@article {pmid41896164,
year = {2026},
author = {Goodchild, K and Parkinson, E and Cross, JL},
title = {Interventions to support young carers/supporters of people living with dementia: a mixed methods systematic review.},
journal = {International journal of qualitative studies on health and well-being},
volume = {21},
number = {1},
pages = {2650367},
doi = {10.1080/17482631.2026.2650367},
pmid = {41896164},
issn = {1748-2631},
mesh = {Humans ; *Dementia/nursing ; *Caregivers/psychology ; Child ; *Social Support ; },
abstract = {PURPOSE: Despite children being young carers for people living with dementia globally, and evidence suggesting they need more support, there is limited research evaluating best practice for dementia-care related interventions for children. The purpose of this work was therefore to comprehensively summarise the existing literature by synthesising studies appraising existing child-focused and dementia-care relevant interventions.

METHOD: A mixed methods systematic review with a convergent integrated synthesis approach. Four databases were systematically searched from 1st January 2013 to 9th February 2024. Qualitative, quantitative, and mixed methods studies evaluating any intervention programme that aimed to improve children's understanding and/or support for people living with dementia were included.

RESULTS: Seventeen studies, evaluating 15 different interventions (1,345 participants), were eligible for inclusion. Extracted data were inductively synthesised into 18 categories, forming six integrated findings relating to what makes interventions useful for helping children to understand and/or support people living with dementia.

CONCLUSIONS: The findings can inform the development of interventions for children with dementia care responsibilities, and further robust research.},
}

Humans
*Dementia/nursing
*Caregivers/psychology
Child
*Social Support

@article {pmid41896174,
year = {2026},
author = {Yang, Q and Li, T and Jester, HM and Su, Q and Zhou, X and Ryazanov, AG and Ma, T},
title = {Synaptic Potentiation in Hippocampus by eEF2K Inhibitor A484954.},
journal = {Hippocampus},
volume = {36},
number = {3},
pages = {e70091},
doi = {10.1002/hipo.70091},
pmid = {41896174},
issn = {1098-1063},
support = {R01 AG073823/AG/NIA NIH HHS/United States ; RF1 AG082388/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Elongation Factor 2 Kinase/antagonists & inhibitors/genetics/metabolism ; *Long-Term Potentiation/drug effects/physiology ; *Hippocampus/drug effects/physiology ; Mice, Transgenic ; Mice ; Mice, Knockout ; Mice, Inbred C57BL ; Male ; Dose-Response Relationship, Drug ; Excitatory Postsynaptic Potentials/drug effects ; },
abstract = {An important mechanism controlling protein synthesis is through phosphorylation of the eukaryotic elongation factor 2 (eEF2) by its kinase eEF2K. Hyperphosphorylation of eEF2 is linked to many neuronal diseases characterized by cognitive impairments. Consistently, recent studies show that the inhibition of the eEF2K signaling via genetic or pharmacological approaches can alleviate synaptic failure and dementia syndromes in mouse models of Alzheimer's disease (AD) and related dementias (ADRDs). One commonly used tool to study eEF2K signaling is A-484954 (or AG), a small molecule compound that is considered a highly selective and potent eEF2K antagonist. Here we reported that the AG compound (at three doses) can induce chemical long-term potentiation (LTP) in acute hippocampal slices from mice. Taking advantage of two transgenic mouse models with eEF2K knockout or overexpression, we further demonstrated that eEF2K-independent mechanisms contribute to chemical LTP induced by AG (dose-dependent). Our data suggest cautious interpretation of findings on neuronal effects of eEF2K inhibitors such as AG. Future investigations are warranted to elucidate the detailed molecular mechanisms underlying the effects of AG compound and other eEF2K inhibitors on synaptic and cognitive function.},
}

Animals
*Elongation Factor 2 Kinase/antagonists & inhibitors/genetics/metabolism
*Long-Term Potentiation/drug effects/physiology
*Hippocampus/drug effects/physiology
Mice, Transgenic
Mice
Mice, Knockout
Mice, Inbred C57BL
Male
Dose-Response Relationship, Drug
Excitatory Postsynaptic Potentials/drug effects

@article {pmid41896453,
year = {2026},
author = {Napolitano, L and Vadukul, DM and Bigi, A and Palladino, P and Cecchi, C and Chiti, F and Cascella, R and Aprile, FA},
title = {Engineering a dimeric single-domain antibody for improved detection and neutralization of amyloid-β oligomers.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-09740-6},
pmid = {41896453},
issn = {2399-3642},
support = {Progetto Prama//Regione Toscana (Tuscany Region)/ ; Fondi Ateneo//Università degli Studi di Firenze (University of Florence)/ ; Fondi Ateneo//Università degli Studi di Firenze (University of Florence)/ ; Fondi Ateneo//Università degli Studi di Firenze (University of Florence)/ ; Fondi Ateneo//Università degli Studi di Firenze (University of Florence)/ ; ARUK-PG2019B-020//Alzheimer's Research UK (ARUK)/ ; },
abstract = {Soluble Aβ oligomers are regarded as major neurotoxic agents in Alzheimer's disease. Several monoclonal antibodies have been developed to target Aβ oligomers, but most of them show limited specificity binding also to monomers and fibrils. To generate an antibody with high specificity for the oligomers, we aimed to increase the efficiency and sensitivity of a human VH-derived Aβ-oligomer-specific single domain antibody, called DesAb-O. We engineered a dimeric DesAb-O variant, DiDesAb-O, which showed significantly higher binding affinity for Aβ oligomers as compared to the monomeric sdAb. DiDesAb-O selectively detected Aβ42 oligomers not only in vitro and in cultured cells using synthetic preparations, but also in the cerebrospinal fluid from Alzheimer's patients. Moreover, it inhibited the binding of these toxic species to cellular membranes and neutralized their neurotoxicity both in cells and in patient-derived cerebrospinal fluid at lower concentrations compared to DesAb-O. These results indicate that rational dimerization of single-domain antibodies can substantially enhance target engagement and functional efficacy, providing a promising strategy for the development of improved diagnostic and therapeutic molecules for Alzheimer's disease.},
}

@article {pmid41896522,
year = {2026},
author = {Yu, Q and Du, F and Puerta-Alvarado, V and Goodman, JH and Waites, CL},
title = {APOE4 exacerbates glucocorticoid stress hormone-induced tau pathology via mitochondrial dysfunction.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08543-1},
pmid = {41896522},
issn = {2041-4889},
support = {R01NS080967//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; RF1AG069941//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R21AG085473//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {APOE4 is the leading genetic risk factor for Alzheimer's disease, and chronic stress is a leading environmental risk factor. Studies suggest that APOE4 confers vulnerability to the behavioral and neuropathological effects of chronic stress, representing a potential mechanism by which this genetic variant accelerates Alzheimer's onset and progression. Whether and how APOE4-mediated stress vulnerability manifests in neurons of the hippocampus, a brain region particularly susceptible to stress and Alzheimer's pathology, remains unexplored. Using a combination of in vivo and in vitro experiments in humanized APOE4 and APOE3 knockin mice and primary hippocampal neurons from these animals, we investigated whether and how APOE4 confers sensitivity to glucocorticoids (GCs), the main stress hormones. We found that a hallmark of stress/GC-induced brain damage, tau pathology (i.e., tau accumulation, hyperphosphorylation, and spreading) is exacerbated in APOE4 versus APOE3 mice. Moreover, APOE4 animals exhibit underlying mitochondrial dysfunction and enhanced glucocorticoid receptor activation in the hippocampus, factors that likely contribute to tau pathogenesis in both the presence and absence of stress/GCs. Supporting this concept, opening of the mitochondrial permeability transition pore (mPTP) drives mitochondrial dysfunction and tau pathology in APOE4 mice, while pharmacological inhibition of the mPTP is protective against ApoE4-mediated mitochondrial damage, tau phosphorylation and spreading, and downstream hippocampal synapse loss. These findings shed light on the mechanisms of stress vulnerability in APOE4 carriers and identify the mPTP as a potential therapeutic target for ameliorating Alzheimer's pathogenesis in this population.},
}

@article {pmid41896724,
year = {2026},
author = {Connell, E and Sami, S and Khondoker, M and Minihane, AM and Pontifex, MG and Müller, M and McArthur, S and Le Gall, G and Vauzour, D},
title = {Circulatory dietary and gut-derived metabolites predict early cognitive decline.},
journal = {Gut microbes},
volume = {18},
number = {1},
pages = {2649487},
doi = {10.1080/19490976.2026.2649487},
pmid = {41896724},
issn = {1949-0984},
mesh = {Humans ; *Cognitive Dysfunction/microbiology/blood/metabolism/diagnosis ; Male ; *Gastrointestinal Microbiome ; Female ; Aged ; Middle Aged ; *Bacteria/metabolism/classification/genetics/isolation & purification ; Biomarkers/blood ; Dysbiosis/microbiology ; Diet ; Bile Acids and Salts/blood ; Methylamines/blood ; Aged, 80 and over ; Tryptophan/blood ; },
abstract = {INTRODUCTION: A key component of disease prevention is the identification of at-risk individuals. Microbial dysbiosis in the early stages of cognitive decline and Alzheimer's disease (AD) and can modulate the levels of microbe-derived metabolites (MDM), thought to contribute to neuroinflammation, blood‒brain barrier dysfunction, and neuronal degeneration. However, the precise role of MDM in this process, as well as their potential value as risk factors, remains poorly understood.

METHODS: Mass spectrometry platforms determined the serum concentration of 33 metabolites (13 tryptophan-related compounds, 15 bile acid compounds, 3 TMAO-related metabolites and 2 cresol metabolites) from cognitively healthy subjects, subjective cognitive impairment (SCI) participants and mild cognitive impairment (MCI) participants (n = 50 per group, matched for age, BMI and sex). Multiple linear regression and machine learning techniques were applied to identify a metabolite panel capable of classifying early cognitive decline. 16S rRNA amplicon sequencing was employed to identify bacterial taxa associated with these metabolic changes.

RESULTS: Multiple linear regression modelling, adjusted for sex, BMI, age, albumin (for its role in metabolite transport), liver and kidney function, and background diet, identified key neuroprotective metabolites, namely choline, 5-hydroxyindole acetic acid, and indole propionic acid (IPA), as lower in SCI and MCI individuals compared to healthy controls. In contrast, the cytotoxic metabolite, indoxyl sulfate, and kynurenic acid were elevated. A random forest algorithm with multiclass classification further validated these findings, highlighting six metabolites (indoxyl sulfate, choline, 5-hydroxyindole acetic acid, IPA, kynurenic acid, and kynurenine) as classifiers of early cognitive decline, achieving an area under the curve (AUC) of 0.79.

CONCLUSION: These findings suggest that MDM may serve as putative composite biomarkers of early cognitive decline, offering potential clinical relevance for metabolic risk stratification and supporting the future development of minimally invasive screening tools.},
}

Humans
*Cognitive Dysfunction/microbiology/blood/metabolism/diagnosis
Male
*Gastrointestinal Microbiome
Female
Aged
Middle Aged
*Bacteria/metabolism/classification/genetics/isolation & purification
Biomarkers/blood
Dysbiosis/microbiology
Diet
Bile Acids and Salts/blood
Methylamines/blood
Aged, 80 and over
Tryptophan/blood

@article {pmid41896988,
year = {2026},
author = {Ma, Y and Xie, M and Ibáñez, CF},
title = {Palmitoylation of death receptor p75[NTR] contributes to Alzheimer's disease progression by regulating APP trafficking and degradation.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02032-5},
pmid = {41896988},
issn = {1758-9193},
}

@article {pmid41896998,
year = {2026},
author = {van der Schaar, J and van der Flier, WM and Visser, LNC and van de Giessen, E and van Harten, AC and Sikkes, SAM and van Leeuwenstijn-Koopman, MSSA and Hendriksen, HMA and Trieu, C and Bredenoord, AL and van den Hoven, MA and Asscher, ECA},
title = {Longterm impact of disclosing amyloid PET results to individuals with subjective cognitive decline.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02026-3},
pmid = {41896998},
issn = {1758-9193},
support = {73305095007/ZONMW_/ZonMw/Netherlands ; 73305095007/ZONMW_/ZonMw/Netherlands ; 73305095007/ZONMW_/ZonMw/Netherlands ; LSHM20106//Health∼Holland, Topsector Life Sciences & Health/ ; LSHM20106//Health∼Holland, Topsector Life Sciences & Health/ ; LSHM20106//∼Holland, Topsector Life Sciences & Health/ ; },
}

@article {pmid41897293,
year = {2026},
author = {Çelik, H and Çelik, O and Aydın, Ş and Küçükler, S and Çomaklı, S and Akay, R and Gönüllü, S and Yıldız, MO and Alım, B and Özdemir, S},
title = {Evaluation of Plasma-Derived hsa_circ_003077 for Non-Invasive Diagnosis of Alzheimer's Disease.},
journal = {Biomolecules},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/biom16030356},
pmid = {41897293},
issn = {2218-273X},
mesh = {*Alzheimer Disease/diagnosis/blood/genetics ; Humans ; *RNA, Circular/blood ; Biomarkers/blood ; Male ; Female ; Aged ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; Peptide Fragments/blood ; Aged, 80 and over ; ROC Curve ; Middle Aged ; Receptor Protein-Tyrosine Kinases/blood ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting the central nervous system and is the most common form of dementia in the elderly. Current diagnostic methods are limited in the early and definitive diagnosis of the disease, necessitating the need for new and more reliable biomarkers. Circular RNAs (circRNAs) are non-coding, single-stranded, and highly stable RNA molecules commonly found in the eukaryotic transcriptome. Recent studies have shown that changes in the expression levels of circRNAs may play a role in AD pathogenesis. Furthermore, these molecules are considered as potential non-invasive biomarkers for early diagnosis of AD. In this study, we comprehensively assessed plasma levels of classical neurodegenerative biomarkers [amyloid-β42/amyloid-β40 (Aβ42/Aβ40) ratio, total Tau (tTau), and phosphorylated Tau (pTau)], as well as glial and inflammatory mediators, TAM receptor family members (Tyro3 and AXL), and the newly identified circular RNA molecule hsa_circ_003077. The findings revealed that the expression levels of TAM receptors were significantly increased, the Aβ42/Aβ40 ratio decreased, and both total Tau and phosphorylated Tau levels were significantly increased in AD patients. In the receiver operating characteristic (ROC) curve analysis performed to determine the diagnostic potential of hsa_circ_003077, the area under the curve (AUC) was 0.90 (95% CI: 0.82-0.97). This high AUC value suggests that hsa_circ_003077 may be a strong and novel biomarker candidate for the non-invasive diagnosis of AD. The data obtained confirmed the diagnostic efficacy of classical AD biomarkers and revealed that hsa_circ_003077 is a promising biomarker for early and accurate detection of the disease. However, in order to assess the transferability of these findings to clinical practice, confirmatory studies with larger sample groups are needed to ensure reproducibility of the results.},
}

*Alzheimer Disease/diagnosis/blood/genetics
Humans
*RNA, Circular/blood
Biomarkers/blood
Male
Female
Aged
Amyloid beta-Peptides/blood
tau Proteins/blood
Peptide Fragments/blood
Aged, 80 and over
ROC Curve
Middle Aged
Receptor Protein-Tyrosine Kinases/blood

@article {pmid41897340,
year = {2026},
author = {Di Spiezio, A and Zonta, M},
title = {Astrocyte Ca[2+] Dysregulation in Alzheimer's Disease Mouse Models: Revisiting the Dogma of Hyperactivity.},
journal = {Biomolecules},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/biom16030404},
pmid = {41897340},
issn = {2218-273X},
support = {GMR23T1234//Telethon Foundation/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Astrocytes/metabolism/pathology ; Disease Models, Animal ; *Calcium/metabolism ; Mice ; *Calcium Signaling ; Humans ; Mice, Transgenic ; },
abstract = {Astrocytes are essential gatekeepers of brain homeostasis, and the disruption of their functions can contribute to the development of several neurological diseases. Among astrocyte signaling pathways, the intracellular second messenger Ca[2+] plays a pivotal role in regulating the release of gliotransmitters, which actively modulate fundamental processes in the brain such as synaptic plasticity and memory function. Several studies over the years support the idea that dysregulated astrocytic Ca[2+] homeostasis represents a relevant mechanism in Alzheimer's disease pathogenesis. Early works in transgenic mice modelling Alzheimer's disease reported increased Ca[2+] activity in astroglial cells, supporting the idea of hyperactivity as a common trait of astrocytes in this pathology. However, recent studies have described astrocyte Ca[2+] hypoactivity in various mouse models, revealing a more complex and heterogeneous scenario. In this review, we summarize and critically discuss the main studies addressing the direction(s) of astrocytic Ca[2+] signaling dysfunction in mouse models of Alzheimer's disease. We prioritize investigations performed in ex vivo and in vivo conditions, carefully comparing the different experimental approaches used to measure Ca[2+] activity in astrocytes. By integrating results across multiple mouse models and methodological strategies, we aim to provide a more complete picture of astrocyte Ca[2+] dysregulation in Alzheimer's disease.},
}

Animals
*Alzheimer Disease/metabolism/pathology
*Astrocytes/metabolism/pathology
Disease Models, Animal
*Calcium/metabolism
Mice
*Calcium Signaling
Humans
Mice, Transgenic

@article {pmid41897410,
year = {2026},
author = {De la Fuente, M and Garrido, A and Vida, C and Manassra, R and Gimenez-Llort, L},
title = {Peripheral Oxidation-Inflammation and Immunosenescence in Triple-Transgenic Mice for Alzheimer's Disease (3xTg-AD) at Early Neuropathological Stages of Disease and Decrease of Immune Impairment by Voluntary Exercise.},
journal = {Biomolecules},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/biom16030475},
pmid = {41897410},
issn = {2218-273X},
support = {910379//Complutense University of Madrid/ ; },
mesh = {Animals ; *Alzheimer Disease/immunology/pathology/metabolism/genetics ; Mice, Transgenic ; Male ; Mice ; Female ; *Inflammation/immunology/metabolism/pathology ; *Physical Conditioning, Animal ; *Immunosenescence ; Oxidation-Reduction ; Oxidative Stress ; Disease Models, Animal ; Spleen/immunology/metabolism ; Thymus Gland/immunology ; Cytokines/metabolism ; Leukocytes/immunology/metabolism ; Aging ; },
abstract = {Inflammatory-oxidative stress generated by immune cells plays an important role in aging and in age-related neurodegenerative disorders such as Alzheimer's disease (AD). Triple-transgenic mice for AD (3xTg-AD) are a suitable model for mimicking this disease in an age-dependent manner. We previously showed that peritoneal leukocyte functions and their redox-inflammatory state are altered early in female 3xTg-AD mice, which exhibit premature aging compared to non-transgenic (NTg) animals. However, their characteristics at 9 months of age, when they present an early neuropathological state, and the sex differences are not known. Here, we analyzed several spleen and thymus leukocyte functions (chemotaxis, natural killer activity, and lymphoproliferation in response to mitogens), pro-inflammatory (IL-1B, TNF-alpha) and anti-inflammatory (IL-10) released cytokine concentrations, and redox parameters (glutathione concentrations and glutathione peroxidase, glutathione reductase, and xanthine oxidase activities) in male and female 3xTg-AD mice compared to age-matched controls. We also analyzed the effects of voluntary physical exercise on immune functions. Our results show that 9-month-old male and female 3xTg-AD mice have worse immune functions, redox state, and inflammation than NTg counterparts. Physical exercise improves immune function. Thus, accelerated aging reflected by peripheral immunosenescence and oxidation-inflammation in 3xTg-AD mice precedes hallmark neuropathology, and exercise can slow down AD progression.},
}

Animals
*Alzheimer Disease/immunology/pathology/metabolism/genetics
Mice, Transgenic
Male
Mice
Female
*Inflammation/immunology/metabolism/pathology
*Physical Conditioning, Animal
*Immunosenescence
Oxidation-Reduction
Oxidative Stress
Disease Models, Animal
Spleen/immunology/metabolism
Thymus Gland/immunology
Cytokines/metabolism
Leukocytes/immunology/metabolism
Aging

@article {pmid41897462,
year = {2026},
author = {Zhang, M and Zhu, L and Wang, Y and Chen, W and He, Z},
title = {A Nasal Taxifolin Hydrogel Targets the TLR4/NF-κB/HIF-1α Axis to Suppress Ferroptosis in Alzheimer's Disease.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/antiox15030316},
pmid = {41897462},
issn = {2076-3921},
support = {YDZJ202502CXJD077//Construction of Jilin Province International Science and Tech-nology Cooperation Key Laboratory: Jilin Province Sika Deer Efficient Breeding and Product De-velopment International Cooperation Key Laboratory/ ; 2025ZDYFNS06//Changchun Key Research and Development Program: Research and Application Promotion of Sika Deer Full Industry Chain Technology/ ; },
abstract = {In order to further explore new therapeutic targets for Alzheimer's disease (AD), this study, under the guidance of network pharmacology and molecular docking analysis, focused on the TLR4/NF-κB/HIF-1α signal axis and ferroptosis and verified the mechanism of a nasal taxifolin thermosensitive hydrogel (TF-Gel). In the Okada acid (OA)-induced AD mouse model, intranasal administration of TF-Gel significantly improved cognitive dysfunction and reduced neuroinflammation and oxidative stress. Mechanism studies have shown that TF-Gel effectively reduces the accumulation of reactive oxygen species in the hippocampus, enhances mitochondrial membrane potential, and improves mitochondrial ultrastructure by specifically inhibiting the TLR4/NF-κB/HIF-1α pathway, thereby effectively inhibiting neuronal ferroptosis. Western blot analysis confirmed the regulation of ferroptosis, synaptic function, and apoptosis-related proteins by TF-Gel. Of particular importance, the therapeutic benefits of TF-Gel were completely abolished by co-administration of the ferroptosis inducer Erastin, directly confirming that ferroptosis inhibition is the core link in its neuroprotective effect. This study reveals for the first time that TF-Gel exerts a multi-target neuroprotective effect by precisely regulating the TLR4/NF-κB/HIF-1α axis ferroptosis pathway, providing a new perspective for research into the mechanism and treatment of AD.},
}

@article {pmid41897492,
year = {2026},
author = {Arrighi, F and Berrino, E and Guglielmi, P and Carradori, S and Marconi, GD and Pizzicannella, J and Guarnieri, S and Tuccinardi, T and Poli, G and Pepi, F and Troiani, A and Salvitti, C and Di Noi, A and Coluccia, M and Buttitta, G and Pontecorvi, V and Granese, A and Chimenti, P and Secci, D and Petzer, A and Petzer, JP and Diomede, F},
title = {Novel Insights on Benzo[b]thiophene Analogues for MAO-B Inhibition and Neuroprotection: Design, Synthesis, Molecular Modelling Studies and Biological Activity.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/antiox15030346},
pmid = {41897492},
issn = {2076-3921},
support = {2022HXMY4P//European Union-Next Generation EU/ ; },
abstract = {Neurodegenerative disorders (NDs), such as Alzheimer's disease and Parkinson's disease (PD), represent a significant challenge for ageing populations, with their prevalence increasing worldwide. Elevated human Monoamine Oxidase B (hMAO-B) activity has been related to neurodegenerative progression, where it contributes, among others, to oxidative stress and neuroinflammation. The identification and optimization of selective hMAO-B inhibitors is therefore pivotal in addressing the progression of NDs. In this work we introduced 2-aroylbenzothiophene analogues as promising agents to mitigate neurodegeneration. The synthesized compounds were screened against hMAO-A and hMAO-B, identifying compounds 4, 11, and 12 as the most promising. In vitro studies in hGF and SH-SY5Y cells revealed distinct toxicity profiles, with compound 4 being the least tolerated at 100 µM. ROS generation was investigated as a possible mechanism underlying this toxicity. Compounds 4 (12.5 µM), 11, and 12 (100 µM) were further evaluated for neuroprotective effects against 6-hydroxydopamine (6-OHDA)-induced toxicity in SH-SY5Y cells, showing a modest neuroprotective effect after 72 h at a sub-toxic 6-OHDA concentration (250 µM), comparable to the clinically used hMAO-B inhibitor (R)-(-)-Deprenyl at 100 µM. Finally, molecular modelling studies revealed that compound 4 establishes key stabilizing interactions within hMAO-B, accounting for its high inhibitory potency and selectivity over hMAO-A.},
}

@article {pmid41897493,
year = {2026},
author = {Chen, T and Chen, H and Qiu, Y and Liu, Y and Xie, M and Huang, S and Feng, K and Zhuang, J and Chen, L and Chen, Y and Li, H and Yang, M and Yang, Z and Zhu, H},
title = {Effects and Mechanisms of Probiotics, Prebiotics, Synbiotics, and Postbiotics for the Prevention and Management of Alzheimer's Disease: A Narrative Review.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/antiox15030347},
pmid = {41897493},
issn = {2076-3921},
support = {82473619//National Natural Science Foundation of China/ ; 82504409//Young Scientists Fund of the National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is a rapidly escalating global health crisis with limited effective treatments. Emerging research underscores the pivotal role of the microbiota-gut-brain axis in AD pathogenesis, prompting the exploration into gut microbiota-targeted interventions. This narrative review aimed to comprehensively synthesize the latest epidemiological, experimental, and clinical evidence regarding the effects and mechanisms of probiotics, prebiotics, synbiotics, and postbiotics (PPSPs) in AD prevention and management. We conducted a narrative review of relevant literature from the Web of Science and PubMed databases. The search focused on articles published within the last 5 years using keywords such as "Alzheimer's disease", "AD", "gut-brain axis", "gut microbiota", "probiotics", "prebiotics", "synbiotics", and "postbiotics". The findings suggest that PPSPs mitigate AD pathology and improve cognitive performance by modulating gut microbiota, strengthening intestinal barrier integrity, decreasing amyloid-beta (Aβ) deposition and tau hyperphosphorylation, reducing neuroinflammation and oxidative stress, regulating neurotransmitter metabolism, and promoting synaptic plasticity. Some studies also report varied outcomes, attributable to factors like strain specificity, dosage, intervention duration, patient heterogeneity, and methodological differences. In conclusion, targeting the microbiota-gut-brain axis with PPSPs offers a promising, mechanism-based strategy for AD, though further research is essential to optimize specific interventions for clinical application.},
}

