSP70, IL-1β) and antioxidant enzymes (CAT, GPX, SOD) in vitro and whether it improves inactive avoidance memory in an animal model. SLNs were produced by melting tripalmitin and palmitic acid, adding resveratrol, Tween, and butanol, then combining with water and stirring for 1 day. The resulting formulations were characterized using FTIR, electron microscopy, and DLS. Neural stem cells (NSCs) were treated with SLNs, resveratrol, and SLN/resveratrol, and the expression of oxidative stress enzymes, HSP70, and IL-1β was analyzed. In vivo, a passive avoidance memory model was induced in rats via electrical destruction of the nucleus basalis of Meynert. Molecular analysis showed that resveratrol increased HSP70 expression by 3.1-fold and significantly decreased IL-1β levels. SLN treatment had no notable effect on these genes, but the SLN/resveratrol increased HSP70 expression by fourfold and significantly reduced IL-1β. Resveratrol significantly upregulated the antioxidant enzymes CAT and GPX, whereas SLNs alone had no effect. The SLN/resveratrol also markedly enhanced CAT and GPX levels. Behavioral tests demonstrated that the SLN/resveratrol treatment improved passive avoidance memory in the Alzheimer's model. Collectively, these results indicate that SLN/resveratrol robustly enhances neuroprotection by modulating signaling pathways, reducing oxidative stress, and improving memory, with the SLN delivery system potentially increasing bioavailability and neural exposure.},
}

*Resveratrol/pharmacology/administration & dosage/chemistry
Animals
*Nanoparticles/chemistry/ultrastructure
*Neuroprotective Agents/pharmacology/administration & dosage/chemistry
Male
Rats
Oxidative Stress/drug effects
*Lipids/chemistry
Antioxidants/pharmacology
Neural Stem Cells/drug effects/metabolism
*Behavior, Animal/drug effects
Rats, Sprague-Dawley
Interleukin-1beta/metabolism
Memory/drug effects

@article {pmid41493675,
year = {2026},
author = {Usman, AS and Manoharan, SD and Che Mohd Nassir, CMN and Abdul Hamid, H and Hein, ZM and Norazit, A and Murthy, J and Zainol, M and Kamaruzzaman, MA and Chiroma, SM and Mustapha, M and Mohd Moklas, MA and Mehat, MZ},
title = {Neuroprotective Effects of Ficus deltoidea in Alzheimer's Disease-Like Rat Model: Insights from Behavior, Histology, and Amyloid Pathology.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {345},
pmid = {41493675},
issn = {1559-1182},
support = {(FRGS/1/2021/SKK0/UPM/02/15)//the Ministry of Higher Education under the Fundamental Research Grant Scheme/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/drug therapy/metabolism ; *Ficus/chemistry ; *Neuroprotective Agents/pharmacology/therapeutic use ; Male ; Rats, Wistar ; Disease Models, Animal ; *Plant Extracts/pharmacology/therapeutic use ; Plaque, Amyloid/pathology/drug therapy ; Amyloid beta-Peptides/metabolism ; Hippocampus/pathology/drug effects/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Maze Learning/drug effects ; Rats ; *Behavior, Animal/drug effects ; Spatial Memory/drug effects ; Aspartic Acid Endopeptidases/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, memory impairment, and accumulation of amyloid-β (Aβ) plaques. While current treatments offer limited efficacy, medicinal plants such as Ficus deltoidea (FD), a traditional remedy, have shown promise due to their neuroprotective and anti-inflammatory properties. An AD-like phenotype was induced in male Wistar rats using D-galactose and aluminum chloride over 70 days. FD extract was administered orally at 50, 100, and 200 mg/kg. Spatial memory was evaluated using the T-maze test. Histological analyses of the hippocampi's Cornu Ammonis 1 and 3 (CA1 and CA3) regions were conducted via hematoxylin and eosin (H&E) staining, and Aβ plaques deposition was assessed with Congo red. Enzyme-linked immunosorbent assay (ELISA) was used to quantify hippocampal levels of Aβ (1-42) and β-secretase-1 (BACE-1). FD treatment significantly enhanced spatial memory, preserved pyramidal neuron integrity in CA1 and CA3, and reduced amyloid plaque formation. Biochemically, FD markedly decreased hippocampal Aβ (1-42) and BACE-1 concentrations in a dose-dependent manner. Thus, FD exhibits multi-target neuroprotective effects in an AD-like model, potentially via modulation of amyloidogenic pathways. Further studies are warranted to explore its mechanisms and therapeutic potential in other brain regions implicated in AD.},
}

Animals
*Alzheimer Disease/pathology/drug therapy/metabolism
*Ficus/chemistry
*Neuroprotective Agents/pharmacology/therapeutic use
Male
Rats, Wistar
Disease Models, Animal
*Plant Extracts/pharmacology/therapeutic use
Plaque, Amyloid/pathology/drug therapy
Amyloid beta-Peptides/metabolism
Hippocampus/pathology/drug effects/metabolism
Amyloid Precursor Protein Secretases/metabolism
Maze Learning/drug effects
Rats
*Behavior, Animal/drug effects
Spatial Memory/drug effects
Aspartic Acid Endopeptidases/metabolism

@article {pmid41493656,
year = {2026},
author = {Cicero, CE and Angelini, L and Abbadessa, G and Bruno, M and Fiume, G and Nucera, B and Ornello, R and Arabia, G and Giuliano, L and Guarnieri, B and Lugaresi, A and Perani, D and Sacco, S and Tassorelli, C and Nicoletti, A and Pellecchia, MT and , },
title = {Sex and gender-related differences in neurological diseases: current challenges and recommendations for clinical practice.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {1},
pages = {108},
pmid = {41493656},
issn = {1590-3478},
mesh = {Humans ; *Nervous System Diseases/therapy/epidemiology ; Female ; *Sex Characteristics ; Male ; Pregnancy ; },
abstract = {Neurological diseases include a large variety of conditions ranging from inflammatory, vascular and neurodegenerative disorders to epilepsy and headache. The impact of sex and gender on various aspects of these conditions (epidemiology, risk factors, pathophysiology, clinical features, treatment, and management of pregnancy and breastfeeding) is still not entirely taken into consideration, despite a rapidly increasing body of evidence. This position paper covers six neurological conditions (Alzheimer's Disease, Cerebrovascular disease, Parkinson's disease, Epilepsy, Headache disorders, Multiple Sclerosis) providing an overview of available evidence on sex and gender differences, identifying knowledge gaps and providing recommendations for clinical practice and future studies. We recommend taking into consideration modifiable sex and gender specific risk factors, the role of hormones across women's lifespan and a personalized treatment approach based on gender. We also recommend that future efforts should be devoted to increase the representation of women in clinical studies, to promote sex and gender-based guideline production and to better characterize the safety profile in pregnancy of newer drugs.},
}

Humans
*Nervous System Diseases/therapy/epidemiology
Female
*Sex Characteristics
Male
Pregnancy

@article {pmid41491579,
year = {2026},
author = {Kamali, M and Ansari, M and Nooraee, P and Tajadini, H and Kamali, H and Dehesh, T and Ashrafzadeh, A and Sharififar, F},
title = {Preliminary clinical evaluation of capsules containing standard hydroalcoholic extract of Myrtus communis L. in patients with mild to moderate Alzheimer' disease: a randomized, double-blind parallel-group clinical trial.},
journal = {BMC complementary medicine and therapies},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12906-025-04994-9},
pmid = {41491579},
issn = {2662-7671},
abstract = {BACKGROUND: This study evaluated the effectiveness of Myrtus communis L. extract, known for its antioxidant and anticholinesterase properties, to enhance cognitive function and mitigate disease progression in individuals with mild to moderate Alzheimer's disease (AD).

METHODS: Fifty elderly patients with mild to moderate AD residing in a Kerman nursing home were enrolled in a randomized, placebo-controlled trial conducted between November 2019 to February 2020. Participants were randomly assigned to either an intervention group (n = 25), receiving M. communis L. capsules (500 mg each capsule), or a control group (n = 25), receiving placebo capsules. Cognitive function was assessed at baseline and after four weeks using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scales. Statistical analyses, performed using SPSS version 22, considered a significance level of p < 0.05.

RESULTS: All fifty patients completed the four-week trial. Baseline characteristics-including sex, mean age, and education level-were well-matched between the intervention and control groups. After four weeks of treatment, the intervention group demonstrated a statistically significant improvement in cognitive function, as evidenced by significantly higher MMSE scores compared to the placebo group (23.4 ± 0.25 vs. 19.6 ± 0.25; p < 0.0001). Concurrently, the intervention group exhibited a significant reduction in dementia severity, indicated by lower CDR scores compared to the control group (0.8 ± 0.04 vs. 1.5 ± 0.04; p < 0.0001).

CONCLUSIONS: These findings suggest that M. communis L. holds promise as a potential complementary therapy for AD, capable of improving cognitive function and potentially slowing disease progression. However, further research is necessary to corroborate these results, elucidate the underlying mechanisms of action, and optimize treatment parameters before definitive conclusions can be drawn.

TRIAL REGISTRATION: irct.ir, ID: 20170702034861N8. Registered on 26/08/2019.},
}

@article {pmid41491073,
year = {2026},
author = {Wasim, R and Azmi, S and Ahmad, A and Srivastava, A},
title = {NLRP3 inflammasome and Alzheimer's disease: bridging inflammation and neurodegeneration.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41491073},
issn = {1568-5608},
abstract = {The progressive neurodegenerative disease known as Alzheimer's disease (AD) is characterized by widespread neuronal death, memory loss, and cognitive decline. The NLRP3 inflammasome has emerged as a key modulator of neuroinflammation, which is increasingly implicated in the pathophysiology of AD. In response to endogenous and pathogenic danger signals, the innate immune system's multiprotein complex known as the NLRP3 inflammasome is activated. Pyroptosis and neuroinflammatory cascades are eventually triggered by its activation, which causes caspase-1 to be cleaved and pro-inflammatory cytokines like interleukin-1β and interleukin-18 to be released. NLRP3 activation is strongly stimulated by tau aggregation and β-amyloid plaques in AD, which accelerates neuronal damage and prolongs chronic inflammation. The control and activation of inflammasomes are involved in both canonical and non-canonical pathways as well as mitochondrial dysfunction. Significantly, animal models indicate that NLRP3's therapeutic potential is highlighted by the reduction of amyloid burden and amelioration of cognitive decline that results from its inhibition or genetic deletion. Small-molecule inhibitors and natural substances that can alter NLRP3 activity have been discovered recently, providing intriguing approaches to AD treatment. Despite tremendous advancements, issues with medication selectivity and blood-brain barrier penetration still need to be resolved before these discoveries can be used in clinical settings. Comprehending the complex relationship between NLRP3 activation and Alzheimer's pathology may open the door to new, focused treatments meant to slow or stop the progression of the illness.},
}

@article {pmid41490490,
year = {2026},
author = {Wang, W and Huang, R and Lv, L and Ma, X and Li, Z and Zhang, Y and Wu, J and Wu, S and Xu, J and Hu, Y and Turck, CW and Li, H and Hu, X},
title = {Long-term effects of forty-hertz auditory stimulation as a treatment of Alzheimer's disease: Insights from an aged monkey model study.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {2},
pages = {e2529565123},
doi = {10.1073/pnas.2529565123},
pmid = {41490490},
issn = {1091-6490},
mesh = {Animals ; *Alzheimer Disease/therapy/pathology/cerebrospinal fluid ; Macaca mulatta ; tau Proteins/cerebrospinal fluid ; Disease Models, Animal ; Amyloid beta-Peptides/cerebrospinal fluid ; *Acoustic Stimulation/methods ; Male ; Female ; *Aging ; Humans ; Brain/pathology ; },
abstract = {Based mainly on rodents studies, forty-hertz (40-Hz) physical stimulation has been regarded as a potential noninvasive treatment for Alzheimer's disease (AD). Considering the brain differences between rodents and humans, the effects of 40-Hz physical stimulation need to be further validated using nonhuman primates before its clinical application. Here, we took advantage of a rare opportunity to expose nine aged rhesus monkeys (26 to 31 y old) to 40-Hz auditory stimulation. Given the strong correlation between cerebrospinal fluid (CSF) Aβ and Tau concentrations and corresponding AD pathology in brain parenchyma in clinical practice, we investigated the effects of 40-Hz stimulation on AD pathology by monitoring changes in CSF Aβ and Tau concentrations. Our results revealed that 7 consecutive days of 40-Hz auditory stimulation triggered a rapid and significant increase of Aβ levels by more than 200%, but no effect on Tau levels in the CSF. Additionally, we observed that the elevation of CSF Aβ levels persisted for more than 5 wk after cessation, which had not been reported in any previous studies. After this, a pathological examination of the temporal cortices of 4 of the experimental monkeys was carried out and the data demonstrated that all of them had prevalent extracellular Aβ senile plaque pathology, whereas Tau pathology was negative or very weak. These results provide a good explanation for the differences between the CSF Aβ and Tau protein levels. Together, these first-time results from monkeys suggest that 40-Hz auditory stimulation has strong potential of a noninvasive AD treatment method.},
}

Animals
*Alzheimer Disease/therapy/pathology/cerebrospinal fluid
Macaca mulatta
tau Proteins/cerebrospinal fluid
Disease Models, Animal
Amyloid beta-Peptides/cerebrospinal fluid
*Acoustic Stimulation/methods
Male
Female
*Aging
Humans
Brain/pathology

@article {pmid41490210,
year = {2026},
author = {Giuffrè, GM and Battisti, F and Tudor, AM and Lenkowicz, J and Avitabile, A and Rosati, AM and Martellacci, N and Patarnello, S and Torelli, F and Cesario, A and Marra, C},
title = {Redefining management of mild cognitive impairment and Alzheimer's disease through the shift from clinical to clinical-biological diagnosis: Insights from a single-center experience.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411461},
doi = {10.1177/13872877251411461},
pmid = {41490210},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) diagnosis has shifted from a purely clinical framework to a clinical-biological paradigm, driven by biomarker integration. This evolution is motivated by the wider availability of reliable biomarkers and the advent of disease-modifying treatments.ObjectiveTo assess changes over time in clinical characteristics, diagnostic pathways, and healthcare resource utilization in a real-world cohort of individuals with cognitive impairment attending a Memory Clinic.MethodsThis secondary data retrospective observational study analyzed two patient cohorts with newly diagnosed cognitive impairment: one from 2017-2019 and another from 2021-2023. Anonymized medical records and structured hospital data were examined using natural language processing to extract demographic and clinical information, diagnostic pathways, treatment patterns and comorbidities.ResultsThe 2021-2023 cohort was significantly younger, exhibited higher baseline Mini-Mental State Examination scores, and underwent more instrumental assessments than the 2017-2019 cohort. These findings likely reflect a shift in public awareness and attitudes toward cognitive health. AD diagnoses increased in both cohorts over time, while mild cognitive impairment diagnoses declined. The use of diagnostic combinations was more frequent in the recent cohort, in which clinical-biological diagnoses were significantly more prevalent.ConclusionsThis study provides real-world insights into the evolving landscape of cognitive impairment diagnostics and care, underscoring a shift toward earlier, biologically grounded diagnosis, supporting precision medicine in AD care. The expanded use of biomarkers reflects evolving practice standards and prepares the ground for disease-modifying therapies in AD.},
}

@article {pmid41490207,
year = {2026},
author = {Liu, Y and Su, H and Guan, T and Li, X and Dong, C and Hu, Z and Zhang, Y},
title = {Risk prediction of progression from normal cognitive function to Alzheimer's disease in elderly aged 65 and above based on deep learning methods.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251410937},
doi = {10.1177/13872877251410937},
pmid = {41490207},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a severe neurological disorder for which a complete cure is not currently available. Therefore, predicting the risk of AD in elderly individuals with normal cognitive function is crucial for early prevention, treatment, and family-provided daily care preparation.ObjectiveThis study aimed to establish a risk prediction model for the progression from normal cognitive function to AD in elderly via deep learning (DL) methods to provide a reference for clinical decision-making and the development of screening tools for the early diagnosis of AD.MethodsDeepSurv, DeepHit, and Cox models were constructed, and the consistency index (C-index), integrated Brier score (IBS), and area under the ROC curve (AUC) were used to evaluate the accuracy, calibration and discriminative power of the three prediction models.ResultsThe overall predictive ability of the model was relatively stable, with concordance indices of 0.82 (DeepSurv), 0.83 (DeepHit), and 0.81 (Cox) and IBSs of 0.08, 0.07, and 0.05, respectively. From the perspective of the C-index indicator, the consistency of the deep learning model was better than that of the Cox model.ConclusionsRisk prediction models for the progression from normal cognitive function to AD can be established using easily obtainable early-stage predictors, which are expected to be used for rapid screening of the risk of developing AD in elderly after clinical validation.},
}

@article {pmid41490027,
year = {2026},
author = {Yang, JW and Jiang, J},
title = {Association between varicella-zoster virus and Alzheimer's disease: A systematic review and meta-analysis of comprehensive evidence from infection, treatment to prevention.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411573},
doi = {10.1177/13872877251411573},
pmid = {41490027},
issn = {1875-8908},
abstract = {BackgroundThe association between varicella-zoster virus (VZV) infection and Alzheimer's disease (AD) risk has shown inconsistent results. Given difficulties in early diagnosis and limited therapeutic options for AD, identifying modifiable risk factors is significant for prevention.ObjectiveTo systematically evaluate the impact of VZV infection on AD risk and explore protective effects of antiviral treatment and vaccination.MethodsWe searched PubMed and Web of Science databases up to April 2025. The Newcastle-Ottawa Scale assessed study quality. Random-effects models were used for meta-analysis using risk ratios (RR) as the primary effect measure, with sensitivity and subgroup analyses conducted.ResultsTwenty-one studies were included. Meta-analysis showed: (1) herpes zoster patients had significantly higher AD risk (RR = 1.12, 95% CI: 1.01-1.24, p = 0.04); (2) patients receiving antiviral treatment had lower AD risk (RR = 0.55, 95% CI: 0.37-0.82, p = 0.003); (3) vaccinated individuals had lower AD risk (RR = 0.72, 95% CI: 0.68-0.78, p < 0.0001). The strongest association occurred in the >70 years age group, demonstrating age as an important effect modifier.ConclusionsThis meta-analysis provides systematic evidence supporting that VZV infection increases AD risk while confirming protective effects of antiviral treatment and vaccination. These findings support including herpes zoster vaccination in preventive healthcare for elderly populations.},
}

@article {pmid41488982,
year = {2025},
author = {Ressa, R and Ettinger, J and Chowdhury, E and Graham, L and Ndirangu, K and Mancebo, JZ and Bodnar, C},
title = {A value assessment of patient-level outcomes and productivity loss for intravenous and subcutaneous lecanemab for patients with early Alzheimer's disease.},
journal = {Journal of medical economics},
volume = {29},
number = {1},
pages = {118-134},
doi = {10.1080/13696998.2025.2609499},
pmid = {41488982},
issn = {1941-837X},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Injections, Subcutaneous ; Markov Chains ; Patient Preference ; Administration, Intravenous ; Cost-Benefit Analysis ; Caregivers ; Efficiency ; Decision Support Techniques ; },
abstract = {AIMS: Intravenous (IV) lecanemab is approved for the treatment of patients with early Alzheimer's disease (AD); a subcutaneous (SC) option may offer additional benefits. We assessed the overall value of SC treatments, and direct/indirect outcomes associated with IV and SC lecanemab.

METHODS AND MATERIALS: For the narrative review, PubMed was searched (February 2025) for studies comparing patient preferences for IV/SC treatment administration published between 2015-2025. Study eligibility was determined using patient, intervention, comparator, outcomes, and study criteria. For the decision-analytic model, a Markov model was developed with four lecanemab treatment scenarios. Scenarios one to three included IV initiation (10 mg/kg biweekly) to month 18, followed by either IV initiation continued (10 mg/kg biweekly), SC maintenance (250 mg weekly) or IV maintenance (10 mg/kg every 4 weeks). Scenario four included SC initiation (500 mg weekly) for an 18-month period, followed by SC maintenance (250 mg weekly). Outcomes were administration time/frequency; patient, caregiver, and healthcare professional time; and caregiver productivity loss.

RESULTS: Forty-three publications reported patient treatment preferences. Most (88.4%) reported that patients preferred SC over IV. Key reasons for this were time savings (n = 13/43 studies; 30.2%), convenience (n = 11/43; 25.6%), treatment frequency (n = 12/43; 27.9%). Two studies (n = 2/43; 4.7%) reported an IV preference over SC; for three studies (n = 3/43; 7.0%), treatment preference was driven by administration frequency. Decision-analytic modeling of lecanemab treatment scenarios revealed that IV initiation to IV maintenance had the lowest number of administrations, whereas SC initiation to SC maintenance had the lowest number of treatment hours and caregiver productivity losses.

LIMITATIONS: Caution must be taken when generalizing these results for all AD patients.

