@article {pmid41699413,
year = {2026},
author = {Shaldam, MA and Carradori, S and Balaha, M and Guglielmi, P and Diomede, F and D'Agostino, I and Tawfik, HO},
title = {Patents involving monoamine oxidase (MAO): a comprehensive update (2022-2025) on its inhibitors and applications.},
journal = {Expert opinion on therapeutic patents},
volume = {},
number = {},
pages = {},
doi = {10.1080/13543776.2026.2633345},
pmid = {41699413},
issn = {1744-7674},
abstract = {INTRODUCTION: Monoamine oxidases (MAOs) A and B are key enzymes for the oxidative deamination of monoamine neurotransmitters, including dopamine, serotonin, norepinephrine, and tyramine. Selective MAO-B inhibitors are clinically employed as adjuvant therapies for neurodegenerative disorders, whereas selective MAO-A inhibitors are mainly considered third-line options in the treatment of depression. However, due to their function in regulating synaptic activity and exogenous monoamine metabolism, research in this field is continually expanding.

AREAS COVERED: This review summarizes patents on MAO inhibitors between 2022 and 2025. For the most investigated chemotypes (14 synthetic cores along with compounds from natural sources), biological activities were analyzed. The compounds are divided into two main categories, naturally occurring molecules and newly synthesized derivatives, with a total of 114 compounds discussed. To provide a more comprehensive perspective on the therapeutic potential of these inhibitors, additional treatment alternatives are also outlined.

EXPERT OPINION: Recently patented MAO inhibitors show notable properties, including significant isoform selectivity and therapeutic potential toward other diseases, such as fibromyalgia, CDKL5-deficient disorder, neuropathic pain, and Alzheimer's disease.},
}

@article {pmid41699353,
year = {2026},
author = {Casciati, A and Colantoni, E and Camera, F and Fratini, E and Casula, EP and Mencarelli, L and Di Lorenzo, F and Bonnì, S and Koch, G and Tanno, B and Merla, C},
title = {Deregulation of Synaptic Plasticity-Related MicroRNAs After Repetitive Transcranial Magnetic Stimulation in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {442},
pmid = {41699353},
issn = {1559-1182},
support = {Regione Lazio POR FESR Lazio 2014-2020 n. A0375-2020-36546//Regione Lazio/ ; },
abstract = {Repetitive transcranial magnetic stimulation (rTMS) is an emerging non-invasive therapeutic approach to slow down cognitive and functional decline in Alzheimer's disease (AD), potentially through plasticity-related mechanisms. MicroRNAs (miRNAs) play a crucial role in synaptic plasticity, and their deregulation contributes to AD-related cognitive impairment. In the present study, we first used a dosimetric model to translate rTMS field applied in AD patients to an in vitro system, identifying miRNAs as potential biomarkers responsive to rTMS. We found that rTMS induced in vitro deregulation of miR-26b, miR-125b, miR-181c, and miR-146a. Then, we investigated the effects of rTMS over precuneus during a 3-week, randomized, sham-controlled trial in AD patients. In patient serum, miR-26b, miR-30b, and miR-125b were significantly modulated in AD patients compared to healthy controls, though no significant modulation emerged between sham and rTMS groups before or after stimulation. Subsequently, the correlation analyses, which incorporated patients' cognitive scores, revealed that reduced miR-25 levels were significantly associated with cognitive improvement. However, no significant differences emerged between Real- and sham-rTMS correlation coefficients, likely due to the limited sample size, indicating that miR-25 may represent a general prognostic marker rather than a treatment-specific indicator. Furthermore, the ability of this miRNA to discriminate responders from non-responders, shown by ROC analysis, highlights its potential as a promising predictor of rTMS treatment efficacy to be validated in a larger patient cohort. Altogether, our findings suggest, for the first time, that rTMS may modulate specific miRNAs in AD patients, with miR-25 representing a pivotal key target for future validation studies.},
}

@article {pmid41699331,
year = {2026},
author = {Ercin, N and Besli, N and Beker, M and Celik, U},
title = {Non-canonical cell death in neurodegeneration: emerging mechanisms and therapeutic Frontiers.},
journal = {Apoptosis : an international journal on programmed cell death},
volume = {31},
number = {3},
pages = {72},
pmid = {41699331},
issn = {1573-675X},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/pathology/metabolism/genetics ; *Cell Death/drug effects ; Animals ; Necroptosis/drug effects ; Ferroptosis/drug effects ; Neuroprotective Agents/therapeutic use/pharmacology ; Pyroptosis/drug effects ; Oxidative Stress ; },
abstract = {Neurodegenerative diseases, specifically Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are defined by progressively increased neuronal loss that lacks curative therapies. Increasing evidence supports that non-canonical regulated cell death pathways including ferroptosis, necroptosis, pyroptosis, and parthanatos, are implicated in pathological mechanisms of neuroinflammation, and oxidative stress, and mitochondrial dysfunction, likely impacting neurodegenerative pathologies. In this review, we summarize the existing literature on the molecular pathways and potential pathogenic implications of these cell death pathways in neurodegenerative diseases, highlighting their upstream triggers, regulatory proteins, and downstream effectors. We also briefly describe representative pharmacological agents, including ferrostatin-1, necrostatin-1, MCC950 and PARP-inhibitors, that have shown neuroprotective effects in experimental studies. Experimental studies provide valuable information, but translation to clinical treatments presents barriers including overlapping regulated cell death mechanisms, constraints of bloodbrain barrier penetrance and concern for safety. Future development may come through concepts such as biomarker-based patient stratification strategies, multivalent interventions, and improved translational models. Identifying these new regulated cell death pathways may eventually provide new avenues to slow the progression of neurodegeneration and develop more targeted therapies.},
}

Humans
*Neurodegenerative Diseases/drug therapy/pathology/metabolism/genetics
*Cell Death/drug effects
Animals
Necroptosis/drug effects
Ferroptosis/drug effects
Neuroprotective Agents/therapeutic use/pharmacology
Pyroptosis/drug effects
Oxidative Stress

@article {pmid41699298,
year = {2026},
author = {Monroe, KM and Hong, S and Lewcock, JW and Yang, AC},
title = {Therapeutic targeting of neuroimmune mechanisms in neurodegeneration.},
journal = {Nature reviews. Drug discovery},
volume = {},
number = {},
pages = {},
pmid = {41699298},
issn = {1474-1784},
abstract = {Effective treatments for age-related chronic neurodegenerative diseases such as Alzheimer's disease remain limited, in part because the molecular drivers of cognitive decline are still not fully understood. Human genetic studies, together with detailed analysis of disease pathology, indicate that the immune system has an important influence on disease progression. Research to date has focused largely on microglia - specialized innate immune cells that reside within the central nervous system (CNS) - as functional studies combined with deep transcriptional profiling have improved our understanding of this innate immune cell type in neurodegeneration and have identified several potential therapeutic targets. Increasing evidence now shows that microglia coordinate diverse CNS and peripheral cell populations to shape disease outcomes. In this Review, we discuss these neuroimmune interactions, which reveal a more intricate framework for how the central and peripheral immune systems may influence neurodegeneration. These insights could redirect future drug discovery efforts towards immune targets that complement existing therapies aimed at core pathological features. We also outline how this knowledge suggests new therapeutic strategies and highlight a critical need for disease-specific neuroimmune biomarkers.},
}