@article {pmid41897548,
year = {2026},
author = {Mo, C and Bajgai, J and Rahman, MH and Ma, H and Pham, TT and Zhang, H and Cao, B and Jeong, ES and Kim, CS and Lee, KJ},
title = {Neuroprotective Effects of Molecular Hydrogen via Oxidative Stress and Neuroinflammation Regulation in a 5xFAD Mouse Model.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/antiox15030404},
pmid = {41897548},
issn = {2076-3921},
support = {RS-2023-00253240//National Research Foundation of Korea (NRF), funded by the Korean government (MSIT)/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which amyloid-beta (Aβ) accumulation, oxidative stress (OS), and chronic inflammation drive synaptic dysfunction and cognitive decline. Molecular hydrogen (H2) has emerged as a candidate neuroprotective gas with selective antioxidant and anti-inflammatory properties, although its efficacy in amyloid-driven pathology remains incompletely defined. In this study, 5xFAD transgenic mice harboring human amyloid precursor protein (APP) and presenilin-1 (PSEN1) mutations and age-matched C57BL/6 wild-type mice were exposed to 2% H2 by inhalation for 1 h/day over 4 weeks. H2 inhalation reduced hippocampal reactive oxygen species (ROS), increased systemic catalase activity, and enhanced hippocampal ATP levels. In serum, H2 decreased tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β, restored IL-10, and partially normalized IL-13, shifting the peripheral environment toward a less pro-inflammatory profile. In the hippocampus, H2 upregulated nuclear factor erythroid 2-related factor 2 (NRF2), attenuated nuclear factor kappa B (NF-κB) activation, reduced the BAX/BCL-2 ratio, preserved neuronal nuclei (NEUN) expression, and decreased hippocampal Aβ42 burden. Collectively, these findings indicate that H2 inhalation confers multi-faceted neuroprotection in 5xFAD mice by restoring redox homeostasis, suppressing inflammation, improving mitochondrial function, and limiting Aβ accumulation.},
}

@article {pmid41897568,
year = {2026},
author = {Ali, A and Shahbaz, H and Ganie, SM and Alfuraydan, MM},
title = {X-ViTCNN: A Novel Network-Level Fusion of Transfer Learning and Customized Vision Transformer for Multi-Stage Alzheimer's Disease Prediction Using MRI Scans.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/diagnostics16060835},
pmid = {41897568},
issn = {2075-4418},
support = {Grant No: KFUXXXXXX//King Faisal University/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by an overall decline in cognitive functioning and represents a major public health crisis. It remains critical to be able to accurately and quickly diagnose patients with AD; however, recent deep learning approaches using MRI data do not provide sample generalization, have high computational requirements, and offer little interpretability. Methods: In this study, we present a new framework called eXplorative ViT-CNN (X-ViTCNN) that combines a customized Vision Transformer model with two previously trained CNNs (DenseNet201 and MobileNetV2). With our proposed preprocessing approach using contrast-enhanced preprocessing to highlight neuroanatomical features as well as Bayesian Optimization to tune hyperparameters, we fuse local structural features originating from the CNNs with global representations from the transformer and feed the final result to fully connected dense layers for multi-stage classification. We also use Grad-CAM visualizations to provide insight into how our model arrived at its classification. Results: Experiments conducted on ADNI and OASIS datasets demonstrate the superiority of X-ViTCNN, achieving accuracies of 97.98% and 94.52%, respectively. The model outperformed individual baselines and other pre-trained architectures, showing balanced sensitivity and specificity across all AD stages. Conclusions: The proposed X-ViTCNN framework is a powerful, interpretable method for predicting the development of multi-stage Alzheimer's disease using MRI scans. The combination of complementary feature learning, automatic hyperparameter optimization and interpretability through visualization make it an excellent potential tool for clinicians to support their decision making in the early diagnosis and ongoing monitoring of persons with Alzheimer's disease.},
}

@article {pmid41897801,
year = {2026},
author = {Dimopoulou, M and Madesis, P and Dimopoulou, A and Gortzi, O},
title = {Optimizing Omega-3 Polyunsaturated Fatty Acids for Healthy Ageing: Human Intake Evidence and Dairy Cow Dietary Interventions for Milk Enrichment.},
journal = {Foods (Basel, Switzerland)},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/foods15061079},
pmid = {41897801},
issn = {2304-8158},
abstract = {As populations around the world continue to age, promoting healthy ageing has become a key public health priority. Nutrition plays a vital role in maintaining physical and cognitive function later in life, and omega-3 polyunsaturated fatty acids (PUFA) are essential components of cell membranes and are known for their anti-inflammatory and cardio-protective effects. Chronic inflammation and oxidative stress are major contributors to age-related decline, and omega-3s help mitigate these processes by modulating immune responses and improving endothelial function. This systematic review aims to examine the potential of omega-3 fatty acids to reduce inflammatory markers and improve overall health. Moreover, it aims to present the most effective dietary interventions in dairy cows that increase PUFA content in milk. PubMed, Web of Science, Scopus, and the Cochrane Library databases were searched for relevant articles published up to November 2025. Evidence suggests that older adults who consume higher levels of PUFA tend to have better cardiovascular health, preserved cognitive function, and a lower risk of age-related diseases such as Alzheimer's and arthritis, and reduce the risk of frailty and disability in later years. Dietary manipulation to enhance PUFA in bovine milk represents a promising strategy for improving human nutrition while potentially benefiting cow health.},
}

@article {pmid41898169,
year = {2026},
author = {Schreiner, TG and Ciobanu, RC and Schreiner, OD},
title = {Tau Protein Aggregation Inhibitors-Therapeutic Strategy for Concurrent Tau and Amyloid Aggregation Inhibition.},
journal = {Biomedicines},
volume = {14},
number = {3},
pages = {},
doi = {10.3390/biomedicines14030522},
pmid = {41898169},
issn = {2227-9059},
abstract = {Tau protein, a microtubule-associated protein widely distributed in the central nervous system, aggregates abnormally and forms neurofibrillary tangles in neurodegenerative diseases. Particularly in Alzheimer's disease, pathological tau protein aggregates disrupt the structure and function of neurons, triggering other neurodegenerative-related processes such as neuroinflammation and amyloid plaque formation, and finally leading to neuronal death. Several classes of drugs targeting neurofibrillary tangles have recently been studied, with tau protein aggregation inhibitors as a key research direction. In the context of emerging therapeutic perspectives, this review aims to provide an updated, practical overview of currently available tau protein aggregation inhibitors and future research directions. The first part of the manuscript highlights the pathophysiological basics of tau protein aggregation and tau-related changes in neurodegenerative disorders, with a focus on Alzheimer's disease pathology. Subsequently, the most relevant classes of drugs that inhibit tau protein aggregation, including small-molecule inhibitors and natural compounds, are presented, with examples from recent clinical trials. Finally, beyond summarizing established classes of tau aggregation inhibitors, this review places particular emphasis on emerging and comparatively underexplored compounds with dual activity against both tau and amyloid-β pathology. The originality and novelty of this work arise from the systematical analysis of recent preclinical and clinical evidence with a translational, practice-oriented perspective, highlighting mechanistic convergence, repurposing opportunities, and therapeutic combinations that may better reflect the multifactorial nature of neurodegenerative diseases. Thus, this work provides a forward-looking framework for future drug development and identifies promising candidates that may shape the next generation of disease-modifying therapies.},
}

@article {pmid41898187,
year = {2026},
author = {Danish Mujib, M and Mubashir, N and Rao, AZ and Nasir, N and Ikhlaq, A and Sehar Hussain, S and Zia, F and Mohiuddin Asim, G and Alokaily, AO and Almadi, MA and Qazi, SA and Abul Hasan, M},
title = {Binaural Beat Stimulation Enhances Cognitive Function in Alzheimer's Disease via Temporal Lobe Activation: An sLORETA Study.},
journal = {Biomedicines},
volume = {14},
number = {3},
pages = {},
doi = {10.3390/biomedicines14030540},
pmid = {41898187},
issn = {2227-9059},
abstract = {Background: The global prevalence of Alzheimer's disease (AD) has reached 55.2 million. AD is characterized by progressive deterioration in cognition and working memory (WM), which are essential for attention, reasoning, and learning. These impairments are associated with pathological changes in cortical and subcortical regions. Binaural beats (BBs), a non-invasive auditory neuromodulation technique, have demonstrated cognitive enhancement effects in healthy individuals; however, their impact on WM in patients with AD remains largely unexplored. Methods: This study investigated the effects of BB stimulation on WM and cognitive function in the temporal lobe of patients with AD using standardized Low-Resolution Electromagnetic Tomography (sLORETA). Twenty-five patients with AD were randomly assigned to either an experimental group (n = 15) that received BB stimulation or a control group (n = 10) that received standard auditory stimulation. EEG recordings were obtained before and after the intervention. Results: Paired t-tests conducted on timeframe and frequency-wise sLORETA images revealed significant increases (p < 0.05) in theta, alpha1, and alpha2 frequency bands in the experimental group. Activated regions included the inferior, middle, superior, and transverse temporal gyri; Brodmann areas (BA) 20, 21, 22, 40, and 42; as well as networks associated with working memory and cognition. Conclusions: These findings suggest that BB stimulation induces temporal lobe activation, thereby enhancing working memory and cognitive function in patients with AD.},
}

@article {pmid41898208,
year = {2026},
author = {Baek, H and Park, M and Lee, HJ},
title = {Nobiletin Ameliorates Alzheimer's Disease Pathology by Reducing Oxidative Stress and Neuroinflammation Through the AMPK/SIRT1/PGC-1α and PI3K/Akt-CREB-BDNF Pathways in 5XFAD Mice.},
journal = {Biomedicines},
volume = {14},
number = {3},
pages = {},
doi = {10.3390/biomedicines14030561},
pmid = {41898208},
issn = {2227-9059},
support = {RS-2024-00401736//This work was supported by the Korea Institute of Planning and Evaluation for Technology in Food, Agriculture and Forestry (IPET) through the Agricultural Microbiome R&D Program for Advancing Innovative Technology Program, funded by the Ministry of Agricu/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) involves amyloid-β (Aβ) deposition, oxidative stress, and neuroinflammation, leading to cognitive decline. Nobiletin, a citrus-derived polymethoxylated flavonoid, exerts antioxidant and anti-inflammatory effects. This study explored its neuroprotective mechanisms in the 5XFAD mouse model. Methods: Male 5XFAD and C57BL/6J mice received oral nobiletin (20 or 40 mg/kg/d) for 4 weeks. Cognitive function was assessed by the Y-maze test. Amyloid-β burden was quantified by Congo red staining and ELISA. Serum cytokine levels and antioxidant enzyme activities were measured by ELISA. Western blotting and RT-PCR were used to assess proteins and genes related to amyloidogenesis, inflammation (TLR4/MyD88/NF-κB), mitochondrial biogenesis (AMPK/SIRT1/PGC-1α), and synaptic plasticity (PI3K/Akt-CREB-BDNF). Results: Nobiletin improved working memory, reduced amyloid-β40/42 deposition, and downregulated APP, BACE1, and PS1 expression, while enhancing ADAM10 expression. It lowered serum IL-6, IL-1β, and TNF-α, increased SOD, CAT, and GPx activities, and suppressed TLR4/MyD88/NF-κB signaling. Furthermore, it activated AMPK/SIRT1/PGC-1α and NRF2 pathways, enhancing antioxidant defenses, and promoted PI3K/Akt-CREB-BDNF signaling, increasing PSD95 and synaptophysin. Conclusions: Nobiletin exerts strong neuroprotective and antioxidant effects by targeting multiple signaling cascades, mitigating amyloid pathology and neuroinflammation, and improving synaptic plasticity. It represents a promising therapeutic agent against AD.},
}

@article {pmid41898218,
year = {2026},
author = {Damian, SI and David, SM and Nour, M and Halitchi, GL and Ciurlea, SA and Stefanache, A and Duma, OO and Calin, G and Spaiuc, D},
title = {Intranasal Drug Delivery in Neuropharmacology: Advances in Brain-Targeted Therapies and Bioethical Challenges.},
journal = {Biomedicines},
volume = {14},
number = {3},
pages = {},
doi = {10.3390/biomedicines14030571},
pmid = {41898218},
issn = {2227-9059},
abstract = {Intranasal drug delivery represents a transformative "backdoor" to the brain, bypassing the blood-brain barrier (BBB) that bars 98% of small molecules and nearly all large biopharmaceuticals. By harnessing the unique anatomy of the olfactory and trigeminal nerves, therapeutics can travel directly from the nasal cavity to the central nervous system, achieving therapeutic concentrations without the systemic toxicity of traditional routes. Clinical and preclinical evidence highlight the efficacy of intranasal insulin (INI) in treating Alzheimer's disease (AD) and delirium, with studies showing significant improvements in cognitive scores and reduced hospital stays (7.9 vs. 12.9 days; p = 0.014). Additionally, other peptides can be administered intranasally like oxytocin, neuropeptide Y, and novel metabolic modulators for neuroprotection and affective disorders (AD, autism, Down syndrome). Despite these promises, critical translational gaps remain, including anatomical differences between macrosmatic rodents and microsmatic humans, and significant sex-based dosing dimorphism. The ease of intranasal administration introduces profound bioethical dilemmas regarding neuroenhancement, authenticity, and informed consent in vulnerable populations. The current literature concludes that realizing the full potential of nose-to-brain (N2B) therapy requires a commitment to precision medicine, utilizing specialized delivery devices and objective biomarkers to ensure safe and equitable clinical application.},
}

@article {pmid41898257,
year = {2026},
author = {Chen, X and Deng, W and Chen, X and Yu, Y},
title = {Magnesium Transporter SLC41A1 Links Magnesium Homeostasis to NMDA Receptor-Related Synaptic Dysfunction: A Transdiagnostic Therapeutic Target for Neuropsychiatric Disorders.},
journal = {Biomedicines},
volume = {14},
number = {3},
pages = {},
doi = {10.3390/biomedicines14030610},
pmid = {41898257},
issn = {2227-9059},
support = {2021A1515011322//Guangdong Basic and Applied Basic Research Foundation/ ; },
abstract = {Background: Neuropsychiatric disorders such as Alzheimer's disease (AD), bipolar disorder (BD), and depression exhibit shared glutamatergic abnormalities, although their upstream molecular mechanisms remain poorly defined. Magnesium (Mg[2+]) serves as a key regulator of N-methyl-D-aspartate (NMDA) receptor function; however, the role of Mg[2+] transporters, particularly SLC41A1, has not been systematically investigated. As NMDA receptor dysregulation contributes to emotional and cognitive impairments, elucidating Mg[2+]-NMDA signaling may enable the development of novel therapeutic strategies. Methods: We integrated Mendelian randomization, locus colocalization, human brain transcriptomics, functional enrichment, and co-expression analyses to determine whether SLC41A1 functions as a cross-disorder molecular driver. In addition, in vitro electrophysiological experiments using field potential recordings in hippocampal Schaffer-CA1 synapses were conducted to validate its functional role in NMDA receptor-mediated synaptic transmission. Results: Genetically elevated SLC41A1 expression increased the risk of AD, BD, depression, and alcohol dependence, with strong colocalization analyses supporting shared causal variants. Transcriptomic profiling revealed SLC41A1 upregulation in AD and BD, with enrichment in magnesium transport, mitochondrial function, and synaptic signaling pathways. Co-expression networks across GTEx brain regions demonstrated strong correlations with NMDA-related genes (e.g., GRINA, CAMK2G, GRIN2C). Under NMDAR-selective recording conditions, both imipramine treatment and SLC41A1 knockdown significantly reduced NMDAR-mediated fEPSP amplitudes, supporting a role for SLC41A1 in regulating NMDA receptor-dependent synaptic responses. Conclusions: This study identifies SLC41A1 as a magnesium-centered, transdiagnostic therapeutic target that links Mg[2+] homeostasis to NMDA-dependent synaptic dysfunction. These findings provide a mechanistic foundation for developing SLC41A1-modulating or magnesium-based therapeutic approaches for mood and cognitive disorders.},
}

@article {pmid41898328,
year = {2026},
author = {Nesci, S},
title = {Mitochondrial Dysfunction in the Inflammatory Process of Neurodegenerative Diseases.},
journal = {Biomedicines},
volume = {14},
number = {3},
pages = {},
doi = {10.3390/biomedicines14030682},
pmid = {41898328},
issn = {2227-9059},
abstract = {Neurodegenerative diseases share a mitochondrial-immune axis in which impaired oxidative phosphorylation reshapes neuronal metabolism and drives chronic inflammation. Complex I play a redox gatekeeper role at the coenzyme Q (CoQ) junction: catalytic defects, misassembly, or reverse electron transport over-reduce the CoQ pool, increase electron leak, and elevate ROS. How respiratory supercomplex plasticity (CI-CIII2, CIII2-CIVn, or CI-CIII2-CIVn) modulates carrier channelling, flux control, and ROS propensity through dynamic reorganization of the electron transport chain is highlighted. Excess ROS damages lipids and mitochondrial DNA, promoting the release of mitochondrial damage-associated molecular patterns s that activate NLRP3 inflammasome signalling, cGAS-STING-dependent interferon programs, and endosomal TLR9 pathways, establishing feed-forward loops between mitochondrial injury and neuroinflammation. Disease-focused sections integrate evidence from Parkinson's, Alzheimer's, amyotrophic lateral sclerosis, and Huntington's models, and map these mechanisms onto therapeutic opportunities spanning electron transport chain support, supercomplex stabilization, and consider mtDNA-sensing inflammatory nodes.},
}

@article {pmid41898384,
year = {2026},
author = {Akama, Y and Maeda, S and Udono, M and Nakamura, U and Yamashita, Y and Kim, Y and Shirouchi, B and Teruya, K and Katakura, Y},
title = {GABA-Induced Exosomes Improve Memory Impairment in Aged Mice.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062519},
pmid = {41898384},
issn = {1422-0067},
support = {25K01969//JSPS KAKENHI/ ; },
mesh = {Animals ; *gamma-Aminobutyric Acid/pharmacology ; *Exosomes/metabolism/drug effects ; Mice ; Male ; Mice, Inbred C57BL ; *Aging ; Hippocampus/metabolism/drug effects ; *Memory Disorders/drug therapy/metabolism ; Humans ; Mitochondria/metabolism/drug effects ; MicroRNAs/genetics/metabolism ; },
abstract = {Gamma-aminobutyric acid (GABA) has been implicated in gut-brain interactions and neuronal activation. We hypothesized that GABA could ameliorate memory decline. We investigated whether oral GABA administration ameliorated age-related cognitive decline in aged mice (C57BL/6J, male) and explored the role of circulating exosomes in mediating these effects. Aged mice that drank water containing 0.5% GABA exhibited significantly improved discrimination index scores compared with that of controls, indicating enhanced memory function. Their plasma-derived exosomes induced neurite outgrowth and mitochondrial activation and restored neuronal activity in SH-SY5Y cells. GABA enhanced the exosomal expression of several miRNAs linked to neuronal activation, longevity, and anti-senescence pathways. Plasma-derived exosomes also restored object recognition memory, reduced hippocampal neuroinflammation, and decreased senescent cell markers (p21 and γH2AX) in aged mice. Additionally, mitochondria- and neurite-related genes were upregulated, and pathways associated with oxidative phosphorylation and Alzheimer's disease were enriched. Collectively, long-term GABA administration was found to improve cognitive function of aged mice through the secretion of functional exosomes.},
}

Animals
*gamma-Aminobutyric Acid/pharmacology
*Exosomes/metabolism/drug effects
Mice
Male
Mice, Inbred C57BL
*Aging
Hippocampus/metabolism/drug effects
*Memory Disorders/drug therapy/metabolism
Humans
Mitochondria/metabolism/drug effects
MicroRNAs/genetics/metabolism

@article {pmid41898412,
year = {2026},
author = {Rakovskaya, A and Volkova, E and Pchitskaya, E},
title = {Neuronal Calcium Signaling and Cytoskeletal Dynamics in Neurodegeneration.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062550},
pmid = {41898412},
issn = {1422-0067},
support = {25-74-10019//Russian Science Foundation/ ; },
mesh = {Humans ; *Calcium Signaling ; *Cytoskeleton/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Neurons/metabolism/pathology ; Calcium/metabolism ; },
abstract = {Neuronal function relies on the precise coordination between intracellular calcium (Ca[2+]) signaling and the cytoskeletal architecture that underpins synaptic transmission, plasticity, and structural stability. Disruption of this calcium-cytoskeleton interplay has been noted in numerous neurodegenerative diseases. We discuss how Ca[2+]-dependent cytoskeletal remodeling governs long-term potentiation and depression, dendritic spine morphology, and presynaptic function, highlighting the functions of end-binding proteins, STIM (Stromal Interaction Molecule)/Orai-mediated store-operated calcium entry, and the spine apparatus. Disease-specific manifestations of cytoskeletal-calcium dysregulation are reviewed across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, tauopathies, and prion disorders. Finally, we evaluate emerging therapeutic strategies targeting calcium homeostasis, cytoskeletal dynamics, and their downstream effectors, including multi-target approaches.},
}

Humans
*Calcium Signaling
*Cytoskeleton/metabolism
Animals
*Neurodegenerative Diseases/metabolism/pathology
*Neurons/metabolism/pathology
Calcium/metabolism

@article {pmid41898478,
year = {2026},
author = {Jiang, T and Xiang, L and Qi, J},
title = {Myrtenol from Lavender Essential Oil Possesses Neuroprotective Effects and Promotes Neurite Outgrowth by Potentially Targeting TrkA and IGF-1R in PC12 Cells.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062615},
pmid = {41898478},
issn = {1422-0067},
support = {2022YFE0104000//National Key R&D Program of China/ ; },
mesh = {Animals ; PC12 Cells ; Rats ; *Oils, Volatile/pharmacology/chemistry ; *Neuroprotective Agents/pharmacology/chemistry ; *Receptor, trkA/metabolism ; Lavandula/chemistry ; *Neuronal Outgrowth/drug effects ; *Plant Oils/pharmacology/chemistry ; Oxidative Stress/drug effects ; *Receptor, IGF Type 1/metabolism ; Signal Transduction/drug effects ; Hydrogen Peroxide/toxicity ; Amyloid beta-Peptides/toxicity ; *Monoterpenes/pharmacology ; Acyclic Monoterpenes/pharmacology ; Peptide Fragments/toxicity ; },
abstract = {Alzheimer's disease (AD) is a prevalent chronic neurodegenerative disorder; the progression of this disease is driven by cellular determinants such as oxidative stress and dysregulated neurotrophic signaling. Lavender essential oil is traditionally used in aromatherapy for neuronal regulation and neuroprotection, suggesting its potential neuroprotective effects for chronic neurodegenerative disorders like AD. However, the key active constituents responsible for its benefits and the specific molecular pharmacological mechanisms remain unclear. In this study, we isolated myrtenol from lavender essential oil under the guidance of activity evaluation. Its neuroprotective effects were evaluated in PC12 cells via neurite outgrowth, anti-Aβ/H2O2 cytotoxicity, and antioxidant assays. Targets and pathways were explored using inhibitor experiments, cell thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), and Western blot. Myrtenol significantly induced neurite outgrowth in PC12 cells and effectively mitigated cytotoxicity and oxidative stress damage induced by Aβ25-35 and H2O2. Mechanistic studies revealed that myrtenol's effects are associated with the modulation of tyrosine kinase receptor A (TrkA) and insulin-like growth factor-1 receptor (IGF-1R), activating phospholipase C (PLC)/protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways to jointly mediate neuroprotection effects against the pathology of AD. This study demonstrates that myrtenol as a highly active component of lavender essential oil possesses NGF-like neuritogenic activity and neuroprotective effects. It provides a foundation for understanding the cellular mechanisms of myrtenol as a small-molecule lead for further investigation in neurodegeneration-related research.},
}

Animals
PC12 Cells
Rats
*Oils, Volatile/pharmacology/chemistry
*Neuroprotective Agents/pharmacology/chemistry
*Receptor, trkA/metabolism
Lavandula/chemistry
*Neuronal Outgrowth/drug effects
*Plant Oils/pharmacology/chemistry
Oxidative Stress/drug effects
*Receptor, IGF Type 1/metabolism
Signal Transduction/drug effects
Hydrogen Peroxide/toxicity
Amyloid beta-Peptides/toxicity
*Monoterpenes/pharmacology
Acyclic Monoterpenes/pharmacology
Peptide Fragments/toxicity