CONCLUSIONS: SC treatments show value as a therapeutic option. IV and SC lecanemab availability may offer benefits to patients, caregivers, and society, and improve shared decision making.},
}

Humans
*Alzheimer Disease/drug therapy
Injections, Subcutaneous
Markov Chains
Patient Preference
Administration, Intravenous
Cost-Benefit Analysis
Caregivers
Efficiency
Decision Support Techniques

@article {pmid41488470,
year = {2026},
author = {Cho, Y and Lee, J and Choi, BY and Yun, JH and Han, S and Baek, SH and Park, J and Cho, Y and Kim, HK and Kim, E and Palomera, LF and Lim, J and Jeon, Y and Im, J and Hong, JM and Kim, TK and Kim, SH and Yim, JH and Jo, DG},
title = {Ramalin Ameliorates Alzheimer's Disease Pathology by Targeting BACE1, HDAC6, and MAPK Pathways.},
journal = {MedComm},
volume = {7},
number = {1},
pages = {e70518},
pmid = {41488470},
issn = {2688-2663},
abstract = {Aberrant deposition of β-amyloid (Aβ) and hyperphosphorylated tau, along with neuroinflammation, are key drivers of Alzheimer's disease (AD) pathology. Here, we identify ramalin, a natural antioxidant, as a promising therapeutic agent that alleviates AD pathology by modulating β-site APP cleaving enzyme 1 (BACE1), histone deacetylase 6 (HDAC6), and the mitogen-activated protein kinases (MAPK) pathway. Ramalin reduced BACE1 protein levels, independently of its transcription, translation, or enzymatic activity, an effect mediated by inhibition of HDAC6. Consistently, HDAC6 knockout similarly decreased BACE1 levels, highlighting HDAC6 as a key regulator of BACE1. Ramalin further suppressed neuroinflammatory responses by downregulating inducible nitric oxide synthase (iNOS) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. In AD mouse models, ramalin treatment significantly attenuated neuroinflammation, Aβ plaque burden, and tau hyperphosphorylation, while improving cognitive performance. Notably, ramalin reversed Aβ oligomer-induced synaptic transmission impairment and restored synaptic vesicle recycling in hippocampal neurons. Transcriptomic analysis identified modulation of the MAPK pathway, with reduced phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) implicated in tau pathology. These findings establish ramalin as a disease-modifying intervention that provides neuroprotection through concurrent regulation of BACE1, HDAC6, and MAPK signaling pathway. Collectively, our findings highlight ramalin as a compelling disease-modifying candidate with the potential to drive a breakthrough approach targeting AD pathology.},
}

@article {pmid41488323,
year = {2025},
author = {Lotlikar, MS and Zellmer, JC and Bhattacharyya, R},
title = {Sigma receptors and mitochondria-associated ER membranes are converging therapeutic targets for Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1733659},
pmid = {41488323},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) begins decades before clinical symptoms emerge. The "amyloid hypothesis" suggests that amyloid-β (Aβ) deposition initiates a cascade of tau hyperphosphorylation, neuroinflammation, and neuronal loss leading to cognitive decline. The recent success of anti-Aβ therapies such as Leqembi in prodromal or mild cognitive impaired patients underscores the importance of early intervention and Aβ clearance. However, safety and cost limitations highlight the need for alternative therapeutic strategies. Small-molecule modulators of Sigma-1 and Sigma-2 receptors (σ1R and σ2R) have emerged as promising candidates for AD treatment. σ1R agonists exhibit neuroprotective and anti-amnestic effects under pathological conditions without affecting normal cognition. Beyond AD, σ1R is implicated in several neurodegenerative diseases including ALS (amyotrophic lateral sclerosis), Parkinson's, and Huntington's diseases, stroke, and epilepsy. σ1R plays a key role at mitochondria-associated ER membranes (MAMs)-specialized lipid raft-like domains that form functional membrane contact sites between the endoplasmic reticulum (ER) and mitochondria. β-secretase (BACE1), γ-secretase, and their substrates APP and palmitoylated APP (palAPP) localize in the MAMs, promoting amyloidogenic Aβ production. MAMs serve as dynamic hubs for inter-organelle communication, calcium signaling, and lipid metabolism. The "MAM hypothesis" proposes that MAM dysregulation drives early AD pathology and persists throughout disease progression, contributing to neurofibrillary tangle formation, calcium imbalance, and neuroinflammation. This review aims to summarize the current understanding of σ1R-mediated regulation of MAMs and its neuroprotective mechanisms, highlighting potential therapeutic opportunities for targeting σ1R in AD and other neurodegenerative disorders.},
}

@article {pmid41487944,
year = {2026},
author = {Rus Prelog, P and Zupan, M and Gregorič Kramberger, M and Frol, S},
title = {The Concomitant Use of Selective Serotonin Reuptake Inhibitors and Anti-Amyloid Treatment in Alzheimer's Disease: Balancing Benefits and Risks.},
journal = {Dementia and geriatric cognitive disorders extra},
volume = {16},
number = {1},
pages = {1-3},
pmid = {41487944},
issn = {1664-5464},
}

@article {pmid41487496,
year = {2025},
author = {Cheng, R and Kim, J},
title = {Intranasal delivery of iron chelators and management of central nervous system disease.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1709259},
pmid = {41487496},
issn = {1663-9812},
abstract = {Brain iron dyshomeostasis plays a critical role in the pathology of multiple central nervous system (CNS) disorders, including neurodegenerative and neuropsychiatric diseases. Iron chelators such as deferoxamine (DFO) and deferiprone (DFP) have demonstrated therapeutic potential in mitigating disease progression in these conditions. However, systemic administration is hindered by poor blood-brain barrier (BBB) permeability, dose-limiting toxicity, and poor patient compliance due to frequent dosing regimens. In recent years, intranasal (IN) drug delivery has emerged as a promising strategy to bypass the BBB, providing a direct nose-to-brain delivery route via olfactory and trigeminal pathways while minimizing systemic exposure. This review provides a comprehensive summary of the current status of iron chelation therapy for CNS disorders with a focus on pharmacokinetics, efficacy, and translational potential of IN administration. While IN DFO has been extensively studied in preclinical models of Alzheimer's disease and stroke, recent developments have expanded the scope to other chelators such as DFP. We compare traditional systemic routes, including oral and intravenous, with intranasal administration, highlighting their respective advantages and limitations for CNS delivery. With ongoing advances in formulation and delivery technologies, IN iron chelators provide a promising alternative for the treatment of CNS disorders characterized by impaired iron homeostasis in the brain.},
}

@article {pmid41487012,
year = {2026},
author = {Verma, R and Bahadur, S},
title = {A Comprehensive Review of Naringin Loaded Nano Drug Delivery System in Treatment of CNS Disorders.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128407188251116030341},
pmid = {41487012},
issn = {1873-4286},
abstract = {Citrus fruits are an abundant source of the polyphenolic phytoconstituent naringenin, which belongs to the class of flavanones. NRG shows a lot of potential as a drug for treating a number of CNS disorders, such as neuroprotective activity, antiamyloidosis, antiparkinson, antialzheimer activity, and more. However, naringenin's hydrophobic nature, which results in limited absorption, limits its therapeutic potential. In this article, we provide an outline of the variety of nanocarriers employed for delivering naringenin as carriers. Some of them include solid lipid nanoparticles, liposomes, micelles, polymeric nanoparticles, nanostructured lipid carriers, nanosuspensions, and nanoemulsions, among others. These formulations of naringenin nanomedicine have been used for the potential treatment of a series of CNS disorders. Based on various research reports, it can be said that with the right nanocarriers, naringenin proves to be a promising therapeutic alternative for the treatment of several CNS ailments, including neurological diseases, Alzheimer's, Parkinson's disease, cerebral ischemia, etc. Therefore, the present manuscript highlights the various aspects of naringenin and its pharmacological activities. Further, naringenin-loaded nanocarriers have been enlisted and discussed in detail.},
}

@article {pmid41486993,
year = {2026},
author = {Cai, M and Yan, S and Sun, Y and Huo, Q and Dai, X},
title = {miRNAs: Promising Biomarkers for Alzheimer's Diagnosis and Treatment.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050427877251118111643},
pmid = {41486993},
issn = {1875-5828},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque deposition, neurofibrillary tangles of hyperphosphorylated tau protein, and chronic neuroinflammation, leading to synaptic dysfunction and cognitive decline. Current diagnostic methods rely on clinical symptoms and limited biomarkers, while available treatments only provide symptomatic relief without halting disease progression. MicroRNAs (miRNAs), small non-coding RNAs of 19-22 nucleotides, have emerged as crucial regulators of gene expression through post-transcriptional mechanisms and show distinct dysregulation patterns in AD patients' blood, cerebrospinal fluid (CSF), and brain tissues. Key miRNAs such as miR-132, miR-146a, miR-34a, and miR-125b demonstrate consistent alterations in expression levels, correlating with disease progression and offering potential as non-invasive diagnostic tools. This review comprehensively examines the dual role of miRNAs as diagnostic biomarkers and therapeutic targets for AD. We also provide an analysis of specific miRNA signatures in different biofluids (plasma, serum, CSF) and brain regions that correlate with disease stages, highlighting their potential for early and non-invasive diagnosis. Therapeutically, miRNAs modulate multiple AD-related pathways, including neuroinflammation via NF-κB signaling, Aβ production through BACE1 inhibition, and tau phosphorylation via GSK3β regulation. miRNAs also influence synaptic plasticity, mitochondrial function, and autophagy, presenting multifaceted opportunities for intervention. However, challenges, including miRNA heterogeneity, stability, and targeted delivery, remain critical impediments. Advances in nanocarriers, exosomal miRNAs, and viral vectors show promise in overcoming these obstacles, enabling precise miRNA modulation. In addition, we underscore the need for standardized protocols, further validation in clinical cohorts, and the development of cost-effective detection methods to translate miRNA-based approaches into practical diagnostics and therapies. By integrating miRNA biomarkers with existing diagnostic tools and exploring combinatorial therapeutic strategies, researchers can harness the potential of miRNAs to revolutionize AD intervention, paving the way for early detection and effective treatment of this devastating disease.},
}

@article {pmid41486988,
year = {2026},
author = {Ranjbari, F and Dadkhah, M and Pirdel, Z and Fathi, F},
title = {Margatoxin Peptide: Preparation and the Potential Use for Biological Applications in Cancer and Neurological Disorders.},
journal = {Protein and peptide letters},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298665415268251024053300},
pmid = {41486988},
issn = {1875-5305},
abstract = {Scorpion venom compounds are known to contain nucleotides, polypeptides, mucoproteins, lipids, biogenic amines, and other unidentified macromolecules. Several peptides in scorpion fluids have demonstrated a wide range of biological activities with strong specificity for their targeted sites. Margatoxin, isolated from the venom of the scorpion, exhibits desirable properties, including high selectivity, good permeability, and stability in cancer cells, which can be achieved at picomolar doses, thereby blocking voltage-gated K+ channels. This narrative review consolidates results from an extensive literature search conducted in major electronic databases up to September 2024. Important studies were identified using keywords associated with scorpion venom peptides, Kv1.3 channels, cancer treatment, and neurodegenerative disorders. The amino acids that make up Margatoxin have an effective molecular function in blocking voltage-gated K+ channels 1.3. Due to the abnormally high expression of voltage-gated K[7] channel 1.3 in various types of cancers, blockers of this channel can inhibit apoptosis, metabolic changes, tumor angiogenesis, invasion, and migration. On the other hand, these channel blockers have emerged as a promising therapeutic approach for neurological disorders, such as Alzheimer's and Parkinson's diseases. The strong efficacy and targeted action of margatoxin further position it as a promising drug candidate. As the number of individuals affected by cancer and neurological conditions continues to rise, research into scorpion venom peptides like margatoxin may lead to innovative therapeutic options for future treatments.},
}

@article {pmid41486697,
year = {2026},
author = {Pan, H and Cheng, X and Zhang, J and Hou, K and Murray, KA and Manglani, K and Zhu, C and Hsu, HK and Mekkittikul, M and Halladay, T and Mirbaha, H and Elezi, G and Abskharon, R and Sawaya, MR and Bombino, A and Williams, CK and DeTure, M and Dickson, DW and Vinters, HV and Whitelegge, JP and Harran, PG and Cole, GM and Frautschy, SA and Eisenberg, DS},
title = {In Vitro and In Vivo Evaluation of Small-Molecule Disassemblers of Pathological Tau Fibrils.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00940},
pmid = {41486697},
issn = {1948-7193},
abstract = {Aggregation of the microtubule-binding protein tau is the histopathological hallmark of Alzheimer's disease (AD) and other neurodegenerative diseases, which are collectively known as tauopathies. Tau aggregation in AD patients is correlated with neuron loss, brain atrophy, and cognitive decline, and pro-aggregation tau mutations are sufficient to cause neurodegeneration and dementia in humans and tauopathy model mice. Thus, reversing tau aggregation is a potential therapeutic avenue for AD. In a previous study, we discovered CNS-11, a small molecule that disaggregates AD patient brain-extracted tau fibrils in vitro. In this study, we identify two chemical analogs of CNS-11, named CNS-11D and CNS-11G, that disaggregate AD patient brain-extracted tau fibrils and prevent seeding in a tau aggregation cell culture model. We also demonstrate that 8 weeks of treatment with either CNS-11D or CNS-11G reduces levels of insoluble tau in a mouse model of tauopathy. Our work defines the properties of two small molecules that diminish aggregation of tau in vivo and provides further support for structure-based methods to target tau for treatment of AD.},
}

@article {pmid41486173,
year = {2026},
author = {Silva-Llanes, I and Smith, LA and Abdelkader-Guillén, A and Jiménez-Villegas, J and Sarrió, D and Moreno-Bueno, G and Lastres-Becker, I},
title = {GASDERMIN D-mediated pyroptosis as a therapeutic target in TAU-dependent frontotemporal dementia mouse model.},
journal = {Journal of biomedical science},
volume = {33},
number = {1},
pages = {6},
pmid = {41486173},
issn = {1423-0127},
support = {PID2022-136854OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; PID2022-137065OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; CB16/12/00295//Centro de Investigación Biomédica en Red de Cáncer/ ; CB06/05/0089//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; },
mesh = {Animals ; *Pyroptosis/genetics ; Mice ; *tau Proteins/metabolism/genetics ; Disease Models, Animal ; Humans ; *Phosphate-Binding Proteins/metabolism/genetics ; Mice, Transgenic ; *Intracellular Signaling Peptides and Proteins/metabolism/genetics ; *Frontotemporal Dementia/genetics/metabolism/drug therapy/pathology ; Male ; Female ; Alzheimer Disease/genetics ; Mice, Inbred C57BL ; Aged ; Hippocampus/metabolism ; Gasdermins ; },
abstract = {BACKGROUND: Recent research has revealed a strong connection between neuroinflammation and TAU protein-related neurodegeneration. A key discovery shows that the NLRP3 inflammasome, when activated, can significantly impact TAU pathology and subsequent neuronal death. This process involves pyroptosis, a lytic form of programmed cell death driven by inflammasome activation, leading to GASDERMIN D (GSDMD) cleavage and the subsequent release of inflammatory molecules IL-1β and IL-18. In this study, we explore the role of pyroptosis and GSDMD in Alzheimer's disease (AD) and tauopathy models, focusing on the TAU-induced neuroinflammatory process and its correlation with synaptic plasticity loss.

METHODS: Hippocampal tissue from AD patients at Braak stage II-III has been analyzed using qPCR to assess pyroptosis-related gene expression. To determine the role of TAU in pyroptosis and neuroinflammation, we used two different models: one based on intracerebral injection of an adeno-associated virus that specifically overexpresses TAU in the neurons of the hippocampus (AAV-TAU[P301L]), and a transgenic mouse model Tg-TAU[P301S] at 8 and 10 months of age. Gene expression, protein levels, and neuroinflammation markers were evaluated using qPCR and immunofluorescence. Additionally, both genetic (GSDMD-deficient mice) and pharmacological (dimethyl fumarate, DMF) interventions targeting pyroptosis have been explored to assess their impact on neuroinflammation and synaptic plasticity.

RESULTS: AD patients exhibited increased expression of pyroptosis-related genes, supporting the involvement of pyroptosis in neurodegeneration. Furthermore, TAU overexpression induced pyroptosis in both mouse models, and GSDMD protein levels increased alongside reactive microglial morphology. Our data supports that TAU-induced neuroinflammation correlated with synaptic plasticity impairment. GSDMD deficiency significantly reduced pyroptosis-related markers associated to TAU, but unexpectedly worsened synaptic plasticity deficits, suggesting GSDMD may play a dual role in inflammation and synaptic function. Finally, we showed that DMF treatment suppressed pyroptosis gene expression, reduced GSDMD levels, and alleviated neuroinflammation, correlating with improved synaptic marker expression.

CONCLUSION: Our findings demonstrate that TAU-induced pyroptosis contributes to neuroinflammation and synaptic dysfunction. While GSDMD inhibition mitigates inflammation, its absence exacerbates synaptic impairment, highlighting its complex role in tauopathies. Our results indicate that DMF treatment could offer a promising therapeutic avenue to modulate pyroptosis and neuroinflammation, and restore synaptic integrity in tauopathies.},
}

Animals
*Pyroptosis/genetics
Mice
*tau Proteins/metabolism/genetics
Disease Models, Animal
Humans
*Phosphate-Binding Proteins/metabolism/genetics
Mice, Transgenic
*Intracellular Signaling Peptides and Proteins/metabolism/genetics
*Frontotemporal Dementia/genetics/metabolism/drug therapy/pathology
Male
Female
Alzheimer Disease/genetics
Mice, Inbred C57BL
Aged
Hippocampus/metabolism
Gasdermins

@article {pmid41485615,
year = {2026},
author = {Pariya Gholizadeh Dangheralou, SK and Khazaeifard, F and Mehr, SR and Mansouri, SM and Rad, NR and Abbasi-Maleki, S},
title = {Evaluation of neurobiochemical and behavioral responses to carvone nanoemulsion: A neuroprotective approach for Alzheimer's disease-associated dementia in a rat model.},
journal = {Brain research},
volume = {},
number = {},
pages = {150143},
doi = {10.1016/j.brainres.2026.150143},
pmid = {41485615},
issn = {1872-6240},
abstract = {BACKGROUND: Antioxidant supplements have emerged as promising strategies to mitigate the impact of Alzheimer's disease (AD) and associated dementia. We explored the neuroprotective potential of Carvone nanoemulsion (CANO) using a rat model of AD-associated dementia.

METHOD: Our experimental groups comprised non-AD control rats (CON), untreated AD rats (AD), and AD rats treated with CANO at two different dosages: 40 mg/kg (CANO40) and 80 mg/kg (CANO80). We assessed various behavioral parameters, malondialdehyde (MDA) and brain-derived neurotrophic factor (BDNF) levels,ferric-reducing ability of plasma (FRAP).

RESULTS: AD induction caused a significant reduction in step-through latency (P < 0.001), center time (P < 0.001), the number of visits (P < 0.001), and total distance traveled (P < 0.001), time spent in open arms (P < 0.001), and both FRAP (P < 0.001) and BDNF levels (P < 0.001) in comparison to the CON group, while elevating escape latency, time in target zone and platform location latency, and MDA levels (P < 0.001). Treatment with CANO, particularly at the CANO80 dosage, significantly improved these parameters compared to the AD group, resulting in decreased time in the target zone (P < 0.001), escape latency (P < 0.001), and platform location latency (P < 0.001) and higher FRAP (P < 0.05) and BDNF levels (P < 0.05), along with decreased MDA levels (P < 0.05).

CONCLUSION: CANO, especially at the 80 mg/kg dosage, shows promise in alleviating symptoms associated with AD-associated dementia. However, further research is warranted to validate and expand upon these findings.},
}

@article {pmid41485573,
year = {2026},
author = {Pi, G and Zhang, L and Lei, H and Zhong, T and Zhang, F and Lu, Y and Qiu, X and Qi, Y and Dong, Y and Zhu, R and Qin, Q and Wang, J and Sarapultsev, A and Luo, S and Cheng, X and Yang, Y and Wang, JZ and Hu, D},
title = {Ursolic acid reduces Aβ-driven aggression via Gab1-mediated autophagy and dorsal hippocampal circuit modulation in Alzheimer's disease.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2025.12.054},
pmid = {41485573},
issn = {2090-1224},
abstract = {INTRODUCTION: Aggression is one of the most debilitating neuropsychiatric symptoms in Alzheimer's disease (AD), posing significant challenges for both patients and caregivers. However, the underlying mechanism remains unclear, and effective therapeutic strategies are lacking.

OBJECTIVES: This study aimed to investigate the neural circuit mechanisms underlying amyloid-beta (Aβ)-driven aggression in AD and explore the therapeutic potential of ursolic acid (UA) in alleviating this behavior.

METHODS: A combination of virus tracing, electrophysiological recording, in vivo Ca2 + recording, and a aggressive behavior test was utilized to investigate the neural circuit vulnerable to Aβ-driven aggression. optogenetic or chemogenetic manipulation was used to identify the regulation of the neural circuit on aggressive behavior. Proteomics and molecular targeting were employed to explore the underlying mechanisms of Aβ-driven aggression and evaluate UA's effects.

RESULTS: We identified that Aβ accumulation drove hyperexcitability of dorsal hippocampal CA3 (dCA3) neurons projecting to the dorsal lateral septum (dLS), thereby triggering aggressive behavior in the 5xFAD mouse model. Optogenetic activation of the dCA3-dLS circuit in wild-type mice induced aggression, whereas either optogenetic or chemogenetic inhibition of this projection alleviated aggression in 5xFAD animals. Proteomic profiling of dCA3 tissue identified Grb2-associated binding protein 1 (Gab1) as a key mediator upregulated in 5xFAD mice and normalized by ursolic acid (UA) treatment. UA reduced Aβ plaque burden, restored autophagic flux (increasing LC3B-II and decreasing p62), and suppressed dCA3-dLS circuit hyperactivity, resulting in durable attenuation of aggressive behavior. Viral knockdown of Gab1 in dCA3 mimicked UA's effects on autophagy, Aβ clearance, circuit excitability, and aggression, whereas Gab1 overexpression blocked UA's benefits.