@article {pmid41699292,
year = {2026},
author = {Nagai, M and Dote, K and Dasari, TW},
title = {Increased blood pressure variability - A risk of Alzheimer's disease?.},
journal = {Hypertension research : official journal of the Japanese Society of Hypertension},
volume = {},
number = {},
pages = {},
pmid = {41699292},
issn = {1348-4214},
}

@article {pmid41698644,
year = {2026},
author = {Xu, Z and Li, X and Wang, S and Lyu, J and Zhu, S and Chen, S and Li, Y and Zhang, Y and Wang, F and Duan, R},
title = {Diminazene attenuates astrocytic oxidative stress and neuronal ferroptosis via miR-10b-3p/NOX4 axis in Alzheimer's Disease Model.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110880},
doi = {10.1016/j.neuropharm.2026.110880},
pmid = {41698644},
issn = {1873-7064},
abstract = {PURPOSE: Diminazene (DIZE), an agonist of the Ang-(1-7) system, has been proven to suppress astrocytic neuroinflammatory responses in Alzheimer's disease (AD). NADPH oxidase 4 (NOX4) is abundantly expressed in astrocytes and critically mediates oxidative stress damage and ferroptosis. However, the mode of DIZE in AD-related NOX4 overactivation and ferroptosis remains to be revealed.

METHODS: Male APP/PS1 mice received DIZE and the ferroptosis inhibitor Liproxstatin-1 (LIP) treatment. Behavioral tests, Nissl staining, Western blotting, ELISA and immunofluorescence were performed to evaluate the effects of DIZE on neuronal loss, synaptic damage, inflammation and iron accumulation. Astrocytes from APP/PS1 mice were underwent high-throughput miRNA sequencing to identity the most differentially expressed miRNAs after DIZE administration. Subsequently, the role of this miRNA in DIZE's anti-ferroptosis impact within primary astrocytes was explored.

RESULTS: DIZE markedly reduced iron accumulation while lowering oxidative stress and inflammation in APP/PS1 mice. Simultaneously, DIZE significantly mitigated cognitive deficits and synaptic injury in APP/PS1 mice. DIZE suppressed the expression level of NOX4 and upregulated miR-10b-3p. Importantly, miR-10b-3p levels were notably elevated in astrocytes of APP/PS1 mice administered DIZE, targeting the NOX4 protein. Inhibition of miR-10b-3p expression significantly reversed the therapeutic effect of DIZE.

CONCLUSION: These findings indicate that DIZE suppresses astrocytic oxidative stress and neuronal ferroptosis via miR-10b-3p/NOX4 axis in AD model.},
}

@article {pmid41698629,
year = {2026},
author = {Patwekar, F and Patwekar, M and Wei, LS and Rather, GA and Mohammed, A and Hussain, MS and Gupta, G and Fuloria, S and Fuloria, NK},
title = {Marine-Derived bioactive compounds from Aquaculture: Receptor-Mediated neuroprotection in neurodegenerative disorders.},
journal = {Brain research},
volume = {},
number = {},
pages = {150208},
doi = {10.1016/j.brainres.2026.150208},
pmid = {41698629},
issn = {1872-6240},
abstract = {Neurodegenerative diseases, like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and ischemic stroke (IS), are a major global health challenge because of their complex, multifactorial pathology, and the lack of effective disease-modifying therapies. In recent years, aquaculture-derived marine bioactive molecules like fucoidan, phlorotannins, fucoxanthin, laminarin, alginate oligosaccharides, and C-phycocyanin have developed as promising agents for neuroprotection with their structural diversity and multi-target biological activity. This review showcase predominantly preclinical evidence, including in silico molecular docking analyses, in vitro functional assays, and in vivo animal models, to critically understand the receptor-mediated mechanisms with the neuroprotective actions of marine bioactives originated from aquaculture systems. Available studies shows these compounds can modulate large neuro-receptor systems, like cholinergic, dopaminergic, GABAergic, glutamatergic, toll-like, and nuclear receptors, leading in attenuation of oxidative stress, lowering of neuro-inflammation, regulation of neurotransmission, and conservation of mitochondrial and synaptic function. However, the positive approach of mechanistic evidence varies across compounds and receptor classes, with large interactions assisted by functional outcomes instead of direct receptor-binding validation. The review even discusses emerging and enabling technologies like brain organoids, multi-electrode array platforms, omics-based profiling, and artificial intelligence assisted drug discovery, which are increasingly utilized to refine mechanistic understanding and optimize marine-derived products. Importantly, current evidence stay largely preclinical, with little human studies and a lack of validated receptor-specific biomarkers. Overall, this review provides a well-balanced, evidence-based assessment of aquaculture-derived marine bioactive as potential neurotherapeutic agents.},
}

@article {pmid41698556,
year = {2026},
author = {Zavala-Ocampo, LM and Mendoza-Franco, G and Aparicio-Bautista, DI and López-Camacho, PY and García-Sierra, F and Basurto-Islas, G},
title = {Petiveria alliacea L. Methanolic Extract Inhibits Amyloid-β Aggregation and Enhances Cell Viability in SH-SY5Y Cells: In Vitro and In Silico Evidence.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121381},
doi = {10.1016/j.jep.2026.121381},
pmid = {41698556},
issn = {1872-7573},
abstract = {Petiveria alliacea L. is a member of the Petiveriaceae botanical family, distributed in America and some Asian countries, and is used as a medicinal plant to enhance memory. Pharmacological studies have demonstrated that it reduces oxidative damage and regulates the cholinergic function in the brain, exhibiting a significant memory-enhancing potency.

AIM OF THE STUDY: This study evaluated the effect of P. alliacea by inhibiting polymerization and disassembly of amyloid β (Aβ) oligomers in SH-SY5Y cells.

MATERIAL AND METHODS: SH-SY5Y cells were incubated with Aβ peptide oligomers and treated with either methanol (PMF) or hexane fraction (PHF) of P. alliacea at different time points. Cellular viability and toxicity were assessed by MTT assay. Inhibition of Aβ polymerization in cells was assessed using the thioflavin T (ThT) assay and immunofluorescence. The chemical profile of P. alliacea was analyzed by GC-MS. Bioinformatic data analysis was performed using the STITCH database, and PPIs were identified using STRING.

RESULTS: PMF inhibited polymerization and induced disassembly of Aβ oligomers, leading to a possible neuroprotective effect in SH-SY5Y cells. A total of 73 compounds were identified in PHF and 70 in PMF; among these, 14 were associated with Aβ activity based on bioinformatic analyses. Bioinformatic analysis identified that several metabolites from P. alliacea may interact with proteins involved in neuroinflammatory pathways.