@article {pmid41898539,
year = {2026},
author = {Lee, SH and Son, Y and Jang, H and Kim, HY and Kim, KS and Lee, HS and Lee, HJ},
title = {Fluoxetine Repurposing Mitigates Alzheimer's Disease Pathology via the GSK3β-CREB-ADAM10 Axis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062676},
pmid = {41898539},
issn = {1422-0067},
support = {RS-2025-24873145//National Research Foundation of Korea/ ; },
mesh = {*Fluoxetine/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Animals ; *Glycogen Synthase Kinase 3 beta/metabolism ; Mice ; Humans ; *Drug Repositioning ; *Cyclic AMP Response Element-Binding Protein/metabolism ; *Amyloid Precursor Protein Secretases/metabolism ; *ADAM10 Protein/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Signal Transduction/drug effects ; Phosphorylation/drug effects ; Male ; Selective Serotonin Reuptake Inhibitors/pharmacology ; Cell Line, Tumor ; *Membrane Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the aging population. Drug repurposing provides a cost-effective strategy to identify novel therapeutics that may mitigate age-associated pathologies. Here, we report the therapeutic potential of fluoxetine, a selective serotonin reuptake inhibitor commonly used as an antidepressant, in alleviating cognitive impairment and AD-like pathology in 5xFAD mice, a transgenic model of familial AD. Chronic fluoxetine administration significantly ameliorated anxiety-like behavior and cognitive deficits in 5xFAD mice, as assessed by open field, Y-maze, and novel object recognition tests. Fluoxetine treatment was associated with reduced amyloid plaque deposition in the hippocampus and cortex, attenuation of microglial activation, and decreased expression of inflammatory cytokines. At the molecular level, fluoxetine increased phosphorylation of GSK3β at Ser9, which was associated with enhanced CREB phosphorylation and upregulation of the α-secretase ADAM10. These effects were further examined in SH-SY5Y neuronal cells, where CREB phosphorylation and ADAM10 expression were significantly modulated by GSK3β inhibition, whereas CaMKII inhibition had no detectable effect under our experimental conditions. Our findings suggest that fluoxetine modulates amyloid-associated signaling pathways in the 5xFAD model, in part through regulation of the GSK3β-CREB signaling framework. These results provide mechanistic insight into how fluoxetine may influence APP processing in an amyloid-driven pathological context, although further studies are required to clarify its translational implications in human AD.},
}

*Fluoxetine/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/metabolism/pathology
Animals
*Glycogen Synthase Kinase 3 beta/metabolism
Mice
Humans
*Drug Repositioning
*Cyclic AMP Response Element-Binding Protein/metabolism
*Amyloid Precursor Protein Secretases/metabolism
*ADAM10 Protein/metabolism
Mice, Transgenic
Disease Models, Animal
Signal Transduction/drug effects
Phosphorylation/drug effects
Male
Selective Serotonin Reuptake Inhibitors/pharmacology
Cell Line, Tumor
*Membrane Proteins/metabolism

@article {pmid41898603,
year = {2026},
author = {Dębiec, M and Rojek, M},
title = {Adult Neurogenesis in Neurodegenerative Diseases: Mechanisms of Dysregulation in Alzheimer's and Parkinson's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062742},
pmid = {41898603},
issn = {1422-0067},
support = {BNW-02-058/N/3/J.//Medical University of Silesia/ ; },
mesh = {Humans ; *Neurogenesis ; *Parkinson Disease/metabolism/pathology/physiopathology ; *Alzheimer Disease/metabolism/pathology/physiopathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; Neurons/metabolism/pathology ; },
abstract = {Adult neurogenesis, the process of generating new, functional neurons in the mature central nervous system, represents a key mechanism of brain plasticity and a potential source of regeneration. This process occurs primarily within specialised neurogenic niches: the subgranular zone of the hippocampal dentate gyrus (SGZ) and the subependymal zone (SEZ). It is regulated by a complex network of endogenous factors (e.g., hormones, neurotrophins, growth factors) and exogenous factors (environment, stress, diet, physical activity). Impairments in neurogenesis are linked to the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). In their course, chronic inflammation, mitochondrial dysfunction, oxidative stress, and the accumulation of pathological proteins (β-amyloid, Tau protein, α-synuclein) create a microenvironment that inhibits the proliferation, differentiation, and survival of new neurons. This results in the exacerbation of cognitive and memory deficits. A review of the literature indicates that modulating neurogenesis through non-pharmacological interventions (e.g., a diet rich in anti-inflammatory compounds, physical exercise) and targeted therapeutic strategies represents a promising, albeit complex, research avenue. The primary challenge remains not only stimulating neuron generation but also ensuring their proper maturation, survival, and functional integration into existing neuronal circuits. A deeper understanding of the molecular and environmental mechanisms regulating adult neurogenesis may open new therapeutic possibilities for slowing the progression of neurodegenerative diseases.},
}

Humans
*Neurogenesis
*Parkinson Disease/metabolism/pathology/physiopathology
*Alzheimer Disease/metabolism/pathology/physiopathology
Animals
*Neurodegenerative Diseases/metabolism/pathology
Neurons/metabolism/pathology

@article {pmid41898651,
year = {2026},
author = {Lei, D and Zhou, C and Zheng, H and Kang, Y and Yan, Z},
title = {Fecal Microbiota Transplantation from APP/PS1 Mice Induces Th17-Related Inflammatory Parameters and Pathological Changes in the Gut-Brain Axis of Healthy C57BL/6J Mice.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062791},
pmid = {41898651},
issn = {1422-0067},
support = {No. 2024YFHZ0334//Sichuan Provincial Science and Technology Support Program/ ; },
mesh = {Animals ; *Th17 Cells/immunology/metabolism ; *Fecal Microbiota Transplantation/adverse effects ; Mice ; *Gastrointestinal Microbiome ; Mice, Inbred C57BL ; *Inflammation/pathology ; *Alzheimer Disease/microbiology/pathology/therapy ; *Brain/pathology/metabolism ; Disease Models, Animal ; Male ; Ileum/microbiology/pathology ; Mice, Transgenic ; *Brain-Gut Axis ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {The gut-brain axis is increasingly implicated in Alzheimer's disease (AD) pathogenesis, but the potential correlation between AD-associated gut microbiota and central inflammation remains largely unclear. This study aimed to explore their correlative link, with a focus on changes and involvement of Th17 cell-related factors in the gut-brain axis. Healthy C57BL/6J mice were pretreated with antibiotics for 1 week to deplete the indigenous gut microbiota, followed by 2 weeks of fecal microbiota transplantation (FMT) using feces from APP/PS1 AD model mice. Hematoxylin-eosin (H&E) staining, ELISA, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), 16S rDNA sequencing, and correlation analysis were performed to evaluate ileal and central pathological changes, Th17 cell-related inflammatory mediators, ileal microbiota composition, and their potential correlations. The results demonstrated that AD-FMT significantly induced ileal inflammatory infiltration and central inflammation in recipient mice, which was accompanied by abnormal expression of Th17 cell-related indicators, elevated levels of Th17-associated inflammatory factors, upregulated RORγt mRNA expression, and perturbed ileal microbiota composition. Correlation analysis further suggested that specific ileal bacterial taxa were closely correlated with Th17 cell-related inflammatory factors. These findings suggest a potential correlation between AD-associated microbiota and central inflammation, possibly by regulating intestinal Th17 cell-related indicators and altering gut microbial composition. This study provides correlative evidence supporting the involvement of the gut-brain axis in AD-related pathogenesis, highlighting the link between gut microbiota, central inflammation and Th17-related factors.},
}

Animals
*Th17 Cells/immunology/metabolism
*Fecal Microbiota Transplantation/adverse effects
Mice
*Gastrointestinal Microbiome
Mice, Inbred C57BL
*Inflammation/pathology
*Alzheimer Disease/microbiology/pathology/therapy
*Brain/pathology/metabolism
Disease Models, Animal
Male
Ileum/microbiology/pathology
Mice, Transgenic
*Brain-Gut Axis
Amyloid beta-Protein Precursor/genetics

@article {pmid41898669,
year = {2026},
author = {Promprom, W and Chatan, W and Homwutthiwong, K and Apaijit, K and Cheepsunthorn, P and Mairuae, N},
title = {Anti-Inflammatory and Antioxidant Properties of Bauhinia thailandica Leaf Extract in Microglial Cells.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062809},
pmid = {41898669},
issn = {1422-0067},
support = {//Thailand Science Research and Innovation and Faculty of Medicine, Mahasarakham University./ ; },
mesh = {*Plant Extracts/pharmacology/chemistry ; *Microglia/drug effects/metabolism ; *Plant Leaves/chemistry ; *Antioxidants/pharmacology/chemistry ; *Anti-Inflammatory Agents/pharmacology/chemistry ; *Bauhinia/chemistry ; Animals ; Mice ; Lipopolysaccharides ; Reactive Oxygen Species/metabolism ; Cell Line ; Nitric Oxide/metabolism ; Oxidative Stress/drug effects ; Cell Survival/drug effects ; },
abstract = {Neuroinflammation is pivotal in the development of numerous neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Microglial cells, the principal immune cells of the central nervous system (CNS), are essential mediators of this process. Upon exposure to pathogenic stimuli such as lipopolysaccharide (LPS), microglia activate and release pro-inflammatory mediators, leading to heightened oxidative stress and neuronal damage. Therefore, targeting microglial activation is a promising therapeutic approach to prevent or slow neurodegeneration. This study aimed to investigate the antioxidant and anti-inflammatory effects of the leaf extract of the newly identified species Bauhinia thailandica on LPS-activated BV2 microglia. The phytochemical compound of the B. thailandica leaf extract was also investigated. BV2 cells were treated with LPS (1 μg/mL) for 24 h in the presence or absence of B. thailandica leaf extract (12.5 and 25 µg/mL). The levels of reactive oxygen species (ROS), nitric oxide (NO), and interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-alpha (TNF-α) were quantified with CM-H2DCFDA, Griess reagent assay, and ELISA, respectively. Treatment with LPS resulted in significant increases in ROS, NO, IL-6, IL-1, and TNF levels compared to untreated cells (p < 0.01). However, co-treatment with B. thailandica leaf extract significantly suppressed the production of these inflammatory markers (p < 0.01 for 25 µg/mL across all parameters, except TNF-α; p < 0.05). The results also showed that B. thailandica leaf extract possessed significant levels of total phenolic content (TPC; 70.55 mg GAE/g dry extract), total flavonoid content (TFC; 249.47 mg QE/g dry extract), and tannins (397.50 mg TAE/g dry extract). Phytochemical screening also revealed the presence of saponins and cardiac glycosides in the extract. In conclusion, the leaf extract of B. thailandica is a potent source of phytochemicals exhibiting antioxidant capabilities and has shown both antioxidant and anti-inflammatory actions in LPS-activated BV2 microglial cells. The findings indicate that B. thailandica leaf extract shows significant promise as a novel herbal treatment for neuroinflammatory disorders mediated by microglia. Further research is necessary to clarify the underlying mechanisms of action and to investigate the active substances responsible for these effects.},
}

*Plant Extracts/pharmacology/chemistry
*Microglia/drug effects/metabolism
*Plant Leaves/chemistry
*Antioxidants/pharmacology/chemistry
*Anti-Inflammatory Agents/pharmacology/chemistry
*Bauhinia/chemistry
Animals
Mice
Lipopolysaccharides
Reactive Oxygen Species/metabolism
Cell Line
Nitric Oxide/metabolism
Oxidative Stress/drug effects
Cell Survival/drug effects

@article {pmid41898672,
year = {2026},
author = {Davis, A and Casmedes, IY and Burton, MD},
title = {Radical Revelations: The Interplay of Nitrosative Stress, the Endocannabinoid System, and Treatment of Age-Related Disorders.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062813},
pmid = {41898672},
issn = {1422-0067},
support = {GM147094//National Institute of Health/ ; DK130015//National Institute of Health/ ; },
mesh = {Humans ; *Endocannabinoids/metabolism ; *Nitrosative Stress/drug effects ; Animals ; *Reactive Nitrogen Species/metabolism ; *Alzheimer Disease/metabolism/drug therapy ; *Aging/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Parkinson Disease/metabolism/drug therapy ; Signal Transduction ; },
abstract = {The crosstalk between the endocannabinoid system (ECS) and reactive nitrogen species (RNS) has emerged as an important area of investigation in recent years. Although many aspects of this interaction remain elusive, accumulating evidence demonstrates that the ECS plays a critical role in regulating RNS-mediated signaling under physiological conditions. This modulation can be either inhibitory or stimulatory, depending on the specific receptor subtype, cell type, and tissue location involved. While ECS-RNS interactions support normal cellular homeostasis, their dysregulation contributes to various disease states, particularly neurodegenerative disorders. Studies in both rodent models and human subjects show that ECS modulation can reduce anxiety, attenuate neuroinflammatory responses, and slow disease progression in neurodegenerative conditions. This review examines how cannabinoid-based interventions modulate nitrosative stress and neuroinflammation in Alzheimer's disease (AD) and Parkinson's disease (PD), highlighting their potential as targeted therapeutics that address multiple pathological mechanisms simultaneously and may offer advantages over conventional treatment approaches.},
}

Humans
*Endocannabinoids/metabolism
*Nitrosative Stress/drug effects
Animals
*Reactive Nitrogen Species/metabolism
*Alzheimer Disease/metabolism/drug therapy
*Aging/metabolism
*Neurodegenerative Diseases/metabolism/drug therapy
*Parkinson Disease/metabolism/drug therapy
Signal Transduction

@article {pmid41898675,
year = {2026},
author = {Baranich, TI and Sukhorukov, VS and Velts, OV and Voronkov, DN and Shcherbak, EV and Egorova, AV and Romanenko, AS and Lazarev, DS and Raksha, AP and Charyeva, IG and Yatskovskiy, AN and Glinkina, VV and Illarioshkin, SN},
title = {Immunohistochemical Markers of Mitochondrial Electron Transport Chain Instability in Human Brain Regions: A Study of Aging and Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062816},
pmid = {41898675},
issn = {1422-0067},
support = {075-15-2024-638//Ministry of Education of Russia for large-scale scientific projects in priority areas of scientific and technological development/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Mitochondria/metabolism/pathology ; *Aging/metabolism/pathology ; Aged ; Male ; *Brain/metabolism/pathology ; Female ; Aged, 80 and over ; Immunohistochemistry ; Biomarkers/metabolism ; Oxidative Stress ; *Electron Transport Chain Complex Proteins/metabolism ; Neurons/metabolism ; Electron Transport ; Hippocampus/metabolism/pathology ; Middle Aged ; Adult ; },
abstract = {Expanding research indicates that oxidative stress, particularly mitochondrial oxidative stress, is one of the key components in the pathogenesis of Alzheimer's disease (AD). Mitochondrial oxidative stress is largely driven by impaired function of electron transport chain (ETC) complexes and their regulators. This study conducted an immunohistochemical analysis of ETC proteins (α-subunit of complex V, subunits MTCO1 and MTCO2 of complex IV) and mitochondrial complex V inhibitor IF-1 in the neurons of the caudate nucleus head, hippocampus, anterior cingulate gyrus, middle frontal gyrus, and inferior parietal lobule using autopsy material from patients with sporadic AD. Comparisons were made with similar brain regions in autopsy material from age-matched elderly patients and young patients. The results revealed a pattern of ETC impairment in AD fundamentally distinct from that observed in physiological aging. Specifically, a hippocampus-specific failure of the adaptive response was identified: unlike other brain regions, compensatory upregulation of ATP synthase does not occur here despite critical reduction in the protective protein IF-1, directly explaining the heightened vulnerability of hippocampal neurons to damage. Our data deepen the understanding of AD pathogenesis by highlighting region-specific mitochondrial defects as promising targets for tailored therapeutic intervention.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Mitochondria/metabolism/pathology
*Aging/metabolism/pathology
Aged
Male
*Brain/metabolism/pathology
Female
Aged, 80 and over
Immunohistochemistry
Biomarkers/metabolism
Oxidative Stress
*Electron Transport Chain Complex Proteins/metabolism
Neurons/metabolism
Electron Transport
Hippocampus/metabolism/pathology
Middle Aged
Adult

@article {pmid41898738,
year = {2026},
author = {Sun, F and Liu, K and Xi, E and Zhao, Y and Gao, N},
title = {Constructing Curcumin-Based Biological Metal-Organic Frameworks (MOFs) for the Treatment of Alzheimer's Disease Through the Pyroptosis Pathway.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062871},
pmid = {41898738},
issn = {1422-0067},
support = {2022YFB3805902//National Key R&D Program of China/ ; 22077118//National Natural Science Foundation of China/ ; B18012//the "111" project/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Animals ; *Metal-Organic Frameworks/chemistry/pharmacology ; *Pyroptosis/drug effects ; *Curcumin/chemistry/pharmacology ; Mice ; Mice, Transgenic ; Quercetin/analogs & derivatives/chemistry/pharmacology ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Humans ; Disease Models, Animal ; Antioxidants/pharmacology/chemistry ; },
abstract = {Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disorder that presents as neuronal cell death caused by the pyroptosis pathway. Currently, curcumin is widely reported in the treatment of AD due to its dual inhibitory effects on NLRP3-associated inflammasome activation, but it suffers from poor bioavailability. Therefore, in this study, a highly stable curcumin-based Zn-organic framework (medi-MOF-1) loaded with taxifolin (TAX@medi-MOF-1) was presented to overcome the defect with a specific surface area of 2530.652 m[2] g[-1]. The loaded TAX could further enhance the anti-inflammatory and antioxidant properties. In 5×FAD transgenic mice, TAX@medi-MOF-1 significantly improved cognitive and motor functions, reduced Aβ plaque deposition, and downregulated key pyroptosis proteins (NLRP3, caspase-1, and GSDMD-N). The dual-drug system exhibited synergistic effects, offering a promising multi-target therapeutic strategy for AD.},
}

*Alzheimer Disease/drug therapy/metabolism/pathology
Animals
*Metal-Organic Frameworks/chemistry/pharmacology
*Pyroptosis/drug effects
*Curcumin/chemistry/pharmacology
Mice
Mice, Transgenic
Quercetin/analogs & derivatives/chemistry/pharmacology
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
Humans
Disease Models, Animal
Antioxidants/pharmacology/chemistry

@article {pmid41898760,
year = {2026},
author = {Debnath, D and Housini, M and Sariya, S and Phillips, NR and Pathak, GA and Barber, RC},
title = {Locus- and Gene-Level Insights into the Inverse Association Between Alzheimer's Disease and Cancer.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062900},
pmid = {41898760},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/genetics/epidemiology ; *Neoplasms/genetics/epidemiology ; Genome-Wide Association Study ; *Genetic Predisposition to Disease ; Male ; Female ; Polymorphism, Single Nucleotide ; Transcriptome ; },
abstract = {Alzheimer's disease (AD) and cancer are both age-related conditions, yet numerous large-scale epidemiological studies have consistently documented an inverse association, with individuals diagnosed with cancer exhibiting a reduced risk of AD and vice versa. Although this relationship has been replicated across diverse populations, its biological basis remains poorly understood. To address this gap, the present study applies a framework that integrates locus-level genetic correlation (rg) with genetically regulated gene expression to clarify the molecular factors contributing to the inverse epidemiological patterns observed between the two diseases. We used the largest available genome-wide association studies (GWAS) (Nmax = 448,150) to quantify local genetic correlations between AD and several age-associated cancers, including breast, prostate, lung, colorectal, melanoma, basal cell carcinoma, bladder, and endometrial cancer. Eight genomic regions showed significant negative local rg, at the 19q13.31-19q13.32 locus demonstrating strong negative correlations across multiple cancers, including breast, prostate, lung, melanoma, and endometrial cancer. To evaluate the contribution of genetically regulated gene expression, we conducted transcriptome-wide association studies (TWAS) using precomputed gene expression weights from cancer tissues (The Cancer Genome Atlas-TCGA), disease-agnostic tissues (Genotype-Tissue Expression-GTEx), and brain tissue (dorsolateral prefrontal cortex-DLPFC). For each AD-cancer pair, we prioritized genes that were nominally significant in both traits (p < 0.05) and exhibited inverse TWAS Z scores. This analysis identified 24 genes with opposite effect directions between AD and at least three cancer types. TWAS signals also aligned with local rg findings at the 19q13.31-19q13.32 region, suggesting that regulatory variation near this locus contributes to shared but opposing genetic effects beyond the canonical APOE signal. Across cancer types, genes inversely associated with AD converged on pathways involved in cell cycle regulation, apoptosis, DNA-damage response, and metabolic processes. These results support the hypothesis that biological mechanisms promoting proliferation and survival in cancer may oppose those contributing to neurodegeneration in AD.},
}

Humans
*Alzheimer Disease/genetics/epidemiology
*Neoplasms/genetics/epidemiology
Genome-Wide Association Study
*Genetic Predisposition to Disease
Male
Female
Polymorphism, Single Nucleotide
Transcriptome

@article {pmid41898768,
year = {2026},
author = {Yoo, YM and Joo, SS},
title = {Physiological Implications of Pancreatic Amyloid Polypeptide Aggregation and Its Inhibition by Melatonin.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062910},
pmid = {41898768},
issn = {1422-0067},
support = {2020R1I1A1A01060627//the Basic Science Research Program through the National Research Foundation of Korea (NRF)/ ; },
mesh = {*Melatonin/pharmacology/metabolism ; Humans ; *Islet Amyloid Polypeptide/metabolism/chemistry ; Animals ; Amyloid beta-Peptides/metabolism ; Alzheimer Disease/metabolism/drug therapy/pathology ; *Protein Aggregation, Pathological/metabolism/drug therapy ; Diabetes Mellitus, Type 2/metabolism/drug therapy ; Protein Aggregates/drug effects ; },
abstract = {Type 2 Diabetes (T2D) is characterized by the toxic aggregation of human islet amyloid polypeptide (hIAPP or amylin) within pancreatic β-cells. IAPP is also a neuropancreatic hormone that plays a significant role in Alzheimer's disease (AD) by co-depositing with amyloid-beta (Aβ) and Tau, supporting the Type 3 Diabetes (T3D) hypothesis. Soluble IAPP accelerates Aβ aggregation through cross-seeding and causes neurotoxicity by impairing the blood-brain barrier and activating neuroinflammation. Melatonin inhibits these processes by disrupting hydrophobic interactions in both hIAPP and Aβ, preventing the formation of toxic β-sheet structures. Furthermore, melatonin promotes amyloid clearance via the glymphatic and lymphatic systems, protects neurons from oxidative damage, and reduces Tau hyperphosphorylation. This suggests that melatonin serves as a promising multitarget therapeutic agent for both metabolic and neurodegenerative disorders by modulating structural protein transformations.},
}

*Melatonin/pharmacology/metabolism
Humans
*Islet Amyloid Polypeptide/metabolism/chemistry
Animals
Amyloid beta-Peptides/metabolism
Alzheimer Disease/metabolism/drug therapy/pathology
*Protein Aggregation, Pathological/metabolism/drug therapy
Diabetes Mellitus, Type 2/metabolism/drug therapy
Protein Aggregates/drug effects

@article {pmid41899174,
year = {2026},
author = {Bülbül, NG and Baytaş, İM and Kavalcı, E and Karasu, E and Okcu Korkmaz, BC and Belen, BG and Musaoğlu, İS and Övüt, AR and Arslanoğlu, NE and Urhan, M and Mutlu, H and Özdağ, MF},
title = {Real-World Multimodal Machine Learning for Risk Enrichment Across the Alzheimer's Disease Spectrum.},
journal = {Journal of clinical medicine},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/jcm15062250},
pmid = {41899174},
issn = {2077-0383},
support = {121E594//TÜBİTAK National Observatory/ ; },
abstract = {Background and Objectives: Mild cognitive impairment (MCI) is heterogeneous within the Alzheimer's disease (AD) continuum, and categorical labels may not reflect biological variability. We evaluated whether multimodal machine learning using routine clinical data and neuroimaging could support biologically informed enrichment across MCI and AD in a real-world memory clinic cohort. Methods: We analyzed 474 patients (1547 visits) with clinical and cognitive measures, laboratory parameters, MRI regional volumes, and FDG-PET regional uptake. Elastic Net and gradient boosting models were trained using nested cross-validation with strict patient-level separation. Results: Model discrimination improved as additional data modalities were added, and FDG-PET contributed the largest performance improvement. Hypometabolism in posterior default mode network regions consistently emerged as the most influential predictor. In the MCI subgroup, AD-like scores showed a continuous distribution consistent with biological enrichment. Conclusions: Multimodal models may provide an interpretable enrichment framework in heterogeneous memory clinic populations.},
}

@article {pmid41899281,
year = {2026},
author = {Takahashi, T and Muguruma, K},
title = {Alzheimer's Disease: From Pathogenesis to Emerging Therapeutic Targets.},
journal = {Journal of clinical medicine},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/jcm15062357},
pmid = {41899281},
issn = {2077-0383},
abstract = {Alzheimer's disease (AD) is the most prevalent cause of dementia and can be conceptualized as a tauopathy initiated by the accumulation of amyloid-β (Aβ) in the brain. The clinical introduction of anti-Aβ antibody therapies has marked the beginning of a new era in disease-modifying treatment for dementia. While the deleterious effects of Aβ on postsynaptic spines and axonal microtubules have been increasingly clarified, recent studies have shifted attention beyond extracellular Aβ deposition as senile plaques to the pathogenic significance of intracellular Aβ. In particular, accumulating evidence highlights lysosomes as critical sites of intracellular Aβ toxicity. Interactions between Aβ and gangliosides, v-ATPase-dependent lysosomal acidification, and lysosomal membrane integrity are the key determinants of disease progression. In parallel, additional molecular players, including components of the complement cascade and asparaginyl endopeptidase, have been implicated in linking Aβ pathology to tau dysregulation and neurodegeneration. As therapeutic strategies targeting Aβ enter clinical practice, these emerging pathways represent promising targets for the next generation of AD treatment. Here, we summarize current insights and ongoing therapeutic developments centered on these mechanisms.},
}