CONCLUSION: Together, these results define a novel Gab1-dependent autophagy-circuit mechanism for Aβ-induced aggression and establish UA as a promising candidate for alleviating neuropsychiatric symptoms in AD.},
}

@article {pmid41485354,
year = {2025},
author = {Lin, X and Tang, L and Hu, Z},
title = {Causal relationship between tractography-based brain white matter structural connectome and risk of psychiatric disorders: A bidirectional Mendelian randomization study.},
journal = {Psychiatry research. Neuroimaging},
volume = {357},
number = {},
pages = {112131},
doi = {10.1016/j.pscychresns.2025.112131},
pmid = {41485354},
issn = {1872-7506},
abstract = {AIM: This study sought to explore the causal link between 206 tractography-derived white matter connectivity metrics in the brain and the risk of nine psychiatric disorders, employing a bidirectional two-sample Mendelian randomization (MR) approach.

METHOD: Summary datasets of 9 psychiatric disorders including anxiety disorder, Alzheimer's disease (AD), major depressive disorder (MDD), autism spectrum disorder (ASD), bipolar disorder (BD), schizophrenia, Tourette syndrome(TS), attention-deficit hyperactivity disorder (ADHD), and cannabis use disorder (CUD) were used. MR analyses were performed using the inverse variance weighted (IVW), weighted median, MR-Egger, MR-PRESSO, and MR-robust adjusted profile score (MR-RAPS) method.

RESULTS: Forward MR analysis showed that the left-hemisphere dorsal attention network to the right-hemisphere limbic network connectome was causally associated with a 32 % higher risk of anxiety disorder [odds ratio(OR) = 1.32; 95 % confidence interval (CI): 1.16, 1.51). Reverse MR analysis indicated that AD was associated with a 7 % higher risk for the left-hemisphere limbic network to the right-hemisphere control network connectome(OR = 1.07; 95 % CI: 1.03, 1.10).

CONCLUSIONS: Our MR analysis reveals causal relationships between brain white matter structural connectivity and psychiatric disorders, advancing our knowledge of the neural mechanisms that contribute to psychiatric disorders and providing evidence for targeted interventions in psychiatric treatment.},
}

@article {pmid41485137,
year = {2026},
author = {Zhu, Z and Steward, A and Dehsarvi, A and Roemer-Cassiano, SN and Dewenter, A and Biel, D and Hirsch, F and Frontzkowski, L and Pescoller, J and Klonowski, M and Gnörich, J and Pontecorvo, MJ and Shcherbinin, S and Schöll, M and Buckley, R and Ossenkoppele, R and Xie, F and Guo, T and , and Höglinger, G and Brendel, M and Franzmeier, N},
title = {Defining patient-centered amyloid PET thresholds for the onset of tauopathy in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71064},
pmid = {41485137},
issn = {1552-5279},
support = {AARG-22-973496/ALZ/Alzheimer's Association/United States ; //Gerhard and Ilse Schick Foundation/ ; BMBF 01KU2203//ERAPerMed/ ; },
mesh = {Humans ; *Positron-Emission Tomography ; Male ; *Alzheimer Disease/diagnostic imaging/metabolism ; Female ; *Tauopathies/diagnostic imaging/metabolism ; Aged ; tau Proteins/metabolism ; Aged, 80 and over ; *Amyloid/metabolism ; Sex Factors ; Age Factors ; Brain/diagnostic imaging/metabolism ; Carbolines ; },
abstract = {INTRODUCTION: Amyloid-induced tauopathy drives clinical decline in Alzheimer's disease (AD). Because age and sex shape tau trajectories, defining patient-centered amyloid thresholds for tauopathy onset could facilitate pre-tauopathy AD identification and aid treatment decisions and prognosis.

METHODS: By including two samples (Alzheimer's Disease Neuroimaging Initiative [ADNI, n = 301]; and 18F-AV-1451-A05 [A05, n = 143]), we explored whether age and sex affect tauopathy transition and determined patient-centered amyloid positron emission tomography (PET) thresholds that mark tauopathy onset.

RESULTS: We found a consistent amyloid PET × age interaction on global tau PET increase in men (ADNI/A05: p = 0.0078/0.018), with younger men showing faster amyloid-associated tau accumulation. We then established patient-centered, amyloid PET-inferred tauopathy transition cut-offs. Women reached this transition at lower amyloid PET levels, and these cutoffs predicted both earlier onset and accelerated cognitive decline (p < 0.001).

DISCUSSION: This study highlights the effect of age and sex on the amyloid-to-tauopathy transition, establishes patient-centered amyloid PET thresholds for tauopathy onset, and links these thresholds to accelerated cognitive decline.

HIGHLIGHTS: Younger age is related to faster amyloid-related tau accumulation in men. We defined a series of amyloid positron emission tomography (PET) thresholds to enable patient-centered inference of amyloid-related tauopathy. Crossing the amyloid PET-defined tauopathy phase is associated with more progressive tau deposition and cognitive decline.},
}

Humans
*Positron-Emission Tomography
Male
*Alzheimer Disease/diagnostic imaging/metabolism
Female
*Tauopathies/diagnostic imaging/metabolism
Aged
tau Proteins/metabolism
Aged, 80 and over
*Amyloid/metabolism
Sex Factors
Age Factors
Brain/diagnostic imaging/metabolism
Carbolines

@article {pmid41484932,
year = {2026},
author = {Nitzan, K and Bentulila, Z and Bregman-Yemini, N and Ayalon, N and David, D and Break, E and Sarne, Y and Doron, R},
title = {Sex-dependent effects of ultra-low-dose-THC preventive treatment on neuroinflammation and cognitive decline in 5xFAD mice.},
journal = {Biology of sex differences},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13293-025-00815-3},
pmid = {41484932},
issn = {2042-6410},
support = {3-2021-2022b//National Institute for Psychobiology in Israel, Hebrew University of Jerusalem/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) remains the most prevalent cause of dementia, yet no existing treatment effectively prevents its onset. Current therapies primarily aim to slow disease progression or manage symptoms, leaving a critical gap in preventive strategies. Recent findings suggest that ultra-low-dose tetrahydrocannabinol (ULD-THC) may exert neuroprotective effects without the adverse consequences associated with chronic THC use. This study investigates whether preventive ULD-THC treatment can mitigate neuroinflammation and early cognitive decline in the 5xFAD mouse model of AD, with a specific focus on sex differences in treatment response.

METHODS: Male and female 5xFAD mice received monthly ULD-THC injections from 3 to 5 months of age, before significant pathology emerged. At 6 months, behavioral assessments were conducted, followed by molecular analyses of hippocampal and prefrontal cortex (PFC) tissue.

RESULTS: Results indicated that ULD-THC attuned AD-related cognitive decline in both males and females, with sex-specific neuroinflammatory responses. Males exhibited reduced hippocampal inflammation, whereas females showed reduced inflammation in the PFC, suggesting distinct neuroprotective mechanisms across sexes.

CONCLUSIONS: These findings highlight ULD-THC's potential as a preventive strategy for AD, emphasizing the importance of sex-dependent therapeutic approaches. By attenuating neuroinflammatory processes before cognitive deficits fully manifest, ULD-THC offers a novel, biologically targeted approach to AD prevention. Future research should explore its long-term efficacy and translational potential in clinical settings.},
}

@article {pmid41484644,
year = {2026},
author = {Kim, T and Hong, YJ and Kim, M and Bae, Y and Lee, SB and Kim, SH and Lee, MA and Ko, E and Park, JW and Yang, DW},
title = {Impact of dose and compliance of antidementia medications on long-term outcomes in Alzheimer's disease: a nationwide real-world study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01942-0},
pmid = {41484644},
issn = {1758-9193},
abstract = {BACKGROUND: Antidementia medications are widely prescribed for Alzheimer's disease (AD), but their long-term real-world effectiveness remains uncertain. This study investigated whether long-term outcomes differ according to medication dosage and compliance using nationwide data.

METHODS: Data from the Korean National Health Insurance Service (NHIS) covering 47 million individuals were analyzed. Prescription data for acetylcholinesterase inhibitors and memantine were analyzed for dosage and compliance. Among 1,704,547 dementia cases (2010-2016), 466,773 patients with clinically diagnosed AD were included. Medication dosage and compliance during the first three years after diagnosis were categorized to define optimal versus suboptimal treatment. Clinical outcomes included progression to moderate to severe dementia, institutionalization, and mortality. Multivariable logistic regression identified factors associated with outcomes.

RESULTS: Patients who maintained optimal dosage and compliance during the first three years after diagnosis showed a lower rate of progression to moderate to severe dementia than those receiving suboptimal treatments consistently across all classification criteria. Regression analyses revealed that optimal compliance and dosage were strongly associated with reduced progression (OR 0.807 and 0.704, respectively; p < 0.0001) and early mortality within five years. In contrast, mortality and institutionalization rates were not significantly different between groups except that mortality within five years.

CONCLUSIONS: Both medication dosage and persistence were independently associated with better long-term outcomes in AD. Maintaining optimal treatment during the early disease period may delay disease progression and improve survival within five years. This nationwide real-world study provides robust evidence supporting the importance of sustained, adequate antidementia therapy in clinical practice.},
}

@article {pmid41484454,
year = {2026},
author = {Ibrahim, M and Khalil, AM and Attia, H and Alseekh, S and Mohamed, AF and El-Yamany, MF},
title = {Gut Microbiome-Sphingolipid Metabolism-Brain Axis Interactions: Neuroprotective Effects of Amitriptyline as Functional Inhibitor of Acid Sphingomyelinase in a Mouse Model of Tauopathy.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {3},
pmid = {41484454},
issn = {1557-1904},
mesh = {Animals ; *Sphingomyelin Phosphodiesterase/antagonists & inhibitors/metabolism ; *Gastrointestinal Microbiome/drug effects/physiology ; Mice ; *Amitriptyline/pharmacology/therapeutic use ; Mice, Transgenic ; *Tauopathies/metabolism/drug therapy ; *Brain/drug effects/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Sphingolipids/metabolism ; Disease Models, Animal ; Male ; Mice, Inbred C57BL ; },
abstract = {Tauopathies are neurodegenerative diseases characterized by accumulation of hyperphosphorylated tau protein (P-tau). The gut microbiota (GM) is symbiotic with the host and altered in neurodegenerative diseases. Amitriptyline (AMI) is a functional inhibitor of acid sphingomyelinase (ASM) which is abnormally highly expressed in brains of Alzheimer patients. Little data is known about the role of colonic ASM in management of tauopathy. Therefore, the aim of this study was to investigate the role of AMI on reversing gut dysbiosis, ceramide levels, colonic inflammation and intestinal barrier disruption in tauopathy through the bidirectional gut-brain axis. P301S transgenic mice were administered AMI for 35 days. Colonic ASM, ceramides, inflammation and membrane integrity were assessed besides fecal microbiome analysis and serum lipopolysaccharides to assess intestinal membrane disruption. Levels of hippocampal P-tau, protein phosphatase 2 A and neurogenesis were assessed along with cognitive behavior. AMI treatment significantly reduced colonic ASM, ceramide levels, increased abundance of Harryflintia, Dubosiella, and Parasutterella and decreased abundance of Lactobacillus, Lachnoclostridium, Oscillibacter, Oscillospiracea UCG-003, Colidextribacter, Roseburia, Butyricicoccus, and Sphingomondales. In contrast, P301S mice displayed an altered GM profile with enriched Firmicutes and Clostridia, and low proportions of Bacteroidota- a phylum associated with intestinal barrier protection-, and Ruminococcaceae. Also, AMI treatment decreased inflammation and restored colonic membrane integrity with subsequent decrease in serum lipopolysaccharides, P-tau in hippocampus and improvement in cognitive behaviour and neurogenesis. The current results indicate that AMI has neuroprotective effects against tauopathy through modulation of ASM activity, associated ceramide levels, GM composition, colonic inflammation and membrane integrity through bidirectional gut-brain axis.},
}

Animals
*Sphingomyelin Phosphodiesterase/antagonists & inhibitors/metabolism
*Gastrointestinal Microbiome/drug effects/physiology
Mice
*Amitriptyline/pharmacology/therapeutic use
Mice, Transgenic
*Tauopathies/metabolism/drug therapy
*Brain/drug effects/metabolism
*Neuroprotective Agents/pharmacology/therapeutic use
*Sphingolipids/metabolism
Disease Models, Animal
Male
Mice, Inbred C57BL

@article {pmid41484306,
year = {2026},
author = {Huang, H and Wu, J and Fang, Z and Wang, Y and Xie, J and Guan, Y},
title = {Recent Advances of the Role of Dl-3-n-Butylphthalide in the Treatment of Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {340},
pmid = {41484306},
issn = {1559-1182},
support = {202510159035//Innovation and Entrepreneurship Training Program for China Medical University Students/ ; },
mesh = {Humans ; *Benzofurans/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; Oxidative Stress/drug effects ; },
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder affecting approximately 55.2 million individuals globally, with complex pathogenesis involving amyloid-β (Aβ) aggregation, tau pathology, neuroinflammation, oxidative stress, and synaptic dysfunction. Current treatments offer only symptomatic relief without halting disease progression. Dl-3-n-butylphthalide (NBP), a small-molecule compound originally derived from celery seeds, has emerged as a promising multi-target therapeutic candidate for AD. Preclinical studies demonstrate that NBP exerts its therapeutic effects in AD by alleviating oxidative stress, enhancing superoxide dismutase (SOD) and glutathione activities, suppressing neuroinflammation by inhibiting NLRP3 inflammasome activation and pro-inflammatory cytokine release (e.g., IL-1β, TNF-α), reducing Aβ deposition and tau hyperphosphorylation, promoting autophagy, and improving synaptic plasticity. A meta-analysis of six trials (n = 851) confirmed that NBP improves Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores with a favorable safety profile, primarily mild gastrointestinal symptoms and transient liver enzyme elevations. This review systematically summarizes recent advances in NBP research, integrating both preclinical mechanisms and clinical evidence, and highlights its potential as a novel multi-target strategy for AD treatment. Further large-scale, long-term trials are warranted to validate its efficacy and explore optimized delivery systems and combination therapies.},
}

Humans
*Benzofurans/therapeutic use/pharmacology
*Alzheimer Disease/drug therapy/metabolism
Animals
Oxidative Stress/drug effects

@article {pmid41483724,
year = {2025},
author = {Strain, JF and Rahmani, M and Phuah, CL and Dierker, D and Luo, J and Owen, C and Vlassenko, AG and Jafri, H and Bourgeat, P and Fripp, J and Jin, L and Moulder, K and Benzinger, T and Xiong, C and Lee, JM and Weiner, M and Masters, CL and Morris, JC and Womack, K and Goyal, MS and , },
title = {Regional growth rates of white matter hyperintensities are associated with beta-amyloid burden.},
journal = {Neurobiology of aging},
volume = {160},
number = {},
pages = {22-32},
doi = {10.1016/j.neurobiolaging.2025.12.006},
pmid = {41483724},
issn = {1558-1497},
abstract = {There is increasing evidence for an association between white matter hyperintensities (WMH) and brain beta-amyloid deposition. How WMH are longitudinally associated with brain beta-amyloid burden requires further investigation, particularly with respect to co-existent vascular risk factors and differences across white matter regions. We measured WMH on MRI and vascular risk factors in a combined neuroimaging data set of cognitively normal and individuals with dementia comprised of the ADNI, AIBL and OASIS3 studies, which includes harmonized centiloid estimates of beta-amyloid burden from PET imaging. WMH were measured using the TrUE-Net algorithm. Vascular risk factors were extracted from provided clinical data and used to calculate individual revised Framingham Stroke Risk Profile (FSRP) scores. Linear mixed effects modelling was used to determine the relationship between the growth rate of WMH and baseline beta-amyloid burden, controlling for age, sex, APOE4 status, and vascular risk factors. 1243 participants [49 % female, mean age 71.7 y (SD 7.6 y)] had at least 3 brain MRIs. Linear mixed models demonstrate robust independent cross-sectional relationships between WMH and baseline beta-amyloid burden (beta coefficient=0.27, p < 0.001), age (beta coefficient=0.04, p < 0.001) and vascular risk factors (beta coefficient=0.25, p < 0.001). Growth rates of WMH increased with baseline beta-amyloid burden (slope=0.021, p < 0.001) and decreased with anti-hypertensive medications (slope=-0.019, p = 0.002), above and beyond age, APOE4 status, and other vascular risk factors. The longitudinal association for beta-amyloid burden persisted in a similar analysis for parietal WM. Our study suggests that in Alzheimer disease research cohorts, WMH progression is associated with age and beta-amyloid burden, particularly in parietal white matter, and slowed by anti-hypertensive treatment.},
}

@article {pmid41482856,
year = {2026},
author = {Kalita, R and Sarma, A and Baruah, H and Zaman, A and Goswami, D},
title = {Nose to Brain Delivery of Curcumin Loaded Therapeutic Nanostructures for Neurodegenerative Diseases.},
journal = {Biopharmaceutics & drug disposition},
volume = {},
number = {},
pages = {},
doi = {10.1002/bdd.70021},
pmid = {41482856},
issn = {1099-081X},
abstract = {Neurodegenerative diseases are progressive disorders that damage and eventually kill neurons in the central nervous system (CNS). In recent years, various research has been done on reliable and effective treatment methods for the most common neurodegenerative diseases such as Parkinson's, Alzheimer, and Migraine diseases. Different neurodegenerative disorders such as Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic, Lewy body disease can be treated by curcumin, which is a strong antioxidant polyphenol with neuroprotective and anti-amyloid properties. However, Blood-brain barrier (BBB) and blood cerebrospinal fluid barrier restricts the permeation of curcumin to the brain leads poor distribution of the drug in brain tissue. The intranasal pathway holds promise for enhancing the treatment of CNS disorders since it bypasses the BBB and increases the brain bioavailability of drug. As nanotechnology continues to improve, research on the delivery of drug through intranasal route has grown significantly in last 10 years. Several nanocarriers have been developed such as nano-emulsions, microspheres, dendrimers, liposomes, carbon-based nanoformulation, and nanoparticles to deliver curcumin to the brain via intranasal route for the treatment of neurodegenerative diseases. This study provided a thorough analysis of several curcumin nano-formulations used in intranasal pathway as a novel treatment for neurodegenerative diseases.},
}

@article {pmid41482153,
year = {2025},
author = {Yan, Y and Su, J and Xie, M and Kong, Y and Wang, C and Yuan, G and Fang, Y and Hwang, K and Kim, CY and Han, H and Zhang, Z},
title = {Low Intensity Ultrasound-facilitated exosome delivery promotes hippocampal neurogenesis in Alzheimer's disease.},
journal = {Brain stimulation},
volume = {},
number = {},
pages = {103015},
doi = {10.1016/j.brs.2025.103015},
pmid = {41482153},
issn = {1876-4754},
abstract = {BACKGROUND: Low-intensity ultrasound (LIUS) and human adipose-tissue mesenchymal stem cell-derived exosomes (hADSC-Exos) have shown neuroprotective potential, but their combined effects in Alzheimer's disease (AD) remain unclear.

OBJECTIVE: To evaluate the safety and efficacy of intranasal hADSC-Exos alone or combined with LIUS in APP/PS1 mice, and explore underlying molecular mechanisms.

METHODS: Female APP/PS1 mice (30 weeks) were randomized into five groups (n=6). Treatments included intranasal hADSC-Exos, LIUS, or both for 2 months. Behavioral tests, histology, and hippocampal RNA-seq were performed.

RESULTS: LIUS enhanced Exo uptake in HT22 cells by ∼8% without toxicity. Combined treatment improved learning and memory (escape latency ↓45 s→20 s; P<0.01), increased neurogenesis markers (GFAP/SOX2, DCX, Ki67), and reduced amyloid and microglial activation. RNA-seq identified 93 specific DEGs in the combination group, with enrichment in synaptic and mitochondrial pathways. Fos and Kcnj13 were top DEGs and both downregulated after therapy (P<0.05).