CONCLUSIONS: P. alliacea demonstrates substantial anti-amyloidogenic capabilities and protects SH-SY5Y cell viability in an Aβ-induced cytotoxicity model. Our findings suggest that P. alliacea is a promising candidate for the development of novel therapeutic interventions for neurodegenerative diseases such as Alzheimer's disease.},
}

@article {pmid41698553,
year = {2026},
author = {Pocevičiūtė, D and Roth, B and Olofsson, A and Hansson, O and Wennström, M},
title = {APOE isotype-dependent regulation of IgG and IgA levels against different IAPP epitopes.},
journal = {Immunology letters},
volume = {},
number = {},
pages = {107152},
doi = {10.1016/j.imlet.2026.107152},
pmid = {41698553},
issn = {1879-0542},
abstract = {The efficient clearance of IAPP oligomers (IAPPo) by autoantibodies is crucial as increased plasma levels of IAPPo can induce microvascular alterations and Alzheimer's disease (AD)-characteristic amyloid-β deposition in the brain. We have recently demonstrated that plasma immunoglobulin (Ig) A levels against IAPPo, but not IgG, are reduced in an Apolipoprotein E (APOE) ε4 allele dose-dependent manner. In this study, we aimed to investigate if this APOE genotype-dependent impact can be explained by differences in IAPP epitope recognition by IgA and IgG. We found that the specificity for IAPP epitopes does not differ between IgG and IgA autoantibodies and that IgG and IgA autoantibodies are directed foremost against the C-terminus of the IAPP. However, IgG autoantibody levels against the N-terminus and midportion of IAPP increased significantly in AD patients with APOE44 compared to controls with APOE33, while the opposite was seen in IgA autoantibody levels. We propose that the IgG and IgA levels against different IAPP epitopes are APOE isotype-dependent, possibly due to differences in cytokine profile between various APOE genotypes or the need for different effector functions of IgG or IgA.},
}

@article {pmid41698489,
year = {2026},
author = {Bloch, L and Borys, K and Nensa, F and Friedrich, CM and , },
title = {MRI-based Radiomics and volumetrics for predicting the onset of Alzheimer's Disease with explainable machine learning.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121813},
doi = {10.1016/j.neuroimage.2026.121813},
pmid = {41698489},
issn = {1095-9572},
abstract = {The detection of Alzheimer's Disease (AD) using structural Magnetic Resonance Imaging (MRI) and Machine Learning (ML) often focuses on late-stage atrophy patterns. End-to-end deep learning models address this by considering MRI signal intensities. However, their explainability components typically focus on attention regions, neglecting underlying patterns. This work overcomes both problems by training and explaining time-to-event models utilizing Radiomics features. SHapley Additive exPlanations (SHAP) and high-level explanations were combined to interpret the effects of MRI texture, shape, and volumes, as well as neuro-psychological and cognitive tests, and socio-demographic features on the AD risk score. All models were trained and internally validated on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. External validation was performed on the Australian Imaging Biomarkers and Lifestyle flagship study of Ageing (AIBL) and the Open Access Series of Imaging Studies version 3 (OASIS-3). The results demonstrate that Radiomics features add value to models trained on cognitive tests, socio-demographics, genetics, and MRI volumes, particularly for long-term AD predictions. On average, the Radiomics-based models slightly outperformed the comparison models by between 0.11% points and 3.02% points in terms of Brier scores for the eight-year prediction. Despite varying data distributions during external validation, the models demonstrate moderate to high reproducibility. The analysis of Radiomics features uncovered complex associations with AD, including tissue with complex texture in the left entorhinal cortex, an irregular shape of the right amygdala, and a fine-granular texture of the left middle temporal gyrus. All models showed reasonable concordance with the Voxel-Based Morphometry (VBM).},
}

@article {pmid41698287,
year = {2026},
author = {Bengs, B and Swerdlow, RH and Burns, J and Slawson, C and , and McCoy, M and Sardiu, ME},
title = {Digital siblings unveil distinct molecular and clinical subtypes in Alzheimer's disease via omics-driven profiling.},
journal = {Journal of the neurological sciences},
volume = {482},
number = {},
pages = {125812},
doi = {10.1016/j.jns.2026.125812},
pmid = {41698287},
issn = {1878-5883},
abstract = {Alzheimer's Disease (AD) is a multifactorial neurodegenerative disorder marked by extensive biological and clinical heterogeneity, complicating prognosis and personalized treatment strategies. Because of this, data-driven methods that characterize patient similarity and subgroup-specific molecular signatures are essential for advancing precision medicine in AD. We applied manifold learning techniques to fuse proteomic, demographic, and clinical data from 438 AD patients, enabling the identification of "digital siblings"-patients with closely related molecular and clinical profiles within a learned latent space. This framework enabled robust clustering and stratification of patient subgroups, revealing distinct pathway enrichments associated with clinical traits such as age, alcohol use, and comorbidities. Moreover, structural and network analyses of key protein interactions within these subgroups provided insights into the molecular mechanisms potentially driving disease heterogeneity. While this approach primarily clustered patients based on comprehensive molecular patterns, it lays critical groundwork for developing predictive models that incorporate longitudinal progression and intervention outcomes. Overall, our results underscore the potential of "digital sibling"-based stratification to refine patient subgroup characterization and serve as a foundation for future dynamic modeling in AD.},
}

@article {pmid41698243,
year = {2026},
author = {Khan, F and Pandit, D and Lalan, S and Rane, MR},
title = {Comprehensive multimodal prediction of Alzheimer's disease.},
journal = {Biomedical physics & engineering express},
volume = {},
number = {},
pages = {},
doi = {10.1088/2057-1976/ae4630},
pmid = {41698243},
issn = {2057-1976},
abstract = {Alzheimer's disease (AD) classification using machine learning has increasingly relied on multimodal inputs such as Magnetic Resonance Imaging (MRI), cognitive assessments, and biological markers. This study evaluates whether integrating these sources enhances predictive performance compared to using them independently. Neural networks were trained on data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to classify subjects into Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and AD categories using unimodal, bimodal, and trimodal input configurations. Contrary to expectations, multimodal models did not consistently outperform unimodal ones. The highest test accuracy (81%) was achieved by both the cognitive-only and trimodal models, with the former also demonstrating superior class-wise performance. These findings suggest that neuropsychological features may carry greater diagnostic value than imaging or fluid biomarkers, underscoring the importance of more targeted data fusion strategies. Furthermore, the inclusion of biological markers did not significantly improve early MCI detection, likely due to their limited dimensionality and the model's constrained ability to extract meaningful patterns from such inputs.},
}