@article {pmid41899485,
year = {2026},
author = {Ramírez-Expósito, MJ and Cueto-Ureña, C and Martínez-Martos, JM},
title = {Neurotransmitter Systems in Alzheimer's Disease.},
journal = {Current issues in molecular biology},
volume = {48},
number = {3},
pages = {},
doi = {10.3390/cimb48030334},
pmid = {41899485},
issn = {1467-3045},
abstract = {Alzheimer's disease (AD), the leading cause of global dementia, is a multifactorial process that goes beyond the accumulation of β-amyloid (Aβ) plaques and tau protein tangles, including glia cell-mediated neuroinflammation, vascular dysfunction, metabolic alterations, and synaptic loss. Its complex etiology also involves oxidative stress and mitochondrial dysfunction. Multiple neurotransmitter systems involved in the pathogenesis and the various cognitive and non-cognitive symptoms of AD are thus altered. The cholinergic system, historically the first to be associated with AD, suffers early degeneration and loss of neurons/receptors, correlating with cognitive impairment. The glutamatergic system, the main excitatory system, exhibits excitotoxicity due to increased extracellular glutamate and alterations in NMDA/AMPA receptor distribution, exacerbating neuronal damage. The GABAergic system, the main inhibitor, shows alterations in parvalbumin-positive interneurons, leading to hyperexcitability and dysfunction of neuronal networks. Monoaminergic systems (serotonergic, dopaminergic and noradrenergic) undergo early degeneration in key nuclei such as the raphe and locus coeruleus, contributing to the apathy, depression and sleep disturbances characteristic of AD. Other less explored systems, such as histaminergic and purinergic, are also crucial in cognitive modulation and neuroinflammation. The endocannabinoid system acts as a master modulator with neuroprotective and anti-inflammatory effects. These systems do not operate in isolation; their complex interactions generate pathological circuits that amplify neuronal dysfunction. The limited efficacy of current therapies, which are primarily symptomatic, highlights the need for multimodal approaches that may transform AD treatment toward personalized and more effective interventions.},
}

@article {pmid41899699,
year = {2026},
author = {Bricaud, I and Masala, GL and , },
title = {Multi-Architecture Deep Learning for Early Alzheimer's Detection in MRI: Slice- and Scan-Level Analysis.},
journal = {International journal of environmental research and public health},
volume = {23},
number = {3},
pages = {},
doi = {10.3390/ijerph23030322},
pmid = {41899699},
issn = {1660-4601},
mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; *Deep Learning ; Humans ; *Magnetic Resonance Imaging/methods ; Cognitive Dysfunction/diagnostic imaging ; Aged ; Female ; Male ; Early Diagnosis ; },
abstract = {Alzheimer's disease (AD), the most common form of dementia, is a progressive and irreversible neurodegenerative disorder. Structural MRI is widely used for diagnosis, revealing brain changes associated with AD. However, these alterations are often subtle and difficult to detect manually, particularly at early stages. Early intervention during prodromal stages, such as mild cognitive impairment (MCI), can help slow disease progression, highlighting the need for reliable automated methods. In this work, we introduce a dual-level evaluation framework comparing fifteen deep learning architectures, including convolutional neural networks (CNNs), Transformers, and hybrid models, for classifying AD, MCI, and cognitively normal (CN) subjects using the ADNI dataset. A central focus of our work is the impact of robust and standardized preprocessing pipelines, which we identified as a critical yet underexplored factor influencing model reliability. By evaluating performance at both slice-level and scan-level, we reveal that multi-slice aggregation affects architectures asymmetrically. By systematically optimizing preprocessing steps to reduce data variability and enhance feature consistency, we established preprocessing quality as an essential determinant of deep learning performance in neuroimaging. Experimental results show that CNNs and hybrid pre-trained models outperform Transformer-based models in both slice-level and scan-level classification. ConvNeXtV2-L achieved the best scan-level performance (91.07%), EfficientNetV2-L the highest slice-level accuracy (86.84%), and VGG19 balanced results (86.07%/88.52%). ConvNeXtV2-L and SwinV1-L exhibited scan-level improvements of 7.60% and 9.04% respectively, while EfficientNetV2-L experienced degradation of 2.66%, demonstrating that architectural selection and aggregation strategy are interdependent factors. These findings suggest that carefully designed preprocessing not only improves classification accuracy but may also serve as a foundation for more reproducible and interpretable Alzheimer's disease detection pipelines.},
}

*Alzheimer Disease/diagnostic imaging/diagnosis
*Deep Learning
Humans
*Magnetic Resonance Imaging/methods
Cognitive Dysfunction/diagnostic imaging
Aged
Female
Male
Early Diagnosis

@article {pmid41899901,
year = {2026},
author = {Xiang, S and Ling, H and Wu, M},
title = {Cross-Modal Alignment and Rectified Flow-Based Latent Representation Synthesis for Enhanced Speech-Driven Alzheimer's Disease Detection.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {13},
number = {3},
pages = {},
doi = {10.3390/bioengineering13030370},
pmid = {41899901},
issn = {2306-5354},
support = {2025J0111//Natural Science Foundation of Fujian Province/ ; 32071057//National Natural Science Foundation of China/ ; 61673322//National Natural Science Foundation of China/ ; 31200769//National Natural Science Foundation of China/ ; },
abstract = {To address the limited accuracy of speech-based Alzheimer's Disease (AD) screening and the shortage of paired multimodal data, this paper proposes a detection framework based on feature alignment and Rectified Flow-driven latent representation generation. The EEG dataset consists of 36 AD patients and 29 Healthy Controls (HC). The speech dataset contains 399 samples, which include 114 AD cases, 132 Mild Cognitive Impairment (MCI) cases, and 153 HC cases. We extracted multidimensional features of EEG signals, such as time-domain and frequency-domain characteristics, alongside behavioral representations of speech. A heterogeneous alignment network was used to map these features into a common semantic subspace, where an adaptive interpolation strategy reconstructed the missing pathological trajectories of MCI within the latent space. On this basis, a conditional Rectified Flow model was introduced to learn the optimal transport mapping from speech to EEG. This model generated physiological-information-rich latent representations to compensate for semantic gaps. Experimental results showed that the fused features from speech and latent representations achieved a three-class classification accuracy of 89.08%, a precision of 88.77%, and a recall of 88.71%. This performance represented an accuracy improvement of 9.28% compared with the speech-based baseline system. Our method combines the convenience of speech screening with the high reliability of neurophysiological signals, and it provides a new approach for low-cost early detection of AD.},
}

@article {pmid41900050,
year = {2026},
author = {Lopes, LES and Oliveira, MR and Neto, RVB and Santos, TB and De Conto, JF and Oliveira, MBPP and Gomes, MZ and Santos, KS},
title = {Preclinical Evaluation of Tradescantia spathacea Phenolic Extract-Loaded Silica in a Parkinson's Disease Model.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {6},
pages = {},
doi = {10.3390/molecules31060950},
pmid = {41900050},
issn = {1420-3049},
support = {CNPq/MCTI Universal Project (Process No. 407015/2023-0, Call No. 10/2023 - UNIVERSAL)//National Council for Scientific and Technological Development/ ; UID/50006//the PT national funds (FCT/MECI) - Laboratório Associado para a Química Verde - Tecnologias e Processos Limpos/ ; },
mesh = {Animals ; *Plant Extracts/chemistry/pharmacology ; *Silicon Dioxide/chemistry ; Rats ; *Parkinson Disease/drug therapy ; Disease Models, Animal ; *Phenols/chemistry/pharmacology ; Rats, Wistar ; *Neuroprotective Agents/pharmacology/chemistry ; Male ; *Thymelaeaceae/chemistry ; },
abstract = {The current limitations in Parkinson's Disease (PD) treatments necessitate innovative approaches. To this end, phenolic compounds from Tradescantia spathacea (T. spathacea) and bioactive silica demonstrate potential therapeutic efficacy in the prevention or treatment of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Hence, this study explores the neuroprotective potential of silica loaded with T. spathacea extract (SiO2-TS) in a preclinical model of PD. The aqueous extract of T. spathacea (AETS) was prepared via infusion and characterized in terms of overall yield (21.9 ± 0.4%), total phenolic compounds (25.51 ± 2.39 mg GAE/g), and total flavonoid content (6.10 ± 0.16 mg RE/g). Silica loaded with AETS was synthesized and tested in adult Wistar rats (PD-like symptoms). The rats were treated with daily intranasal administration of SiO2-TS (10 or 30 mg/kg) for 15 days. Quantitative behavioral analysis showed significant motor improvement and reduced anxiety-like behavior in the 30 mg/kg SiO2-TS group compared to the 6-OHDA (6-hydroxydopamine) control. Immunohistochemistry revealed preserved dopaminergic neurons and reduced astrogliosis (GFAP expression) in the same SiO2-TS group. These results suggest SiO2-TS has significant neuroprotective effects and warrants further study for Parkinson's disease treatment.},
}

Animals
*Plant Extracts/chemistry/pharmacology
*Silicon Dioxide/chemistry
Rats
*Parkinson Disease/drug therapy
Disease Models, Animal
*Phenols/chemistry/pharmacology
Rats, Wistar
*Neuroprotective Agents/pharmacology/chemistry
Male
*Thymelaeaceae/chemistry

@article {pmid41900806,
year = {2026},
author = {Cho, E and Youn, K and Kwon, H and Bae, HJ and Moon, M and Jun, M and Kim, DH},
title = {2,3,4-Trihydroxybenzophenone Disassembles Amyloid β Aggregates and Ameliorates Synaptic Deficits.},
journal = {Pharmaceutics},
volume = {18},
number = {3},
pages = {},
doi = {10.3390/pharmaceutics18030320},
pmid = {41900806},
issn = {1999-4923},
support = {2024//Konkuk University/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which no disease-modifying therapy that halts or substantially slows disease progression is currently available. Although antibody therapies targeting amyloid β (Aβ) have recently received FDA approval, their high cost, limited efficacy, and potential adverse effects highlight the need for alternative solutions. Therefore, the development of low-molecular-weight compounds capable of reducing toxic Aβ aggregates is of considerable interest. In this study, we investigated the effects of 2,3,4-trihydroxybenzophenone (THB) on the inhibition and disassembly of Aβ1-42 aggregates through in vitro and in vivo experiments. Methods: In vitro assays were performed to evaluate the effects of THB on Aβ1-42 aggregation and fibril disassembly. Cell viability assays and hippocampal slice electrophysiology were conducted to assess neurotoxicity and synaptic function. In vivo effects were examined in Aβ1-42 aggregate-injected mice and in 5 Familial AD mutations (5XFAD) mice using behavioral, histological, and electrophysiological analyses. Results: THB inhibited Aβ1-42 aggregation in a concentration-dependent manner and promoted the disassembly of preformed fibrils. THB attenuated Aβ1-42-induced Neuro2a cell death and restored Aβ1-42 aggregate-associated long-term potentiation (LTP) deficits in hippocampal slices. In Aβ1-42 aggregate-injected and 5XFAD mice, THB reduced amyloid pathology and neuroinflammatory markers and improved synaptic function and memory performance. Conclusions: These findings suggest that THB modulates pathogenic Aβ1-42 assemblies and provides a structural basis for the development of small-molecule modulators of Aβ1-42 aggregation with potential preventive or disease-modifying applications in AD.},
}

@article {pmid41900916,
year = {2026},
author = {Papaliagkas, V and Kalinderi, K and Moschou, M and Arnaoutoglou, M and Koutsouraki, E and Kimiskidis, VK},
title = {The Role of Transcranial Magnetic Stimulation for the Treatment of Alzheimer's Disease: A Narrative Review.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/life16030397},
pmid = {41900916},
issn = {2075-1729},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease that accounts for 60-80% of all dementia cases and affects millions of people worldwide. At present, standard drug therapies provide only limited symptomatic relief. Therefore, the exploration of novel therapeutic approaches is crucial for improving patient outcomes. Transcranial magnetic stimulation (TMS) has emerged as a promising non-invasive neuromodulation technique that may provide benefit in AD management. This review discusses the pathophysiological mechanisms by which TMS operates, evaluates its clinical efficacy in AD patients, assesses its safety profile, and suggests future directions for research.},
}

@article {pmid41901028,
year = {2026},
author = {Stanciu, GD and Costachescu, I and Dascalu, C and Tamba, BI},
title = {Smart Drug-Delivery Approaches for Enhanced Management of Comorbid Conditions in Alzheimer's Disease.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/life16030510},
pmid = {41901028},
issn = {2075-1729},
support = {330783//This work was supported by a project funded under Smart Growth, Digitalization and Financial Instruments Program (PoCIDIF) 2021-2027, Priority 1, Policy Objective RSO1.1, project title "Versa-tile controlled release system for advanced topical formulation/ ; },
abstract = {Alzheimer's disease (AD) remains a major unmet medical challenge due to its complex pathology, high interpatient heterogeneity and frequent association with systemic comorbidities. Conventional pharmacotherapy is limited by poor blood-brain barrier permeability, off-target effects and reduced efficacy in polymedicated elderly populations. Smart drug-delivery systems (DDS), particularly nanotechnology-based platforms, have emerged as promising strategies to enhance brain targeting, optimize controlled drug release and mitigate systemic toxicity. This review examines recent advances in intelligent DDS for AD, with a focus on nanocarriers designed to modulate amyloid aggregation, neuroinflammation, oxidative stress and cholinergic dysfunction. Special attention is given to the impact of the most common comorbid conditions on DDS pharmacokinetics, safety and clinical performance. Furthermore, the challenges associated with clinical translation, such as long-term safety, immunogenicity, manufacturing scalability and regulatory harmonization, are critically discussed. In this context, versatile controlled release platforms that integrate rational design, predictive modeling and Quality by Design-driven manufacturing are highlighted as key enablers of translational success. By bridging intelligent formulation design with scalable production and regulatory readiness, advanced controlled release systems offer a pathway toward precision and patient-centered therapies. Such platforms hold significant potential to accelerate the safe integration of smart DDS into Alzheimer's disease management and broader neurotherapeutic applications.},
}

@article {pmid41901082,
year = {2026},
author = {Kumari, A and Zeng, XA},
title = {Dietary Bioactives in Alzheimer's Disease: A Critical Appraisal of Clinical Trials and Future Nutritional Strategies.},
journal = {Nutrients},
volume = {18},
number = {6},
pages = {},
doi = {10.3390/nu18060907},
pmid = {41901082},
issn = {2072-6643},
support = {32172348//National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease ; Humans ; *Dietary Supplements ; *Phytochemicals/therapeutic use/administration & dosage ; Clinical Trials as Topic ; Cognition/drug effects ; *Diet ; Biomarkers ; },
abstract = {Background: Alzheimer's disease (AD) remains a major public health challenge. Observational associations between dietary patterns and reduced dementia risk have prompted investigations of dietary bioactives (DBs) as cognitive nutraceuticals. Methods: This critical narrative review examines interventional trials for nine prominent DBs relevant to AD: docosahexaenoic acid (DHA), curcumin, resveratrol, epigallocatechin gallate (EGCG), nicotinamide riboside (NR), tricaprilin, vitamin E (α-tocopherol), cannabinoids, and NIC5-15 (D-pinitol). Trials were identified through ClinicalTrials.gov (search date: December 2024) and supplemented by PubMed searches for published results. Data were extracted on trial phase, design, cognitive/functional endpoints, biomarker outcomes, and development status. Findings are synthesized qualitatively; no formal meta-analysis or risk of bias assessment was conducted. Results: None of the nine bioactives demonstrated consistent cognitive efficacy in AD. Phase III trials of DHA, curcumin, and tricaprilin did not meet primary cognitive endpoints. Resveratrol reduced CSF Aβ40 without cognitive benefit. Cannabinoids improved behavioral symptoms but showed no measurable cognitive effects. High-dose vitamin E slowed functional decline, while cognition remained unchanged. In contrast, trials in preclinical or at-risk populations reported preliminary cognitive signals for EGCG and biomarker engagement for NR, suggesting potential for early intervention. Conclusions: Current clinical evidence does not support high-dose DBs supplementation as an effective treatment for AD. Predominantly negative late-phase findings highlight limitations, with potential contributors including limited bioavailability, late intervention, insufficient target engagement, and biological heterogeneity. Future research may benefit from early biomarker-defined populations, optimized formulations, multi-nutrient or dietary approaches, and precision nutrition strategies considering genetic risk and baseline nutrient status. DBs may be better positioned for prevention or early-stage intervention rather than late-stage therapy.},
}

*Alzheimer Disease
Humans
*Dietary Supplements
*Phytochemicals/therapeutic use/administration & dosage
Clinical Trials as Topic
Cognition/drug effects
*Diet
Biomarkers

@article {pmid41901135,
year = {2026},
author = {Baek, HI and Joo, JC and Kim, SK and Park, MH and Cho, GH and Shen, L and Park, SJ},
title = {Efficacy and Safety of Standardized Ethanol Extract of Purple Perilla (Perilla frutescens Britton var. acuta Kudo) Leaves in Cognitive Impairment: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.},
journal = {Nutrients},
volume = {18},
number = {6},
pages = {},
doi = {10.3390/nu18060960},
pmid = {41901135},
issn = {2072-6643},
support = {Food Functionality Evaluation program//Ministry of Agriculture, Food and Rural Affairs/ ; 2026-RISE-13-WSU//Ministry of Education/ ; },
mesh = {Humans ; Double-Blind Method ; *Plant Extracts/therapeutic use/adverse effects/pharmacology ; Male ; Female ; *Cognitive Dysfunction/drug therapy/blood ; *Plant Leaves/chemistry ; *Perilla frutescens/chemistry ; Aged ; Middle Aged ; Cognition/drug effects ; Brain-Derived Neurotrophic Factor/blood ; Ethanol/chemistry ; Amyloid beta-Peptides/blood ; Treatment Outcome ; Biomarkers/blood ; Phytotherapy ; },
abstract = {Objectives: This randomized, double-blind, placebo-controlled 12-week clinical trial evaluated the efficacy and safety of a standardized ethanol extract of purple perilla leaves (Perilla frutescens Britton var. acuta Kudo; PE) in adults with cognitive impairment. Methods: Subjects who met the inclusion criteria were randomly assigned in a 1:1 ratio to one of two groups and received PE (n = 50, 500 mg/day) or placebo (n = 50) for 12 weeks. The primary efficacy outcomes included cognitive function, which was assessed by the Korean mini-mental status examination-2 (K-MMSE-2) and the Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog), and plasma amyloid β (Aβ) and brain-derived neurotrophic factor (BDNF) levels, which were measured as secondary biochemical markers. The safety biomarkers were also assessed before and after the intervention. Results: After 12 weeks of intervention, the K-MMSE-2 total score, the K-MMSE-2 subdomain scores (attention and calculation and language), the ADAS-Cog total score, and the ADAS-Cog subscale scores (word recall, commands, delayed word recall, naming, word recognition, and recall instructions) showed statistically significant between-group improvements compared with the placebo group. Improvements were observed in both groups, whereas the magnitude of cognitive enhancement was greater in the PE group, indicating an effect beyond placebo-related responses. No statistically significant between-group differences were observed in plasma Aβ or BDNF levels. The safety evaluation found no clinically significant changes. Conclusions: Twelve-week administration of PE significantly improved cognitive outcomes without safety concerns, suggesting its potential as a standardized botanical ingredient for supporting cognitive function in individuals with early cognitive impairment.},
}

Humans
Double-Blind Method
*Plant Extracts/therapeutic use/adverse effects/pharmacology
Male
Female
*Cognitive Dysfunction/drug therapy/blood
*Plant Leaves/chemistry
*Perilla frutescens/chemistry
Aged
Middle Aged
Cognition/drug effects
Brain-Derived Neurotrophic Factor/blood
Ethanol/chemistry
Amyloid beta-Peptides/blood
Treatment Outcome
Biomarkers/blood
Phytotherapy

@article {pmid41901170,
year = {2026},
author = {Kwaśniewska, K and Fic, W and Polak-Szczybyło, E},
title = {Vitamins as Modulators of Neurodegenerative Disease Pathways: Mechanisms and Therapeutic Perspectives.},
journal = {Nutrients},
volume = {18},
number = {6},
pages = {},
doi = {10.3390/nu18060995},
pmid = {41901170},
issn = {2072-6643},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Vitamins/therapeutic use/pharmacology/administration & dosage ; *Neuroprotective Agents/pharmacology ; *Dietary Supplements ; Antioxidants ; Oxidative Stress/drug effects ; Ubiquinone/analogs & derivatives ; Animals ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, currently represent one of the major challenges in contemporary medicine and geriatrics. Progressive degeneration of the nervous system affects not only patients' physical functioning but also their psychosocial well-being, often leading to social isolation and disruption of interpersonal relationships. These processes are most strongly associated with individuals over 65 years of age, in whom metabolic syndrome is frequently diagnosed and constitutes a significant factor predisposing them to the exacerbation of neuropathological changes. This review analyzes the role of selected vitamins in modulating the course of neurodegenerative disorders, with particular emphasis on their neuroprotective potential. Specific attention is given to their involvement in antioxidant defense mechanisms, regulation of inflammatory pathways, prevention of abnormal protein aggregation, participation in neurotransmitter synthesis, and support of mitochondrial function and cellular energy metabolism. The review also considers key interactions between vitamins and coenzyme Q10, which synergistically enhance neuroprotective mechanisms. Deficiencies in certain vitamins may exacerbate oxidative stress, impair synaptic transmission, and intensify neuroinflammatory responses, thereby contributing to disease progression. The study analyzes the available data on therapeutic doses of vitamins and compares them with the recommended dietary intake and the upper tolerable intake levels (UL). The available evidence suggests that personalized vitamin supplementation, when integrated with a well-balanced and nutrient-dense diet, may constitute a valuable adjunctive therapeutic strategy. Such an approach may help attenuate disease progression, support neuronal integrity, and improve functional outcomes. Ultimately, targeted nutritional interventions may enhance overall well-being and quality of life in patients affected by neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/drug therapy/metabolism
*Vitamins/therapeutic use/pharmacology/administration & dosage
*Neuroprotective Agents/pharmacology
*Dietary Supplements
Antioxidants
Oxidative Stress/drug effects
Ubiquinone/analogs & derivatives
Animals

@article {pmid41901214,
year = {2026},
author = {Lou, X and Ni, Z and Cui, S and He, Z and Zong, Y and Chen, W and Geng, J and Zhou, J and Li, Z and Zhao, Y and Teng, H},
title = {Self-Assembled Rg3/Naringenin Nanoparticles for Targeted Brain Delivery: A Promising Therapeutic Approach for Early Alzheimer's Disease.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {3},
pages = {},
doi = {10.3390/ph19030367},
pmid = {41901214},
issn = {1424-8247},
support = {De-velopment and Demonstration of Medical Products from Sika Deer//The Sanjiang Laboratory of Jilin Province./ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) has an irreversible disease course, making early intervention a key measure to delay disease progression. However, existing therapies are limited by weak brain-targeted delivery efficiency due to the blood-brain barrier (BBB) and low bioavailability of drugs, making it difficult to address the complexity of AD's pathological mechanisms. Methods: Addressing these limiting factors, this research aims to develop an early AD intervention formulation with "high targeting, high bioavailability, and high biosafety." Based on the principle of drug synergistic effects, this study employed the reverse solvent method and optimized the combination ratio of Ginsenoside Rg3 and Naringenin (Nar) to design and prepare a self-assembling nano-delivery system (Rg3-Nar-NPs, GNN). The study utilized intranasal administration to bypass the BBB through the direct pathway between the nasal mucosa and central nervous system. Results: This approach enabled targeted accumulation of the drug in brain lesion areas, significantly reducing Aβ deposition, oxidative stress, and inflammatory factor surges caused by early AD, thereby improving cognitive dysfunction in mice. Moreover, GNN demonstrated superior biosafety and bioavailability compared to the individual components. Through transcriptomic analysis, the study elucidated for the first time that GNN can activate the OXT/ERK/Fos pathway to break the malignant cycle of ROS-neuroinflammation, inhibiting the amplification effect of early AD pathological damage. Conclusions: This research provides new molecular targets and drug options for multi-target synergistic intervention of early AD, showing potential as a candidate strategy for precise early AD intervention and laying theoretical and experimental foundations for subsequent clinical translation.},
}

@article {pmid41901221,
year = {2026},
author = {Watt, G and Olaya, J and Muench, G and Garner, B and Karl, T},
title = {Effects of Chronic 100 mg/kg Cannabidiol Treatment in Male Double Transgenic APPSwe/PS1∆E9 Mice.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {3},
pages = {},
doi = {10.3390/ph19030374},
pmid = {41901221},
issn = {1424-8247},
support = {n.a.//Alzheimer's Australia Dementia Research/ ; #1102012, #1141789, and #1095215//National Health and Medical Research Council/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is a neurodegenerative disease for which there are no highly effective treatments, which highlights the need for novel therapeutics. Cannabidiol (CBD) has demonstrated antioxidant, anti-inflammatory and neuroprotective properties. Chronic CBD treatment (20 mg/kg and 50 mg/kg) reverses social recognition memory deficits of APPSwe/PS1∆E9 (APP/PS1) transgenic mice; however, it does not produce effects on AD-relevant brain pathology. Methods: Here, we investigated whether chronic high-dose CBD treatment (i.e., 100 mg/kg intraperitoneally) in early symptomatic 7.5-month-old APP/PS1 males would reverse cognitive deficits while also influencing neuropathological markers relevant to AD. Mice were assessed for anxiety, recognition memory, and social and aggressive behaviours before carrying out neuropathological analyses of collected brain tissue. Results: Vehicle-treated APP/PS1 transgenic males demonstrated reduced aggressive behaviour and increased socio-positive behaviour. A moderate deficit in social recognition memory was restored by CBD. APP/PS1 mice also exhibited elevated cortical proBDNF levels under vehicle treatment, and hippocampal levels of TNF-α and IL-1β were reduced in all APP/PS1 mice. AD transgenic mice exhibited no changes in soluble or insoluble Aβ42 levels or PPARγ isoforms. Conclusions: This study found that high-dose CBD restored a moderate social recognition memory deficit. However, CBD did not have marked effects on AD-relevant neuropathological markers assessed, most likely because the AD transgenic mice were evaluated at a disease stage too early to detect significant pathological changes. Thus, the underlying mechanisms for CBD's effect on social recognition memory require further investigation.},
}