CONCLUSIONS: Intranasal hADSC-Exos combined with LIUS is safe, enhances brain delivery, and synergistically improves cognition and neurogenesis in AD mice. The Fos-Kcnj13 axis may mediate these effects, suggesting a promising noninvasive therapeutic strategy.},
}

@article {pmid41482111,
year = {2025},
author = {Zheng, R and Liu, X and Liao, Z and Wan, R and Qiu, G and Li, M and Tang, C and Zhou, R and Song, J},
title = {Electroacupuncture ameliorates tau-driven cognitive decline by modulating NF-κB/NLRP3 inflammasome signaling in P301S mice.},
journal = {Experimental neurology},
volume = {398},
number = {},
pages = {115637},
doi = {10.1016/j.expneurol.2025.115637},
pmid = {41482111},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) progression is driven by a vicious cycle wherein pathological Tau hyperphosphorylation promotes microglial activation and NF-κB/NLRP3 inflammasome signaling, leading to excessive secretion of proinflammatory cytokines that reciprocally exacerbate Tau pathology. While pharmacological NLRP3 inhibitors hold therapeutic potential for AD, critical barriers-including poor blood-brain barrier penetration, suboptimal target selectivity, and safety concerns-persist. This study investigated whether electroacupuncture (EA), a non-pharmacological neuromodulatory approach, could disrupt this Tau-inflammasome cycle. Using P301S Tau transgenic mice, two EA regimens were tested at the GV20 (Baihui) acupoint: 6-month-old mice receiving a 1-month EA intervention, and 6-month-old mice undergoing a prolonged 3-month EA intervention. Cognitive function was evaluated via Y-maze, novel object recognition (NOR), and Morris water maze (MWM) tests, while corticospinal function was assessed using tail-suspension limb-clasping scoring. Hippocampal Tau pathology and inflammatory signaling were analyzed by Western blot and immunohistochemistry, targeting total Tau, phosphorylated Tau, NF-κB, NLRP3, caspase-1, IL-1β, IL-18, TNF-α, and microglial morphology. Short-term (1-month) EA treatment significantly improved spatial working memory and recognition memory. Mechanistically, EA reduced p-Tau levels, suppressed NF-κB activation (decreased p-P65/P65 ratio), downregulated NLRP3 inflammasome components (NLRP3, cleaved caspase-1) and proinflammatory cytokines (IL-1β, IL-18 and TNF-α), and mitigated microglial hyperactivation. Importantly, long-term (3-month) EA treatment persistently suppressed p-Tau accumulation and neuroinflammation, thereby consolidating cognitive benefits even in P301S mice with severe corticospinal dysfunction. These findings establish EA as a multi-targeted immunomodulatory strategy that attenuates Tau-driven neuroinflammation through the TNF-α/NF-κB/NLRP3 signaling axis, highlighting its potential as a safe, non-pharmacological adjunct or alternative therapy for AD and related tauopathies.},
}

@article {pmid41482107,
year = {2025},
author = {Chen, X and Yao, H and Ma, S and Zhu, H and Xu, Y and Zhu, Y and Ying, Y and Wang, L and Zhang, Q and Zheng, C and Zhou, Y and Tong, Z and Huang, K and Shentu, Y},
title = {FGF22/FGFR2/YAP modulates ferroptosis to suppress neurodegeneration and cognitive impairment in Alzheimer's disease.},
journal = {Experimental neurology},
volume = {398},
number = {},
pages = {115630},
doi = {10.1016/j.expneurol.2025.115630},
pmid = {41482107},
issn = {1090-2430},
abstract = {Ferroptosis, a programmed cell death triggered by iron accumulation and lipid peroxidation, has been increasingly recognized as a critical mechanism underlying neurodegenerative processes, including Alzheimer's disease (AD). The mechanosensitive regulator YAP is implicated in AD progression and ferroptosis. Here we confirmed that FGF22, a fibroblast growth factor, amelitorated cognitive deficits in β-Amyloid (1-42) (Aβ1-42) treated AD model mice through the FGFR2/YAP pathway, which was further ascertained by various biochemical analyses. Additionally, FGF22 treatment effectively reduced ferroptosis and neuronal apoptosis, thereby attenuating synaptic impairments and neuronal injury in the AD model mice and Aβ1-42-exposed HT22 cells. Collectively, the data presented herein implicate FGF22 as a potential neuroprotective agent in AD models, with its efficacy likely mediated through engaging of the FGFR2/YAP signaling axis.},
}

@article {pmid41481960,
year = {2026},
author = {Fazal, F and Dar, NJ and Ahamad, S and Khan, S and Bano, N and Saha, S and Nazir, A and Bhat, SA},
title = {cGAS-STING signaling in Alzheimer's disease: Microglial mechanisms and therapeutic opportunities.},
journal = {Molecular aspects of medicine},
volume = {107},
number = {},
pages = {101444},
doi = {10.1016/j.mam.2025.101444},
pmid = {41481960},
issn = {1872-9452},
abstract = {Alzheimer's disease (AD) is increasingly recognized as a neuroinflammatory disorder driven by microglial dysfunction. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway plays a critical role in neuroinflammation and has been strongly implicated in the pathology of AD. Chronic activation of cGAS-STING contributes to neurodegeneration by driving persistent type I interferon release and excessive pro-inflammatory cytokine production. However, the pathway exhibits context-dependent effects. Transient activation promotes antiviral defense, autophagy, and cellular quality control in the central nervous system. Sustained engagement exacerbates neuroinflammation and synaptic loss. Preclinical studies demonstrate that pharmacological inhibitors (such as NR, TSG, H-151, TDI-6750, TDI-8246) mitigate amyloid beta and tau pathology, attenuate microglial reactivity, and enhance cognitive outcomes. Yet, its essential physiological roles, including antimicrobial immunity and autophagy regulation, pose challenges for therapeutic targeting. This potentially disrupts neuroimmune homeostasis. In this review, we highlight the role of cGAS-STING in AD and explore its potential as a therapeutic target using small-molecule drug candidates. Despite these promising findings, challenges remain, including optimizing blood-brain barrier (BBB) penetration, ensuring immune specificity, and addressing long-term safety concerns. Due to these challenges, no cGAS-STING inhibitors have entered clinical trials for AD. However, the future of AD treatment may involve modulation of neuroinflammatory pathways, with cGAS-STING inhibitors playing a central role in reshaping neuroimmune homeostasis.},
}

@article {pmid41481335,
year = {2026},
author = {Noreen, S and Nazir, R and Khan, M and Shah, SA},
title = {Schiff Base Complex rescues mice against scopolamine-induced cognitive dysfunction.},
journal = {Drug and chemical toxicology},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/01480545.2025.2606103},
pmid = {41481335},
issn = {1525-6014},
abstract = {Alzheimer's disease (AD) is a common and debilitating neurodegenerative disease characterized by progressive cognitive impairment, and oxidative stress is a recognized contributor. Despite numerous studies, effective treatments remain scarce. This study synthesized and assessed the neuroprotective effects of a Schiff base complex, Copper(II) 4-(benzylideneamino)-3-hydroxynaphthalene-1-sulfonic acid [Cu(BAHN)2], against scopolamine-induced (SCOP) cognitive and synaptic deficits in adult albino mice. Eight-week-old male BALB/c mice were randomly split into 4 groups: (1) controls (normal saline, 0.9%), (2) SCOP (1 mg/kg), (3) SCOP and Schiff base complex (30 mg/kg) and (4) Schiff base complex alone (30 mg/kg). Cognitive function was assessed using the Morris Water Maze (MWM) and Y-maze test. To assess the biochemical effects of the complex, antioxidant enzyme activities, and western blot analyses were performed. Treatment with the Schiff base complex significantly restored the activity of important antioxidant enzymes-catalase (CAT), peroxidase (POD), superoxide dismutase (SOD) and reduced glutathione (GSH) which were decreased by SCOP exposure. In addition, lipid peroxidation (LPO) rates were decreased. The complex also counteracted SCOP-induced decreases in both pre- and post-synaptic proteins, in line with improved behavioral performance in both cognitive challenges. Mechanistically, the compound activated phosphorylated Akt (p-Akt) and upregulated Nrf2 signaling, as well as downregulating nuclear factor kappa B (NF-kB) and interleukin-1β (IL-1β), show a decrease in neuroinflammation. In summary, these data suggest that the Schiff base complex reduces the oxidative, inflammatory, and synaptic deleterious effects of SCOP, probably, by regulating the p-Akt/Nrf2 pathway. Additional mechanistic studies are needed to understand its potential therapeutic implications in dementia.},
}

@article {pmid41481312,
year = {2026},
author = {Banik, A and Amaradhi, R and Sau, M and Rawat, V and Dingledine, R and Ganesh, T},
title = {Antagonism of the EP2 Receptor Reveals Sex-Specific Protection in a Two-Hit Mouse Model of Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00780},
pmid = {41481312},
issn = {1948-7193},
abstract = {Neuroinflammation is evident in Alzheimer's disease (AD) brains, exacerbating the pathology and ensuing cognitive deficits in patients. The prostaglandin-E2 receptor EP2 emerged as a neuroinflammatory target in several neurodegenerative diseases, including AD. Antagonism of EP2 mitigates neuroinflammation and cognitive deficits in status epilepticus and stroke models. Here, we investigated the efficacy of a potent and selective EP2 antagonist TG11-77.HCl on the cognitive behavior and neuroinflammation in a two-hit 5xFAD mouse model of AD. We exposed adult 5xFAD mice on B6SJL genetic background and their nontransgenic littermates to a low dose of lipopolysaccharide and administered TG11-77.HCl or the vehicle in the drinking water for 12 weeks. Mice were subjected to Morris water maze and Y-maze testing during their last week of drug treatment. Blood samples were subjected to complete blood count (CBC) analysis and brain tissues were processed to examine the levels of inflammatory transcripts and glial marker expression (mRNA), followed by the quantification of congophilic amyloid deposition and microglial activation (IBA[+]) in the brain by immunohistochemistry. TG11-77.HCl treatment enhanced the spatial memory performance and ameliorated mRNA expression of proinflammatory mediators, chemokines, and cytokines in the neocortex of 5xFAD males only and attenuated astroglia and microglia activation in both male and female 5xFAD mice and the congophilic amyloid load in 5xFAD males only. CBC analysis revealed no changes in peripheral inflammation, irrespective of sex, on treatment with TG11-77.HCl. This study reveals sex-specific protection of selective EP2 antagonism in a two-hit mouse model of AD and supports a prudent therapeutic strategy against neuroinflammation and associated cognitive impairment in AD.},
}

@article {pmid41480618,
year = {2025},
author = {Hu, G and Gogzheyan, C and Panja, S and Sil, S and Gendelman, HE},
title = {Extracellular vesicle-based therapies for neurodegenerative diseases.},
journal = {NeuroImmune pharmacology and therapeutics},
volume = {4},
number = {4},
pages = {377-390},
pmid = {41480618},
issn = {2750-6665},
abstract = {Extracellular vesicles (EVs) are mediators of neurodegeneration and emerging therapeutic tools for central nervous system disorders. On the one hand, they help spread beta amyloid, tau, α-synuclein, TDP-43, and mutant SOD1, contributing to the signs and symptoms of Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, and Huntington's Diseases. By activating glial cells, they promote chronic neuroinflammation through carrying cytokines, inflammasomes, and chemokines. On the other hand, EVs' ability to transport neuroregulatory products and cross the blood-brain barrier makes them ideal vehicles for drug delivery. Their function can be surface-modified to deliver targeted therapies, including anti-inflammatory and neuroprotective regulatory RNAs, proteins, and lipids, as well as factors that help maintain neural homeostasis. Notably, we suggest that colostrum-derived EVs, enriched with growth factors and immune-regulatory microRNAs, offer a natural, scalable, and biocompatible source for neuroprotective treatment. Although EVs can act as "Janus-faced" entities - serving both as disease initiators and versatile therapeutic vehicles - controlling their activity can enable immune-based therapeutics for neurodegenerative diseases.},
}

@article {pmid41480410,
year = {2026},
author = {Tang, S and Luo, W and Wu, S and Yuan, M and Wen, J and Zhong, G and Shen, L and Jiang, W and Cheng, C and Wu, X and Xiao, X},
title = {Hippocampus-targeted BDNF gene therapy to rescue cognitive impairments of Alzheimer's disease in multiple mouse models.},
journal = {Genes & diseases},
volume = {13},
number = {2},
pages = {101649},
pmid = {41480410},
issn = {2352-3042},
abstract = {Brain-derived neurotrophic factor (BDNF) can protect neurons from apoptosis and maintain normal synaptic structures, indicating a significant potential for Alzheimer's disease (AD) treatment. However, the method of in vivo BDNF delivery requires further optimization, and the therapeutic efficacy of BDNF in AD animal models needs to be further evaluated. Here, we demonstrated that a newly engineered adeno-associated virus (AAV) serotype termed AAVT42 showed better tropism for neurons than AAV9 in the central nervous system (CNS). We analyzed the therapeutic potentials of AAVT42-delivered BDNF in three AD mouse models: amyloid precursor protein/presenilin-1 (APP/PS1), rTg4510, and 3 × Tg. Long-term BDNF expression in the hippocampus mitigated neuronal degeneration or loss in these AD mice, and alleviated their cognitive impairment, with no discernible effect on amyloid-β deposition or tau phosphorylation. Furthermore, transcriptomic analysis in 3 × Tg mice revealed that BDNF orchestrated the up-regulation of genes associated with neuronal structural organization and synaptic transmissions, such as Neuropeptide Y (Npy), Corticotropin-releasing hormone (Crh), Tachykinin precursor 1 (Tac1), and the down-regulation of Bone morphogenetic proteins (Bmps). Our study highlighted the efficacy of AAVT42 in gene delivery to CNS and validated the therapeutic benefits of BDNF in treating AD, which will be useful for future translational research on AD treatment using an AAV delivery system.},
}

@article {pmid41479956,
year = {2025},
author = {Massara, M and Vedovelli, L and Masina, F and M J Edelstyn, N and Silvia Bisiacchi, P and Di Rosa, E},
title = {From cigarettes to compulsions: a longitudinal study in de novo Parkinson's disease.},
journal = {Frontiers in psychology},
volume = {16},
number = {},
pages = {1708535},
pmid = {41479956},
issn = {1664-1078},
abstract = {INTRODUCTION: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. Among the environmental and lifestyle factors associated with disease onset, cigarette smoking represents one of the most paradoxical. While substantial evidence has demonstrated a protective effect of smoking against the development of PD, smoking appears to worsen symptomatology, particularly by exacerbating impulsive-compulsive behaviors (ICBs) in people with PD (PwPD). However, longitudinal studies examining the effects of cigarette smoking on the progression of PD remain limited. Moreover, recent studies often involve mixed samples of treated and untreated PwPD, potentially confounding the impact of dopamine replacement therapy with that of smoking on ICBs.

METHODS: In the present study, we investigated a cohort of de novo PwPD, tracking their motor, cognitive, affective, and behavioral outcomes over 5 years, to better clarify the role of smoking in disease progression. Data were obtained from the Parkinson's Progression Markers Initiative and included 166 PwPD (119 non-smokers and 47 former smokers) and 79 healthy controls (48 non-smokers and 31 former smokers).

RESULTS: Our results revealed that a significantly higher percentage of former-smoker PwPD (28%) exhibited at least one ICB compared to non-smoker PwPD (13%; Pearson's [2](1) = 5.45, p = 0.02). No other significant differences between non-smokers and former smokers emerged in motor or non-motor symptoms, either in PwPD or in healthy individuals.

DISCUSSION: In conclusion, the novelty of our findings lies in showing that smoking-related influences on impulsive-compulsive behaviors in PD are most evident at the de novo stage, before any dopaminergic treatment. This temporal specificity may help resolve previous inconsistencies in the literature and underscores the importance of distinguishing between environmental and pharmacological effects on symptom development.},
}

@article {pmid41478829,
year = {2026},
author = {Meade, J and Mesa, H and Alamgir, S and Bieniecka, I and Liu, L and Zhang, Q},
title = {Synaptic toxicity of OGA inhibitors and the failure of ceperognastat.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100456},
doi = {10.1016/j.tjpad.2025.100456},
pmid = {41478829},
issn = {2426-0266},
abstract = {O-GlcNAcase inhibitors (OGAi) have emerged as a promising therapeutic strategy in Alzheimer's disease (AD) by enhancing O-GlcNAcylation, which competes with tau phosphorylation and reduces tau aggregation. However, the Phase II clinical trial failure of ceperognastat, marked by accelerated cognitive decline in the treatment group, has raised significant safety concerns. Here, we examined the acute synaptic effects of three structurally distinct OGAi compounds-ceperognastat, ASN90, and MK8719-in mouse hippocampal slices. Electrophysiological recordings revealed suppression of both short- and long-term synaptic plasticity, including paired-pulse facilitation/depression and long-term potentiation. Immunohistochemical analysis confirmed disrupted synaptic protein levels (increased PSD-95, reduced Synaptophysin 1) and a biphasic shift in tau phosphorylation. These convergent findings suggest a class-wide synaptotoxic mechanism and call for a great caution in the development of disease-modifying therapies in AD. We argue that preclinical drug screening for synaptic functionality is essential in CNS-targeted therapeutic pipelines.},
}

@article {pmid41478820,
year = {2026},
author = {Wang, P and Wu, X and Sun, F and Zhang, H and Jiang, Y and Wang, Q and Ding, H and Zhou, Y and Liu, F and Liu, H},
title = {Multi-omics integration reveals shared genetic architecture between metabolic markers and gray matter atrophy in Alzheimer's Disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100452},
doi = {10.1016/j.tjpad.2025.100452},
pmid = {41478820},
issn = {2426-0266},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by widespread gray matter volume (GMV) reductions. Emerging evidence links glucose and lipid metabolic dysregulation to AD pathophysiology. However, the extent to which AD-related GMV alterations and metabolic traits share a common genetic basis remains poorly understood.

OBJECTIVES: To explore the shared genetic architecture between GMV alterations in AD and metabolites related to glucose and lipid metabolism, aiming to provide biological insights into the prevention and treatment of AD.

DESIGN: This is a multimodal, cross-disciplinary study combining neuroimaging meta-analysis, transcriptome-neuroimaging association analysis, conjunctional false discovery rate (conjFDR) analysis, and functional enrichment analysis to identify the shared genetic architecture between AD-related brain structural alterations and metabolic traits.

SETTING: Public databases and European populations.

PARTICIPANTS: The meta-analysis included 49 studies (1945 CE patients and 2598 controls). The largest genome-wide association study (GWAS) summary statistics were used for AD (Ncase = 39,918; Ncontrol =358,140), two glycemic traits-glucose (GLU, N = 459,772) and glycated hemoglobin (HbA1c, N = 146,864), and three lipid traits (N = 1320,016)-high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG).

MEASUREMENTS: We conducted a voxel-based morphometric meta-analysis of GMV in AD by systematically reviewing 49 neuroimaging studies, identified through a literature search in PubMed and Web of Science using a predefined search strategy. Building upon these neuroanatomical findings, we performed a transcriptome-neuroimaging association analysis using data from the Allen Human Brain Atlas to identify genes spatially correlated with GMV alterations. To further explore the shared genetic architecture, we integrated GWAS summary statistics for AD and five metabolic markers using conjFDR analysis. Finally, functional enrichment analyses were performed to elucidate the biological relevance of the identified genes through this integrative framework.

RESULTS: Consistent GMV reductions in AD were observed in the bilateral middle temporal gyrus, right superior temporal gyrus, and other key subcortical regions. The conjFDR analysis identified 20, 17, 78, 87, and 82 genes shared between AD-related GMV reductions and GLU, HbA1c, HDL-C, LDL-C, and TG, respectively. Notably, 6 genes were shared across all five metabolic markers. Enrichment analysis implicated these genes in biological processes related to Aβ aggregation and phosphatidylinositol metabolism.

CONCLUSIONS: This study reveals a convergent genetic architecture underlying AD-related GMV atrophy and metabolic dysfunction. These findings may offer novel insights into the molecular interplay between systemic metabolism and neurodegeneration in AD and highlight potential targets for therapeutic strategies.},
}

@article {pmid41478818,
year = {2026},
author = {Mummery, CJ and Li-Hsian, CC and Lasagna-Reeves, CA and Ossenkoppele, R and Rowe, CC and Scharre, DW and Wang, H and Kyaga, S and Cummings, JL},
title = {Tau in Alzheimer's disease: Shaping the future patient journey.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100447},
doi = {10.1016/j.tjpad.2025.100447},
pmid = {41478818},
issn = {2426-0266},
abstract = {Alzheimer's disease is a complex and multifactorial disease characterized by two key pathological hallmarks: amyloid-beta plaques and tau neurofibrillary tangles. Recent progress has led to the development and approval of disease-targeted therapies for Alzheimer's disease in the form of anti-amyloid-beta monoclonal antibodies. However, findings suggest that amelioration of multiple pathological drivers may be required to maximize clinical effect. An increasing body of evidence suggests that tau is a critical player in Alzheimer's disease pathophysiology, contributing significantly to neurodegeneration and cognitive decline. There are now several tau-targeting drugs in clinical development. In this review, we build on research and advancements in the field of tau to envision how an increasing focus on tau could shape the future Alzheimer's disease patient journey. We highlight the potential of tau as both a promising therapeutic target and a valuable biomarker, with the potential to inform treatment decisions and provide insight into disease trajectories. We also consider what a greater focus on tau may bring to an already evolving patient care pathway characterized by an increased influx of patients presenting earlier in the disease continuum, changes in workflow and infrastructural requirements, and increased complexity in treatment decision-making, treatment administration, treatment monitoring, and patient tracking. This review underscores the critical changes that may be required and knowledge gaps to be elucidated to ensure healthcare system preparedness for additional classes of disease-targeted therapy to move toward a next-generation, individualized treatment approach to Alzheimer's disease diagnosis and care.},
}

@article {pmid41478817,
year = {2026},
author = {Qi, L and Zheng, F and Tu, M and Abdullah, R and Zhao, Y and Su, X and Zhou, D and Peng, G},
title = {Safety profiles of lecanemab: A systematic review and meta-analysis of randomized controlled trials and real-world evidence.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100473},
doi = {10.1016/j.tjpad.2025.100473},
pmid = {41478817},
issn = {2426-0266},
abstract = {BACKGROUND: Safety profiles of lecanemab, an anti-amyloid-β antibody for the treatment of early Alzheimer's disease (AD), remain uncertain and may vary between randomized controlled trials (RCTs) and real-world evidence (RWE) studies.