@article {pmid41697960,
year = {2026},
author = {Hupalo, D and McCauley, JL and Gomez, L and Griswold, AJ and Hoher, G and Konidari, I and Lorenzo, J and Parker, GS and Pascual, J and Sandford, AR and Whitehead, PL and Davis, DA and Garamszegi, S and Gultekin, SH and Sun, X and Vontell, RT and Chatigny, M and Chernicky, D and Constant, MM and Darling, IG and Ennulat, DJ and Esposito, JM and Morris, K and Lawton, ES and Morakabati, NR and Oduor, P and Rodgers, AP and Sang, LA and Sullivan, KM and Tabit, CJ and Turpin, T and Zeabi, A and Zheng, T and Berretta, S and Klengel, T and Ruzicka, WB and Oakley, DH and Blanchard, T and Ho, E and Johnson, R and LeFevre, A and Bustamante, M and Haroutunian, V and Marino, C and Purohit, DP and Wysocki, M and Glausier, JR and Lewis, DA and Nagra, RM and Alba, C and Martin, J and Rice, E and Rosenberger, J and Smith, G and Sukumar, G and Tompkins, M and Wilkerson, MD and Dalgard, CL and Scott, WK},
title = {The NeuroBioBank whole-genome catalogue of human brain donors with central nervous system disorders.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag057},
pmid = {41697960},
issn = {1460-2156},
abstract = {CNS diseases are a prevailing cause of morbidity and mortality worldwide, and are influenced by environmental and biological factors, including genetic risk. Here, we generated genome-wide genetic data on a large cohort of brain tissue donors with in-depth clinical and neuropathological phenotyping, allowing for broad investigations into the risk and mechanisms of these neurological, neurodevelopmental, and psychiatric conditions. This resource consists of 9,663 donors with array-based genotyping and 9,543 donors with whole-genome sequencing completed. The clinical diagnoses of these donors include 148 central nervous system diseases clustered into 15 broad categories by International Classification of Diseases-10 (ICD-10) coding. These donors were collected by six repositories comprising the National Institutes of Health NeuroBioBank, with an average participant age of 60 years. While primarily older individuals of European descent, the cohort also contains younger donors and individuals from non-European backgrounds. Variants were detected in whole-genome sequencing (WGS), normalized and annotated to describe their functional impact, resulting in 171,121,209 unique variants and 1,078,774 non-silent variants. These raw and normalized data have been made available as a neurogenomics resource in the National Institute of Mental Health Data Archive (NIMH NDA) (nda.nih.gov), combined with donor-matched deep demographic and phenotypic data from the NeuroBioBank Portal (neurobiobank.nih.gov). To illustrate applications, we replicated the strong association observed in previous studies between pathogenic CAG nucleotide repeat expansions in the HTT gene with the clinical diagnosis of Huntington's disease, as well as associations of the APOE gene with Alzheimer's disease, and examined the association of polygenic risk scores with the three most common disease diagnoses in the cohort.},
}

@article {pmid41697952,
year = {2026},
author = {Jamuna, NA and Arumugam, D and Mandal, S},
title = {Hydration Shell of PEO-PPO-PEO Block Copolymer Assembly Controls the Modulation of Protein Aggregation: Synergistic Inhibition of Fibrillation Using Trehalose and Protection from Cu[2+]-Induced Fibrillation.},
journal = {ACS applied bio materials},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsabm.5c02236},
pmid = {41697952},
issn = {2576-6422},
abstract = {Amyloid aggregation is a key process involved in many neurodegenerative diseases including Alzheimer's disease. It affects the brain and peripheral tissues, where different types of protein aggregates are accumulated. Pluronic PEO-PPO-PEO block copolymer self-assemblies are widely used as nanocarriers for the brain-targeted delivery of therapeutic agents. Elucidating protein aggregation at these polymer interfaces can provide critical insights into how macromolecular crowding and protein-polymer interactions influence the kinetics of protein aggregation. Here, we investigate the roles of two pluronic copolymers, namely, P123 and F127, which have a similar size of hydrophobic PPO block but different PEO block length on protein aggregation using hen egg white lysozyme (HEWL) as a model protein. Our study reveals that the more hydrated F127 self-assemblies with thicker PEO hydration shells accelerate the onset of protein-aggregation yet moderately retard the extent of overall fibril formation. On the other hand, the less hydrated P123 self-assemblies with compact hydration shells significantly delay the onset of protein aggregation and efficiently inhibit fibril formation. The binding of protein within the hydrated and longer PEO corona of F127 micelles favors accelerated kinetics of β-rich oligomers and fibril formation without a delay phase through soft-chemical interactions. For the less hydrated P123 micellar assemblies, the hydrophobic interactions and strong excluded volume effects probably contribute to stabilization of the protein. The addition of the widely used osmolyte trehalose further delays the protein aggregation and significantly retards the fibril formation through the synergistic inhibitory effects of trehalose and polymer assemblies. The trehalose-bearing pluronic micelles can, therefore, emerge as a potentially efficient inhibitor with great promise in therapeutic applications. The pluronic self-assemblies are also found to be highly effective in protecting the protein from toxicity associated with Cu[2+] induced enhanced amyloid fibrillation. The binding of Cu[2+] within the hydrated PEO corona makes them inaccessible to protein interactions and fibril formation.},
}

@article {pmid41697903,
year = {2026},
author = {Muniz-Perez, A and Meyer-Acosta, KK and Boyana, S and Ponnala, V and McMahon, CL and Aruk, A and Elizalde, A and Hsieh, J},
title = {Modest neurodevelopment impacts of APOE4 in a human brain organoid model of low-grade SARS-CoV-2 infection.},
journal = {Developmental neuroscience},
volume = {},
number = {},
pages = {1-15},
doi = {10.1159/000550957},
pmid = {41697903},
issn = {1421-9859},
abstract = {INTRODUCTION: The long-term neurological consequences of SARS-CoV-2, the virus responsible for the COVID-19 pandemic, are an area of growing concern, particularly for prenatally exposed individuals. Prior research has shown that APOE4, the leading genetic risk factor for late-onset Alzheimer's disease, is associated with increased COVID-19 severity and enhanced SARS-CoV-2 neurotropism. However, whether the interaction between APOE4 and SARS-CoV-2 infection leads to adverse neurodevelopmental outcomes remains unclear. Using human induced pluripotent stem cell derived cortical and ganglionic eminence organoids (COs and GEOs) to model neurodevelopment, we have previously reported that SARS-CoV-2 preferentially infects glial cells, and that APOE4 promotes gliogenesis in COs and accelerates GABAergic neuron differentiation in GEOs. Here, we build upon our previous work by using COs and GEOs to examine how APOE4 modifies cellular responses to SARS-CoV-2 during late gestational development.

METHODS: Using low viral titers to better mimic natural infection, COs and GEOs were infected at 220-270 DIV, aligning with the third trimester, and were analyzed 7 days post infection.

RESULTS: We observed region-specific, APOE4-dependent changes. In infected COs, APOE4 elevated immature astrocyte marker, suggesting a genotype-dependent glial response. Additionally, infected GEOs exhibited reduced marker expression for mature neurons within both genotypes. Notably, APOE4 and infection interacted to modulate immature neuron expression in a region-specific manner.