@article {pmid41901348,
year = {2026},
author = {Wang, Z and Wang, L and Zhang, Y and Yang, S and Shi, B and Liu, D and Zhang, H and Xiao, W and Zhang, J and Han, X and Wei, D},
title = {Yixin Yangshen Granules Target HIF-1 Signaling to Modulate the Neuroimmune Microenvironment in Alzheimer's Disease: Insights from Integrative Multi-Omics and Deep Learning.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {3},
pages = {},
doi = {10.3390/ph19030502},
pmid = {41901348},
issn = {1424-8247},
support = {82174210//National Natural Science Foundation of China/ ; 102160222020040009016//Scientific Research Facility Special Foundation for Operation and Maintenance/ ; 160202001000210007//Scientific Research Facility Special Foundation for Operation and Maintenance/ ; ZZ14-FL-005//Fundamental Research Funds for the Central Public Welfare Research Institutes/ ; 2022ZD0211600//STI2030-Major Projects/ ; ZZ13-YQ-073//Fundamental Research Funds for the Central Public Welfare Research Institution/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) involves amyloid and tau pathology with neuroimmune dysregulation, and Yixin Yangshen Granules (YXYS) shows neuroprotective promise, though mechanisms remain unclear. This study aimed to elucidate the multi-target mechanisms of YXYS in AD. Methods: The study began by analyzing a public human AD hippocampal snRNA-seq dataset to identify cell-type-specific pathological pathways and profiled YXYS constituents by UPLC-QTOF-MS. In vitro, YXYS cytoprotection against mitochondrial dysfunction and oxidative stress was tested in Aβ25-35-challenged HT22 cells; in vivo efficacy was assessed in Aβ1-42-induced mice via behavioral and histopathological analyses. Integrated transcriptomic and proteomic profiling of brain tissue, with ELISA, qRT-PCR, and Western blot validation, confirmed pathway targets. Using the intersection of transcriptomic and proteomic targets as biological input, the DTIAM deep learning framework was employed to prioritize active YXYS constituents. Finally, molecular docking and 100-ns dynamics simulations demonstrated direct binding of Ganosporelactone A to HIF-1α. Results: AD snRNA-seq analysis highlighted HIF-1 and AGE-RAGE signaling as prominent pathways in the AD hippocampus, particularly enriched in brain microvascular endothelial cells, implicating neurovascular hypoxic and inflammatory stress. In Aβ-induced mice, YXYS improved cognition, reduced Aβ pathology, suppressed neuroinflammation, and promoted neuronal survival, consistent with in vitro evidence of restored mitochondrial function. Multi-omics confirmed convergence on HIF-1 and AGE-RAGE pathways, with YXYS rebalancing the neuroimmune microenvironment by reducing pro-inflammatory M0 macrophages. Screening against these consensus signaling hubs, deep learning analysis prioritized Ganosporelactone A as the top-ranked modulator, and molecular further demonstrated the stable binding of Ganosporelactone A to HIF-1α, linking YXYS to mitigation of hypoxic stress. Conclusions: Guided by multi-omics and deep learning, our findings suggest that YXYS may alleviate AD-related phenotypes through multi-target modulation of the HIF-1 and AGE-RAGE pathways, with associated improvements in neuro-immune homeostasis and reductions in oxidative stress, neuroinflammation, and hypoxia.},
}

@article {pmid41901610,
year = {2026},
author = {Choi, HJ and Cho, A and You, JH and Park, S and Lee, SH and Kim, DH},
title = {Differentiating Early Alzheimer's Disease from MCI Using Comprehensive Semiquantitative Parameters in Dual-Phase Amyloid PET: A Pilot Study.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {3},
pages = {},
doi = {10.3390/medicina62030529},
pmid = {41901610},
issn = {1648-9144},
support = {HURF-2024-38//Hallym University/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/diagnostic imaging ; Pilot Projects ; *Cognitive Dysfunction/diagnosis/diagnostic imaging ; Male ; Female ; Aged ; *Positron-Emission Tomography/methods ; Diagnosis, Differential ; Magnetic Resonance Imaging/methods ; ROC Curve ; Aged, 80 and over ; Amyloid/analysis ; Middle Aged ; *Positron Emission Tomography Computed Tomography/methods ; Sensitivity and Specificity ; },
abstract = {Background and Objectives: Dual-phase amyloid PET imaging has been proposed to provide complementary information regarding amyloid burden and cerebral perfusion. This exploratory pilot study evaluated whether semiquantitative parameters derived from dual-phase PET/CT could differentiate individuals operationally classified as Alzheimer's disease with mild functional impairment (AD-MFI) from those with mild cognitive impairment (MCI). Materials and Methods: Twenty-four participants (AD-MFI, n = 19; MCI, n = 5) underwent dual-phase amyloid PET/CT and structural MRI. Early phase SUV (eSUV), delayed-phase SUV (dSUV), standardized uptake value ratios (SUVR), and the difference between early and delayed uptake (SUVdiff) were analyzed across predefined cortical regions. Group differences were assessed using nonparametric tests, with false discovery rate (FDR) and Bonferroni corrections applied for multiple comparisons. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis. Results: Several regional parameters demonstrated nominally significant group differences in uncorrected analyses; however, none remained statistically significant after correction for multiple comparisons. Among the evaluated metrics, SUVdiff demonstrated the highest diagnostic performance (sensitivity 84.2%, specificity 80.0%), followed by eSUV (68.4%, 100%) and MRI cortical volume (47.4%, 100%). Delayed-phase parameters alone showed limited discriminatory robustness despite observed group-level differences. Conclusions: In this exploratory cohort, SUVdiff showed moderate discriminatory potential between AD-MFI and MCI. However, given the small sample size and multiplicity of comparisons, the results should be interpreted as hypothesis-generating. Larger, prospective studies are required to determine the reproducibility and clinical utility of dual-phase semiquantitative parameters.},
}

Humans
*Alzheimer Disease/diagnosis/diagnostic imaging
Pilot Projects
*Cognitive Dysfunction/diagnosis/diagnostic imaging
Male
Female
Aged
*Positron-Emission Tomography/methods
Diagnosis, Differential
Magnetic Resonance Imaging/methods
ROC Curve
Aged, 80 and over
Amyloid/analysis
Middle Aged
*Positron Emission Tomography Computed Tomography/methods
Sensitivity and Specificity

@article {pmid41887928,
year = {2026},
author = {Zhao, X and Wang, X and Sheng, Y and Lin, S and Xu, S and Hu, Z and Ling, X and Chen, C and Cao, M and Cui, H and Lu, Y},
title = {Rational Engineering of Phospholipase D Unlocks Robust Catalysis for Phosphatidylserine Formation.},
journal = {Journal of agricultural and food chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.5c17951},
pmid = {41887928},
issn = {1520-5118},
abstract = {Phosphatidylserine (PS), a major brain phospholipid, supports the central nervous system's health and may alleviate cognitive decline, including in Alzheimer's disease. A key challenge in green enzymatic PS synthesis is the suppression of hydrolysis while enhancing PLD-catalyzed transphosphatidylation. Here, we developed a mechanism-guided engineering strategy for Streptomyces antibioticus phospholipase D (SaPLD). The substitution of W187I increased the PS yield to 58.3%, while V380W improved thermostability. Combining beneficial mutations generated SaPLD-R7 (W187I/V380W/G381A), which overcame the activity-stability trade-off and achieved up to 95.8% PS yield using the enzyme produced by 5 L scale fermentation. Molecular dynamics simulations showed that SaPLD-R7 enhanced substrate binding and catalysis by shortening the key active site distances and reducing local flexibility. Solvent contact and energy analyses further indicated improved stability. This work establishes a structure-mechanism-function framework for enhancing PLD transphosphatidylation and provides a robust enzymatic route for high-efficiency PS production as a valuable functional food ingredient.},
}

@article {pmid41888060,
year = {2026},
author = {Mao, KL and Fu, JX and Chen, J and Liao, YL and Huang, ML and Chen, Z and Lin, LM and Shi, Q and Gao, BM},
title = {From marine predator to pharmacology: Conotoxin diversity, discovery, and therapeutic potential.},
journal = {Zoological research},
volume = {47},
number = {2},
pages = {378-403},
doi = {10.24272/j.issn.2095-8137.2025.553},
pmid = {41888060},
issn = {2095-8137},
mesh = {*Conotoxins/chemistry/pharmacology/therapeutic use/genetics ; Animals ; *Conus Snail/chemistry ; Drug Discovery ; Humans ; },
abstract = {Cone snails (Conus spp.) biosynthesize a highly specialized venom comprising a vast arsenal of neurotoxic peptides, termed conotoxins. These peptides exhibit exceptional structural and functional diversity, characterized by unique disulfide-bond architectures, highly variable amino acid sequences, and precise interactions with defined molecular targets. This review presents a comprehensive synthesis of current knowledge on conotoxin biology, beginning with evolutionary origin and proceeding through the classification systems used to define their gene superfamilies and pharmacological families. Advances in discovery methodologies are also examined, with particular emphasis on the transformative role of high-throughput multi-omics in expanding conotoxin identification and characterization. Furthermore, this review analyzes the pharmacological properties of representative conotoxins acting on key ion channels and receptors and evaluates the structure-activity relationships that determine their potency, selectivity, and functional profile. Mechanistic insights derived from these studies have established conotoxins as powerful neuropharmacological tools and a rich reservoir for drug discovery. Their significant therapeutic potential is underscored by efficacy in chronic pain management, exemplified by the US FDA-approved drug ziconotide, and by growing evidence supporting applications in neuroprotection in disorders such as Alzheimer's disease and Parkinson's disease, as well as in selected cardiovascular conditions. Future perspectives are also discussed, with progress likely dependent on the integration of computational design, peptide engineering, and bioengineering platforms to accelerate the translation of these marine peptides into next-generation clinical therapeutics.},
}

*Conotoxins/chemistry/pharmacology/therapeutic use/genetics
Animals
*Conus Snail/chemistry
Drug Discovery
Humans

@article {pmid41888300,
year = {2026},
author = {Sanchez-Mico, MV and Calvo-Rodriguez, M and Bacskai, BJ},
title = {Role of dysregulated calcium homeostasis in astrocytes in neurodegenerative disorders.},
journal = {Nature reviews. Neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41888300},
issn = {1471-0048},
abstract = {Calcium signalling in astrocytes is a fundamental mechanism for maintaining brain homeostasis, shaping neuronal activity, and coordinating vascular and immune responses. Once considered secondary to neuronal signalling, astrocytic Ca[2+] dynamics are now recognized as highly versatile, spatially compartmentalized and essential for regulating neurotransmitter uptake, ion buffering, metabolic support and mitochondrial function. Accumulating evidence shows that these Ca[2+] signalling pathways are progressively remodelled during ageing and become profoundly dysregulated in neurodegenerative diseases, including Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis. Importantly, astrocyte Ca[2+] alterations are heterogeneous and context-dependent, ranging from aberrant spontaneous activity to loss of signalling in specific subcellular domains, reflecting the disease stage, brain region and molecular pathology. Disruption of astrocyte Ca[2+] homeostasis compromises core homeostatic functions and contributes to neuronal vulnerability, circuit dysfunction and impaired neurovascular regulation. By integrating current evidence across physiological, ageing and disease contexts, this Review highlights astrocytic Ca[2+] signalling as a central node in neurodegenerative pathophysiology and underscores its potential as a target for therapeutic intervention.},
}

@article {pmid41888327,
year = {2026},
author = {Zeng, Y and Shao, Y and Zhou, D and Qiu, M and Wang, Z and Xi, Q},
title = {Whole-Brain Static Functional Connectivity Disruptions Based on the Default Mode Network in Patients with Mild Cognitive Impairment.},
journal = {Brain topography},
volume = {39},
number = {3},
pages = {},
pmid = {41888327},
issn = {1573-6792},
support = {Grant No. 20254Y0168//the Commission of Shanghai Municipal Health/ ; Grant No. PWRl2022-05//the Outstanding Leaders Training Program of Pudong Health Bureau of Shanghai/ ; Grant No. 23Y11907500//the Science and Technology Commission of Shanghai Municipality/ ; },
mesh = {Humans ; *Cognitive Dysfunction/physiopathology/diagnostic imaging ; Male ; Female ; Magnetic Resonance Imaging/methods ; Aged ; *Brain/physiopathology/diagnostic imaging ; *Default Mode Network/physiopathology/diagnostic imaging ; Middle Aged ; Brain Mapping ; Retrospective Studies ; Neural Pathways/physiopathology/diagnostic imaging ; *Nerve Net/physiopathology/diagnostic imaging ; Alzheimer Disease/physiopathology ; },
abstract = {Mild cognitive impairment (MCI) is regarded a potential early stage of Alzheimer's disease (AD) and associated with a significantly increased risk of progression to AD. This study aims to evaluate whole-brain static functional connectivity (SFC) disruptions with the default mode network (DMN) seed points in patients with MCI by resting-state functional magnetic resonance imaging (rs-fMRI), and to explore whether these disruptions could serve as potential markers for MCI progression to AD. Retrospective rs-fMRI data with MCI (n = 36) and corresponding matched healthy controls (HCs) (n = 26) were collected for comparison. Independent component analysis (ICA) was used to extract DMN regions, and SFC was calculated for four seed points within the DMN. Two-sample t-tests were performed to compare group differences in SFC strength between the MCI and HC groups, and Pearson correlation analyses were conducted. Compared to HCs, the MCI group showed both increased and decreased SFC between four subregions and multiple brain regions, decreased SFC was more widely distributed than increased SFC. Abnormal connectivity was more prominent in the first two key nodes compared to the latter two. Affected regions primarily located in the precuneus, frontal gyri, temporal gyri, postcentral gyrus, caudate nucleus, lingual gyrus, and fusiform gyrus. The SFC value between the right angular gyrus and the right insula was significantly negatively correlated with MoCA scores (r = - 0.385, p < 0.05, FDR-corrected). It reveals a decline in the functional integration capacity within the DMN, as well as complex reorganization and abnormal connectivity patterns between the DMN and other brain networks. The altered interactions between DMN subregions and abnormal brain areas are significantly associated with episodic memory disturbance in MCI.},
}

Humans
*Cognitive Dysfunction/physiopathology/diagnostic imaging
Male
Female
Magnetic Resonance Imaging/methods
Aged
*Brain/physiopathology/diagnostic imaging
*Default Mode Network/physiopathology/diagnostic imaging
Middle Aged
Brain Mapping
Retrospective Studies
Neural Pathways/physiopathology/diagnostic imaging
*Nerve Net/physiopathology/diagnostic imaging
Alzheimer Disease/physiopathology

@article {pmid41888480,
year = {2026},
author = {Xu, Z and Mijalkov, M and Sun, J and Chang, YW and Sala, A and Volpe, G and Severino, M and Veronese, M and Garcia-Ptacek, S and Pereira, JB and , },
title = {Mapping individual molecular connectomes in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71310},
doi = {10.1002/alz.71310},
pmid = {41888480},
issn = {1552-5279},
support = {W81XWH-12-2-0012//U.S. Department of Defense/ ; //National Institutes of Health Grant/ ; //Gun och Bertil Stohnes Stiftelse/ ; //KI Foundations/ ; //Gamla Tjänarinnor Foundation/ ; //Karolinska Institute Consolidator Position grant/ ; //Strategic Research Area Neuroscience/ ; //Kung Gustav:S & Viktorias Stiftelse/ ; //Swedish Alzheimer Foundation/ ; //Blomquist family/ ; //European Union - NextGenerationEU and the Romanian Government/ ; //KI Research Incubator/ ; 2022-01108//Swedish Research Council/ ; 2025-03210//Swedish Research Council/ ; AF-1032782//Alzheimer Foundation/ ; 2-3980/2025//Blomqvist Foundation/ ; FO2025-0059//Swedish Brain Foundation/ ; 760250/28.12.2023//Romania's National Recovery and Resilience Plan/ ; PNRR-C9-I8-CF109/31.07.2023//Romania's National Recovery and Resilience Plan/ ; //Omanian Ministry of Research, Innovation and Digitalization/ ; //StratNeuro/ ; //KI Consolidator Grant/ ; //King Gustaf V and Queen Victoria's Foundatio/ ; //Dementia Foundation/ ; //Lars Hierta Memorial Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism/genetics/pathology ; *Connectome/methods ; Positron-Emission Tomography ; Male ; Female ; Aged ; tau Proteins/metabolism ; *Brain/diagnostic imaging/metabolism ; Amyloid beta-Peptides/metabolism ; Disease Progression ; Aged, 80 and over ; Longitudinal Studies ; },
abstract = {INTRODUCTION: Mapping individual differences is crucial to improve personalized medicine approaches in Alzheimer's disease (AD), which is characterized by strong inter-individual variability in the accumulation patterns of tau and amyloid beta pathology.

METHODS: We assess the progression of AD across the disease continuum by building individual molecular connectomes using longitudinal positron emission tomography (PET) data.

RESULTS: We demonstrate that these connectomes constitute a unique fingerprint, capable of identifying a single individual from a large group of subjects. Alterations in the connectomes discriminate different diagnostic groups and predict cognitive decline to a higher extent than conventional PET measures. We introduce a novel gene-specific transcription network analysis that linked individual tau and amyloid connectomes to a common transcriptomic profile of apoptosis, with the tau connectome being specifically related to pyrimidine metabolism, and the amyloid connectome to histone acetylation.

DISCUSSION: Individual molecular connectome mapping provides a novel and sensitive framework to monitor AD progression.},
}

Humans
*Alzheimer Disease/diagnostic imaging/metabolism/genetics/pathology
*Connectome/methods
Positron-Emission Tomography
Male
Female
Aged
tau Proteins/metabolism
*Brain/diagnostic imaging/metabolism
Amyloid beta-Peptides/metabolism
Disease Progression
Aged, 80 and over
Longitudinal Studies

@article {pmid41888691,
year = {2025},
author = {Dwarkanth, PS and Anitha, R and Babu, GH and Ahammad, SKH and Karamati, H and Kumar, A and Oza, AD and Moges, DM},
title = {An efficient Alzheimer's disease detection by NV classifier with BWTDL approach using MRI image.},
journal = {BMC medical imaging},
volume = {26},
number = {1},
pages = {},
pmid = {41888691},
issn = {1471-2342},
}

@article {pmid41888907,
year = {2026},
author = {Tsai, AP and Martin, AK and Mi, A and Yeh, AE and Ramirez Lopez, E and Wyss-Coray, T},
title = {PLCG2 signaling and genetic resilience in Alzheimer's disease.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {},
pmid = {41888907},
issn = {1750-1326},
}

@article {pmid41888956,
year = {2026},
author = {Li, M and Yu, Q and Yu, S and Cheng, Q and Wu, S and Jin, Y and Cui, Z and Chen, H and Zhao, X and Wu, X and Lu, Z},
title = {Plasma EV LINE-1 mRNA as a diagnostic biomarker for differentiating Alzheimer's disease from non-Alzheimer's dementias.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02034-3},
pmid = {41888956},
issn = {1758-9193},
support = {ZR2025QC1673//Natural Science Foundation of Shandong Province/ ; tsqnz20240852//Taishan Scholars Program of Shandong Province/ ; 82502804//National Natural Science Foundation of China/ ; },
}

@article {pmid41888976,
year = {2026},
author = {Li, M and Qiu, N and Niu, W and Qian, C and Zhang, Y and Yang, W and Ding, F and Wang, H and Xu, X and Xia, J and Zhang, X},
title = {A novel PGK1 activator improves Alzheimer's disease by regulating glycolysis.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02029-0},
pmid = {41888976},
issn = {1758-9193},
support = {2021-I2M-1-069//CAMS Innovation Fund for Medical Sciences/ ; },
}

@article {pmid41889068,
year = {2026},
author = {Wang, P and Xue, M and Mao, Y and Wang, C and Yao, X and Biswal, BB},
title = {Dynamic Alterations of Functional Systems in Alzheimer's Disease: A Co-Activation Pattern Analysis.},
journal = {Human brain mapping},
volume = {47},
number = {5},
pages = {e70509},
doi = {10.1002/hbm.70509},
pmid = {41889068},
issn = {1097-0193},
support = {NSFC62401106//National Natural Science Foundation of China/ ; NSFC62171101//National Natural Science Foundation of China/ ; 2024NSFSC1661//Sichuan Province Science and Technology Support Program/ ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnostic imaging ; Male ; Magnetic Resonance Imaging ; Female ; Aged ; *Cognitive Dysfunction/physiopathology/diagnostic imaging ; *Nerve Net/diagnostic imaging/physiopathology ; *Connectome/methods ; Middle Aged ; Aged, 80 and over ; *Default Mode Network/diagnostic imaging/physiopathology ; *Brain/physiopathology/diagnostic imaging ; },
abstract = {While resting-state brain dysfunctions have been extensively investigated in Alzheimer's disease (AD), the dynamic alterations of functional systems remain poorly understood. We employed co-activation pattern (CAP) analysis to characterize the functional-state alterations in 243 participants using resting-state fMRI data and applied graph theory analysis to estimate corresponding topological properties. The CAP analysis identified five distinct brain states across groups: State 1 (limbic network dominated), State 2 (dorsal attention network (DAN) and central executive network dominated), State 3 (default mode network and central executive network dominated), State 4 (somatomotor network and ventral attention network dominated), and State 5 (DAN, sensorimotor, and visual networks dominated). Compared to cognitively unimpaired individuals, State 3 demonstrated significantly reduced persistence and resilience in both mild cognitive impairment (MCI) and AD groups. Additionally, both clinical groups (MCI and AD) exhibited decreased transitions from State 2 to State 5 and reduced self-transitions within State 3. Graph theory analysis revealed that compared to cognitively unimpaired individuals, MCI and AD individuals had increased node degree centrality and node efficiency, alongside decreased node local efficiency in regions within the default mode network (DAN) and visual network, which corresponded well with CAP analysis results. Our findings provide a multiscale framework linking dynamic state instability to static network reorganization, advancing understanding of the dynamic functional alterations underlying cognitive decline in AD spectrum disorders.},
}

Humans
*Alzheimer Disease/physiopathology/diagnostic imaging
Male
Magnetic Resonance Imaging
Female
Aged
*Cognitive Dysfunction/physiopathology/diagnostic imaging
*Nerve Net/diagnostic imaging/physiopathology
*Connectome/methods
Middle Aged
Aged, 80 and over
*Default Mode Network/diagnostic imaging/physiopathology
*Brain/physiopathology/diagnostic imaging

@article {pmid41889233,
year = {2026},
author = {Santos, LRC and de Almeida, JNB and Frias, CC and Almeida, WP and Maistro, EL},
title = {Evaluation of DNA/Chromosome Integrity and Cell Death in Human Metabolically Noncompetent and Competent Cells Exposed to N'-(3,5-Difluorobenzylidene)Pyridine-4-Carbohydrazide.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.70171},
pmid = {41889233},
issn = {1099-1263},
support = {Finance code 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 303604/2021-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Universidade Estadual Paulista/ ; },
abstract = {The N-acylhydrazone scaffold is recognized as a privileged structure for the design of bioactive substances with increasing applications in medicinal chemistry research. Ensuring the safety of newly developed molecules is a critical step for both human health and environmental protection. Accordingly, this study aimed to evaluate the cytotoxic and genotoxic properties of N'-(3,5-difluorobenzylidene)pyridine-4-carbohydrazide in two cellular models: nonmetabolizing leukocytes and metabolically active hepatic cells (HepG2/C3A). The resazurin-based cytotoxicity analysis, performed with concentrations between 1 and 600 μg/mL, indicated that only the uppermost concentration caused a marked decrease in viability of both cell populations after 48 h of incubation. Regarding genotoxicity at 50, 100, and 200 μg/mL concentrations, no DNA damage was detected in the comet assay, but in the micronucleus test, a significant increase in chromosome alterations in leukocytes at 200 μg/mL concentration was detected, with a decrease in cell proliferation in both cell types. The data indicate that, at the concentrations where the biological effects of acylhydrazone were previously observed, the substance appeared to be safe, but at higher concentrations and/or during chronic exposure, caution and further studies are needed.},
}