OBJECTIVES: This systematic review and meta-analysis aimed to evaluate the safety, tolerability, and acceptability of lecanemab based on findings from both RCTs and emerging RWE studies.

METHODS: We systematically searched major databases and clinical trial registries from their inception to June 2025. Random-effects meta-analyses were performed to estimate the pooled incidence of key safety outcomes, including amyloid-related imaging abnormalities (ARIA), infusion-related reactions (IRRs), and treatment discontinuation (due to ARIA, adverse events [AEs], or any cause). The risk of ARIA according to the ApoE4 genotype was assessed via relative risk (RR). This study was registered with PROSPERO (No. CRD420251110679).

RESULTS: A total of two RCTs and five RWE studies encompassing 1576 patients were included. The pooled ARIA incidence was 19% (95% CI: 16%-23%), which was significantly modulated by ApoE4 status (RR 1.45 for heterozygotes, 3.54 for homozygotes vs noncarriers) and the pooled symptomatic ARIA incidence was 3% (95% CI: 2%-4%). IRRs occurred in 26% (95% CI: 19%-34%), with heterogeneity reduced in patients receiving specific pre-infusion prophylaxis. The pooled rate of discontinuation due to AEs was 8% (95% CI: 5%-11%), with discontinuation due to ARIA occurring in 5% (95% CI: 3%-7%) of patients in RWE studies.

CONCLUSIONS: Lecanemab-related ARIA demonstrates a clear ApoE4 gene-dose effect, supporting routine ApoE4 genotyping before treatment. Standardizing pre-infusion prophylaxis may reduce variability in IRRs incidence, while prompt recognition and management of ARIA are critical for improving treatment tolerability. These findings provide important evidence to support the safe clinical use of lecanemab.},
}

@article {pmid41478541,
year = {2025},
author = {Zafar, I and Khan, MS and Jamal, A and Shafiq, S and Bahwerth, FS and Khan, NU},
title = {Precision therapeutic strategies for Alzheimer's disease: Amyloid β-targeted foundations and multimodal next-generation approaches.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104070},
doi = {10.1016/j.mcn.2025.104070},
pmid = {41478541},
issn = {1095-9327},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia and a significant unmet medical challenge, pathologically characterized by amyloid β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction, and chronic neuroinflammation. Although Aβ has long been a central therapeutic target, clinical translation has historically been hindered by late-stage intervention, inadequate blood-brain barrier (BBB) penetration, and the molecular heterogeneity of AD. Recent advances with Aβ-targeted monoclonal antibodies, particularly lecanemab and donanemab, have provided the first clinical evidence of disease modification, demonstrating robust amyloid clearance and measurable slowing of cognitive decline in early-stage AD. These results validate the Aβ hypothesis but also highlight persistent barriers, including amyloid-related imaging abnormalities (ARIA), questions about the durability of benefit, challenges in patient stratification, and the high economic burden of biologics. To overcome these limitations, next-generation strategies are emerging that extend beyond single-pathway targeting toward multimodal and precision-based frameworks. Innovative approaches include tau-directed therapies to prevent the propagation of neurofibrillary tangles, immunomodulatory strategies to enhance microglial clearance of aggregated proteins, and neuroprotective interventions to counteract oxidative and inflammatory stress. Concurrently, nanotechnology-based drug delivery systems are being engineered to efficiently traverse the BBB and deliver multifunctional payloads, while artificial intelligence (AI)- driven discovery platforms are accelerating target identification, biomarker integration, and patient stratification. Future perspectives emphasize the importance of preclinical-stage intervention, long-term efficacy trials, and the adoption of personalised treatment paradigms that integrate genomic, biomarker, and digital profiling to optimise outcomes. Collectively, these advances signal a paradigm shift in AD therapeutics, positioning Aβ-targeted therapies as a foundation while paving the way for combination strategies that more effectively address the disease's multifactorial nature.},
}

@article {pmid41478465,
year = {2025},
author = {Bandarupalli, T and Noonan, C and Hansen, K and Weaver, R and Baumann, K and Banks, WA and Erickson, MA and Rhea, EM},
title = {Acute peripheral versus central inhibition of insulin receptors differentially alters cytokine and blood-brain barrier responses to an inflammatory stimulus.},
journal = {Brain, behavior, and immunity},
volume = {133},
number = {},
pages = {106251},
doi = {10.1016/j.bbi.2025.106251},
pmid = {41478465},
issn = {1090-2139},
abstract = {The blood-brain barrier (BBB)'s role in protecting the brain from exposure to harmful circulating factors has led to its disruption being implicated in neurodegenerative diseases such as vascular dementia and Alzheimer's disease. Insulin resistance, defined by an impaired response to insulin, is a common feature of metabolic disorders and neurodegenerative diseases. Importantly, individuals can possess peripheral insulin resistance independent of central insulin resistance and vice versa. States of insulin resistance, like diabetes mellitus for peripheral insulin resistance and Alzheimer's disease for central insulin resistance, are associated with inflammation and BBB disruption. However, the contributions of acute impairment of insulin receptor signaling solely in the periphery versus the brain to inflammation and BBB disruption are not clear. As central vs peripheral insulin resistance could have different effects on inflammation, we characterized the effects of acute central versus peripheral insulin receptor inhibition with or without an inflammatory insult, using lipopolysaccharide (LPS) as a prototypic immune stimulus. Male CD-1 mice were treated with an insulin receptor antagonist (S961), peripherally (intraperitoneal) or centrally (intranasal). This treatment was then followed by an intraperitoneal administration of either saline or LPS 30 min later, at a single 3 mg/kg dose known to cause inflammation and BBB disruption. Assays of BBB disruption and brain and serum collection were done 28 h after the injections. Metabolic hormones, cytokines, and the acute phase protein serum amyloid a (SAA) were then measured in serum and brain homogenates. In the absence of LPS, central S961 reduced serum hormones including ghrelin, gastric inhibitory peptide (GIP), and glucagon. Peripheral S961 significantly increased many cytokines in both brain and blood, whereas central S961 decreased serum SAA and increased a few cytokines. BBB integrity was not affected by S961 alone, but central S961 decreased LPS-induced BBB disruption and also lowered serum levels of SAA. These findings highlight the differential effects of peripheral versus central insulin receptor inhibition on cytokine responses and BBB integrity in the presence and absence of acute inflammation, elucidating differences in the molecular mechanisms for insulin receptor signaling depending on the location of signaling dysfunction. The results suggest a potential neuroprotective role of acute central insulin inhibition during acute inflammation.},
}

@article {pmid41478424,
year = {2025},
author = {Zhang, Y and Chen, L and Jin, J and Xin, Y and Wang, J and Zhang, A},
title = {Therapeutic application of fecal microbiota transplantation for neurological diseases: Exploring novel mechanisms and perspectives.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115631},
doi = {10.1016/j.expneurol.2025.115631},
pmid = {41478424},
issn = {1090-2430},
abstract = {Recently, fecal microbiota transplantation (FMT) has garnered widespread attention as an emerging therapeutic approach in the field of neurological disorders. In this study, we review the research progress of FMT in treating neurological disorders. First, the development, safety, and efficacy of FMT are introduced. Subsequently, the application and potential mechanisms of FMT in neurodegenerative diseases (such as Parkinson's disease and Alzheimer's disease), neurodevelopmental disorders (such as autism spectrum disorder and attention deficit hyperactivity disorder), and other neurological conditions are elaborated in detail. Particularly, we explore the pivotal role of the microbiota-gut-brain axis in FMT for treating neurological disorders, as well as how FMT influences neurological function by regulating the gut microbiota and its metabolites, immune system and inflammatory responses, and neurotransmitters. However, FMT also faces numerous challenges in the treatment of neurological disorders, such as ethical issues, safety concerns, and standardization problems. Therefore, this review also prospects the future development directions of FMT in the treatment of neurological diseases, including personalized therapy and combination therapies. FMT may be a feasible and promising option for treating various neurological disorders, but a comprehensive understanding of its working principles and continuous improvement of its application in clinical practice are still ongoing.},
}

@article {pmid41477991,
year = {2025},
author = {Hu, H and Cheng, Q and Li, D and Li, Y and Li, X and Chen, Y and Guo, Y and Tian, S and Jiang, Y and Chen, Y and Liu, Y and Li, S},
title = {Ponicidin ameliorates Alzheimer's disease through dual inhibition of RIPK1-mediated neuroinflammation and necroptosis.},
journal = {International immunopharmacology},
volume = {171},
number = {},
pages = {116095},
doi = {10.1016/j.intimp.2025.116095},
pmid = {41477991},
issn = {1878-1705},
abstract = {Ponicidin (Pon), a diterpenoid isolated from Rabdosia rubescens, exhibits a broad range of pharmacological activities, including anti-inflammatory effects. However, its therapeutic potential in Alzheimer's disease (AD), particularly in modulating receptor-interacting protein kinase 1 (RIPK1)-mediated neuroinflammation and necroptosis, remains underexplored. This study aims to investigate the mechanism through which Pon targets RIPK1 to alleviate AD pathogenesis. The interaction between Pon and RIPK1 was confirmed using bio-layer interferometry (BLI) and drug affinity responsive target stability (DARTS) assays. In vitro, the effects of Pon on inflammatory responses and necroptosis were evaluated in BV2 microglial cells (BV2 cells) and HT22 hippocampal neuronal cells (HT22 cells) using Enzyme-linked immunosorbent assay (ELISA), Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), Western blotting (WB), and flow cytometry. In vivo, Pon's therapeutic efficacy was assessed in the 5 × FAD transgenic mouse model of AD through behavioral tests, histological analysis, and biochemical assays. Pon was found to bind RIPK1 with high affinity (KD = 135 nM) and enhance RIPK1's resistance to proteolytic degradation. In microglial cells, Pon effectively inhibited the release of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) by disrupting the RIPK1-janus kinase 1 (JAK1)-signal transducer and activator of transcription 1 (STAT1) signaling pathway. In neurons, Pon suppressed RIPK1-mediated necroptosis by blocking the RIPK1-RIPK3-mixed lineage kinase domain-like protein (MLKL) cascade. Behavioral analysis of 5 × FAD mice revealed that Pon treatment significantly improved cognitive function, reduced amyloid-beta (Aβ) plaque deposition, and alleviated neuroinflammation and necroptosis in the brain. Pon exerts dual neuroprotective effects by targeting RIPK1, mitigating both neuroinflammation and necroptosis, two critical pathological processes in AD. These findings underscore Pon's potential as a disease-modifying therapy for AD and provide a foundation for the clinical development of natural product-derived RIPK1 inhibitors in neurodegenerative diseases.},
}

@article {pmid41477911,
year = {2026},
author = {Yu, W and Zhuang, D and Wang, K and Qu, Y},
title = {JWX-A1223 attenuates cognitive deficits and tau protein hyperphosphorylation via the Akt/GSK3β pathway in APP/PS1 mice.},
journal = {Archives of physiology and biochemistry},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/13813455.2025.2610481},
pmid = {41477911},
issn = {1744-4160},
abstract = {BACKGOUND: Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive decline, affecting memory, thinking, and behaviour. Its neuropathology includes amyloid plaques and neurofibrillary tangles in the brain.

MATERIALS: Amyloid plaques consist of misfolded beta-amyloid protein, while tangles are made of hyperphosphorylated tau protein.

METHOD: After treatment with JWX-A1223, the APP/PS1 mice showed significant cognitive improvement in the Morris water maze test. They had shorter escape latency, reduced swimming distance, and longer stay time in the target quadrant, indicating enhanced spatial learning and memory.

RESULTS: The treatment with JWX-A1223 also significantly reduced the phosphorylation levels of tau protein at Ser202, Ser396 and Ser404 sites in the cerebral cortex and hippocampus of mice, while increasing the phosphorylation levels at Ser473 site of Akt and Ser9 site of GSK3β.

CONSLUSION: It indicates that by regulating the activity of the Akt/GSK3β pathway, it alleviates the excessive phosphorylation of tau protein and thereby improves cognitive impairment.},
}

@article {pmid41477735,
year = {2026},
author = {Tsai, HR and Lin, YJ and Loh, CH and Lee, YC and Huang, HK},
title = {Risk of Alzheimer Disease and Related Dementia after Retinal Vascular Occlusion: A Nationwide Cohort Analysis.},
journal = {Ophthalmology. Retina},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.oret.2025.10.017},
pmid = {41477735},
issn = {2468-6530},
abstract = {PURPOSE: To evaluate the risk of developing Alzheimer disease (AD) and related dementia in patients with newly diagnosed retinal vascular occlusion.

DESIGN: A nationwide population-based cohort study using claims data from Taiwan's National Health Insurance Research Database (NHIRD).

PARTICIPANTS AND CONTROLS: A total of 39 540 individuals with diagnoses of retinal vascular occlusion between 2011 and 2019 in Taiwan and 395 400 age- and sex-matched nonretinal vascular occlusion individuals without prior diagnoses of any dementia.

METHODS: Patients with newly diagnosed retinal vascular occlusion were identified in the NHIRD, and baseline characteristics were collected. The study endpoints, including AD, vascular dementia (VD), and all-cause dementia, were determined by ≥2 separate outpatient diagnoses or a single discharge diagnosis. Inverse probability of treatment weighting (IPTW) was applied to balance baseline covariates and control potential confounders. Cox proportional hazards models were used to estimate the hazard ratio (HR) for each outcome.

MAIN OUTCOME MEASURES: Development of AD, VD, and all-cause dementia.

RESULTS: After IPTW, 38 522 patients with retinal vascular occlusion and 395 740 nonretinal vascular occlusion individuals were included. Patients with retinal vascular occlusion had increased risks of AD (HR, 1.57; 95% confidence interval [CI], 1.39-1.80), VD (HR, 1.76; 95% CI, 1.58-1.95), and all-cause dementia (HR, 1.58; 95% CI, 1.50-1.65). Both retinal artery occlusion and retinal vein occlusion were associated with increased risks of AD (HR, 1.59; 95% CI, 1.14-2.23; and HR, 1.58; 95% CI, 1.39-1.80, respectively), VD (HR, 1.79; 95% CI, 1.32-2.43; and HR, 1.77; 95% CI, 1.59-1.98, respectively), and all-cause dementia (HR, 1.62; 95% CI, 1.42-1.86; and HR, 1.58; 95% CI, 1.52-1.67, respectively).

CONCLUSIONS: Patients with retinal vascular occlusion had moderately increased risks of AD and related dementias. Therefore, monitoring for dementia symptoms in patients with retinal vascular occlusion may facilitate earlier detection and intervention.

FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.},
}

@article {pmid41477525,
year = {2025},
author = {Zheng, M and Hong, X and Liao, P and Huang, H and Zhang, Y and Xu, W and Li, H},
title = {Plant-Derived Exosome-Like Nanoparticles: A Promising Therapeutic for Neurological Disorders and Drug Delivery.},
journal = {International journal of nanomedicine},
volume = {20},
number = {},
pages = {15769-15791},
pmid = {41477525},
issn = {1178-2013},
mesh = {Humans ; *Exosomes/chemistry ; *Nanoparticles/chemistry ; Animals ; *Nervous System Diseases/drug therapy ; Blood-Brain Barrier/metabolism ; *Drug Delivery Systems/methods ; *Plants/chemistry ; },
abstract = {Neurological disorders, including ischemic stroke, Alzheimer's disease, and Parkinson's disease, exhibit high incidence rates and pose significant health challenges. Current pharmacological treatments often fail to adequately address clinical needs due to obstacles such as limited penetration of the blood-brain barrier and suboptimal efficacy. Plant-derived exosome-like nanoparticles (PELNs) have emerged as promising therapeutic agents due to their superior biocompatibility, low toxicity, ability to traverse the blood-brain barrier, and abundance of lipids, microRNAs, and other bioactive compounds. This review provides a comprehensive overview of recent advancements in PELNs preparation technologies, elucidates the mechanisms of action of their principal bioactive components, and explores their therapeutic applications across various neurological disorders, thereby offering a theoretical foundation for the development of related treatment strategies. Nonetheless, researches on PELNs continue to encounter significant challenges. At the production level, there is an absence of standardized isolation protocols, and the yields remain inadequate to satisfy clinical requirements. Clinically, the efficacy in humans has yet to be established, and the available safety data are insufficient. Technically, the lack of standardized storage conditions and the susceptibility of biological stability to external factors further complicate the field. This review delineates these challenges to offer insights for advancing both fundamental research and the clinical translation of PELNs.},
}

Humans
*Exosomes/chemistry
*Nanoparticles/chemistry
Animals
*Nervous System Diseases/drug therapy
Blood-Brain Barrier/metabolism
*Drug Delivery Systems/methods
*Plants/chemistry

@article {pmid41477168,
year = {2025},
author = {Xiao, Y and Li, H and Han, X and Liu, Y and Sun, J and Sun, C and Wang, Y and Ye, T and Cheng, X},
title = {Qi-Fu-Yin ameliorates physiological frailty in male 5xFAD mice through remodeling the gut microbiota and modulating the cerebral cortex metabolism.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1622286},
pmid = {41477168},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease that can only be managed rather than cured, bringing a substantial burden to society. Frailty and cognition are intertwined in a cycle of decline, affecting the prognosis of AD. Qi-Fu-Yin (QFY) is a classic prescription in traditional Chinese medicine for dementia. While most studies have focused on cognitive impairment, research on physiological frailty remains relatively scarce in AD, especially in 5xFAD mice. We aimed to investigate the impacts of QFY on the physiological frailty of male 5xFAD mice.

METHODS: Male 5xFAD mice received QFY, followed by grip strength test, rotarod test, grading score of frailty, lipofuscin staining, SA-β-gal and Aβ co-staining. The metabolite alteration and the intestinal flora composition were analyzed by non-targeted metabolomics and 16S rRNA sequencing. Moreover, Spearman's correlation analysis was used to integrate behavioral results, differentially expressed metabolites, and altered bacterial genera.

RESULTS: We discovered that QFY improved grip strength, riding time, score of frailty, lipofuscin deposition, SA-β-gal, and Aβ in male 5xFAD mice. The results of untargeted metabolomics showed that metabolites such as proline, PS (18:1/18:0), and PFSA-CI were downregulated in the male 5xFAD mice compared with C57BJ/6JXSJL mice, while PE (18:1/18:1) was upregulated. QFY treatment reversed these changes, restoring metabolite levels toward those of C57BJ/6JXSJL mice. Arginine and proline metabolism, alanine, aspartate and glutamate metabolism, and butyrate metabolism were filtered out as the important metabolic pathways between the C57BJ/6JXSJL mice and the male 5xFAD mice, as well as between the 5xFAD mice and the 5xFAD mice with QFY treatment. Moreover, Ruminococcaceae, Subdoligranulum, Bacteroides, Alistipes, Rikenellaceae_RC9_gut_group, and Odoribacter, which were lower in male 5xFAD mice, were improved after QFY intervention.

DISCUSSION: The differential intestinal flora might improve the metabolism of brain tissue as well as muscle strength and coordination through Short-chain fatty acids (SCFAs). The differential metabolites caused by QFY intervention also have an improving effect on physiological frailty. We suggest that QFY exerts protective impacts against the physiological frailty in AD by adjusting the muscle-gut-brain axis.},
}

@article {pmid41477167,
year = {2025},
author = {Garcia, ML and Denton, AR and Jackson, NL and Scofield, MD and McMahon, LL},
title = {Pharmacologically increasing O-GlcNAcylation increases complexity of astrocytes in the dentate gyrus of TgF344-AD rats.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1690410},
pmid = {41477167},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) pathology begins two or three decades prior to the onset of cognitive symptoms and is characterized by amyloid-β (Aβ) and hyperphosphorylated tau (pTau) accumulation, reactive glial cells, increased inflammation, and neuronal degeneration in later stages. Preclinical studies report that increasing the post-translational modification, O-GlcNAcylation, involving the addition of a single N-acetylglucosamine (GlcNAc) moiety to serine or threonine residues, can reduce amyloidogenic processing of amyloid precursor protein (APP) and compete with serine phosphorylation on tau, decreasing hyperphosphorylated tau accumulation. Protein O-GlcNAcylation can have anti-inflammatory effects, suggesting the possibility that increasing O-GlcNAcylation may decrease reactive gliosis and other pathological changes in AD.

METHODS: This study aimed to assess the possible beneficial effects of pharmacologically enhancing O-GlcNAcylation by inhibiting O-GlcNAcase (OGA), the enzyme responsible for the removal of O-GlcNAc moieties, on progressive AD pathology using female TgF344-AD rats. The selective OGA inhibitor thiamet-G [TMG; 10 mg/kg, subcutaneously (s.c.)] was administered three times per week for 3 months starting at 6 months of age, a time point when Aβ pathology is evident in the hippocampus. Western blot analysis was used to measure protein levels of GFAP, Iba-1, and Aβ. Immunohistochemistry and confocal imaging were used to assess Aβ plaques, astrocyte and microglia complexity, and degeneration of tyrosine hydroxylase-positive (TH+) axons.