CONCLUSION: Taken together, this study suggests that APOE4 modulates region-specific responses to low-grade SARS-CoV-2 infection, underscoring the importance of exploring how genetic risk factors alter neurodevelopmental vulnerability to prenatal viral infection.},
}

@article {pmid41697767,
year = {2026},
author = {De Oliveira, RL and Pinz, MP and Voss, GT and Da C Rodrigues, K and Vogt, AG and Dos S Barboza, V and De A Vaucher, R and Giongo, JL and Lima, AS and Alves, D and Quines, CB and Fidelis, EM and Pinton, S and Savegnago, L and Luchese, C},
title = {Redox modulation contributes to the antidepressant-like and neuroprotective effects of 7-chloro-4-(phenylselanyl)quinoline in an Alzheimer's disease model.},
journal = {Redox report : communications in free radical research},
volume = {31},
number = {1},
pages = {2626641},
doi = {10.1080/13510002.2026.2626641},
pmid = {41697767},
issn = {1743-2928},
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; Mice ; Male ; *Neuroprotective Agents/pharmacology/therapeutic use ; Disease Models, Animal ; *Antidepressive Agents/pharmacology/therapeutic use ; *Quinolines/pharmacology/therapeutic use ; Oxidation-Reduction/drug effects ; Amyloid beta-Peptides ; Depression/drug therapy ; Lipid Peroxidation/drug effects ; Acetylcholinesterase/metabolism ; Corticosterone/blood ; Hippocampus/drug effects/metabolism ; },
abstract = {OBJECTIVES: Alzheimer's disease (AD) is characterized by cognitive impairment and neuropsychiatric disturbances, including depression, both tightly linked to redox imbalance and neuroinflammatory activation. This study investigated whether the selenium-containing compound 7-chloro-4-(phenylselanyl)quinoline (4-PSQ) mitigates behavioral and biochemical alterations in a β-amyloid (Aβ)-induced mouse model of AD through modulation of redox-regulated pathways.

METHODS: Male Swiss mice received intracerebroventricular Aβ (25-35) or saline (3 µL/site) and were treated orally for seven days with 4-PSQ (1 mg/kg), paroxetine (1 mg/kg), or donepezil (1 mg/kg). Depressive-like behavior and memory performance were assessed, followed by determination of plasma corticosterone, reactive species levels, lipid peroxidation, antioxidant enzyme activities, neuroinflammatory mediators, and acetylcholinesterase (AChE) activity in the hippocampus and prefrontal cortex of mice.

RESULTS: 4-PSQ significantly reversed Aβ-induced depressive behavior and memory impairment. The compound normalized plasma corticosterone levels, reduced reactive species and lipid peroxidation, and restored antioxidant enzyme activity. It also decreased the expression of inflammatory markers while regulating AChE activity, indicating concomitant modulation of redox, neuroimmune, and cholinergic pathways.

CONCLUSION: By restoring redox homeostasis and attenuating neuroinflammatory responses, 4-PSQ effectively counteracted behavioral and biochemical disruptions associated with Aβ toxicity. These findings support 4-PSQ as a promising selenium-based therapeutic candidate targeting redox-driven features of AD, including comorbid depression and cognitive decline.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/chemically induced
Mice
Male
*Neuroprotective Agents/pharmacology/therapeutic use
Disease Models, Animal
*Antidepressive Agents/pharmacology/therapeutic use
*Quinolines/pharmacology/therapeutic use
Oxidation-Reduction/drug effects
Amyloid beta-Peptides
Depression/drug therapy
Lipid Peroxidation/drug effects
Acetylcholinesterase/metabolism
Corticosterone/blood
Hippocampus/drug effects/metabolism

@article {pmid41697669,
year = {2026},
author = {Coughlan, GT and Ourry, V and Townsend, D and Klinger, H and Brown, JA and Cuppels, M and Betthauser, T and Langhough, R and Cody, K and Seto, M and Birkenbihl, C and Li, A and Farrell, M and Thibault, E and Kivisäkk Webb, P and Arnold, S and Rissman, RA and Properzi, M and Schultz, A and Johnson, K and Langford, O and Donohue, MC and Villeneuve, S and Johnson, SC and Yang, HS and Manson, JE and Sperling, R and Buckley, RF and , },
title = {Sex Differences in P-Tau217, Tau Aggregation, and Cognitive Decline.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2025.5670},
pmid = {41697669},
issn = {2168-6157},
abstract = {IMPORTANCE: Among individuals with high levels of amyloid-β (Aβ), women exhibit higher insoluble tau burden and accumulation than age-matched men. It remains unclear whether this sex difference is influenced by soluble phosphorylated tau (p-tau), a biomarker that changes early in Alzheimer disease.

OBJECTIVE: To investigate whether sex and aggregated Aβ synergistically predict plasma phosphorylated tau 217 (p-tau217) levels and whether levels of p-tau217 predict cross-sectional and longitudinal tau aggregation in a sex-specific manner (as measured by positron emission tomography [PET]).

This longitudinal study analyzed data between September 7, 2024, and October 29, 2025, from 1 clinical trial cohort and 4 observational study cohorts including men and women without cognitive impairment who had undergone multiple assessments via tau PET (18F-flortaucipir or 18F-MK-6240) and plasma p-tau217 assay at baseline. Cognitive performance was measured with the Preclinical Alzheimer Cognitive Composite. Data on cognitive performance were available from 3 of the 5 cohorts for a mean of 4.6 years (SD, 3.1 years). Across the 5 cohorts, the mean follow-up for tau PET was 3.6 years (SD, 1.7 years).

EXPOSURES: Self-reported sex (male or female), tau PET, and p-tau217 assay.

MAIN OUTCOMES AND MEASURES: The primary analyses used linear and mixed-effects models to assess baseline and longitudinal sex × p-tau217 interactions for 9 tau PET regions. The secondary analyses assessed sex × p-tau217 interactions for cognitive change using the Preclinical Alzheimer Cognitive Composite.

RESULTS: Across the 5 cohorts, there were a total of 1292 participants (63.6% women; mean age, 70.6 [SD, 6.4] years) with tau PET assessments. Compared with men, women had significantly higher baseline p-tau217 levels at higher aggregated Aβ Centiloid levels (β, -0.21 [95% CI, -0.37 to -0.05], P = .009; highest interaction was found in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration [A4/LEARN] cohort). The sex × p-tau217 interactions at baseline were significant for 1 tau PET region in the Harvard Aging Brain Study (HABS) cohort, for 2 tau PET regions in the A4/LEARN cohort, for 6 tau PET regions in the Wisconsin Registry of Alzheimer's Prevention (WRAP) cohort, and for 4 tau PET regions in the Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) cohort. Longitudinal interactions were significant for 4 tau PET regions in the A4/LEARN cohort, for 5 tau PET regions in both the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort and the WRAP cohort, and for 2 PET regions in both the HABS cohort and the PREVENT-AD cohort. Compared with men, women displayed greater tau deposition and accumulation at higher p-tau217 levels. Use of a secondary model showed women with higher p-tau217 levels also exhibited faster rates of cognitive decline relative to men in the both the WRAP cohort and the ADNI cohort.