@article {pmid41889331,
year = {2026},
author = {Nelvagal, HR and Chiraki, N and Curless, T and Cullinane, PW and Rockliffe, A and Pimparkar, S and Kawamura, H and Ollerenshaw, S and Elahi, I and Brandner, S and Wu, L and Real, R and Ryten, M and Hardy, J and De Pablo Fernandez, E and Warner, TT and Morris, HR and Lim, YM and Jaunmuktane, Z},
title = {Quantitative pathology and APOE genotype reveal dementia risk and progression in Lewy body disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag114},
pmid = {41889331},
issn = {1460-2156},
abstract = {Dementia in Lewy body diseases (LBD) is common and arises through heterogeneous and incompletely understood pathways. Evidence suggests contributions from genetic factors, including APOE ε4 genotype, co-pathology including concomitant Alzheimer's disease pathology and hypoperfusion related to orthostatic hypotension. However, the relative impact of these factors remains unclear. To address this, we analysed 399 post-mortem brains from LBD cases comprising Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies, and controls, integrating APOE genotype, clinical data and assessment of ischaemic pathology alongside large-scale digital pathology quantification. We established an image analysis pipeline utilising machine learning to enable automated, standardised measurement of α-synuclein, amyloid-β, and phosphorylated tau burden across multiple brain regions. Quantitative pathology strongly correlated with semi-quantitative ratings and outperformed conventional staging in predicting dementia. Across multiple analytical approaches, APOE ε3 and ε4 carriers showed distinct dementia risk profiles. APOE ε3 carriers developed dementia at lower quantitative α-synuclein and amyloid-β thresholds than ε4 carriers, although overall dementia risk was dominated by ε4 genotype, consistent with ε4 both promoting greater pathology accumulation and modifying the threshold for dementia onset. Orthostatic hypotension and ischaemic pathology increased dementia risk only in ε3 carriers with low Lewy and Alzheimer's proteinopathy burden, while male sex further modulated dementia risk for this subgroup. The Subtype and Stage Inference (SuStaIn) algorithm identified four trajectories of Lewy pathology progression. Two corresponded to recognised patterns, one brainstem-first and the other with early amygdala and concomitant brainstem involvement. Two further patterns showed early cortical involvement, one with early cingulate cortex involvement together with brainstem pathology and the other starting in neocortex before limbic and brainstem involvement. Co-pathology progression modelling identified subtypes with early predominance of amyloid-β, phosphorylated tau, or α-synuclein, and showed that Lewy subtypes follow two propagation trajectories in opposite directions. Together, these findings demonstrate that integrating quantitative pathology with genotype and clinical data reveals distinct yet overlapping pathways to dementia in LBD, refining disease progression models and providing a basis for genotype- and pathology-informed patient stratification in therapeutic trials.},
}

@article {pmid41889579,
year = {2026},
author = {Vesnupriya, P and Karukuvelraja, R and Rehanaz, N and Shamna, ME and Saranya, N},
title = {Mind gut harmony: psychobiotics effects on the gut-brain axis and harnessing its effects for the mental health.},
journal = {Journal of food science and technology},
volume = {63},
number = {4},
pages = {613-634},
pmid = {41889579},
issn = {0022-1155},
abstract = {The microbiota-gut-brain axis is gaining attention as a potential therapeutic avenue for treating illnesses of the illnesses of the central nervous system. In recent years, there has been a notable increase in literature examining the connection between the gut microbiome and its impact on overall health and wellness. The microbiota-gut-brain axis is a promising therapeutic target for treating central nervous system diseases and reducing drug adverse effects. Probiotics have been shown in pre-clinical and clinical trials to improve health by modulating the microbiota in the gut-brain axis. Psychobiotics are probiotics that modulate the gut-brain axis (GBA) and regulate the central nervous system to improve gastrointestinal function, as well as have antidepressant and anxiolytic properties via neuronal, humoral, and metabolic mechanisms. Some psychobiotic strains have been shown to reduce inflammation and cortisol levels, thereby degenerative and neurodevelopmental illnesses such as Parkinson's disease, Alzheimer's disease, and autism spectrum disorder can be effectively treated with psychobiotics. Alleviating anxiety and depression symptoms. Neurodegenerative and neurodevelopmental illnesses such as Parkinson's disease, Alzheimer's disease, and autism spectrum disorder can be effectively treated with psychobiotics. This review summarizes the psychobiotic potential on the gut-brain axis for the mental health.},
}

@article {pmid41889760,
year = {2026},
author = {Saha, D and Sun, X and Yang, W and Luo, J and Zheng, W},
title = {Residue-Specific Modulation of Aggregation-Associated Interactions by Spermine in Tau, α‑Synuclein, and Aβ40.},
journal = {JACS Au},
volume = {6},
number = {3},
pages = {2040-2054},
pmid = {41889760},
issn = {2691-3704},
abstract = {Preventing neurodegenerative diseases associated with intrinsically disordered proteins (IDPs) remains a major challenge due to the lack of a detailed, sequence-level picture of disease-relevant structure formation and the influence of cellular factors that modulate these transitions. Here, we probe spermine (Spm), a +4 charged polyamine abundant in cells, to determine how it reshapes the conformational ensembles and fibril-associated contact propensities of three disease-linked IDPs: the K18 domain of Tau, α-synuclein (αS), and amyloid-β40 (Aβ40). Using long all-atom molecular dynamics simulations across a range of Spm concentrations, we quantify residue-level changes in intrachain contacts relative to native contacts observed in fibrils and corroborate computational predictions with ThT fluorescence assays for Tau constructs. Spm acts in a sequence- and region-specific manner, not simply through the overall net charge. In K18, Spm binds near the fourth microtubule-binding repeat, disrupting intrachain contacts associated with Alzheimer's fibril structures and thereby inhibiting aggregation. In αS, Spm binds mainly to acidic residues in the C-terminal half of the sequence and redistributes intramolecular contacts to enhance aggregation-prone interactions in the central region, providing a residue-level mechanistic basis for previously reported Spm-enhanced αS aggregation. For Aβ40, Spm neutralizes acidic residues near positions 22-24 and shifts intrachain interactions toward its aggregation-prone core, resulting in a net promotion of fibril-like conformations. These divergent effects show that net charge alone cannot predict the polyamine influence on IDPs. Instead, residue-specific binding hotspots and local reweighting of aggregation-linked contacts determine whether Spm promotes or suppresses fibril-like conformations. This combined simulation-experimental framework provides a mechanistic basis for how small molecules reprogram IDP conformational ensembles and suggests principles for designing ligands that exploit similar residue-level modulation.},
}

@article {pmid41889765,
year = {2026},
author = {Gabani, ZY and Singh, J and Hamlett, ED and Granholm, AC and Margittai, M},
title = {Cofactor-Free Serial Amplification of Tau Filaments from Alzheimer's Disease and Other Tauopathies Depends on the Conformational State of Tau Monomers.},
journal = {JACS Au},
volume = {6},
number = {3},
pages = {1789-1800},
pmid = {41889765},
issn = {2691-3704},
abstract = {Tau filaments are a defining characteristic of Alzheimer's disease (AD) and numerous other neurodegenerative disorders. The deposition of Tau protein into aggregates involves templated recruitment of Tau monomers onto the filament ends via their microtubule-binding repeats. This structural conversion is central to the propagation of Tau pathology, yet its molecular mechanisms are still poorly understood. Specifically, it is unclear whether cofactors are required for templated growth. To gain insights into this process, we probed the serial amplification of pathological Tau filaments from AD, Pick's disease (PiD), and progressive supranuclear palsy (PSP). These filaments are made from different compositions of three- and four-repeat (3R and 4R) Tau. We observe that AD Tau filaments recruit full-length 3R and 4R Tau in the absence of cofactors at low salt concentration but not at physiological salt concentration and that these filaments can be independently amplified over multiple generations. PiD Tau and PSP Tau filaments can be similarly amplified. The generated filaments retain the cross-seeding properties of the pathological seeds; PSP filaments recruit only 4R Tau, PiD filaments recruit only 3R Tau, and AD filaments recruit both. Regardless of the structural fidelity of the amplification process, we show that the Tau monomer ensemble serves as an entry point for templated growth and that the conformational state of this ensemble (expanded versus compact) determines whether propagation occurs.},
}

@article {pmid41889823,
year = {2026},
author = {Qureshi, YH and Williams, CA and Hajdu, I and Kannan, S and Govindarajan, A and Végh, B and Petsko, GA and Young, JE and Závodszky, P and Small, SA},
title = {RhoGEF12 regulates endosomal SORL1-retromer and its inhibition is therapeutic in human neuronal models of Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.06.709427},
pmid = {41889823},
issn = {2692-8205},
abstract = {UNLABELLED: The interaction of the endosomal sorting protein SORL1 with the retromer complex at endosomal membranes controls a recycling pathway whose dysfunction is pathogenic in Alzheimer's disease (AD) and is linked to other neurodegenerative disorders. To search for novel therapeutic targets, we hypothesize that endosomal SORL1-retromer might be regulated by SORL1's cytoplasmic tail. We begin by completing an in vitro analysis of the tail and show that its phosphorylation by ROCK2 (Rho-associated kinase 2) reduces SORL1's affinity to retromer. Since RhoGEF12 (Rho guanine nucleotide exchange factor 12) is an upstream activator of ROCK2 that is upregulated in AD, we used a RhoGEF12 pharmacological inhibitor to mechanistically and therapeutically validate the findings in neuronal cultures. First, in mouse neurons we confirm that the inhibitor increases endosomal SORL1-retromer. Next, we turned to human iPSC-derived neurons to show that the inhibitor reduces Aβ40 and Aβ42, an indicator of pathway upregulation, in a SORL1-dependent manner. Finally, we validate its therapeutic potential by applying the RhoGEF12 inhibitor to human iPSC-derived neurons expressing AD-associated mutations in either APP or SORL1 . Collectively, our results identify a novel and therapeutically amenable mechanism that regulates endosomal SORL1-retromer and preclinically validate RhoGEF12 as a therapeutic target for AD and potentially other neurodegenerative disorders.

ONE SENTENCE SUMMARY: Pharmacological inhibition of RhoGEF12 increases endosomal SORL1-retromer recycling and reduces pathogenic amyloid secretion in human neuronal models, identifying a novel, targetable pathway for treating Alzheimer's disease.},
}

@article {pmid41889829,
year = {2026},
author = {Xia, Q and Wang, Q and Jia, D and Dong, D and Li, M and Sherman, E and Ao, J and Ren, Q and Bao, H and Jiang, L and Cheng, JX},
title = {IR-AMES uncovers structure and composition of Alzheimer's tau oligomers.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.12.711458},
pmid = {41889829},
issn = {2692-8205},
abstract = {Tau misfolding and aggregation are central to cognitive decline in Alzheimer's disease and related neurodegenerative disorders [1-3] . Although soluble tau oligomers are implicated as primary toxic species [4-6] , the structural and compositional determinants of their toxicity remain inaccessible at the single oligomer level. Here we introduce infrared absorbance-modulated evanescent scattering (IR-AMES), a label-free single-molecule spectroscopic imaging approach that photothermally encodes mid-infrared vibrational fingerprints into evanescent scattering from individual biomolecular assemblies under native aqueous conditions. Applying IR-AMES to recombinant human tau resolves random-coil-dominated monomers and captures the emergence of structurally heterogeneous oligomers. Analysis of tau oligomers from postmortem Alzheimer's disease brains uncovers enrichment of antiparallel β-sheet structures and RNA components, features that are largely obscured in ensemble-averaged measurements. Using lipid nanodiscs as a defined membrane mimic, we further show that pathological tau oligomers exhibit enhanced interactions with anionic membranes. Together, these findings establish a link between structure and neurotoxicity of tau oligomers, and position IR-AMES as a platform for uncovering structure-function relationships in complex biomolecular assemblies.},
}

@article {pmid41889831,
year = {2026},
author = {Benbow, SJ and Saxton, AD and Baum, M and Uhrich, RL and Stair, JG and Keene, K and Dahleen, C and Wordeman, L and Liachko, NF and Kow, RL and Kraemer, BC},
title = {Dominant α-tubulin mutations rescue tauopathy neurodegenerative phenotypes in C. elegans.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.18.712642},
pmid = {41889831},
issn = {2692-8205},
abstract = {Tau protein, the primary component in neurofibrillary tangles characteristic of Alzheimer's Disease and related dementia disorders, normally regulates microtubule growth and stability. While tau dysfunction contributes to the progression of tauopathies, the role of microtubules in disease has remained unclear. Through forward genetic screening in Caenorhabditis elegans tauopathy models, we found multiple tubulin gene mutations that rescue tau-mediated neurodegeneration. Whole animal behavioral and in vitro biochemical assays were employed to characterize mutation-driven effects on neuron function, neurodegeneration, and effects on tubulin and tau proteins as well as microtubule function. Mutant tubulin genes were found to confer different levels of suppression correlating with the level of mutant gene expression. Mutant tubulins did not drastically alter total tau protein levels, tau phosphorylation or aggregation, however tau-induced neurodegeneration was rescued. The suppression of tau toxicity by tubulin gene mutations cannot be explained by changes in tau or tubulin expression, tau phosphorylation, or tau aggregation state. Rather the tubulin mutations appear to act by influencing global microtubule properties. In vitro experiments using C. elegans tubulin in semi-isolated and isolated contexts have indicated changes to microtubule properties without observable changes to tau-tubulin affinity. This work suggests that manipulation of microtubules can rescue tauopathy even when pathological tau species persist, supporting the importance of understanding microtubule contributions to disease progression and investigation into microtubule targeted gene therapy or small molecule approaches for tauopathy intervention.},
}

@article {pmid41889854,
year = {2026},
author = {Fitz, NF and Alam, MS and Ostach, MA and Garg, S and Lefterov, I and Koldamova, R},
title = {A novel technique for monitoring Alzheimer's disease associated changes in brain-derived extracellular vesicle cargos in mouse models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.13.711599},
pmid = {41889854},
issn = {2692-8205},
abstract = {Extracellular vesicles (EVs) are critical mediators of intercellular communication, carrying molecular cargos such as small noncoding RNAs (ncRNAs) that reflect the physiological and pathological state of their cells of origin. However, studying brain-derived EVs has been challenging due to the blood-brain barrier. Here, we optimized and validated an open-flow microdialysis (OFM) protocol for sampling EVs directly from brain interstitial fluid (ISF) in wild-type and APP/PS1 transgenic mice. Ex-vivo validation using plasma EVs demonstrated that OFM effectively captures the full EV population. In-vivo cerebral OFM (cOFM) enabled successful collection of brain ISF EVs, which were characterized by nanoparticle tracking analysis (NTA), electron microscopy, and western blotting, confirming their similarity to EVs isolated directly from brain tissue and plasma. Identification of small ncRNA cargos revealed that EVs sampled from brain ISF by cOFM were enriched in brain-specific signatures, many of which are associated with neuronal cell populations and biological functions. Furthermore, we observed a unique small ncRNA signature from the brain ISF EVs in the Alzheimer's disease preclinical model compared to wild-type mice. These small ncRNAs were associated with genes considered important in biological functions associated with neurodegeneration. Our findings demonstrate that cOFM is a powerful tool for in-vivo sampling of brain EVs and highlight the unique molecular landscape of ISF EV small ncRNA cargos. This study offers new opportunities for biomarker discovery and mechanistic insights into neurodegenerative diseases, such as Alzheimer's disease.},
}

@article {pmid41889929,
year = {2026},
author = {Shi, Y and Rozen, SD and Swint, JT and McRoberts, WA and McCurry, SN and Salinas, R and Moffett, EG and Pollock, CM and Goldstein, LR and Katzev, SS and Carter, ME and Bloom, GS and Güler, AD},
title = {LiFE, a multimodal circadian intervention, improves sleep, glycemic control, and recognition memory.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.12.711428},
pmid = {41889929},
issn = {2692-8205},
abstract = {In mammals, sleep is regulated by the central circadian system, which responds to environmental timing cues including light, exercise and availability of food. In this study, we developed a light-, food-, and exercise-based daily lifestyle intervention (LiFE) that combines the effects of multiple circadian entrainment cues on central clock function, ultimately strengthening central clock rhythms. In wild-type (WT) mice, LiFE consolidated nocturnal activity, enhanced suprachiasmatic nucleus rhythmicity, and increased sleep time. Despite comparable caloric intake to control conditions, LiFE lowered baseline blood glucose, reduced glycemic variability, and improved glucose tolerance. We found long-term LiFE treatment improved recognition memory in WT mice. Sleep and circadian disruption are commonly observed in patients with Alzheimer's disease (AD), the most prevalent neurodegenerative disorder. We applied long-term LiFE treatment in two AD mouse models (5xFAD and 5xFAD/PS19). Alongside a subtle reduction in AD histopathology, LiFE produced near-significant trends toward improved motor performance and recognition memory. Together, these findings support multimodal circadian chronotherapy as a non-pharmacological approach in which integrated light, feeding, and exercise entrainment promotes sleep and metabolic health.},
}

@article {pmid41889933,
year = {2026},
author = {Ruff, DA and Sheets, DEG and Srinath, R and Diniz, GB and Griggs, DJ and Beckman, D and Ott, S and Schwartz, K and Erices, C and Muller, S and Kordower, JH and Morrison, JH and Cohen, MR},
title = {Loss of neuronal population organization links pathology to behavior in a model of Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.18.712735},
pmid = {41889933},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) and related dementias (ADRD) are defined by molecular and cellular pathology and cognitive decline, but linking these levels requires understanding how pathology alters large-scale neuronal activity. We longitudinally tracked behavior, multi-area neuronal population activity, and fluid and histological biomarkers in a macaque model of early-stage ADRD. As pathology progressed, visually guided behavior became increasingly disorganized, reflected in less structured exploration despite preserved task performance. Guided by systems neuroscience principles linking neuronal population activity with organized goal-directed behavior, we found progressive reductions in coordinated neuronal population activity within and between visual and parietal cortices, even as single-neuron tuning and basic feature encoding remained stable. These changes emerged when tau pathology was largely confined to regions providing feedback to visual cortex. This disorganized state appears modifiable: proof-of-concept methylphenidate administration was associated with transient improvement in behavioral organization. Together, these findings identify disruption of neuronal population organization as a defining feature of early-stage ADRD and frame early dysfunction as a disorder of coordinated population activity.},
}

@article {pmid41889952,
year = {2026},
author = {Tsagkogianni, C and Trivisonno, M and Willner, JS and Garcia-Molinero, C and Tang, Y and Mattina, B and Latorre-Leal, M and Wang, W and Roussarie, JP and Rodriguez-Rodriguez, P},
title = {Optineurin is a gatekeeper of mitochondrial health and proteostasis in Alzheimer's disease vulnerable neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.15.711617},
pmid = {41889952},
issn = {2692-8205},
abstract = {Alterations in autophagy-related pathways and in mitochondrial function have long been associated with the pathology of several neurodegenerative disorders, including Alzheimer's disease (AD). However, the cascade of events that links these processes and how they contribute to the early degeneration of specific neuronal subpopulations remain to be understood. Here, we use a data-driven approach and identify Optn as a potential regulator of AD pathology that is highly enriched in vulnerable ECII neurons compared to neurons that degenerate later in the disease continuum. We show that Optineurin downregulation triggers early dysregulation of mitochondrial function, followed by alterations in AD-associated processes, including proteostasis, synaptic function, and neuroinflammation. This is accompanied by ECII neuron loss and astrocyte reactivity in EC neuron projecting areas in the hippocampus. Together our results suggest that Optineurin plays a central role in the maintenance of mitochondrial health and bioenergetics in AD vulnerable neurons and that pathological processes that impair this homeostasis may contribute to the early degeneration of vulnerable ECII neurons.},
}

@article {pmid41889956,
year = {2026},
author = {Marshall, CR and Moser, FA and Scott, CF and Ventura-Antunes, L and Romero-Fernandez, W and Migas, ŁG and Tideman, LEM and Colley, ME and Dufresne, M and Schrag, MS and Van de Plas, R and Spraggins, JM},
title = {Multimodal Molecular Mapping of the Vasculature in Human Cortex Reveals Lipid Markers of Cerebral Amyloid Angiopathy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.13.711741},
pmid = {41889956},
issn = {2692-8205},
abstract = {Cerebral amyloid angiopathy (CAA) commonly co-occurs with Alzheimer's disease (AD), yet the molecular changes that accompany vascular β-amyloid deposition in human tissue remain incompletely defined. Herein, we use a novel imaging approach that combines matrix-assisted laser desorption/ionization imaging mass spectrometry (IMS) with immunofluorescence microscopy on the same sections of postmortem human frontal cortex to map the lipid microenvironment of leptomeningeal vasculature in cases with and without CAA. Autofluorescence-guided regions-of-interest were imaged by IMS in both negative and positive ion modes and registered to post-IMS-acquired microscopy images. Immunofluorescence microscopy using collagen IV, α-smooth muscle actin (αSMA), and thiazine red enabled automated segmentation of total, amyloidpositive, and amyloid-negative vasculature regions. A CAA index, the ratio of amyloid-positive area to total vasculature area in a region imaged by IMS, was used to define vasculature and classify each case into having CAA, or CAA-present and not having CAA, or CAA-absent. An interpretable machine learning approach (XGBoost models with Shapley additive explanations for interpretation) was trained on pixel-level spectra and identified lipid signatures of vascular identity shared across groups as well as class-specific marker candidates that distinguished CAA-present from CAA-absent vasculature. CAA-present vessels were enriched for gangliosides (e.g. , GM1), whereas CAA-absent vessels were characterized by higher contributions from phosphatidylserines (e.g. , long-chain polyunsaturated PS species). Univariate differences were inconsistent between the two groups, but multivariate models in negative mode yielded stable discriminatory features. These results define spatial lipid correlates of vascular amyloid pathology in the human brain and establish a multimodal framework for mechanistically linking lipid metabolism, vascular integrity, and CAA in AD.},
}

@article {pmid41890007,
year = {2026},
author = {Park, S and Maldonado, DM and Kadnar, ML and Andrade, M and Fomitchova, AP and Liebman, SW and Derkatch, IL},
title = {Interactions between non-prion and prion domains of Rnq1 direct formation of amyloid vs liquid-like aggregates and create transmission barriers.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.01.14.633072},
pmid = {41890007},
issn = {2692-8205},
abstract = {UNLABELLED: Prions are self-propagating protein conformations usually existing as amyloid aggregates. [ PIN [+] ], a prion form of the Rnq1 protein occasionally found in wild and laboratory yeast strains, facilitates both the de novo formation and destabilization of other yeast prions, and affects aggregation and toxicity of human misfolding disease proteins expressed in yeast. Rnq1 contains a short N-terminus with no confirmed function (the non-prion domain, NPD) and a C-terminus that carries four QN-rich regions and is sufficient for [ PIN [+] ] formation and maintenance (prion domain, PD). In the current study, a genetic screen identified the NPD T27P mutation that blocks transmission of the [ PIN [+] ] prion state from wild type Rnq1 (Rnq1 WT) to mutant Rnq1 T27P . The mutation doesn't prevent Rnq1 T27P from switching to a prion state when overexpressed in vivo , or from forming amyloid fibers in vitro . Furthermore, like [ PIN [+] WT ], the newly formed [ PIN [+] T27P ]s promote the de novo appearance of the Sup35-based prion [ PSI [+] ]. We conclude that the NPD mutation creates a barrier for prion transmission from [ PIN [+] WT ] to Rnq1 T27P . Because fluorescence microscopy shows that Rnq1 T27P efficiently joins [ PIN [+] WT ] aggregates, the barrier is likely due to the inability of Rnq1 T27P to propagate the specific [ PIN [+] WT ] conformational variant. Indeed, the analysis of [ PIN [+] T27P ]s resulting from rare transmission events from [ PIN [+] WT ] indicates that these [ PIN [+] T27P ]s must undergo conformational adaptation to yield more stable prion variants. Deletion analysis revealed that T27P constrains prion conformations through the first two QN-rich regions within the PD. The finding that Rnq1 T27P -YFP readily forms non-amyloid liquid-like droplets, which Rnq1 WT -YFP does not form, supports the idea that the NPD affects aggregation properties of the PD. We propose that these aggregation properties are essential for Rnq1's functions, such as controlling aggregation of other proteins. This provides new insight into the role of heterologous proteins and transmission barriers in the origins of protein misfolding diseases.