RESULTS: In TgF344-AD rats, we found significantly increased astrocyte complexity, defined as increased process length and branches, increased numbers of microglia, loss of noradrenergic axons (NA), and significant Aβ plaques compared to WT, confirming previous work by us and others. Notably, pharmacologically increasing O-GlcNAcylation further increased astrocyte complexity in TgF344-AD rats, specifically those located in close proximity to Aβ plaques, while microglia morphology and Aβ staining were unaffected. O-GlcNAcylation was not able to lessen the loss of TH + axons in TgF344-AD rats, although fewer dystrophic axons were observed, suggesting a possible beneficial effect.

DISCUSSION: Our findings demonstrate that increasing O-GlcNAcylation in TgF344-AD rats using a cyclical treatment protocol at a time when Aβ pathology is already significant does not provide broad beneficial effects on Aβ accumulation, microglial reactivity, or noradrenergic axon loss, although there appears to be fewer dystrophic axons. Importantly, increasing O-GlcNAcylation in TgF344-AD rats has dual beneficial effects on astrocyte reactivity. Astrocytes in close proximity to Aβ plaques are more complex with longer processes and more branches compared to those in saline-treated TgF344-AD rats at the same distance, enabling them to surround plaques and protect nearby neurons. Astrocytes located at more distal locations from plaques are less reactive than those at the same distance in saline-treated TgF344-AD rats, permitting a less pathological local environment for nearby neurons. Our findings offer new insights into the possible mechanisms that might contribute to the beneficial therapeutic effects of increasing O-GlcNAcylation during progressive AD pathology.},
}

@article {pmid41476782,
year = {2025},
author = {Zhu, Y and Liu, H and He, M and Xu, Z and Sun, L and Wu, Z and Niu, X and Huang, S and Wang, J and Ran, X},
title = {Epidemiology and Risk Factors Characteristics of Alzheimer's Disease in Southwestern China: A Cross-Sectional Study.},
journal = {Clinical interventions in aging},
volume = {20},
number = {},
pages = {2685-2704},
pmid = {41476782},
issn = {1178-1998},
mesh = {Humans ; *Alzheimer Disease/epidemiology ; China/epidemiology ; Female ; Male ; Risk Factors ; Aged ; *Cognitive Dysfunction/epidemiology ; Cross-Sectional Studies ; Aged, 80 and over ; Middle Aged ; Prevalence ; Rural Population ; Sex Factors ; Age Factors ; Educational Status ; Comorbidity ; Logistic Models ; },
abstract = {BACKGROUND: To address the regional heterogeneity of Alzheimer's disease, a large-scale epidemiological study of 12,421 elderly individuals was conducted in southwestern China to depict its unique risk characteristics.

METHODS: A total of 12,421 subjects were selected via cluster sampling from southwestern China after low quality data were filtered out. On the basis of investigations and medical imaging examinations, three groups were distinguished: the AD, mild cognitive impairment (MCI), and normal control groups. The risk factors for AD and MCI were analysed via a multivariate logistic regression model.

RESULTS: This study identifies a high burden of cognitive impairment in southwestern China, with 22.07% of adults aged ≥60 years exhibiting cognitive decline and 5.81% diagnosed with Alzheimer's disease rates surpassing national and global averages. Key risk factors included age >80 years, female sex, low education, rural residence, surgical history, and urological comorbidities. These findings underscore the need for region-specific prevention strategies, prioritizing older, less-educated rural women through combined cognitive and vascular interventions, while integrating cognitive screening into primary care in underserved areas for early detection and intervention.

CONCLUSION: Elderly individuals in southwestern China exhibit a high prevalence of cognitive impairment, with AD associated with complex risk factors including established contributors like advanced age, dementia family history, alcohol abuse, and multisystem comorbidities-while notably identifying surgical history and urolithiasis as region specific risk signals. These findings underscore regional, environmental, and ethnic influences on AD pathogenesis, requiring tailored prevention/treatment. Future priorities include integrating brief cognitive screening into primary care, targeting high-risk groups (eg, undereducated rural elderly women), and establishing prospective cohorts to clarify causal links between urolithiasis, surgical history, and cognitive decline for refined region-adapted AD prevention.},
}

Humans
*Alzheimer Disease/epidemiology
China/epidemiology
Female
Male
Risk Factors
Aged
*Cognitive Dysfunction/epidemiology
Cross-Sectional Studies
Aged, 80 and over
Middle Aged
Prevalence
Rural Population
Sex Factors
Age Factors
Educational Status
Comorbidity
Logistic Models

@article {pmid41476179,
year = {2025},
author = {Taheri, E and Raeeszadeh-Sarmazdeh, M},
title = {Evaluating the effect of minimal TIMP variants on protecting and transport across the rat brain microvascular cells (RBMEC).},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-30643-9},
pmid = {41476179},
issn = {2045-2322},
abstract = {Tissue inhibitors of metalloproteinases (TIMPs), endogenous inhibitors of matrix metalloproteinases (MMPs), can be tailored to regulate MMP activity and mitigate the disruptive effects of specific MMPs when dysregulated in diseases. MMPs, especially MMP-9, are major contributors to the degradation of extracellular matrix components, leading to BBB disruption in neurological disorders. The upregulation of MMPs undermines blood-brain barrier (BBB) integrity and drives neuroinflammation. Engineering minimal protein variants offers enhanced modularity, tissue penetration, and BBB permeability. Minimal TIMP variants were engineered, aiming to improve their therapeutic reach across both sides of the BBB, particularly when delivery to the brain is essential. In this study, we assessed the protective effects of mTC1 and mTC3 on BBB integrity using an in vitro model of rat brain microvascular endothelial cells (RBMECs). Barrier function was evaluated following treatment with recombinant MMP-9, either alone or co-treated with native TIMP-1, TIMP-3, or the engineered minimal variants. MMP-9 induced a dose-dependent increase in BBB permeability, reflected by a decrease in trans-endothelial electrical resistance (TEER) and increased paracellular transport of fluorescent tracers. Co-treatment with TIMP-1, TIMP-3, mTC1, or mTC3 significantly attenuated MMP-9-mediated disruption of tight junctions of RBMECs, preserving TEER values and reducing permeability. Immunofluorescence staining for tight junction proteins, ZO-1 and occludin, further validated the preservation of endothelial integrity in the presence of wild-type human TIMPs and engineered TIMP variants. These findings underscore the potential of engineered minimal TIMPs as molecular tools to stabilize the BBB and support their future application in mechanistic studies focused on BBB protection.},
}

@article {pmid41476028,
year = {2026},
author = {Zhang, W and Liu, H and Zhang, C and Li, Y and Fang, K and Zhou, Y and Weng, L and Fang, L and Luo, Y and Xiao, H and Zhou, L and Jiao, B and Shen, L},
title = {Six-month follow-up of ARIA-H and iron deposition in real-world lecanemab therapy for Alzheimer's disease: Evidence from a Chinese 7T MRI cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71044},
pmid = {41476028},
issn = {1552-5279},
support = {U22A20300 82371434//National Natural Science Foundation of China/ ; 2021ZD0201803//STI2030-Major Projects/ ; 2023YFC3603700//the National Key R&D Program of China/ ; 2024JJ2097//the Outstanding Youth Fund of Hunan Provincial Natural Science Foundation/ ; 2024PT5108//the Scientific Research Program of FuRong Laboratory/ ; SMIDF-150-2025A19//the Brain Health Youth Fund of Shanghai Medical Innovation & Development Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Magnetic Resonance Imaging/methods ; Male ; Female ; *Iron/metabolism ; Aged ; Amyloid beta-Peptides/blood ; Follow-Up Studies ; Biomarkers/blood ; *Brain/diagnostic imaging/metabolism/drug effects ; tau Proteins/blood ; Cohort Studies ; China ; Middle Aged ; Peptide Fragments/blood ; East Asian People ; },
abstract = {INTRODUCTION: With the approval of lecanemab for treating Alzheimer's disease (AD), there is an urgent need to evaluate its safety and treatment effects on biomarkers in real-world practice.

METHODS: Patients receiving lecanemab (n = 72) underwent routine 3T and 7T magnetic resonance imaging (MRI) for amyloid-related imaging abnormality (ARIA) monitoring. Longitudinal changes of iron deposition assessed by quantitative susceptibility mapping (QSM) and its association with plasma biomarkers were further evaluated.

RESULTS: With use of 7T MRI, we identified characteristic perivascular features and detected ARIA with hemorrhages/hemosiderin deposition (ARIA-H) ≈4 months earlier than with 3T. QSM detected post-treatment regional susceptibility reductions. Decreased susceptibility in the temporal, frontal lobes, and the thalamus was associated with plasma amyloid beta 42 (Aβ42) and tau phosphorylated at threonine 217 (p-tau217) changes.

DISCUSSION: 7T MRI provides superior ARIA-H detection and iron dynamics monitoring, supporting its role in risk stratification and therapy assessment for lecanemab-treated patients. Iron deposition measured by QSM may serve as a promising neuroimaging marker for amyloid-targeting treatments.

HIGHLIGHTS: Using 7T magnetic resonance imaging (MRI), this study for the first time visualized amyloid-related imaging abnormality with hemorrhages/hemosiderin deposition (ARIA-H) at a submillimeter resolution, characterized by aggregated, clustered cerebral microbleeds in a perivascular distribution, suggesting overlapping pathology with cerebral amyloid angiopathy. The susceptibility-weighted imaging sequence on 7T MRI enabled detection of ARIA-H up to 4 months earlier. Plasma amyloid beta 42 (Aβ42) and tau phosphorylated at threonine 217 (p-tau 217) levels are sensitive biomarkers for amyloid targeted therapy. Quantitative susceptibility mapping (QSM) analysis demonstrated reduced cortical iron burden post-treatment, which has significant associations with plasma Aβ42 and p-tau 217 levels, highlighting QSM-derived iron quantification as a promising neuroimaging indicator for amyloid-targeted therapeutics.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging/metabolism
*Magnetic Resonance Imaging/methods
Male
Female
*Iron/metabolism
Aged
Amyloid beta-Peptides/blood
Follow-Up Studies
Biomarkers/blood
*Brain/diagnostic imaging/metabolism/drug effects
tau Proteins/blood
Cohort Studies
China
Middle Aged
Peptide Fragments/blood
East Asian People

@article {pmid41475761,
year = {2026},
author = {Mei, J and Shi, X and Chen, M and Li, Z and Cui, Y and Fang, C and Wu, X and Chen, X and Zeng, K and Yang, L},
title = {Chitosan/selenium nanoparticles Pickering emulsion prolong quercetin retention time to ameliorates cognitive disorder: Focus on restoring the metabolic disorder and gut microbiota.},
journal = {Carbohydrate polymers},
volume = {375},
number = {},
pages = {124804},
doi = {10.1016/j.carbpol.2025.124804},
pmid = {41475761},
issn = {1879-1344},
mesh = {*Quercetin/chemistry/pharmacology/administration & dosage/pharmacokinetics ; Animals ; *Gastrointestinal Microbiome/drug effects ; *Chitosan/chemistry ; Emulsions/chemistry ; *Nanoparticles/chemistry ; *Selenium/chemistry ; Mice ; Male ; Mice, Inbred C57BL ; *Cognitive Dysfunction/drug therapy ; Brain/metabolism/drug effects ; },
abstract = {Gut microbiota influence brain inflammation and cognitive impairment by regulating lipid metabolism. The therapeutic efficacy of quercetin (Que) in Alzheimer's disease (AD) treatment is significantly limited by its poor water solubility and short residence time in vivo. Herein, Chitosan (CS) modified selenium nanoparticles was used to prepare a high-loading Pickering emulsion (Que-CS/Se-PE), improving bioaccessibility of Que. Simulated gastrointestinal fluid experiments demonstrate that Que-CS/Se-PE exhibits strong stability under acidic conditions. In vitro digestion studies indicate that Que-CS/Se-PE enables QUE to target intestinal fluids and release slowly. In vivo imaging revealed that the gastrointestinal retention time of Que-CS/Se-PE was up to 48 h. In HFD + D-gal-induced mice, Que-CS/Se-PE treatment reduced serum TC and brain TNF-α levels by 40.8 % and 31.5 %, respectively, indicating substantial improvement in lipid metabolism and neuroinflammation. Behavioral tests showed that Que-CS/Se-PE improved cognitive performance, with preference index elevated by 2.1-fold. Moreover, the relative abundances of Akkermansia, Lactobacillus, and Bacteroidota increased by 2.7-, 17.8-, and 4.7-fold, respectively. In conclusion, Que-CS/Se-PE exhibits interfacial stability, excellent adhesion, and sustained-release properties, significantly prolonging the retention time of quercetin in vivo and enhancing its bioavailability. Furthermore, it modulates lipid metabolism and gut microbiota, and finally ameliorates cognitive impairment in obesity and age-related AD.},
}

*Quercetin/chemistry/pharmacology/administration & dosage/pharmacokinetics
Animals
*Gastrointestinal Microbiome/drug effects
*Chitosan/chemistry
Emulsions/chemistry
*Nanoparticles/chemistry
*Selenium/chemistry
Mice
Male
Mice, Inbred C57BL
*Cognitive Dysfunction/drug therapy
Brain/metabolism/drug effects

@article {pmid41474058,
year = {2026},
author = {Naftchi-Ardebili, K and Singh, K and Popelka, GR and Pauly, KB},
title = {A deep-learning model for one-shot transcranial ultrasound simulation and phase aberration correction.},
journal = {Medical physics},
volume = {53},
number = {1},
pages = {e70259},
pmid = {41474058},
issn = {2473-4209},
support = {R01 Grant EB032743//National Science Foundation/ ; },
mesh = {*Deep Learning ; Humans ; *Image Processing, Computer-Assisted/methods ; Skull/diagnostic imaging ; Ultrasonography ; Tomography, X-Ray Computed ; },
abstract = {BACKGROUND: Transcranial ultrasound is a promising non-invasive neuromodulation technique with applications, including neuronal activity modulation, blood-brain barrier opening, targeted drug delivery, and thermal ablation. Its ability to deliver focused ultrasound waves to precise brain regions has led to over 50 clinical trials targeting conditions such as opioid addiction, Alzheimer's disease, dementia, epilepsy, and glioblastoma. However, skull heterogeneity complicates accurate focal spot prediction and energy delivery, requiring rapid yet precise phase aberration correction in clinical workflows.

PURPOSE: To address the trade-off between computational efficiency and accuracy in current focus prediction methods, we introduce TUSNet, a deep learning framework for rapid and accurate transcranial ultrasound pressure field and phase aberration correction computation.

METHODS: TUSNet, an end-to-end neural network, was trained to predict both 2D transcranial ultrasound pressure fields and phase corrections. TUSNet was trained on 180432 synthetic skull Computed Tomography (CT) segments, and tested on 1232 real skull CT segments. Its performance was benchmarked against k-Wave, a MATLAB-based acoustic simulation package, evaluating computation speed, focal spot accuracy, phase correction accuracy, and pressure magnitude estimation.

RESULTS: TUSNet computed pressure fields and phase corrections in 21 ms, which is over 1200 × $\times$ faster than k-Wave, while achieving 98.3% accuracy in peak pressure magnitude estimation and a mean focal positioning error of only 0.18 mm relative to k-Wave ground truth. End-to-end training took approximately 8 h on 4x NVIDIA A100 80 GB GPUs.

CONCLUSIONS: TUSNet demonstrates that deep learning can provide accurate and rapid estimates of phase aberrations and transcranial pressure fields, offering a promising direction for accelerating ultrasound treatment planning. While the present validation is based on simulated, noise-free ultrasound fields, the results establish a foundation that future experimental studies can build on to assess performance under real-world clinical conditions.},
}

*Deep Learning
Humans
*Image Processing, Computer-Assisted/methods
Skull/diagnostic imaging
Ultrasonography
Tomography, X-Ray Computed

@article {pmid41473419,
year = {2026},
author = {Tonegawa-Kuji, R and Karavani, E and Danziger, M and Zhang, P and Hou, Y and Zhou, Y and Bykova, M and Pieper, AA and Rosen-Zvi, M and Cummings, J and Cheng, F},
title = {Critical evaluation of real-world evidence of repurposable medicines in the Alzheimer's disease drug development pipeline using a target trial emulation.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {1},
pages = {e70193},
pmid = {41473419},
issn = {2352-8737},
abstract = {INTRODUCTION: Repurposing Food and Drug Administration (FDA)-approved drugs could accelerate treatment development for Alzheimer's disease (AD).

METHODS: Using the MarketScan claims database (2011 to 2020), we applied a trial emulation approach in two base cohorts: (1) individuals with mild cognitive impairment (MCI cohort) and (2) individuals aged ≥70 years (over-70 cohort). We evaluated drugs represented in clinical trials for AD, comparing them with same-class or active comparators. Covariate-adjusted hazard ratios (HRs) were estimated using inverse-probability-weighted Cox models.

RESULTS: A total of 6 out of 38 (16%) drugs in the MCI cohort and 10 out of 53 (19%) drugs in the over-70 cohort were associated with a lower AD incidence versus same-class comparators. Active comparator analyses indicated that bupropion (vs escitalopram; HR 0.57, 95% confidence interval [CI] [0.49, 0.66]), trazodone (vs sertraline; HR 0.82, 95% CI [0.74, 0.91]), venlafaxine (vs escitalopram; 0.72, 95% CI [0.62, 0.84]), and zolpidem (vs lorazepam; HR 0.69, 95% CI [0.56, 0.85]) were associated with a lower AD incidence in the MCI cohort; these four plus liraglutide were associated with a lower incidence of AD dementia in the over-70 cohort (vs metformin; HR 0.74, 95% CI [0.59, 0.93]).

DISCUSSION: This is the first comprehensive set of trial emulations for FDA-approved drugs that are represented in AD trials. Findings may inform future trial designs.

HIGHLIGHTS: Repurposing FDA-approved drugs originally developed for other diseases could accelerate treatment development for AD.We identified repurposable drugs that are in current or complete clinical trials of AD and emulated trials for these agents using a large-scale insurance claims-based database.Among 54 drugs evaluated, 6/38 (16%) drugs in the MCI cohort and 10/53 (19%) in the over-70 cohort were associated with reduced AD incidence versus same-class comparators. Active comparator analyses indicated that bupropion, trazodone, venlafaxine, and zolpidem were associated with reduced AD incidence in the MCI cohort; these four plus liraglutide were associated with a lower incidence of AD dementia in the over-70 cohort.A minority of repurposed table drugs that are in current or completed clinical trials for AD and meet criteria for inclusion in this study showed no effect in our trial emulation studies.This is the first comprehensive set of trial emulations for FDA-approved drugs that are represented in AD trials. Building on our findings, integrating real-world evidence can inform future trials and accelerate drug development for AD.},
}

@article {pmid41473323,
year = {2025},
author = {Salian, VS and Veerareddy, V and Tang, X and Xiao, Y and Kalari, KR and Kashyap, PC and Kandimalla, KK},
title = {Molecular Mechanisms Underlying the Regulation of VCAM-1 Expression by the Short-Chain Fatty Acid Butyrate.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.15.694447},
pmid = {41473323},
issn = {2692-8205},
abstract = {Over the past decade, cerebrovascular inflammation has been increasingly recognized as a contributor to the progression of neurodegenerative diseases, particularly Alzheimer's disease (AD). One of the molecular hallmarks of cerebrovascular inflammation is the increased expression of vascular cell adhesion molecule (VCAM)-1 on blood-brain barrier (BBB) endothelial cells. Exposure to amyloid beta (Aβ) peptides, one of the primary hallmarks of AD, and pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) induces VCAM-1 expression on the BBB endothelium, which facilitates extravasation of leukocytes into the brain thereby promoting an inflammatory response. Therefore, it is crucial to explore therapeutic agents that can inhibit VCAM-1 expression induced by Aβ and TNF-α. Short-chain fatty acids, such as butyrate, produced by the gut microbiota as byproducts of dietary fiber metabolism, are recognized for their anti-inflammatory properties. In this study, we successfully tested the hypothesis that butyrate mitigates Aβ and TNF-α-induced VCAM-1 expression in polarized human cerebral microvascular endothelial cell monolayers, a widely used BBB in vitro model. Our findings indicated that pre-treatment with butyrate significantly reduced Aβ42 and TNF-α mediated upregulation of VCAM-1. Furthermore, we have shown STAT3/GATA6 axis as a key mediator of anti-inflammatory effects of butyrate. These findings provide mechanistic insight into butyrate's protective role and highlight its potential to mitigate Aβ and TNF-α-induced cerebrovascular inflammation in AD.},
}