CONCLUSION AND RELEVANCE: These findings add to growing evidence that women have a differential tau response to Aβ that may emerge at the point of p-tau secretion. These findings have implications for the therapeutics and diagnostics of preclinical Alzheimer disease.},
}

@article {pmid41697625,
year = {2026},
author = {Günsel, A and Karanlık, CC and Taslimi, P and Günsel, H and Taskin-Tok, T and Bilgiçli, AT and Özden, EM and Gülçin, İ and Erdoğmuş, A and Yarasir, MN},
title = {Water-soluble phthalocyanines with non-peripheral naphthoxy-sulfonate substituents: computational docking, biological and sono-photochemical investigations.},
journal = {Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology},
volume = {},
number = {},
pages = {},
pmid = {41697625},
issn = {1474-9092},
abstract = {This study reports the synthesis of a novel ligand, sodium 6-(2,3-dicyanophenoxy)naphthalene-2-sulfonate (1), and the corresponding non-peripherally substituted metallophthalocyanines (MPcs) [M = Zn(II) (2), Ga(III) (3); X = Cl, In(III) (4); X = Cl]. These compounds were functionalized with 6-naphthoxy-2-sulfonic acid sodium salt groups. Given the limitations of conventional photodynamic therapy (PDT), we investigated the potential of sonophotodynamic therapy (SPDT), a dual-modality approach combining light and ultrasound, to enhance singlet oxygen ([1]O2) production. Among the synthesized metallophthalocyanines, the zinc(II) complex (2) shows the highest [1]O2 production in both organic and aqueous media under both photochemical and sonophotochemical conditions, showing promise for SPDT applications. Furthermore, the inhibitory effects of these complexes on acetylcholinesterase (AChE) and human carbonic anhydrase isoenzymes (hCA I and II), important targets for Alzheimer's disease, glaucoma, and epilepsy, were evaluated. The compounds showed strong inhibition with Ki values ranging from 130.31 ± 6.18 to 157.47 ± 9.37 µM for hCA I (compared to AZA: 177.41 ± 11.40 µM), 99.18 ± 8.13 to 106.72 ± 8.50 µM for hCA II (compared to AZA: 143.51 ± 9.94 µM) and 0.31 ± 0.03 to 1.21 ± 0.01 µM for AChE (compared to TAC: 1.24 ± 0.21 µM). Molecular docking revealed strong binding affinities: In(III)-Pc (4) showed the highest affinity for AChE (BE: -26.96 kcal/mol), while Ga(III)-Pc (3) preferentially bound to hCA I and II (BE: -13.90 and - 15.39 kcal/mol, respectively). These findings position the synthesized MPcs as multifunctional agents for SPDT and enzyme-targeted therapies.},
}

@article {pmid41697572,
year = {2026},
author = {Liu, R and Deng, Q and Gong, L and Yang, L},
title = {Role Shift of Glial Cells from Physiology to Pathology in Alzheimer's Disease: The Regulatory Impact of Exercise.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {41697572},
issn = {1995-8218},
abstract = {Alzheimer's disease (AD) is a widespread neurodegenerative condition with cognitive and behavioral decline. Astrocytes and microglia, the primary glial cells in the central nervous system, are deeply involved in AD development. Their functional impairments, such as astrocytic shifts in phenotype, blood-brain barrier breakdown, and glymphatic failure, along with microglial "dual phagocytic dysfunction", including impaired amyloid-beta (Aβ) clearance and overactive phagocytosis of healthy synapses, imbalanced inflammation, and metabolic abnormalities, are key drivers of disease progression. Growing research indicates that physical activity, as a non-drug intervention, exerts significant regulatory effects on glial cell function. Exercise regulates the polarization of both astrocytes and microglia, enhances their phagocytic abilities, improves mitochondrial metabolism, and alleviates neuroinflammatory responses. This review outlines the normal physiological roles of astrocytes and microglia, details their pathological alterations in AD, and explores how exercise targets these glial cells to alleviate AD pathology, offering valuable perspectives for potential therapeutic approaches.},
}

@article {pmid41697348,
year = {2026},
author = {Mohammadi, S and Ghorbandaiepour, T and Zahmatkesh, M and Karimi-Zandi, L and Mirzakhani, A},
title = {Potential Role of Extrapineal Melatonin as a Neurohormone in the Pathophysiology of Alzheimer's Disease: Unanswered Questions.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00401},
pmid = {41697348},
issn = {1948-7193},
abstract = {Melatonin, the pineal gland hormone, is produced in various extrapineal tissues as well, and its reduction has been reported in sporadic Alzheimer's disease (AD). The exact reason for tissue melatonin synthesis, despite the pineal source of melatonin, is not well understood, although the melatonin decline in the biological fluids of AD patients is a reasonable justification for melatonin therapy in cognitive impairment. However, the effectiveness of melatonin administration in AD patients was insignificant. Additionally, there is evidence of alterations in local melatonin synthesis in pathological situations, and little is known regarding its physiological or pathological modulators. Recently, the decline in the hippocampal enzyme of melatonin synthesis has been reported in amyloid-β neurotoxicity. It has been shown that reduced hippocampal melatonin synthesis by siRNA has been associated with cognitive decline. This review has included AD studies that noticed the impacts of melatonin prescription on memory and cognitive function in both animal research and randomized controlled trials, while also reviewing the available data regarding the alterations in brain tissue melatonin synthesis. This review highlights the role of brain (extrapineal) tissue melatonin synthesis in cognitive function in AD pathophysiology. Understanding the induction pattern of extrapineal melatonin synthesis, dosing optimization of exogenous administration, noting gender-specific differences, and clarifying microbiota-melatonin interactions point toward new approaches that may enhance the effectiveness of melatonin-based interventions for preventing or delaying AD progression.},
}

@article {pmid41697185,
year = {2026},
author = {Cottrell, S and Yoon, S and Wei, X and Dickson, A and Wei, GW},
title = {Computational Drug Repurposing for Alzheimer's Disease via Sheaf Theoretic Population-Scale Analysis of snRNA-Seq Data.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c02862},
pmid = {41697185},
issn = {1520-4804},
abstract = {Single-cell and single-nucleus RNA sequencing are used to reveal heterogeneity in cells, showing a growing potential for precision and personalized medicine. Nevertheless, sustainable drug discovery must be based on a population-level understanding of molecular mechanisms, which calls for a population-scale analysis of this data. This work introduces a sequential target-drug selection model for drug repurposing against Alzheimer's Disease (AD) targets inferred from snRNA-seq data of AD progression- involving hundreds of thousands of nuclei from multipatient and multiregional studies. We utilize Persistent Sheaf Laplacians (PSL) to facilitate a Protein-Protein Interaction (PPI) analysis inferred from disease related differential gene expression (DEG). We then use an ensemble of machine learning models to predict repurpose-able compounds. We screen the efficacy of different small compounds and further examine their central nervous system relevant ADMET properties, resulting in a list of potential molecular targets as well as pharmaceutical lead candidates for AD treatment.},
}

@article {pmid41697144,
year = {2026},
author = {Lee, WT and Wang, JT and Tsai, MH and Fang, YW},
title = {GLP-1 receptor agonists reduce dementia and Alzheimer disease risk in diabetic Patients with CKD.},
journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association},
volume = {},
number = {},
pages = {},
doi = {10.1093/ndt/gfag032},
pmid = {41697144},
issn = {1460-2385},
abstract = {BACKGROUND: Patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) are at increased risk of developing dementia and Alzheimer's disease due to vascular dysfunction, insulin resistance, and chronic inflammation. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown neuroprotective properties; however, their impact on dementia risk in diabetic patients with CKD remains uncertain. This study evaluated the association between GLP-1RAs use and dementia risk in patients with CKD stage 3 or later, compared to dipeptidyl peptidase-4 inhibitors (DPP4is).