AUTHOR SUMMARY: Proteins must fold into the right shapes to work properly. Sometimes they fold incorrectly and stick together, forming long fiber aggregates that damage cells. This kind of "protein misfolding" causes human diseases such as Alzheimer's. Certain yeast proteins behave similarly, making them useful to study this process. We investigate a yeast protein called Rnq1, which has a region that helps it misfold into fibers. These fibers can also cause other, unrelated proteins to misfold. We found that a mutation in a different part of Rnq1- outside the aggregation region - reduces the ability of non-mutant Rnq1 fibers to convert mutant Rnq1 into growing fiber aggregates. We also identified which section of the aggregation region is affected by this mutation. Interestingly, although the rarely converted mutant aggregates grow poorly at first, they can eventually "adapt" into a shape that grows better. The same mutation also pushes Rnq1 to form liquid-like droplets instead of fibers. Our findings show that the non-aggregating part of Rnq1 controls how Rnq1 aggregates, and, consequently, the appearance and elimination of aggregates formed by other proteins. Our work also helps explain how barriers to misfolded protein growth can be overcome, which is relevant to understanding human protein misfolding diseases.},
}

@article {pmid41890022,
year = {2026},
author = {Barbour, AJ and Hoag, K and Lee, VMY and Talos, DM and Jensen, FE},
title = {Seizures drive tau propagation in a tauopathy mouse model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.14.711088},
pmid = {41890022},
issn = {2692-8205},
abstract = {A bidirectional relationship between seizures and neurodegenerative disease has been established with neurodegenerative pathology found in late-onset epilepsy patients, increased risk of seizures in tauopathies, and accelerated Alzheimer's disease progression in patients with epileptiform activity. Tau pathology spreads between interconnected neuronal networks, driving disease progression. We hypothesized that seizures would promote tau propagation throughout the brain in a tauopathy mouse model. To explore the brain-wide relationship between tau pathology and seizure activity, we crossed the T40PL-GFP mouse, which contains a pathogenic MAPT mutation tagged with GFP, with targeted recombination in active population (TRAP; T40PL-TRAP) mice to label all seizure activated neurons with tdTomato. We triggered tau propagation in these mice with intracerebral seeding of human AD brain-derived tau lysate and induced seizures with pentylenetetrazol (PTZ) kindling. With light sheet microscopy, we imaged and mapped tau-GFP and tdT levels throughout whole brain. We found that PTZ induced seizures worsened tau pathology in brain regions with increased tdT levels, including the hippocampus and cortex, and in the fiber tracts in T40PL-TRAP mice. We also found that seizure-activated (tdT+) neurons were more likely to develop somatic tau pathology compared to the surrounding (tdT-) populations. Overall, these data demonstrate that seizures can enhance tau pathology propagation.},
}

@article {pmid41890040,
year = {2026},
author = {Wei, X and Munechika, K and Sun, Y and Wan, Y and Xia, T and Hou, Y and Song, W and Yugandhar, K and Wang, Y and Lee, SI and Sha, Z and Zhou, Y and Feng, W and Zhu, J and Tang, Y and Luo, W and Cheng, F and Gan, L and Yu, H},
title = {Interactome mapping in human excitatory neurons reveals novel risk genes and pathways in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.14.711835},
pmid = {41890040},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disease defined by its molecular hallmarks - amyloid beta peptide plaques and neurofibrillary Tau tangles. Despite significant progress that has been made in uncovering a large number of genetic risk factors through extensive genomic sequencing and genetic studies, the molecular mechanisms driving AD-associated pathology and cognitive decline remain poorly understood. Therefore, alongside the identification of more risk genes, it is also paramount to study how these genes function and influence each other within the cellular pathways and overall molecular networks in AD-relevant brain cell types. However, current human protein-protein interactome datasets were all generated in either yeast or generic human cell lines. Consequently, many important neuronal interactions, especially neuron-specific ones, have yet been discovered. To address this critical gap, we developed a highly scalable, high-quality interactome mapping pipeline in human excitatory neurons derived from induced pluripotent stem cells (iPSC), and generated a comprehensive, neuron-specific interactome map, named ADNeuronNet, for key AD risk genes. ADNeuronNet consists of 1,767 high-confidence interactions among 1,189 proteins and is the only dataset enriched with neuron-specific genes when compared to known protein interactions, including previous large-scale interactome maps, for the same baits in the literature. Within ADNeuronNet, we identified 1,375 novel interactions, many of which are likely neuron specific. For example, we identified a neuron-specific interactor, RIN2, for major AD risk factor BIN1 and confirmed RIN2's function in recruiting BIN1 to RAB5 positive early endosomes, a process that has been well-associated with AD etiology. Additionally, we performed quantitative interaction perturbation analyses on AD risk genes with AD-associated mutations or isoforms and identified significant changes in 99 protein interactions among 11 different protein variants. Finally, we found that subunits from the anaphase-promoting complex/cyclosome (APC/C), another novel BIN1 interactors identified by ADNeuronNet, mediated modulation of Tau-aggregation in neurons via regulation of APOE expression, uncovering a previously unrecognized BIN1-APC/C-APOE regulatory axis in AD pathobiology. In summary, these findings illustrate how our neuron-specific ADNeuronNet can be leveraged to uncover new risk gene candidates and cellular pathways that help advance our understanding of molecular mechanisms underlying AD etiology.},
}

@article {pmid41890046,
year = {2026},
author = {Hu, H and Lin, PB and Zeng, C and Sharma, P and Li, Y and Jiang, H and Nulman, J and Ohara, RA and Wu, T and Li, S and Yokoyama, WM and Artyomov, MN and Murphy, KM and Ulrich, JD and Holtzman, DM},
title = {CD8 [+] T cells are primed by cDC1 and exacerbate tau-mediated neurodegeneration.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.26.708260},
pmid = {41890046},
issn = {2692-8205},
abstract = {There are changes in adaptive immunity in Alzheimer's disease (AD) and increases in activated CD8 [+] T cells in brain correlate with tau pathology [1-3] . However, which cells mediate T cell priming in tau-mediated neurodegeneration remains unclear. In different conditions such as cancer, viral infections, and autoimmune diseases outside the CNS, conventional type-1 dendritic cells (cDC1) perform antigen cross-presentation to prime CD8 [+] T cells [4,5] . We demonstrate that tauopathy mice deficient in cDC1 are markedly protected against tau-mediated neurodegeneration and display a selective decrease in brain CD8 [+] T cell infiltration and glial reactivity. The remaining CD8 [+] T cells showed an antigen inexperienced status with less clonal expansion, indicating suboptimal T cell priming. We confirm that brain derived antigens are presented in secondary lymphoid tissues to prime CD8 [+] T cells. Our study identifies cDC1 cells as critical for CD8 [+] T cell priming outside the CNS. This priming is required for a large increase of activated CD8 [+] T cells in the brain which promotes tau-mediated neurodegeneration.},
}

@article {pmid41890066,
year = {2026},
author = {Sadleir, KR and Gomez, KP and Chandra, S and Ley, ML and Khatri, AW and Guo, J and Xue, Y and Cepko, CL and Vassar, R},
title = {Neuronal overexpression of Nrf2 reduces dystrophic neurites in 5XFAD Alzheimer's disease model mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.16.711596},
pmid = {41890066},
issn = {2692-8205},
abstract = {BACKGROUND: The hallmark lesions of the Alzheimer's disease (AD) brain are amyloid plaques consisting of the β-amyloid protein and neurofibrillary tangles comprised of hyperphosphorylated, aggregated tau protein, which both cause neuronal dysfunction and loss. One goal of neuroprotective therapies is to maintain normal neuronal function and survival in the presence of toxic pathologies such as plaques and tangles. A potential neuroprotective target is nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor, which regulates the expression of many antioxidant and detoxification genes. Nrf2 mRNA is decreased in AD brains, and deletion of the Nrf2 gene causes increased BACE1 and Aβ production and worsened cognitive deficits in amyloid pathology mouse models. Overexpression of Nrf2 in astrocytes has been shown to be protective against neurodegeneration, but the role of Nrf2 is neurons is unclear.

METHODS: We overexpressed Nrf2 from birth in neurons of 5XFAD amyloid pathology model mice using AAV8, hypothesizing that neuronal Nrf2 overexpression decreases cortical neuron loss and reduces plaque load by decreasing BACE1 levels. We quantified protein levels by immunoblot and neuropathology by immunofluorescent staining, using two-way ANOVA to measure differences between genotypes and AAV treatments. To assess genetic changes, we performed bulk mRNA seq.

RESULTS: While neuronal overexpression of Nrf2 in 5XFAD mice did not prevent neuronal loss as measured by NeuN labeling, decrease neuroinflammation by Iba1 or GFAP labeling, or reduce amyloid load by Aβ antibody or methoxy-XO4 staining, we show that increased Nrf2 expression reduces BACE1 protein levels, especially in swollen axonal dystrophic neurites around amyloid plaques. Other proteins that accumulate in dystrophic neurites were also reduced, indicating decreased dystrophic neurites overall. Immunoblot analysis suggested increased autophagy was unlikely to play a role, while bulk mRNA sequencing indicated changes in lipid metabolism and microtubule stability may have contributed to reduced dystrophic neurite formation.

CONCLUSIONS: Dystrophic neurites impair action potential conductance and contribute to tau seeding and spreading. Their reduction by neuronal Nrf2 overexpression may protect neurons against these pathologic changes. Further study of the mechanisms by which Nrf2 reduces dystrophic neurites may lead to therapeutic strategies that can limit neuritic damage caused by cerebral amyloid accumulation.},
}

@article {pmid41890077,
year = {2026},
author = {Lemon, NL and Canepa, E and Vázquez-Torres, R and Parodi-Rullán, R and Hirt, T and Petersohn, LM and Rifat, T and Abyaneh, MH and Ilies, MA and Fossati, S},
title = {Mitochondrial carbonic anhydrase-VB inhibition rescues brain endothelial stress and memory in Alzheimer's disease models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.16.711716},
pmid = {41890077},
issn = {2692-8205},
abstract = {Alzheimer's Disease (AD) is a devastating neurodegenerative disorder with no effective cure, characterized by the cerebral parenchymal and vascular accumulation of aggregated Amyloid-β (Aβ) and hyperphosphorylated tau. Cerebrovascular and mitochondria dysfunction are early causal events in the progression of AD. Previous studies support that inhibiting carbonic anhydrases (CA) may prevent mitochondrial and cerebrovascular dysfunction in AD models. Here, we selectively target the mitochondrial CA isoform CA-VB by pharmacological and genetic manipulation, in human cerebral microvascular endothelial cells (hCMEC) and we confirm the protective effects of the CA-V inhibitor in AD mice. CA-V inhibition and CA-VB KO prevent Aβ induced mitochondria-mediated endothelial apoptosis, loss of barrier resistance, and hCMEC inflammatory activation. Strikingly, CA-V inhibition also mitigates caspase activation and endothelial cell activation in the brains of 3xTg AD mice, resulting in preserved memory function. Our results demonstrate that selective CA-V inhibition is an effective and promising strategy against AD-mediated cerebrovascular pathology, neuroinflammation and cognitive impairment.},
}

@article {pmid41890089,
year = {2026},
author = {Blackhurst, BM and Bhatt, A and Kretchmer, E and Tucker, AE and Kurtz, B and Reagin, KL and Funk, KE},
title = {CD8[+] T cells induce interstrand crosslinking-associated DNA damage in neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.14.711737},
pmid = {41890089},
issn = {2692-8205},
abstract = {UNLABELLED: Viral pathogens cause neurologic sequelae during acute and post-acute phases of infection. CD8 [+] T cells are hypothesized to contribute to these effects, but the mechanisms through which they act are poorly understood. We posited that viral infections and/or antiviral immune responses induce DNA damage, which may underlie neuronal dysfunction. Using a model of neurotropic flavivirus infection, we found that genes associated with interstrand crosslinking (ICL) DNA damage were upregulated post-infection, temporally congruent with T cell infiltration. Using an in vitro co-culture system, our results demonstrate that CD8 [+] T cells induced ICL-like damage in primary neurons, independent of antigen-specific interactions or direct contact. Human transcriptomic data also showed overexpression of genes associated with ICL damage in the brains of people with Parkinson's disease, Alzheimer's disease, and multiple sclerosis, which are neurologic diseases characterized by neuroinflammation. Together, these data indicate that CD8 [+] T cells cause genotoxic DNA damage in neurons, which may underlie the neurologic dysfunction seen in neurodegenerative conditions.

SUMMARY: Results indicate that CD8 [+] T cells induce interstrand crosslinking-like DNA damage in neurons independent of antigen-specificity in a mouse model of viral infection, in vitro primary cell culture system, and human neurologic diseases. These findings provide insight on the mechanistic connection between neuroinflammation and neurologic dysfunction.},
}

@article {pmid41890202,
year = {2026},
author = {Zhu, T and Cai, L and Hu, L and Yang, D and Li, M and Quan, F and Lu, C and Liu, S and Cui, J},
title = {Cognitive improvement by non-pharmacological electrical stimulation modalities in mild cognitive impairment: a protocol for systematic review and network meta-analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1752516},
pmid = {41890202},
issn = {1663-4365},
abstract = {OBJECTIVE: Mild cognitive impairment, characterized by progressive cognitive decline, represents a prevalent transitional state among the global aging population and demonstrates high conversion rates to Alzheimer's disease, establishing itself as a critical window for preventive interventions against AD. Although growing evidence supports the efficacy of various non-pharmacological therapies in enhancing cognitive function, their comparative effectiveness remains insufficiently elucidated. This study aims to analyze the efficacy and safety of different electrical stimulation modalities in treating MCI patients, quantitatively compare the therapeutic benefits across multiple interventions, and provide evidence-based recommendations to facilitate informed clinical decision-making.

METHODS: We will systematically search 13 databases. All relevant studies published from inception until November 1, 2025, will be retrieved. Two reviewers will independently assess the risk of bias for all included studies using the revised Cochrane Risk of Bias tool (RoB 2). The primary outcome will be the Montreal Cognitive Assessment score to evaluate changes in cognitive function. Secondary outcomes will include neuropsychological assessments related to cognition, such as the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), as well as the modified Barthel Index for activities of daily living and the patient-reported Pittsburgh Sleep Quality Index. Data synthesis will be performed using Stata software, employing a random-effects network meta-analysis model to compare the efficacy and safety of non-pharmacological electrical stimulation therapies. The surface under the cumulative ranking curve (SUCRA) will be used to estimate the probability of intervention hierarchies. The strength of evidence will be evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations framework.

CONCLUSION: This study will synthesize evidence from multiple studies on various electrical stimulation therapies for improving cognitive function in patients with mild cognitive impairment, thereby providing a diverse body of evidence to support clinical decision-making by physicians and optimization of treatment strategies for patients.

STUDY PROTOCOLS REGISTRATION: [https://www.crd.york.ac.uk/prospero/], identifier [CRD420251184505].},
}

@article {pmid41890204,
year = {2026},
author = {Yan, P and Du, X and Yang, S},
title = {Distinguishing early from late mild cognitive impairment: a multi-level analysis of regional morphometry and KLS-derived network topology.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1730305},
pmid = {41890204},
issn = {1663-4365},
abstract = {INTRODUCTION: Distinguishing between early Mild Cognitive Impairment (EMCI) and late mild cognitive impairment (LMCI) is crucial for clinical trials, but objective biomarkers are lacking. We therefore examined regional morphometry and network topology across cognitively normal (CN), EMCI, and LMCI groups to address this gap. We also evaluated whether combining these features could effectively classify mild cognitive impairment (MCI) subtypes.

METHODS: We analyzed T1-weighted magnetic resonance imaging (MRI) data from 208 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (67 CN, 83 EMCI, 58 LMCI). We used both voxel- and surface-based morphometry to measure local atrophy and combined this with graph analysis of individual structural covariance networks (SCNs). We also performed correlation and machine learning analyses.

RESULTS: We found that cortical thickness (CT) in EMCI was not significantly different from CN, but it was significantly reduced in the LMCI group. The right hippocampus and the left thalamus, however, showed a significant difference between CN and EMCI. In the Kullback-Leibler (KL) divergence-based similarity (KLS) network analysis, the EMCI group showed a greater randomization when compared to the LMCI group, while LMCI was accompanied by elevated nodal centrality in the left hippocampus and orbital frontal region. Correlation analysis confirmed this was a maladaptive phenomenon, as higher centrality was linked to poorer cognitive performance. Finally, a classifier combining these structural and network features successfully differentiated the MCI subtypes.

CONCLUSION: Our findings suggest that differences in Gray matter volume (GMV) may be more easily observed in the EMCI group. We identified a corresponding non-linear pattern of network topology, characterized by randomization in the EMCI group than in the LMCI. These multi-faceted biomarkers enabled the accurate machine-learning-based differentiation of MCI subtypes, offering a powerful framework for improving patient stratification in clinical trials.},
}

@article {pmid41890356,
year = {2026},
author = {Sun, P and Peng, W and Li, LY and Wang, Y and Pohl, KM},
title = {Evaluation of 3D Counterfactual Brain MRI Generation.},
journal = {Deep generative models : 5th MICCAI workshop, DGM4MICCAI 2025, held in conjunction with MICCAI 2025, Daejeon, South Korea, September 23, 2025, Proceedings. DGM4MICCAI (Workshop) (5th : 2025 : Taejon-si, Korea)},
volume = {16128},
number = {},
pages = {46-56},
pmid = {41890356},
abstract = {Counterfactual generation offers a principled framework for simulating hypothetical changes in medical imaging, with potential applications in understanding disease mechanisms and generating physiologically plausible data. However, generating realistic structural 3D brain MRIs that respect anatomical and causal constraints remains challenging due to data scarcity, structural complexity, and the lack of standardized evaluation protocols. In this work, we convert six generative models into 3D counterfactual approaches by incorporating an anatomy-guided framework based on a causal graph, in which regional brain volumes serve as direct conditioning inputs. Each model is evaluated with respect to composition, reversibility, realism, effectiveness and minimality on T1-weighted brain MRIs (T1w MRIs) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). In addition, we test the generalizability of each model with respect to T1w MRIs of the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA). Our results indicate that anatomically grounded conditioning successfully modifies the targeted anatomical regions; however, it exhibits limitations in preserving non-targeted structures. Beyond laying the groundwork for more interpretable and clinically relevant generative modeling of brain MRIs, this benchmark highlights the need for novel architectures that more accurately capture anatomical interdependencies. Code: https://github.com/pengwei2000/counterfactual_3DMRI.},
}

@article {pmid41890380,
year = {2026},
author = {Devi, MD and Padmavathi, P},
title = {Effectiveness of Nursing Strategies on Memory and Sleep Quality among Patients with Alzheimer's Disease in a Selected Centers at Coimbatore.},
journal = {Journal of pharmacy & bioallied sciences},
volume = {18},
number = {1},
pages = {65-67},
pmid = {41890380},
issn = {0976-4879},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a decline in memory, cognition, sleep quality, and activities of daily living. Non-pharmacological, nursing strategies are increasingly emphasized to improve the quality of life among patients with AD.

AIM: To evaluate the effectiveness of nursing strategies on memory and sleep quality among patients with AD.

METHODS: A quantitative, true experimental pretest-posttest control group design was adopted. The pilot study was conducted among 44 patients with AD (22 experimental and 22 control) selected through simple random sampling from a selected centers at Coimbatore. The experimental group received nursing strategies comprising visual images, mnemonic training, dyadic sleep intervention, and pumpkin seed supplementation for 3 months, while the control group received routine care. Memory was assessed using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Activity of Daily Living (ADL) inventory and sleep quality using the Pittsburgh Sleep Quality Index (PSQI). Descriptive and inferential statistics were used for analysis.

RESULTS: Postintervention, the experimental group demonstrated significant improvement in memory (t = 10.962, P < 0.001) and sleep quality (t = 14.329, P < 0.001) compared to the control group, which showed no significant changes.

CONCLUSION: Nursing strategies were effective in improving memory and sleep quality among patients with AD. These findings support the incorporation of structured nursing interventions into routine Alzheimer's care.},
}

@article {pmid41890415,
year = {2025},
author = {Pinzon, MM and Garcia, DM and Perales-Puchalt, J},
title = {Policy and Organizational Factors that Affect the Utilization of Health Services for Alzheimer's Disease Among the Latino Community - The Primary Care Provider Perspective.},
journal = {Journal of the National Hispanic Medical Association},
volume = {3},
number = {2},
pages = {54-66},
pmid = {41890415},
issn = {2693-8960},
abstract = {BACKGROUND: Latino individuals bear a disproportionate burden of Alzheimer's disease and related dementias (ADRD), with higher risk, underdiagnosis, and limited access to quality care. Primary care providers (PCPs) are crucial for early detection and management. However, organizational and policy factors significantly impact their ability to provide culturally competent and equitable ADRD care for this community. This study explores PCP perspectives on these organizational and policy factors to inform the development of accessible models that improve early diagnosis, preventive care, and quality of life for Latino individuals with ADRD.

METHODS: We used thematic analysis to analyze qualitative interviews with 23 diverse PCPs across the United States. We recruited our sample using snowball sampling. We strengthened the validity of our findings by using rigorous data reduction techniques.

RESULTS: Key themes emerged, highlighting the interplay of organizational and policy factors: 1) Insurance eligibility and care options for those uninsured were foremost, with mandated language services facing access and quality challenges that affected the ability of clinicians to perform an accurate diagnosis. 2) Staffing and available resources dictated the type of care offered, leading to inconsistent protocols and options. Providers reported that workup was influenced by their level of training, time availability, and comfort. 3) While recognized as crucial, comprehensive assessments that include evaluation of their home and social environment were limited by appointment constraints and lack of follow-up resources.

CONCLUSION: Economic and organizational factors, including insurance, costs, staffing models, and resource navigation, shape PCPs' ability to deliver culturally competent and equitable ADRD care. Future interventions should address these barriers by training PCPs in dementia-related diagnostic procedures in Latino communities and developing accessible service models and culturally appropriate diagnostic tools.},
}

@article {pmid41890452,
year = {2026},
author = {Arriaga, P and Vianna, K and Montez, C and Panariello, B and Tran, S and Rodrigues, D and Porto Barboza, E},
title = {Association of Periodontal Pathogens and Their Inflammatory Mediators With Alzheimer's Disease Neurodegeneration: A Systematic Review.},
journal = {Cureus},
volume = {18},
number = {2},
pages = {e104127},
pmid = {41890452},
issn = {2168-8184},
abstract = {Periodontitis is implicated in a range of systemic conditions, including cardiovascular disease, diabetes, and respiratory disorders. Emerging evidence suggests a link between periodontal infection, inflammation, and the neurodegenerative process of Alzheimer's disease (AD). This paper aimed to systematically review observational studies examining the association of periodontal pathogens and their inflammatory products with AD neurodegeneration. The review was registered in the International Prospective Register of Systematic Reviews (PROSPERO - No. CRD42020150043). Methods followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. An electronic search (PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE), Web of Science, Scopus, Cochrane Library, grey literature) was conducted until September 2025 with no language or date restrictions. Two independent reviewers screened and extracted data. The risk of bias was assessed via the Risk Of Bias In Non-randomized Studies - of Exposures (ROBINS‑E) tool. Of 1,421 identified citations, eight studies met the inclusion criteria. Participant numbers ranged from 349 to 2,191, and ages ranged from 40 to 90 years old. Meta‑analysis was not feasible due to methodological heterogeneity. Risk of bias was moderate in five studies and serious in three. Findings indicated that higher serum IgG antibodies to periodontal pathogens and elevated inflammatory mediators, notably tumor necrosis factor-alpha (TNF‑α), correlated with greater cognitive decline and markers of AD neurodegeneration, including MRI outcomes and APOE ε4 status. In conclusion, the current body of evidence suggests a potential association between periodontitis‑related inflammatory mediators, particularly TNF‑α, and elevated antibody responses to periodontal pathogens with AD progression. However, causality remains unestablished. Future prospective cohort and interventional studies are warranted to clarify the role of periodontal infection and inflammation in AD and to guide clinical strategies that may improve outcomes in AD populations.},
}

@article {pmid41890557,
year = {2026},
author = {Aguero, C and Klein, CZ and Haase, G},
title = {Why it should be "Alzheimer disease" rather than "Alzheimer's disease".},
journal = {Free neuropathology},
volume = {7},
number = {},
pages = {7},
pmid = {41890557},
issn = {2699-4445},
abstract = {The terms "Alzheimer's disease" and "Alzheimer disease" are often used interchangeably in the biomedical literature. Yet this seemingly minor grammatical difference carries implications that extend beyond style: the possessive form, marked by the 's eponym, may imply ownership of a disease by an individual, a notion discouraged by several authoritative medical style guides and international health organizations [1]. In this article, we examine the historical emergence of the term "Alzheimer's disease", analyze the trajectories of the possessive and non-possessive eponyms in PubMed-indexed article titles from 1950 to 2025, and assess how the choice of terminology influences literature retrieval. Our analysis indicates that the possessive form has overwhelmingly dominated the literature for decades. However, searches using "Alzheimer's disease" or "Alzheimer disease" retrieve non-identical, only partially overlapping sets of records in PubMed. We argue that adopting the non-possessive form "Alzheimer disease" would improve conceptual clarity, terminological consistency, and the completeness of literature retrieval, particularly in systematic reviews and meta-analyses.},
}

@article {pmid41890613,
year = {2026},
author = {Vazquez-Palomo, A and Betegón, C and Weickenmeier, J and Martínez-Pañeda, E},
title = {A computational framework to predict the spreading of Alzheimer's disease.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {41890613},
issn = {2331-8422},
abstract = {Alzheimer's disease is characterised by the spreading of misfolded proteins and progressive structural changes in the brain. Despite significant clinical research, understanding how microscopic protein dynamics translate into macroscopic tissue degeneration remains a major challenge. In this work, we present a three-dimensional, finite element-based computational framework to model disease progression by combining multi-protein transport and brain tissue deformation within anatomically realistic geometries. The propagation of toxic tau and amyloid-beta proteins is described using reaction-diffusion equations of the Fisher-Kolmogorov type, incorporating prion-like growth mechanisms and anisotropic transport along white matter fibre tracts. Brain atrophy is represented through a hyperelastic constitutive model driven by protein-dependent volume loss. Subject-specific simulations are achieved through an automated preprocessing pipeline that generates finite element meshes and reconstructs axonal orientation fields from medical imaging data. The model reproduces key morphological patterns observed in Alzheimer's disease and shows good quantitative agreement with longitudinal imaging measurements. Overall, the proposed framework offers an extensible computational platform for studying Alzheimer's disease progression across subject-specific brain geometries. The models developed, including the image processing framework (BrainImage2Mesh) and the coupled bio-chemo-mechanical COMSOL finite element implementation, are made freely available to download at https://mechmat.web.ox.ac.uk/codes.},
}

@article {pmid41890703,
year = {2026},
author = {Li, X and Liu, F and Zhu, Y and Shi, H},
title = {Gut Microbiota, Insulin Resistance, and Alzheimer's Disease: A Narrative Review of Mechanistic Links and Therapeutic Perspectives.},
journal = {International journal of general medicine},
volume = {19},
number = {},
pages = {593664},
pmid = {41890703},
issn = {1178-7074},
abstract = {Alzheimer's disease (AD) is increasingly regarded as a "neurometabolic syndrome" wherein systemic insulin resistance exacerbates cerebral glucose hypometabolism, tau hyperphosphorylation, and neuroinflammation. We hypothesize that gut microbiota dysbiosis produces metabolites that are associated with peripheral insulin sensitivity, potentially contributing to disruptions in cerebral insulin signaling and an increased risk of AD. We conducted integrated search of PubMed, Web of Science, and Scopus to synthesize evidence showing: (i) consistent taxonomic shifts in AD, highlighting reduced Firmicutes and increased Proteobacteria and Bacteroidetes, depletion of Ruminococcaceae and enrichment of Blautia and Bilophila; (ii) functional consequences of dysbiosis, leading to lower short-chain fatty acids, altered secondary bile‑acid signaling, elevated lipopolysaccharide and trimethylamine‑N‑oxide, and perturbed tryptophan catabolism; (iii) these microbial metabolites compromising gut and blood-brain barrier integrity, thereby triggering chronic inflammation, potentially modulating the PI3K‑Akt‑GSK‑3β pathway, and linking peripheral insulin resistance to cerebral dysfunction; and (iv) a translational discussion of therapeutic strategies that target both microbiota and insulin pathways, including dietary modulation, probiotics and prebiotics, fecal microbiota transplantation, intranasal insulin, metformin, and metabolite-based agents, show promise. This review uniquely integrates taxonomic, functional, and therapeutic literature to propose a mechanistic microbiota-insulin resistance-AD axis and highlights the need for longitudinal and interventional trials.},
}