@article {pmid41473097,
year = {2025},
author = {Kang, MH and Kang, MA and Jeon, HJ and Shin, HC and Moon, H and Lee, DG and Park, HM},
title = {Evaluation of the safety and efficacy of a donepezil depot injection in dogs with canine cognitive dysfunction.},
journal = {Frontiers in veterinary science},
volume = {12},
number = {},
pages = {1724060},
pmid = {41473097},
issn = {2297-1769},
abstract = {Canine cognitive dysfunction (CCD) is an age-related neurodegenerative disorder for which effective treatments remain limited, and objective diagnostic and therapeutic assessment tools using biomarkers or neuroimaging are still lacking compared with human Alzheimer's disease. This study evaluated the safety and efficacy of a long-acting donepezil depot injection in dogs with CCD, using behavioral scores and serum neurofilament light chain (NfL) as primary outcomes, with baseline MRI for diagnostic support. Thirty-two dogs with clinically diagnosed CCD were randomly assigned to a high-dose group (n = 11), a low-dose group (n = 11), or a control group (n = 10). Diagnosis was established based on the Canine Cognitive Dysfunction Rating Scale (CCDR), the CAnine DEmentia Scale (CADES), and DISHAA scoring, and baseline MRI was performed in selected dogs with owner consent. A single intramuscular injection of donepezil depot was administered on day 0, and evaluations were conducted on days 14 and 28. The high-dose group showed significant improvements in CCDR, CADES, and DISHAA at both 14 and 28 days, whereas the low-dose group improved primarily at day 28, with earlier effects limited to CADES (p < 0.05). At day 28, both treatment groups had significantly lower serum NfL levels than controls (p < 0.05), while within-group values remained stable. Quality-of-life scores improved in activity, sociability, overall condition, and global QoL. Adverse events were mild and transient. These findings suggest that a single intramuscular injection of long-acting donepezil depot demonstrates favorable safety and potential efficacy in dogs with CCD, with improvements in behavioral scores and NfL supporting its therapeutic potential and highlighting the value of integrating clinical and biomarker-based assessments in future CCD management.},
}

@article {pmid41471864,
year = {2025},
author = {Cao, S and Shi, X and Chen, Y and Liu, T and Hu, J and Dong, X and Chen, H and Dai, J and Yin, H},
title = {Gut Microbiota-Targeted Photobiomodulation Ameliorates Alzheimer's Pathology via the Gut-Brain Axis: Comparable Efficacy to Transcranial Irradiation.},
journal = {Microorganisms},
volume = {13},
number = {12},
pages = {},
pmid = {41471864},
issn = {2076-2607},
support = {62175261//National Natural Science Foundation of China/ ; 2023YFB3609103//National Key R&D Program of China/ ; 2021-I2M-1-058//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences/ ; 24JCZDJC00240//Natural Science Foundation of Tianjin/ ; },
abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder with limited effective and affordable therapies. Photobiomodulation (PBM) offers a safe, non-invasive treatment strategy, yet conventional transcranial PBM (tc-PBM) is restricted by low skull penetration. To overcome this limitation, gut microbiota-targeted PBM (gm-PBM) has been proposed to modulate the gut-brain axis, though its efficacy and mechanisms remain unclear. Here, six-month-old APPswe/PS1dE9 mice received gm-PBM or tc-PBM (810 nm, 25 mW/cm[2], 20 min/day for 4 weeks). Behavioral testing revealed that both treatments improved spatial learning and memory, while histological analyses showed reduced amyloid-β deposition and microglial shift toward an anti-inflammatory phenotype. Notably, gm-PBM specifically enriched short-chain fatty acid-producing bacteria, elevated propionate, butyrate, and secondary bile acids, and restored intestinal barrier integrity, whereas tc-PBM induced minimal microbiota changes. These findings suggest that gm-PBM confers neuroprotective effects comparable to or exceeding tc-PBM through modulation of the gut microbiota-metabolism-immune axis, highlighting its potential as a non-invasive and cost-effective therapeutic approach for AD.},
}

@article {pmid41471351,
year = {2025},
author = {Makhaeva, GF and Utepova, IA and Rudakova, EV and Kovaleva, NV and Boltneva, NP and Zyryanova, EY and Musikhina, AA and Lazarev, VF and Vladimirova, SA and Guzhova, IV and Ganebnykh, IN and Astakhova, TY and Timokhina, EN and Chupakhin, ON and Charushin, VN and Richardson, RJ},
title = {1-Azinyl-1'-Alkenylferrocenes with Anticholinesterase, Antioxidant, and Antiaggregating Activities as Multifunctional Agents for Potential Treatment of Alzheimer's Disease.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {12},
pages = {},
pmid = {41471351},
issn = {1424-8247},
support = {24-63-00016//Russian Science Foundation/ ; },
abstract = {Background/Objectives: This study focused on synthesizing novel alkenyl derivatives of azinylferrocenes and evaluating their potential as Alzheimer's disease (AD) therapeutics. Methods: 1-Azinyl-1'-acetylferrocenes were obtained by regioselective acetylation of azinylferrocenes, followed by the Wittig reaction or reduction of 1-azinyl-1'-acetylferrocenes and subsequent dehydration of the resulting alcohols. The synthesized compounds underwent the following biological activity testing relevant to AD: inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and off-target carboxylesterase (CES); antioxidant capacity (ABTS and FRAP assays); inhibition of Aβ42 self-aggregation (thioflavin method); blocking AChE-induced β-amyloid aggregation (propidium displacement); and cytotoxicity in SH-SY5Y and MSC-Neu cells (MTT assay). Results: Quinoline and bipyridine derivatives demonstrated effective cholinesterase inhibition, especially quinoline 7b (AChE IC50 3.32 μM; BChE IC50 3.68 μM), while acridine derivatives were poor inhibitors. Quantum chemical (QC) calculations predicted that acridine derivatives were especially prone to form stable dimers. Molecular docking into protein targets generated by an AlphaFold3 reproduction code showed that these dimers were too bulky to access enzyme active sites, yet they could bind to protein surfaces to inhibit Aβ42 self-aggregation and displace propidium from the AChE peripheral anionic site. All compounds showed high antioxidant activity in ABTS and FRAP assays, with quinoline derivatives being 2-4 times more potent than Trolox. QC calculations supported these findings. Quinoline and bipyridine derivatives also exhibited low cytotoxicity and scant CES inhibition. Conclusions: Overall, the synthesized ferrocenes, particularly the quinoline and bipyridine derivatives, appear promising for further research as multifunctional therapeutic agents targeting AD due to their anticholinesterase, antiaggregating, and antioxidant activities combined with low toxicity.},
}

@article {pmid41471079,
year = {2025},
author = {Trasca, DM and Dorin, PI and Carmen, S and Varut, RM and Singer, CE and Radivojevic, K and Stoica, GA},
title = {Artificial Intelligence in Biomedicine: A Systematic Review from Nanomedicine to Neurology and Hepatology.},
journal = {Pharmaceutics},
volume = {17},
number = {12},
pages = {},
pmid = {41471079},
issn = {1999-4923},
abstract = {Background/Objectives: This review evaluates the expanding contributions of artificial intelligence (AI) across biomedicine, focusing on cancer therapy and nanomedicine, cardiology and medical imaging, neurodegenerative disorders, and liver disease. Core AI concepts (machine learning, deep learning, artificial neural networks, model training/validation, and explainability) are introduced to frame application domains. Methods: A systematic search of major biomedical databases (2010-2025) identified English-language original studies on AI in these four areas; 203 articles meeting PRISMA 2020 criteria were included in a qualitative synthesis. Results: In oncology and nanomedicine, AI-driven methods expedite nanocarrier design, predict biodistribution and treatment response, and enable nanoparticle-enhanced monitoring. In cardiology, algorithms enhance ECG interpretation, coronary calcium scoring, automated image segmentation, and noninvasive FFR estimation. For neurological disease, multimodal AI models integrate imaging and biomarker data to improve early detection and patient stratification. In hepatology, AI supports digital histopathology, augments intraoperative robotics, and refines transplant wait-list prioritization. Common obstacles are highlighted, including data heterogeneity, lack of standardized acquisition protocols, model transparency, and the scarcity of prospective multicenter validation. Conclusions: AI is emerging as a practical enabler across these biomedical fields, but its safe and equitable use requires harmonized data, rigorous multicentre validation, and more transparent models to ensure clinical benefit while minimizing bias.},
}

@article {pmid41471033,
year = {2025},
author = {Park, YC and Seol, E and Lee, J and Hong, JH and Jung, JG and Sunwoo, J},
title = {Pharmacokinetic Evaluation of GB-5001, a Long-Acting Injectable Formulation of Donepezil, in Healthy Korean Participants: Population Pharmacokinetics with Phase 1 Study.},
journal = {Pharmaceutics},
volume = {17},
number = {12},
pages = {},
pmid = {41471033},
issn = {1999-4923},
support = {Not applicable//G2GBIO Inc./ ; },
abstract = {Background/Objectives: Oral donepezil, an acetylcholinesterase (AChE) inhibitor for Alzheimer's disease, faces adherence challenges. Long-acting injectable (LAI) formulations like GB-5001 aim to enhance adherence by reducing dosing frequency. This Phase 1, open-label, active-controlled, dose-escalation study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GB-5001 in healthy male adults. Methods: Participants were assigned to cohorts receiving GB-5001A or GB-5001D (LAI formulations) via intramuscular (IM) or subcutaneous (SC) injection, or oral Aricept[®]. Safety, PK, and PD (AChE inhibition) were assessed. The influence of CYP2D6 phenotype was explored, and modeling/simulation was performed. Results: Fifty healthy male participants completed the study. After IM administration, GB-5001A (70 mg, 140 mg, 280 mg) showed dose-dependent increases in exposure (AUCinf and Cmax), resulting in significantly extended exposure compared to oral Aricept[®] 10 mg. No serious adverse events were reported; the most common AEs were mild injection site reactions, which occurred in all treatment groups except the GB-5001A IM 70 mg group and the Aricept group. GB-5001A also demonstrated sustained AChE inhibition. Conclusions: GB-5001A, an LAI donepezil, showed favorable safety, dose-proportional PK, and sustained plasma exposure. It achieved a 3-4-fold longer half-life than oral donepezil. These findings, supported by modeling, highlight GB-5001A's potential as a once-monthly IM alternative for Alzheimer's disease treatment.},
}

@article {pmid41469705,
year = {2025},
author = {Li, T and Zhang, J and Song, H and Zhang, R and Fan, F and Huang, Z and Zeng, ML and Peng, BW and Zhang, J},
title = {Border-associated macrophages: an emerging perspective from physiological basis and multi-disease roles to the mechanism of vascular cognitive impairment and dementia.},
journal = {Journal of neuroinflammation},
volume = {22},
number = {1},
pages = {302},
pmid = {41469705},
issn = {1742-2094},
support = {82501747//the Natural Science Foundation of China/ ; 82571371//the Natural Science Foundation of China/ ; 2025AFC006//the Natural Science Foundation of Hubei Province/ ; PTXM2025032//Medical Sci-Tech Innovation Platform of Zhongnan Hospital, Wuhan University/ ; ZY2023Z018//Key projects of Traditional Chinese Medicine Scientific research in 2023-2024 by Hubei Provincial Administration of Traditional Chinese Medicine/ ; },
mesh = {Humans ; *Cognitive Dysfunction/pathology/immunology/metabolism ; *Dementia, Vascular/pathology/immunology/metabolism/physiopathology ; Animals ; *Macrophages/pathology/metabolism/immunology ; *Brain/pathology/immunology/metabolism ; },
abstract = {Brain border-associated macrophages (BAMs) are resident immune cells at the border of the central nervous system (CNS), and their physiological functions and roles in neurological diseases have been widely reported. However, the specific mechanisms by which BAMs contribute to vascular cognitive impairment and dementia (VCID) remain unclear. This article systematically reviews the subsets, origin and differentiation, molecular markers of BAMs, and their research progress in various brain diseases such as hypertension, Alzheimer's disease (AD), and stroke. On this basis, this article deeply analyzes the potential hypotheses of BAMs' involvement in the pathogenesis of VCID, including their regulation of neurovascular unit (NVU) homeostasis, their core role in neuroimmune inflammation, their impact on the lipid metabolism pathways in the CNS, and their involvement in the pathogenesis of vascular risk factor-related cognitive impairment (VRFCI). The mechanistic hypotheses proposed in this article aim to provide new perspectives for understanding the pathophysiology of VCID and may open up new directions for the development of early intervention and targeted treatment strategies.},
}

Humans
*Cognitive Dysfunction/pathology/immunology/metabolism
*Dementia, Vascular/pathology/immunology/metabolism/physiopathology
Animals
*Macrophages/pathology/metabolism/immunology
*Brain/pathology/immunology/metabolism

@article {pmid41468784,
year = {2025},
author = {Palanivel, V and Salkar, A and Shenoy, A and Eva, TA and Perera, R and Chitranshi, N and Gupta, V and You, Y and Mirzaei, M and Graham, SL and Gupta, V and Basavarajappa, D},
title = {Neuropeptide Y at the crossroads of neurodegeneration: Mechanistic insights and emerging therapeutic strategies.},
journal = {Neuropeptides},
volume = {115},
number = {},
pages = {102583},
doi = {10.1016/j.npep.2025.102583},
pmid = {41468784},
issn = {1532-2785},
abstract = {Neuropeptide Y (NPY), a widely distributed and highly conserved neuropeptide, plays a central role in the regulation of diverse physiological processes, including stress responses, energy homeostasis, vascular tone, and immune modulation, via activation of its receptor subtypes. Beyond its physiological roles, the dysregulation of NPY expression has been documented in several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Machado-Joseph disease, and retinal disorders such as diabetic retinopathy and glaucoma. These alterations in NPY levels and receptor activity highlight its potential not only as a biomarker for disease progression but also as a promising therapeutic target. Previous evidence revealed that NPY exerts neuroprotection by alleviating excitotoxicity, oxidative stress, mitochondrial dysfunction, and neuroinflammation while concurrently facilitating neurogenesis, synaptic plasticity, and cellular resilience. NPY activates receptor-mediated intracellular signaling cascades like PI3K/Akt, MAPK/ERK, and p38K, that control cellular survival, proteostasis, and inflammation and thereby influence disease trajectories. Understanding NPY operation with these mechanisms can unveil new avenues for targeted therapy. Current insights into the complex roles of NPY in neurodegeneration are discussed in this review, and their implications in diagnostic and treatment strategies are addressed.},
}

@article {pmid41467972,
year = {2025},
author = {Chang, ST and Wu, HY and Chiu, YL and Chuang, YF},
title = {Anti-herpetic treatment reduces dementia risk: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251409323},
doi = {10.1177/13872877251409323},
pmid = {41467972},
issn = {1875-8908},
abstract = {BackgroundHuman herpesvirus (HHV) infections, particularly for herpes simplex virus (HSV) and varicella-zoster virus (VZV), may increase dementia risk, yet the protective effects of anti-herpetic medications remained unclear.ObjectiveThis systematic review and meta-analysis of observational studies aimed to examine the association between anti-herpetic medications and dementia, focusing on HSV or VZV-related infections.MethodsThis study followed PRISMA guidelines (CRD42022368318). Cohort or nested case-control studies published from databases' inception to December 2024 were systematically searched in PubMed, MEDLINE, Embase, Cochrane Library, PsycINFO, and Web of Science. Eligible studies evaluated anti-herpetic medications (e.g., acyclovir, famciclovir, ganciclovir, valacyclovir, valganciclovir) and dementia risk in non-demented adults aged ≥50. Pooled adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) were analyzed using random-effects models. Subgroup and meta-regression analyses were performed to explore potential sources of heterogeneity and effect modifiers.ResultsFourteen cohort studies involving more than 10 million older adults were included. To demonstrate the effects of anti-herpetic medications in various clinical scenarios, the meta-analysis compared: diagnosed and treated versus diagnosed but untreated (aHR=0.77, 95% CI: 0.67-0.89); treated versus untreated regardless of diagnosis (aHR=0.90, 95% CI: 0.87-0.94); and diagnosed and treated versus neither diagnosed nor treated (aHR=0.87, 95% CI: 0.78-0.97). Subgroup analysis and meta-regression identified infection severity as a significant modifier (p < 0.0001), explaining 89.01% of heterogeneity.ConclusionsThis systematic review and meta-analysis reveals notable protective effect of anti-herpetic medication usage on dementia, and the effect is especially pronounced in patients with severe alpha herpesvirus infections.},
}

@article {pmid41467438,
year = {2025},
author = {Zhao, J and Wang, J and Guo, X},
title = {Organoids: Key advances, optimization, and technological iterations in their application to neurodegenerative diseases.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00924},
pmid = {41467438},
issn = {1673-5374},
abstract = {Organoid technology, as an innovative approach, has shown great potential in disease modeling, target screening, and the development of treatment strategies. However, traditional organoids still have three major limitations in research: the absence of specific cell types, the lack of blood-brain barrier structure, and insufficient reproducibility of experimental results. In recent years, researchers have gradually overcome these limitations by introducing innovative techniques such as advanced culture methods, microfluidic systems, bioprinting, organoid transplantation, and assembloid construction. This progress has facilitated the widespread application of organoids in the study of neurodegenerative diseases. This paper aims to systematically review the technological innovations of organoids in the study of neurodegenerative diseases. By summarizing classical organoid construction strategies and their limitations, it emphasizes the value of organoids in comprehensive applications within neurodegenerative disease research. In this review, we focus on five specific neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Research in these diseases demonstrates that organoids improve experimental accessibility and reduce development cycles in disease modeling, target discovery, and therapeutic strategy formation. Using customized equipment and gene editing techniques, these organoids can be tailored to specific needs, providing pathophysiologically relevant disease models and enhancing our understanding of neurodegenerative diseases. Although organoid technology has demonstrated significant advantages in disease research, its potential for treating neurodegenerative diseases has not yet been fully explored, which may become an important direction for future research.},
}

@article {pmid41467376,
year = {2025},
author = {Alexandrova, EG and Abakumova, TR and Ziganshina, LE},
title = {Use of nootropics in Alzheimer's disease: An analysis of regulatory positions and drug policies in the countries of the Commonwealth of Independent States.},
journal = {The International journal of risk & safety in medicine},
volume = {},
number = {},
pages = {9246479251410817},
doi = {10.1177/09246479251410817},
pmid = {41467376},
issn = {1878-6847},
abstract = {ObjectiveTo analyse regulatory positions and drug policies of the Commonwealth of Independent States (CIS), compared to those of the EU, UK, USA i of the nootropics, used in Russia for Alzheimer's disease.MethodsWe searched E-library to reveal the list of nootropics used and studied in Russia for Alzheimer's disease. We assessed official pharmaceutical registries of nine countries for registration status of identified nootropics, 7 National Essential Medicines Lists (EML), and four clinical practice guidelines (CPG) on Alzheimer's disease. We compared the results of Russia with other countries regulatory and policy positions.ResultsE-Library searches identified 11 nootropicspiracetam, citicoline, idebenone, vinpocetine, choline alfoscerate, Cerebrolysin®, Kortexin®, ethylmethylhydroxypyridine succinate, glycine, nicergoline, nimodipine. Eight nootropic have registration for use in all CIS countries (excluding idebenone, nimodipine), four (piracetam, nimodipine, nicergoline, idebenone) - in UK, nimodipine - in the USA, and idebenone - in EU. National EMLs included: nine nootropics (Russia), 8 - Belarus and Kazakhstan, 4 - Uzbekistan, 2 - Armenia. The studied nootropic agents are not included on the WHO Model EML and on the National EML of the Kyrgyz Republic. They are not listed in the CPG for Treatment of dementia and Alzheimer's disease in the USA, the EU, and the UK. Russian CPGs for Alzheimer's disease recommend Cerebrolysin® and choline alfoscerate.ConclusionsThe studied nootropics are registered for use and listed on National EMLs of Russia, Armenia, Belarus, Kazakhstan, Uzbekistan. None is included on the WHO Model EML and the National EML of Kyrgyzstan, Only CPG of the RF recommend using two nootropics as adjuvant therapy of Alzheimer's disease, Cerebrolysin® and choline alfoscerate. CPG of the European Union, the United Kingdom, and the USA do not mention nootropics as potential treatment options for Alzheimer's disease.},
}

@article {pmid41466363,
year = {2026},
author = {de Magalhães, CG and Moldakozhayev, A and Lopez, MV and Bowman, GL and Chhatwal, JP and Kellis, M and Mohs, R and Nisenbaum, L and Quiroz, YT and Raju, RM and Sperling, RA and Moqri, M and Gladyshev, VN},
title = {The Right Person, the Right Treatment, at the Right Time in Alzheimer's Disease: Insights From the 2025 Brain Aging Symposium.},
journal = {Aging cell},
volume = {25},
number = {1},
pages = {e70351},
pmid = {41466363},
issn = {1474-9726},
mesh = {Humans ; *Alzheimer Disease/therapy/pathology/metabolism ; *Brain/pathology/metabolism ; *Aging/pathology ; Biomarkers/metabolism ; },
abstract = {On October 22nd, 2025, Brain Aging Symposium took place at Harvard Medical School bringing together leading researchers from academia and partner organizations to discuss recent advances in measuring and monitoring human brain aging trajectories, with a particular focus on Alzheimer's disease (AD). A central theme emerged: achieving "the right treatment for the right person and the right time" through precision medicine approaches. Key advances included the unprecedented validation of plasma-based biomarkers, particularly brain-derived p-Tau217 that can identify seeding AD pathology with remarkable specificity, making large-scale screening newly feasible. Integrating multi-level "omic" modalities, spanning genetic information, molecular biomarkers of nutrition, lipid and protein signatures, neuroimaging measures, cognitive assessments, and lifestyle factors, enhances disease risk modeling and trajectory prediction beyond the capacity of any single marker. Early findings highlight critical roles for nutritional and lipid metabolism, and myelin integrity in brain aging, with cell and sex-specific vulnerabilities identified in response to nutrition, social isolation, and metabolic stress. Computational approaches that combine single-cell genomics, epigenomics, and artificial intelligence have been shown to accelerate causal discovery and therapeutic development. However, significant challenges remain: current biomarkers explain only half the variance in cognitive decline, racial and ethnic differences in biomarker levels lack mechanistic understanding, and scalable tools for comprehensive brain aging assessment are needed. The symposium underscored that preventing AD will require intervening during the preclinical asymptomatic phase. These multimodal screening platforms, coupled with mechanistically driven therapeutics, reduction in modifiable risk factors, including nutrition, vascular health, and social determinants of health, could profoundly impact the field.},
}