METHODS: This retrospective cohort study analyzed data from the TriNetX global research network, comprising electronic medical records from 67 healthcare organizations in the US Collaborative Network. We identified patients with CKD stage 3 or later and T2DM who were newly prescribed GLP-1RAs or DPP4is between January 1, 2015, and December 31, 2020. Patients with prior GLP-1RAs or DPP4is use, a dementia diagnosis within 12 months before the index date, or recent hospitalization were excluded. The primary outcome was the incidence of dementia, Alzheimer's disease, vascular dementia, frontotemporal dementia, Parkinson's disease, extrapyramidal and movement disorders, and dementia with Lewy bodies, assessed over a follow-up period ranging from 90 days to 5 years. Statistical analyses included Kaplan-Meier survival curves and Cox proportional hazards models.

RESULTS: GLP-1RAs use was associated with a significantly lower risk of dementia (HR: 0.80, 95% CI: 0.71-0.91, p = 0.001) and Alzheimer's disease (HR: 0.76, 95% CI: 0.59-0.98, p = 0.033) compared to DPP4is use. However, no significant differences were observed in vascular dementia, frontotemporal dementia, Parkinson's disease, extrapyramidal and movement disorders, or dementia with Lewy bodies.

CONCLUSIONS: GLP-1RAs therapy may reduce the risk of dementia and Alzheimer's disease in patients with CKD stage 3 or later, offering potential neuroprotective benefits beyond glycemic control. Research is needed to confirm these findings and optimize treatment strategies for this vulnerable population.},
}

@article {pmid41696979,
year = {2026},
author = {Shergill, JK and Azarnia Tehran, D},
title = {Endocytic scaffolds at the crossroads of Alzheimer's disease and neuronal aging.},
journal = {Biological chemistry},
volume = {},
number = {},
pages = {},
pmid = {41696979},
issn = {1437-4315},
abstract = {More than a century after Alois Alzheimer's neuropathological description, the mechanisms driving Alzheimer's disease (AD) remain only partially understood, and the failure of most clinical trials underscores the need to identify and target alternative pathogenic pathways. Recent genetic, biochemical, and cellular studies support the view that AD is characterized by early alterations in the endolysosomal system and implicate multiple endocytic scaffold proteins as key drivers of AD progression. In this review, we summarize the current knowledge of five endocytic scaffold proteins, CALM, AP-2, BIN1, CD2AP, and ITSN1, which have been identified as AD risk factors by genome-wide association studies. We describe how, under physiological conditions, they couple membrane remodeling to intracellular signaling, whereas in AD they influence amyloid precursor protein trafficking, amyloid-β (Aβ) generation, tau pathology, and synaptic integrity. Finally, we propose a model in which cell type-specific and age-dependent dysfunction of endocytic scaffolds defines a pathogenic hotspot of proteostasis failure and offers new entry points for therapeutic intervention.},
}

@article {pmid41696940,
year = {2026},
author = {Li, H and Li, M and Li, C and Liu, D and Kang, Y and Tang, Y and Feng, P and Qian, C},
title = {A Preventable Alzheimer's Disease Microneedle Patch with Synaptic Protection and NLRP3 Inflammasome Suppression in Microglia during Smoking Cessation.},
journal = {ACS nano},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsnano.6c00812},
pmid = {41696940},
issn = {1936-086X},
abstract = {Long-term smoking elevates the risk of Alzheimer's disease (AD), yet it is overlooked that nicotine replacement therapy (NRT) inadvertently exacerbates tau pathology during smoking cessation. Here, we mimicked the nicotine replacement patch to design a microneedle patch for the prevention of Alzheimer's disease (PADM), capable of regulating microglia with synaptic protection and NLRP3 inflammasome suppression during smoking cessation. We first demonstrated that nicotine (NIC) transiently preserved synaptic integrity by upregulating the "do not eat me" signal SIRPα on microglia, reducing aberrant synaptic pruning and enhancing amyloid-β (Aβ) clearance in early AD. However, the NLRP3 inflammasome of microglia was activated after NIC intervention and exhibited tau hyperphosphorylation in neurons in late pathology of AD. To address this, we further integrated a natural NLRP3 inhibitor, resveratrol (RES), with NIC into a bilayer microneedle patch. The tip layer enabled sustained low-dose NIC release for smoking cessation, while the backing gel reservoir slowly released RES to suppress neuroinflammation. In APP/PS1 mice, early smoking cessation intervention improves cognition and reduces Aβ burden, and continuous RES delivery prevented late-stage tau pathology. The PADM patch offers a safe prophylactic approach to AD during smoking cessation in high-risk populations.},
}

@article {pmid41696896,
year = {2026},
author = {Jubair, H},
title = {Glial cells in dementia: From cellular dysfunction to therapeutic frontiers.},
journal = {Cell transplantation},
volume = {35},
number = {},
pages = {9636897251414216},
doi = {10.1177/09636897251414216},
pmid = {41696896},
issn = {1555-3892},
mesh = {Humans ; *Neuroglia/metabolism/pathology ; *Dementia/pathology/therapy/metabolism ; Animals ; },
abstract = {Neurodegenerative dementias, including Alzheimer's disease and vascular dementia, have long been viewed through a neuron-centric lens. However, growing evidence highlights the indispensable and multifaceted roles of glial cells, astrocytes, microglia, and oligodendrocytes in both the onset and progression of these disorders. While prior reviews have cataloged glial dysfunction in isolation, this review offers a novel, integrative framework that maps the interconnected roles of glial subtypes across molecular, cellular, and circuit-level pathology in dementia. We critically synthesize recent advances in single-cell RNA sequencing, spatial transcriptomics, and glial imaging to redefine glial heterogeneity and function in disease states. Special emphasis is placed on the dynamic cross talk between glial populations and the feedback loops that govern their dual roles in neuroprotection and neurodegeneration. Furthermore, we examine emerging therapeutic strategies targeting glial-specific pathways, including NF-κB, JAK/STAT, CSF1R, and TREM2 signaling, as well as remyelinating agents and stem cell-based interventions. By integrating glial biology with therapeutic innovation, this review positions glial cells not as supporting actors but as central regulators and potential gatekeepers of dementia pathogenesis and treatment.},
}

Humans
*Neuroglia/metabolism/pathology
*Dementia/pathology/therapy/metabolism
Animals

@article {pmid41696700,
year = {2025},
author = {Ji, X and Lin, Y and Chen, X and Jiang, X and Wang, Q and Cui, X and Wang, K},
title = {The burden of neurological diseases in G7 countries from 1990 to 2021 and projections for the next 30 years: a Global Burden of Disease study.},
journal = {Frontiers in public health},
volume = {13},
number = {},
pages = {1632773},
pmid = {41696700},
issn = {2296-2565},
mesh = {Humans ; *Global Burden of Disease/trends ; Male ; *Nervous System Diseases/epidemiology/mortality ; Female ; Middle Aged ; Disability-Adjusted Life Years ; Aged ; Adult ; Incidence ; *Global Health/statistics & numerical data ; Forecasting ; Adolescent ; Child ; *Cost of Illness ; Infant ; Prevalence ; Aged, 80 and over ; Young Adult ; Child, Preschool ; },
abstract = {BACKGROUND: Neurological disorders have become a significant global public health challenge due to their high rates of disability and mortality. This study analyzed epidemiological trends of neurological disorders in G7 countries from 1990 to 2021 based on Global Burden of Disease (GBD) 2021 data and predicted the disease burden for the next 30 years.