@article {pmid41890752,
year = {2026},
author = {Wu, Z and Zhang, Y and Wang, L and Yi, Y and Dai, B and Chen, H and Yang, F},
title = {Periodontitis and systemic diseases: insights into the correlation, mechanisms, and clinical implications.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1777955},
pmid = {41890752},
issn = {1664-3224},
mesh = {Humans ; *Periodontitis/immunology/epidemiology ; Cardiovascular Diseases ; Animals ; Oxidative Stress ; Arthritis, Rheumatoid ; Helicobacter Infections ; Alzheimer Disease ; Diabetes Mellitus/epidemiology ; Renal Insufficiency, Chronic ; Inflammation ; },
abstract = {Periodontitis is a chronic oral infectious inflammatory disease caused by dental plaque, affecting approximately 35% - 50% of adults globally. Far from a localized oral condition, it exerts systemic pathogenic effects through multiple biological conduits. This review synthesizes current evidence on the bidirectional associations between periodontitis and a broad spectrum of systemic disorders, including cardiovascular disease (CVD), diabetes mellitus (DM), respiratory diseases, preterm birth, Alzheimer's disease (AD), chronic kidney disease (CKD), rheumatoid arthritis (RA), and Helicobacter pylori (H. pylori) infection. Furthermore, the review delves into the potential pathophysiological mechanisms underpinning these associations, with emphasis on bacterial translocation, systemic inflammation, immune dysregulation, and oxidative stress pathways. The concluding remarks underscore the critical importance of preserving optimal periodontal health as a cornerstone of systemic wellbeing.},
}

Humans
*Periodontitis/immunology/epidemiology
Cardiovascular Diseases
Animals
Oxidative Stress
Arthritis, Rheumatoid
Helicobacter Infections
Alzheimer Disease
Diabetes Mellitus/epidemiology
Renal Insufficiency, Chronic
Inflammation

@article {pmid41890831,
year = {2026},
author = {Haapasalo, K and Heiland, L and Kumar, DKV and Uvarov, P and Moir, A and Maaser-Hecker, A and Wang, X and Juselius, E and Syed, S and Tuhkala, A and Kajander, T and Lappalainen, M and Hytönen, J and Varjosalo, M and Kim, DY and Kamm, R and Meri, T and Choi, SH and Tanzi, R},
title = {Innate Immune Evasion of Lyme Disease Pathogen Drives Alzheimer-Like Pathology.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8804079/v1},
pmid = {41890831},
issn = {2693-5015},
abstract = {The amyloid β (Aβ) peptide is the main component of amyloid plaques in Alzheimer's disease (AD). Growing evidence has pointed to a role for Aβ as an antimicrobial peptide (AMP). However, the interactions of Aβ with neurotropic pathogens and host evasion strategies have remained largely unexplored. Using quantitative proteomic analysis of patient cerebrospinal fluid (CSF), advanced biochemical methods, and four different 3D brain models, ranging from blood-brain barrier (BBB) microfluidic systems to 3D neurovascular networks, we show that Lyme neuroborreliosis (LNB) Borrelia spp. induce molecular and immunological alterations in the central nervous system (CNS) that resemble key pathological features of AD. These include upregulation of the complement cascade and a decrease in CSF Aβ levels. By assessing the antimicrobial action of Aβ against Borrelia spp., we demonstrate that Aβ acts as a pre-opsonin by promoting complement activation on microbial surfaces. We also show that LNB Borrelia spp. exhibit unique survival strategies that reduce Aβ binding and block oligomerization, while halting complement attack by recruiting complement regulator factor H. This facilitates bacterial adhesion to the BBB, and modulation of glial and cytokine responses, fostering CNS invasion. Our findings reveal a previously unrecognized mechanism of bacterial immune escape spanning the entire invasion pathway from the BBB to neuronal compartments, demonstrating that LNB Borrelia spp. evade Aβ-mediated antimicrobial action by interfering with opsonization and oligomerization of the peptide. Collectively, these findings provide a direct mechanistic link between pathogen immune evasion, Aβ dynamics, and neuroinflammatory cascades, advancing our understanding of infection-induced neuropathology, offering insights into novel potential therapeutic targets for AD and neuroborreliosis.},
}

@article {pmid41890852,
year = {2026},
author = {Ramirez, G and Hernandez, D and Teal, A and Chellaganapathy, L and Pianeta, R and Segvich, DM and Wallace, JM and Plotkin, LI},
title = {Moderate Effects of the Arginine to Histidine R47H Variant of the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) on Bone Structure in Male and Female Mice: Insights from the Four Core Genotypes mice.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9076483/v1},
pmid = {41890852},
issn = {2693-5015},
abstract = {Background The Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) gene is expressed in cells of the hematopoietic lineage, like microglia and osteoclasts. A TREM2 gene variant known as TREM2-R47H is associated with an increased risk of developing Alzheimer's disease (AD). Previous studies have shown sex-dimorphic bone and muscle consequences that are associated with the TREM2 variant. Sex chromosomes have also been shown to play a key contributor to skeletal mass and bone strength. Due to the sex-dimorphic bone and skeletal muscle phenotype exhibited by mice expressing the TREM2 gene variant, we investigated the role of chromosomal (XX vs XY) or gonadal (ovaries vs testes) sex. Methods Four Core Genotypes (FCG) C57Bl/6J mice expressing the TREM2-R47H variant were mated to obtain TREM2 wildtype (TREM2 [+/+] , WT) and TREM2 [R47H/+] FCG mice. Four to 5.5-month-old gonadal male (XXT and XYT) and female (XXO and XYT) mice were analyzed. Body weight and bone mineral density were initially measured at baseline and endpoint (5.5 months of age) by DXA/Piximus. Micro-computed tomography, dynamic histomorphometry, 3-point bending test (mechanical properties), and bone turnover markers were measured at the endpoint. Two-way ANOVA analyses were performed through Prism 10 to identify the contributions of chromosome sex, the presence of the TREM2-R47H variant, and their interaction, separately for each gonadal sex. Results Gonadal males: chromosome sex (XX/XY) effects are found for several bone structural parameters in femur and lumbar vertebra 5, whereas there was an interaction between gonadal sex and chromosome sex for other structural measurements in both bones by µCT. Overall, values are higher for TREM2 [R47H/+] than WT for XYT, but not XXT mice, suggesting that the TREM2 genotype effects depend on the presence of the Y chromosome. Mechanical testing shows chromosome sex effects, with higher overall values for XXT mice. Bone formation on the femur cortex and serum formation/resorption markers were unchanged, suggesting that structural changes result from bone modeling/remodeling at an earlier age. Gonadal females: Chromosome sex affects body weight gain (higher in XYO than XXO mice), but no bone mineral density accrual. Chromosome sex affects total lean mass (XYO > XXO) with chromosome sex x TREM2 genotype interaction and differences in total/%fat mass (TREM2 [R47H/+] WT) only for XYO mice. Chromosome sex affects distal femur volumetric bone mass (XYO > XXO), but the TREM2 genotype influences lumbar vertebra trabecular number and separation, which trended higher in TREM2 [R47H/+] vs WT mice for sex complement. Chromosome sex influences femur cortical bone, with overall higher values in XXO mice, independent of TREM2 genotype. Mechanical testing parameters also were XXO > XYO mice. Femur cortical bone formation is higher on the endocortical but lower on the periosteal surface in XXO vs XYO (chromosome sex effect). The opposite effects on the bone surfaces might explain the unchanged serum bone formation marker, Procollagen Type 1 N-terminal propeptide (P1NP). Yet, chromosome sex affects the levels of the resorption marker, C-terminal telopeptide of type 1 collagen (CTX-1), which were lower in XXO mice. Conclusion Our findings suggest that chromosome sex partially affects the consequences of expression of the TREM2-R47H variant on bone structure, whereas the outcomes of the gene variant depend on the mouse gonadal sex.},
}

@article {pmid41890856,
year = {2026},
author = {Rodríguez-Baz, Í and Vaqué-Alcázar, L and Maure-Blesa, L and Pertierra, L and Martinez, JA and Molina-Porcel, L and Aldecoa, I and Ferreira, N and Paradela, R and Videla, L and Barroeta, I and Carmona-Iragui, M and Sánchez-Saudinós, MB and Selma-González, J and Dols-Icardo, O and Aranha, MR and Dolcet, SS and Abdelnour, C and Illán-Gala, I and Alcolea, D and Lleo, A and Suemoto, C and Fortea, J},
title = {Amyloid-linked versus age-driven copathologies in Alzheimer's dementia: differential associations with APOE ε4.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9044264/v1},
pmid = {41890856},
issn = {2693-5015},
abstract = {The mechanisms by which apolipoprotein E (APOE) drives copathologies in established Alzheimer's disease (AD) dementia via amyloid-dependent versus age-driven pathways remain unresolved. Analyzing data from 11,897 autopsied individuals from the National Alzheimer's Coordinating Center, with copathology analyses restricted to amyloid-positive AD dementia, we show that APOE effects followed two distinct trajectories. Cerebral amyloid angiopathy exhibited a striking ε4 dose-response (OR = 5.76, 95% CI: 4.20-7.96, p < 0.001; for ε4/ε4 compared to ε3/ε3), whereas arteriolosclerosis and atherosclerosis risk increased with age, independent of APOE haplotype. Lewy body pathology showed modest APOE associations restricted to limbic/amygdalar-predominant forms and was related to dementia duration, suggesting AD-mediated secondary synucleinopathy. TDP-43 pathology was associated with chronological age, demonstrating regional progression with minimal APOE dependence. These findings suggests that in amyloid-positive AD dementia, APOE ε4 selectively amplifies amyloid-related pathology, particularly cerebral amyloid angiopathy, while other copathologies accumulate through age-driven, APOE haplotype-independent processes.},
}

@article {pmid41891004,
year = {2026},
author = {Roberts, KF and Abrams, ZB and Cappelletti, L and Moqri, M and Heugel, N and Caufield, JH and Bourdenx, M and Li, Y and Banerjee, J and Foschini, L and Galeano, D and Harris, NL and Li, M and Ying, K and Melendez, JA and Barthélemy, NR and Bollinger, JG and He, Y and Ovod, V and Benzinger, TLS and Flores, S and Gordon, BA and Ojewole, AA and Phatak, M and Elbert, DL and Biber, S and Landsness, EC and Mungall, CJ and Bateman, RJ and Reese, JT},
title = {OpenScientist: evaluating an open agentic AI co-scientist to accelerate biomedical discovery.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.15.26348338},
pmid = {41891004},
abstract = {BACKGROUND: Advances in medicine depend on analyzing large and complex data sources, but discovery is partly constrained by the limited time and domain expertise of human researchers. Agentic artificial intelligence (agentic AI) can accelerate discovery by automating components of the scientific workflow, including information retrieval, data analysis, and knowledge synthesis.

AIM: OpenScientist, an open-source agentic AI co-scientist, aims to accelerate biomedical discovery by semi-autonomously investigating scientist-defined queries and generating clinically relevant, verifiable scientific insights.

METHODS: Domain experts evaluated OpenScientist for novel discoveries in four clinical case studies: (1) a prespecified analysis in a community-based Alzheimer's disease biomarker cohort, (2) unsupervised modeling for plasma proteomic survival prediction, (3) hypothesis investigation in single-cell transcriptomic data from neurons with neurofibrillary tangles, and (4) hypothesis generation with validation in a multiple myeloma dataset with a randomized negative control.

RESULTS: OpenScientist completed analyses in minutes that otherwise would take weeks to months of human time and expertise. It identified %ptau217 as the best predictor of amyloid PET status, generated a plasma proteomic survival model with performance comparable to published models, proposed a mechanism linking tau pathology to altered lysosomal acidification, and generated multiple myeloma hypotheses that were validated in an external cohort while distinguishing true signal from randomized controls.

CONCLUSION: OpenScientist demonstrates that open, auditable, agentic AI can support real-world clinical research by generating hypotheses, executing analyses, and discovering insights from complex datasets.},
}

@article {pmid41891033,
year = {2026},
author = {Gong, J and Bloomberg, M and Scholes, S and Hao, X and Salih, DA and Zaninotto, P and Steptoe, A},
title = {Proteomics signatures associated with cognitive trajectories: evidence from the English Longitudinal Study of Ageing.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.19.26348791},
pmid = {41891033},
abstract = {Alzheimer's disease and related dementias (ADRD) pose a growing global health challenge, with early detection critical to slowing cognitive decline and prevent ADRD. We analyzed high-throughput plasma proteomics in 2,460 cognitively healthy adults from the English Longitudinal Study of Ageing (ELSA) to identify proteins linked to 15-year cognitive trajectories, including verbal fluency, episodic memory, and orientation. Mixed-effect linear models revealed 34 proteins associated with faster orientation decline and 18 with accelerated episodic memory decline. Enrichment analyses implicate extracellular matrix remodeling, immune signaling, apoptosis, and lysosomal-autophagic pathways in cognitive deterioration. Subgroup analyses showed sex-specific effects, highlighting heterogeneity in proteomics signatures in cognitive aging. Notably, ten identified proteins are targets of drugs under clinical investigation, suggesting opportunities for therapeutic repurposing. These findings define a plasma proteomic signature associated with decline in domain-specific cognitive functions, offering promising biomarkers and druggable targets to prevent or slow age-related cognitive decline.},
}

@article {pmid41891046,
year = {2026},
author = {Kohli, M and Castro Leal, G and Wyllie, D and Oxtoby, N and Leech, R and Weston, P and Cole, J and , },
title = {AutoML-Multiverse: An Instability-Aware Framework for Quantifying Analytic Variability in Alzheimer's Disease Machine-Learning Studies.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.13.26347938},
pmid = {41891046},
abstract = {UNLABELLED: Machine-learning (ML) models for Alzheimer's disease (AD) frequently yield divergent conclusions, raising concerns about robustness, reproducibility, and interpretability. This instability is partially driven by researcher biases and analytic variability. Coupled with the clinical heterogeneity, mixed pathologies, and cohort differences in AD research, these issues limit the reliability and validity of conclusions from individual models. We introduce AutoML-Multiverse, an instability-aware framework characterising how analytic choices influence ML-based conclusions. The AutoML-Multiverse explores a large space of ∼20,000 analysispipelines and by retaining the full distribution of pipelines, enables direct examination of analytic variability. We evaluate this framework across 20 classification tasks in two independent cohorts studying Alzheimer's disease progression (ADNI, N≤1,930; NACC, N≤1,057), using multiple data modalities: neuroimaging, clinical/cognitive and fluid biomarkers. AutoML-Multiverse performance was equal to or better than non-automated models across all tasks. For example, stable versus progressive mild cognitive impairment (MCI) classification accuracy was 0.68±0.06 (ADNI) and 0.63±0.08 (NACC), while AD versus cognitively normal (CN) classification reached 0.97±0.01 (ADNI). Crucially, each modality's utility was task- and cohort-dependent: clinical measures dominated diagnostic tasks, whereas imaging better predicted progression, with modality preferences often switching between cohorts, highlighting limited generalisability of single-cohort results. Using the AutoML-Multiverse, we obtained strong classification performance without pre-specifying key model design choices. By reducing analysis-driven variability and explicitly characterising uncertainty, instability-aware evaluation can support the development of more robust and clinically applicable prediction models in AD research.

HIGHLIGHTS: AutoML-Multiverse systematically quantifies analytic instability in clinical ML.Analysis of ∼20,000 pipelines across ADNI and NACC cohorts.Pipeline choices substantially alter model rankings and biomarker importance.Cross-cohort variability highlights risks of single-dataset studies.Instability-aware evaluation improves robustness of AI-driven research.},
}

@article {pmid41891120,
year = {2026},
author = {Grande, I and Schmidt, SN and Reines, E and Christensen, MC},
title = {Vortioxetine in Subgroups of Patients with Major Depressive Disorder and Early-Stage Dementia: Further Results from the MEMORY Study.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {549106},
pmid = {41891120},
issn = {1176-6328},
abstract = {BACKGROUND: Depression and dementia are common in older adults; however, many antidepressants have limited effectiveness in patients with major depressive disorder (MDD) comorbid with dementia. In the MEMORY study (NCT04294654), significant improvements in depressive symptom severity, cognitive performance, overall functioning, and health-related quality of life were seen in patients with MDD and early-stage dementia during treatment with vortioxetine. This subgroup analysis was undertaken to further explore the effectiveness of vortioxetine in this patient population.

METHODS: MEMORY was a multinational, open-label, Phase IV study. Patients (n = 82) aged 55-85 years with MDD and early-stage dementia were treated with vortioxetine (5-20 mg/day) for 12 weeks. This was a post-hoc analysis for four key subgroups of patients in this study: (i) those with Alzheimer's disease (n = 35), (ii) those with mixed-type dementia (n = 22), (iii) those receiving concomitant drugs for dementia (n = 34), and (iv) those with severe depression (Montgomery-Åsberg Depression Rating Scale [MADRS] total score ≥30) at baseline (n = 42).

RESULTS: Significant improvement in depressive symptom severity was seen in all patient subgroups from week 1 onwards (P < 0.05). At week 12, the mean change from baseline ranged from approximately -12 to -14 for MADRS total score (P < 0.0001), -6 to -8 for MADRS anhedonia subscore (P < 0.0001), and +3 to +6 for Digit Symbol Substitution Test score (P < 0.05). Improvements in verbal memory, ability to perform activities of daily living, health-related quality of life, and overall disease severity were also observed in all patient subgroups.

CONCLUSION: Our findings provide further support for the effectiveness and tolerability of vortioxetine in patients with MDD and early-stage dementia. Clinically significant improvement in depressive symptoms, cognitive performance, and health-related quality of life during treatment with vortioxetine was observed in patients with Alzheimer's disease, those with mixed-type dementia, patients receiving concomitant treatment with drugs for dementia, and those with severe depression.},
}

@article {pmid41891254,
year = {2026},
author = {Harrison, EM and Maki, PM and Chang, Y and Wu, M and Kamboh, MI and Aizenstein, H and Thurston, RC},
title = {Associations of anxiety and worry symptoms with cognitive performance among midlife women: importance of APOE4 genotype status.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/13803395.2026.2647965},
pmid = {41891254},
issn = {1744-411X},
abstract = {INTRODUCTION: Anxiety symptoms and disorders are the most common psychiatric conditions among women and can have implications for cognitive performance. Anxiety may be notably prevalent during the menopause transition, a midlife transition experienced by most women. There is limited understanding about the relationship of anxiety to women's cognitive performance at midlife. Further, little research has considered how the relationship between anxiety and cognition may vary by apolipoprotein E4 (APOE4) genotype status, a known risk factor for Alzheimer's disease.

METHODS: Two hundred and sixty-one women underwent study procedures, including assessments of anxiety and worry symptoms, a comprehensive neuropsychological battery, and phlebotomy. Factor analysis was used to derive cognitive factors. Associations of anxiety and worry with cognitive factors were tested with linear regression. Interactions by APOE4 were tested.

RESULTS: Associations of trait anxiety and worry symptoms with cognitive factors significantly varied by APOE4 status (interaction p's < 0.05). Among APOE4 carriers, higher trait anxiety was associated with poorer cognitive performance, including poorer verbal learning/memory (b[SE] = -0.361[0.143], p = 0.037), attention/working memory (b[SE] = -0.272[0.121], p = 0.048), and verbal fluency (b[SE] = -0.412[0.117], p = 0.005). Similar patterns were observed for worry.

CONCLUSIONS: Findings underscore the importance of anxiety and worry for women's cognitive performance at midlife among APOE4 carriers. They suggest the potential value of treating anxiety symptoms in APOE4 carriers to support women's cognition at midlife and beyond.},
}

@article {pmid41891380,
year = {2026},
author = {Zeng, X and Li, Y and Hua, L and Lu, R and Franco, LL and Kochunov, P and Chen, S and Detre, JA and Wang, Z and , },
title = {Spatially and temporally progressive hypoperfusion in Alzheimer's disease revealed by normative modeling.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71203},
doi = {10.1002/alz.71203},
pmid = {41891380},
issn = {1552-5279},
support = {R01AG081693/AG/NIA NIH HHS/United States ; R01AG070227/AG/NIA NIH HHS/United States ; R33AG080518/AG/NIA NIH HHS/United States ; R01 EB031080/EB/NIBIB NIH HHS/United States ; //the University of Maryland Baltimore/ ; 1UL1TR003098//Institute for Clinical and Translational Research, University of Maryland, Baltimore/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/physiopathology/pathology ; Male ; Female ; Aged ; Magnetic Resonance Imaging ; *Cognitive Dysfunction/diagnostic imaging/physiopathology/pathology ; *Cerebrovascular Circulation/physiology ; *Brain/diagnostic imaging/pathology/blood supply ; Disease Progression ; Aged, 80 and over ; Spin Labels ; Middle Aged ; },
abstract = {INTRODUCTION: Cerebral perfusion is implicated in Alzheimer's disease (AD), but its development in AD and mild cognitive impairment (MCI) is not well characterized.

METHODS: We constructed a normative model using > 12,000 arterial spin labeling MRI scans and applied generalized additive models for location, scale, and shape (GAMLSS). Individual deviation z scores were derived by normative model, and outlier regions (z ≤ 2.3) were quantified as the total negative proportion (TNP) of extreme hypoperfusion. These metrics were then related to other AD biomarkers through linear modeling.

RESULTS: Compared to cognitively normal controls, AD showed higher TNP and greater longitudinal increases (p = 0.003), indicating progressive hypoperfusion. Progressive MCI exhibited greater perfusion decline than stable MCI (p = 0.01). Perfusion changes correlated with cognition, brain volume, amyloid, and apolipoprotein E status (all p < 0.05).

DISCUSSION: Normative modeling revealed inter-individual heterogeneity in cerebral perfusion trajectories, underscoring its potential relevance for AD development.},
}

Humans
*Alzheimer Disease/diagnostic imaging/physiopathology/pathology
Male
Female
Aged
Magnetic Resonance Imaging
*Cognitive Dysfunction/diagnostic imaging/physiopathology/pathology
*Cerebrovascular Circulation/physiology
*Brain/diagnostic imaging/pathology/blood supply
Disease Progression
Aged, 80 and over
Spin Labels
Middle Aged

@article {pmid41891882,
year = {2026},
author = {Yokoyama, M and Kobayashi, H and Kaneko, N and Naito, H and Ota, K and Sekiya, S and Ikemura, K and Opoku, G and Hirohata, S and Iwamoto, S and Tanaka, K and Tomita, T},
title = {Identification of ADAMTS5 as APP-Cleaving Enzyme at the APP669 Site.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {7},
pages = {e71701},
doi = {10.1096/fj.202600043},
pmid = {41891882},
issn = {1530-6860},
support = {19H01015//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 23H00394//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 17H04313//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 20H00548//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22J14778//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 25KJ1052//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP20dm0207073//Japan Agency for Medical Research and Development (AMED)/ ; JPMJMS2024//MEXT | JST | Moonshot Research and Development Program (Moonshot)/ ; JPMJSP2108//MEXT | JST | Support for Pioneering Research Initiated by the Next Generation (SPRING)/ ; //Japan Science and Technology Agency/ ; },
mesh = {*ADAMTS5 Protein/metabolism/genetics ; Humans ; Animals ; *Amyloid beta-Protein Precursor/metabolism ; Mice ; Alzheimer Disease/metabolism ; ADAMTS4 Protein/metabolism/genetics ; *Amyloid beta-Peptides/metabolism ; *Peptide Fragments/metabolism ; },
abstract = {Cerebral amyloid-β (Aβ) deposition is a pathological hallmark of the earliest phases of Alzheimer disease (AD). We previously reported APP669-711 as a novel Aβ-related peptide detectable in human plasma and developed a composite biomarker that combines APP669-711/Aβ1-42 and Aβ1-40/Aβ1-42 ratios to serve as a plasma surrogate of cerebral Aβ burden. We also identified ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin type 1 motif 4) as an APP669-cleaving enzyme that catalyzes the rate-limiting step of APP669-711 production. However, ADAMTS4 accounts for approximately 40% of APP669-site cleavage, leaving the enzymes responsible for the remaining 60% unknown. Here, we identify ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin type 1 motif 5) as a protease with stronger APP669-site cleavage activity in vitro. We further show that the difference in APP669-site cleavage activity between ADAMTS4 and ADAMTS5 is explained by the regulation through the spacer (Sp) domain. Nonetheless, in vivo experiments did not confirm a role for ADAMTS5 in plasma APP669-711 production under healthy conditions. Because ADAMTS5 expression increases in certain pathological states, our results suggest that ADAMTS5 may contribute to plasma APP669-711 production in AD patients with comorbid conditions.},
}

*ADAMTS5 Protein/metabolism/genetics
Humans
Animals
*Amyloid beta-Protein Precursor/metabolism
Mice
Alzheimer Disease/metabolism
ADAMTS4 Protein/metabolism/genetics
*Amyloid beta-Peptides/metabolism
*Peptide Fragments/metabolism