Humans
*Alzheimer Disease/therapy/pathology/metabolism
*Brain/pathology/metabolism
*Aging/pathology
Biomarkers/metabolism

@article {pmid41465832,
year = {2025},
author = {Pilśniak, J and Węgrzynek-Gallina, J and Bednarczyk, B and Buczek, A and Pilśniak, A and Chmiela, T and Jarosińska, A and Siuda, J and Holecki, M},
title = {The Role of Glucagon-like Peptide-1 Receptor Agonists in Alzheimer's and Parkinson's Disease: A Literature Review of Clinical Trials.},
journal = {Life (Basel, Switzerland)},
volume = {15},
number = {12},
pages = {},
pmid = {41465832},
issn = {2075-1729},
abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes and obesity due to their metabolic effects. Emerging evidence suggests they may also have neuroprotective effects, indicating their potential as disease-modifying therapies in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Preclinical studies in animal models have demonstrated that GLP-1RAs can reduce neuroinflammation, oxidative stress, neuronal apoptosis, and pathological protein aggregation, while enhancing glucose metabolism and mitochondrial function. This narrative review analyzed results from human clinical trials evaluating GLP-1RAs in AD and PD, based on a search of four databases (Web of Science, Medline, Embase, and Clinical Trials). The analysis included eleven studies. In AD, clinical trials suggest that GLP-1RAs such as liraglutide and semaglutide may enhance brain glucose metabolism, facilitate glucose transport across the blood-brain barrier, and benefit neuronal networks. However, most studies did not demonstrate improvements in cognitive functions or radiological markers. Short-term clinical trials of GLP-1RAs, including exenatide and lixisenatide, demonstrated promising effects on motor and selected non-motor symptoms in patients with PD, but their disease-modifying effects remain unproven. GLP-1RAs showed a favorable safety profile. Despite promising findings, small study populations, heterogeneous protocols, and short observation periods limit definitive conclusions. Further larger, long-term studies are needed, particularly to clarify the risk-benefit balance, weight control, and long-term outcomes.},
}

@article {pmid41465466,
year = {2025},
author = {Xu, C and Owen, JE and Gislason, T and Benediktsdottir, B and Ye, J and Robinson, SR},
title = {Limited Microvascular Remodelling Occurs in the Aged Human Hippocampus in Obstructive Sleep Apnoea.},
journal = {International journal of molecular sciences},
volume = {26},
number = {24},
pages = {},
pmid = {41465466},
issn = {1422-0067},
support = {Not applicable//RMIT University/ ; },
mesh = {Humans ; *Sleep Apnea, Obstructive/pathology/physiopathology/therapy ; Male ; Middle Aged ; Female ; Aged ; *Hippocampus/blood supply/pathology ; *Microvessels/pathology/physiopathology ; Adult ; *Aging/pathology ; *Vascular Remodeling ; Continuous Positive Airway Pressure ; },
abstract = {In mice, intermittent hypoxia is associated with an increase in microvessels in the hippocampus, whereas in humans with obstructive sleep apnoea (OSA), microvessels are lost from the heart and retina. The present study investigated microvascular changes in the hippocampus of patients with OSA, and whether patient age or use of continuous positive airway pressure (CPAP) influence microvascularisation. Using autopsy samples from 31 people with confirmed OSA, microvessels were immunolabelled and quantitatively analysed. Compared to the Low OSA group, the High OSA group had larger mean microvessel diameters in the fimbria and CA4, and greater mean microvessel length in the fimbria, which are indicative of microvascular remodelling. An absence of angiogenesis was indicated by similar mean vessel counts in both OSA severity groups. Increased age was associated with microvascular remodelling in the fimbria only. Treatment with CPAP was not associated with changed patterns of microvascularisation. We conclude that: (i) no evidence was found for angiogenesis in the human hippocampus in OSA or ageing; (ii) increased OSA severity is associated with microvascular remodelling in the fimbria and CA4; (iii) microvascular remodelling does not appear to be influenced by CPAP use; (iv) limited adaptability of the microvasculature may underpin the vulnerability of the hippocampus to hypoxic injury, particularly in severe OSA.},
}

Humans
*Sleep Apnea, Obstructive/pathology/physiopathology/therapy
Male
Middle Aged
Female
Aged
*Hippocampus/blood supply/pathology
*Microvessels/pathology/physiopathology
Adult
*Aging/pathology
*Vascular Remodeling
Continuous Positive Airway Pressure

@article {pmid41465142,
year = {2025},
author = {Machowska, M and Leszek, J and Mikołajczyk-Tarnawa, A and Głowacka, K and Trypka, E and Rąpała, M and Piechota, J and Wiela-Hojeńska, A},
title = {The Diagnostic Reliability of BIN1 and TOMM40 Genotyping in Assessing Dementia Risk.},
journal = {Genes},
volume = {16},
number = {12},
pages = {},
pmid = {41465142},
issn = {2073-4425},
support = {RPDS.01.02.01-02-0002/20//Regional Operational Programme of the Lower Silesian Voivodeship 2014-2020, co-financed by the European Union, European Regional Development Fund/ ; },
mesh = {Humans ; *Mitochondrial Precursor Protein Import Complex Proteins/genetics ; Male ; Female ; Aged ; *Cognitive Dysfunction/genetics/diagnosis ; *Tumor Suppressor Proteins/genetics ; Polymorphism, Single Nucleotide ; *Adaptor Proteins, Signal Transducing/genetics ; *Alzheimer Disease/genetics/diagnosis ; *Nuclear Proteins/genetics ; Genotype ; *Dementia/genetics/diagnosis ; *Membrane Transport Proteins/genetics ; Genetic Predisposition to Disease ; Case-Control Studies ; Aged, 80 and over ; Middle Aged ; },
abstract = {OBJECTIVES: Alzheimer's disease (AD) and other dementias represent a growing public health concern, highlighting the need for reliable biomarkers for early diagnosis and treatment monitoring. This study evaluated the potential utility of BIN1 and TOMM40 genotyping in diagnosing mild cognitive impairment (MCI) and early-stage dementia.

METHODS: The BIN1 rs744373 and TOMM40 rs2075650 polymorphisms were genotyped in a cohort of 105 individuals diagnosed with MCI or dementia and in 164 cognitively healthy controls. Genotype distributions were compared between the groups, and the potential role of these variants in diagnostic assessment was explored.

RESULTS: A significantly higher frequency of the TOMM40 rs2075650 GG genotype was observed in patients with AD compared with cognitively healthy controls. In contrast, no statistically significant differences in genotype distribution were found among individuals with mild MCI, vascular dementia, or mixed dementia. Furthermore, the distribution of BIN1 rs744373 alleles did not differ significantly across the analyzed groups.

CONCLUSIONS: Data on the effects of BIN1 rs744373 and TOMM40 rs2075650 polymorphisms in MCI and dementia remain limited and inconsistent. In our study, significant differences were observed only for the TOMM40 rs2075650 GG genotype and G allele, which were more frequent in Alzheimer's disease patients than in controls. No significant associations were found for MCI, vascular dementia, or mixed dementia, nor for the BIN1 rs744373 polymorphism. These results suggest that TOMM40 rs2075650 genotyping may serve as an additional marker for assessing AD risk.},
}

Humans
*Mitochondrial Precursor Protein Import Complex Proteins/genetics
Male
Female
Aged
*Cognitive Dysfunction/genetics/diagnosis
*Tumor Suppressor Proteins/genetics
Polymorphism, Single Nucleotide
*Adaptor Proteins, Signal Transducing/genetics
*Alzheimer Disease/genetics/diagnosis
*Nuclear Proteins/genetics
Genotype
*Dementia/genetics/diagnosis
*Membrane Transport Proteins/genetics
Genetic Predisposition to Disease
Case-Control Studies
Aged, 80 and over
Middle Aged

@article {pmid41463129,
year = {2025},
author = {Eroglu, B and Velez, D and Jones, K and Deak, F and Eroglu, A},
title = {Amelioration of Alzheimer's Disease Pathology in Zebrafish by Photobiomodulation.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
pmid = {41463129},
issn = {2227-9059},
abstract = {Background/Objectives: The zebrafish is a widely used research model due to its characteristics, such as being transparent during development, sharing 70% of its genes with humans, and having conserved features of vertebrate aging, including deterioration of mitochondrial and cognitive functions. While affecting approximately 15% of the world population, neurodegenerative diseases, such as Alzheimer's disease (AD), are currently incurable, requiring testing of alternative treatment strategies. Hence, this study was conducted to test the hypothesis that an optimized photobiomodulation (PBM) therapy improves AD pathology through its multifaceted beneficial effects, including enhancing mitochondrial function and reducing oxidative stress and neuroinflammation. Methods: A pharmacological zebrafish model of AD was developed by adding small amounts (100 nM) of okadaic acid (OKA) directly to fish tanks for nine days. Next, some of OKA-treated and control zebrafish were subjected to an optimized near-infrared PBM therapy while others remain untreated. Results: When examined after OKA treatment, zebrafish brains displayed histological hallmarks of AD including, neurofibrillary tangles, vacuoles, and neuroinflammation. Behavioral tests using a T-maze revealed that OKA-treated zebrafish spent significantly less time in the reward arm than untreated controls (15.2% vs. 50%). In contrast, a sequential PBM therapy significantly reduced formation of neurofibrillary tangles, vacuoles, neuroinflammation, and improved mitochondrial biogenesis in brains of OKA-treated zebrafish while also improving their cognitive function as evidenced by being able to recall the reward arm and spending more time there similar to controls (55 and 57%, respectively). Conclusions: These findings suggest that (1) a fast, cost-effective zebrafish AD model can be developed using OKA treatment and (2) PBM therapy holds promise to ameliorate AD pathology.},
}

@article {pmid41463053,
year = {2025},
author = {N F Guimarães, G and Dos Santos Cardoso, F and Gamboa, L and W Barrett, D and Gonzalez-Lima, F},
title = {Abdominal Photobiomodulation and the Gut-Brain Axis: A Systematic Review of Mechanistic and Translational Evidence.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
pmid = {41463053},
issn = {2227-9059},
abstract = {Background/Objectives: Bidirectional communication between the gut and brain is central to neurological and psychiatric health, and abdominal photobiomodulation (PBM) has emerged as a promising non-invasive way to modulate this axis by targeting intestinal mitochondria, epithelial integrity, and the microbiota. We systematically reviewed preclinical and clinical evidence on abdominal PBM, alone or in combined protocols, reporting microbiome, metabolic, or neurobehavioral outcomes. Methods: Following PRISMA 2020 recommendations, we searched MEDLINE, Scopus, Web of Science, and ScienceDirect through May 2025 for animal and human studies applying PBM to the abdomen and reporting gut-related, metabolic, or brain-related outcomes. Results: Nine studies met the eligibility criteria (five human, four animal). Human trials, mainly in Parkinson's and Alzheimer's disease, used 630-904 nm light and reported gains in mobility, balance, cognition, and olfaction; one trial also showed microbiota modulation with a decreased Firmicutes:Bacteroidetes ratio. Animal models revealed cognitive improvement, reduced neuroinflammation, dopaminergic neuroprotection, and microbial rebalancing. Mechanistic findings converged on enhanced mitochondrial bioenergetics, redox and anti-inflammatory signaling, vagal activation, and short-chain fatty acid-mediated effects. Conclusions: Current evidence, though limited by small samples, heterogeneous dosimetry, combined treatment sites, and few sham-controlled human trials, suggests that abdominal PBM can influence the gut-brain axis through converging mitochondrial, immune, and microbial mechanisms. Adequately powered randomized trials with standardized dosimetry, validated mechanistic biomarkers, and integrative multi-omics analyses are needed to clarify causal pathways and optimize translational applications.},
}

@article {pmid41462869,
year = {2025},
author = {Sarbu, M and Ica, R and Biricioiu, MR and Dehelean, L and Zamfir, AD},
title = {Glycosphingolipids in Dementia: Insights from Mass Spectrometry and Systems Biology Approaches.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
pmid = {41462869},
issn = {2227-9059},
support = {PN-IV-P2-2.1-TE-2023-0175//UEFISCDI/ ; UAV-IRG-1-2025-8//Aurel Vlaicu University of Arad, Romania/ ; },
abstract = {This narrative literature review synthesizes recent evidence on glycosphingolipid (GSL) dysregulation in dementia, emphasizing discoveries enabled by mass spectrometry (MS) and systems biology. Focusing on the research published within the last decade, we selected studies that are relevant to GSL alterations in dementia and notable for their methodological advances. The findings were conceptually integrated to emphasize key molecular, analytical, and systems-level aspects across the major dementia types. The results from MS-based glycolipidomics in Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, Parkinson's disease dementia, and Huntington's disease consistently indicate altered GSL metabolism and shared molecular vulnerabilities in neuronal lipid regulation. At the same time, distinct GSL signatures differentiate individual dementias, reflecting the disease-specific mechanisms of neurodegeneration. The literature also reveals that recent advances in high-resolution MS and integrative analytical workflows have shifted GSL research from descriptive to mechanistic, facilitating the detailed mapping of species linked to neuroinflammation, protein aggregation, and synaptic dysfunction. Systems-level analyses combining MS data with other omics approaches increasingly depict GSLs as active regulators of neuronal function rather than inert membrane components. At the same time, emerging trends position GSLs as promising early biomarkers and potential therapeutic targets, while the growing use of artificial intelligence in MS data analysis is accelerating the detection of their subtle patterns, improving cross-disease comparisons. Together, these results reinforce the major role of MS-based platforms in discovering dementia-associated GSLs, identifying therapeutic targets, and influencing future strategies for diagnosis and treatment.},
}

@article {pmid41462867,
year = {2025},
author = {Fonseca, N and Nunes, M and Silva, PMA and Bousbaa, H and Ricardo, S},
title = {Galanthamine Fails to Reverse P-gp-Mediated Paclitaxel Resistance in Ovarian Cancer Cell Lines.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
pmid = {41462867},
issn = {2227-9059},
abstract = {Background: Ovarian cancer has the poorest prognosis of all gynecological malignancies, largely due to its chemoresistance, which poses significant treatment challenges. In this context, drug repurposing emerges as an innovative strategy that employs non-cancer treatments to interact with various signaling pathways, enhancing chemotherapy efficacy while minimizing toxicity. This study investigated the cytotoxic effects of galanthamine, currently used as an Alzheimer's disease, as a potential treatment for high-grade serous carcinoma, both individually and in combination with paclitaxel. Methods: The Presto Blue assay, viability marker assessments, immunocytochemical analysis of apoptosis, and a cumulative assay were employed to evaluate the functionality of P-glycoprotein. Results: The results indicated that galanthamine did not demonstrate cytotoxic or synergistic effects in either high-grade serous carcinoma cell line tested, suggesting that it is not a viable strategy for overcoming paclitaxel resistance in this context. The immunocytochemistry analysis indicated that galanthamine does not affect the expression of proteins related to cell viability and proliferation and is not associated with chemoresistance. Additionally, functional assays showed that galanthamine treatment did not affect its drug efflux function at the cellular level. Conclusions: Overall, the results indicate that galanthamine is unsuitable for reversing paclitaxel resistance despite some literature suggesting its potential interaction with P-glycoprotein.},
}

@article {pmid41461739,
year = {2025},
author = {Palachai, N and Buranrat, B and Pariwatthanakun, C and Noisa, P and Mairuae, N},
title = {Neuroprotective effects of Cratoxylum formosum (L.) leaf extract on β-amyloid-induced injury in human neuroblastoma SH-SY5Y cells.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {44730},
pmid = {41461739},
issn = {2045-2322},
support = {//the Faculty of Medicine, Mahasarakham University/ ; //Thai Traditional Medical Knowledge Fund/ ; },
mesh = {*Clusiaceae ; *Plant Extracts/chemistry/pharmacology/therapeutic use ; Drug Evaluation, Preclinical ; Humans ; Cell Line, Tumor ; *Alzheimer Disease/drug therapy ; Oxidative Stress/drug effects ; *Amyloid beta-Peptides ; *Neuroprotective Agents/analysis/pharmacology/therapeutic use ; MAP Kinase Signaling System/drug effects ; Flavonoids/analysis ; Peptide Fragments ; },
abstract = {In Alzheimer's disease (AD), Amyloid beta peptide (Aβ), the primary constituent of senile plaques, has been documented as triggering oxidative stress and leading to the death of neuronal cells. Therefore, this research aims to investigate how the Cratoxylum formosum (L.) leaf extract mitigates oxidative stress and cellular damage induced by Aβ in SH-SY5Y cells. The SH-SY5Y cells were treated with Cratoxylum formosum (L.) extract both with and without Aβ25-35. Neuroprotection was evaluated through viability and lactate dehydrogenase (LDH) assays, accompanied by an analysis of various mechanisms including caspase-3/7 activity, levels of reactive oxygen species (ROS), phosphorylation of protein kinase B (Akt), extracellular signal-regulated kinase 1/2 (ERK1/2), and cAMP-responsive element binding protein (CREB), expression of B-cell lymphoma 2 (Bcl-2) proteins, as well as catalase (CAT) and superoxide dismutase (SOD) activities. Results indicated an escalation in oxidative stress in cells exposed to Aβ, evidenced by increased ROS levels. Aβ further exacerbated caspase-3/7 activity, LDH release, and a decline in cell viability. Conversely, treatment with Cratoxylum formosum (L.) extract exhibited a concentration-dependent reduction in Aβ-induced neurotoxicity, manifesting in enhanced cell survival, reduced LDH release and ROS production, and suppression of caspase-3/7 activity. Moreover, it led to increased phosphorylation of Akt, ERK1/2, CREB, upregulated expression of Bcl-2 proteins, and enhanced activity of SOD and CAT. High-performance liquid chromatography (HPLC) analysis identified chlorogenic acid, 1,5-dicaffeoylquinic acid, and ferulic acid as the major phenolic constituents of Cratoxylum formosum (L.) extract. These results imply that the extract may provide protective effects against Aβ-induced neurotoxicity, although further studies are required to clarify its role in AD.},
}

*Clusiaceae
*Plant Extracts/chemistry/pharmacology/therapeutic use
Drug Evaluation, Preclinical
Humans
Cell Line, Tumor
*Alzheimer Disease/drug therapy
Oxidative Stress/drug effects
*Amyloid beta-Peptides
*Neuroprotective Agents/analysis/pharmacology/therapeutic use
MAP Kinase Signaling System/drug effects
Flavonoids/analysis
Peptide Fragments

@article {pmid41461684,
year = {2025},
author = {Saremi, M and Safari, S and Alikhani, MY and Komaki, A and Siadat, SD and Asghari, B},
title = {Evidence for neuroprotection by Bacillus coagulans ATCC 7050 via synaptic plasticity and oxidative balance in Alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {44690},
pmid = {41461684},
issn = {2045-2322},
support = {Grant Number: 140303292888//Vice Chancellor for Research and Technology, Hamadan University of Medical Sciences/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology ; *Oxidative Stress/drug effects ; Male ; *Neuronal Plasticity/drug effects ; Rats ; Rats, Wistar ; *Bacillus coagulans/physiology ; Disease Models, Animal ; Hippocampus/metabolism ; Amyloid beta-Peptides ; *Probiotics/pharmacology/administration & dosage ; Long-Term Potentiation ; *Neuroprotection ; Superoxide Dismutase/metabolism ; Memory, Short-Term ; Glutathione Peroxidase/metabolism ; Malondialdehyde/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic impairment, and oxidative stress. Probiotics with antioxidant and anti-inflammatory properties have been proposed as potential adjunctive strategies. This study examined whether oral administration of Bacillus coagulans ATCC 7050 could attenuate hippocampal oxidative stress, modulate synaptic plasticity, and influence spatial working memory in an Aβ1-42-induced rat model of AD. Adult male Wistar rats were assigned to Sham, AD, BC (probiotic only), and AD + BC groups. Working memory was assessed by Y-maze, synaptic function by perforant path-dentate gyrus long-term potentiation (LTP) recordings, and oxidative status by hippocampal malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) assays. AD rats exhibited reduced alternation percentage, impaired LTP (fEPSP slope and PS amplitude), elevated MDA, and decreased SOD and GPx activities versus Sham. B. coagulans treatment improved alternation percentage without affecting total entries, preserved PS amplitude from 30 min post-HFS, reduced MDA, and restored SOD activity, with partial GPx recovery. fEPSP slope remained reduced. These findings suggest B. coagulans ATCC 7050 mitigates oxidative stress, preserves neuronal excitability, and improves working memory in an Aβ-based AD model, supporting further investigation of its potential as a safe adjunct in early-stage disease.},
}

Animals
*Alzheimer Disease/metabolism/physiopathology
*Oxidative Stress/drug effects
Male
*Neuronal Plasticity/drug effects
Rats
Rats, Wistar
*Bacillus coagulans/physiology
Disease Models, Animal
Hippocampus/metabolism
Amyloid beta-Peptides
*Probiotics/pharmacology/administration & dosage
Long-Term Potentiation
*Neuroprotection
Superoxide Dismutase/metabolism
Memory, Short-Term
Glutathione Peroxidase/metabolism
Malondialdehyde/metabolism