METHODS: Using the Joinpoint regression model and the Nordpred Age-Period-Cohort (APC) model, the study evaluated indicators such as incidence, mortality, and Disability-Adjusted Life Years (DALYs) of neurological disorders. It also analyzed the impact of gender, age, and social factors on the disease burden.

RESULTS: The overall burden of neurological disorders in G7 countries is lower than the global level, but there are significant gender differences. Women have a higher prevalence rate, which may be related to migraine and hormonal fluctuations, while men have more prominent Years of Life Lost (YLL) due to premature death, except in Japan and Italy. Regarding age distribution, the risk of disease gradually increases for individuals over 10 years old, and the mortality rate rises sharply after 70 years old. The association between aging and neurodegenerative diseases (such as Alzheimer's disease) is particularly significant. Historical trend analysis from 1990 to 2021 shows that the global age-standardized incidence and mortality rates have remained stable overall. However, male mortality rates have increased significantly in the United States, Japan, and Germany. Predictions for the next 30 years indicate that despite stabilizing age-standardized rates, the number of neurological disease cases in G7 countries will continue to increase due to population growth and aging.

CONCLUSION: The study untangles the unique challenges faced by G7 countries in preventing and controlling neurological disorders. It emphasizes the need to develop precise intervention strategies that consider age, gender, and social factors, providing valuable insights for developing countries.},
}

Humans
*Global Burden of Disease/trends
Male
*Nervous System Diseases/epidemiology/mortality
Female
Middle Aged
Disability-Adjusted Life Years
Aged
Adult
Incidence
*Global Health/statistics & numerical data
Forecasting
Adolescent
Child
*Cost of Illness
Infant
Prevalence
Aged, 80 and over
Young Adult
Child, Preschool

@article {pmid41696648,
year = {2026},
author = {Hamilton, LJ and Coleman, ME and Sprecher, A and Rutter, LA},
title = {Dementia stigma in the United States: variation by target gender, degree of impairment, and respondent characteristics.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70260},
pmid = {41696648},
issn = {2352-8729},
abstract = {INTRODUCTION: The rising prevalence of Alzheimer's disease and related dementias (ADRD) poses major public health concerns. Public knowledge about ADRD diverges from scientific consensus, and consequently, public stigma presents barriers to diagnosis and care.

METHOD: This study addresses ADRD stigma in the United States using the well-established vignette approach. A stratified quota sample of 1115 adults matching national demographics were randomly assigned to one of six vignettes. Symptoms of the vignette character mirrored the presentation of ADRD and were reviewed by geriatric neuropsychologists for accuracy.

RESULTS: Apart from small vignette effects, stigma was shaped by respondent characteristics. Higher stigma was predicted by less knowledge, being male, non-White race, and living in counties with higher ADRD prevalence. Surprisingly, personal contact showed no effect.

DISCUSSION: Rehumanizing individuals with ADRD and enhancing ADRD knowledge should be public health priorities. Stigma reduction efforts need to address informational deficits and narratives that perpetuate negative perceptions.},
}

@article {pmid41696647,
year = {2026},
author = {Johnson, AS and Houlihan, H and Ziaggi, G and Maldonado, A and Smith, AC and Heuer, LB and Guzmán, DS and Okafor, A and Sanchez, T and Palacios, C and Huey, ED and Talmasov, D and Provenzano, F and Lee, S and Kreisl, WC and Lao, PJ and , },
title = {Hallucinations and delusions are associated with elevated tau PET signal independent of age, clinical severity, and amyloid burden.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70264},
pmid = {41696647},
issn = {2352-8729},
abstract = {INTRODUCTION: Psychosis in Alzheimer's disease (AD) is associated with worse outcomes, yet no established biomarkers exist for early diagnosis and intervention. We compared tau positron emission tomography (PET) burden across older individuals with and without psychotic symptoms.

METHODS: [18F]AV1451 tau PET binding was compared between 32 Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects with psychotic symptoms (delusions and/or hallucinations) and 32 ADNI subjects without psychotic symptoms, matched for age, sex, race/ethnicity, and clinical severity. Tau was assessed in a priori regions of interest (ROIs) and in voxelwise analyses, both corrected for amyloid PET burden.

RESULTS: Tau was greater in individuals with psychotic symptoms in the amygdala, hippocampus, frontal cortex, and early, middle, and late Braak stage regions in primary analyses. When considering subgroups, tau binding was greatest in those with concurrent delusions.

DISCUSSION: Greater than expected tau burden for age, clinical severity, and amyloid burden may be relevant for psychotic symptoms in older adults.

HIGHLIGHTS: Tau positron emission tomography (PET) was elevated in individuals with psychosisElevated tau was independent of Alzheimer's disease (AD) clinical severity and amyloid burdenThere was variability in the regional distribution depending on psychosis type.},
}

@article {pmid41696646,
year = {2026},
author = {Jasim, N and Shatnawi, E and Vasquez, FS and Ali, Y and Phillipson, L and Oliveira, D and Dao-Tran, TH and Steiner-Lim, GZ and Karamacoska, D},
title = {Validation of the Arabic Dementia Diagnosis Attitude Scale (A-DDAS).},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70262},
pmid = {41696646},
issn = {2352-8729},
abstract = {INTRODUCTION: Culturally appropriate scales are needed to efficiently assess stigma among Arabic-speaking communities. This study aimed to validate the Arabic version of the Dementia Diagnosis Attitude Scale (A-DDAS).

METHODS: The translated A-DDAS underwent pre-testing with native speakers in Australia. The final version of the scale was tested with Arabic-speaking adults aged ≥ 18 residing in Australia. The sample (N = 266) was randomly split such that one half (n = 133) underwent exploratory factor analysis and the other half (n = 133) underwent confirmatory factor analysis. Internal consistency reliability was assessed via Cronbach α.

RESULTS: The final 10-item scale consisted of two factors with five items each: "fear of labelling" (α = 0.88) and "fear of discrimination" (α = 0.85), with inter-factor correlation r = 0.51 and high reliability (α = 0.87).

DISCUSSION: The A-DDAS yielded good validity and reliability scores, confirming its suitability for use with Arabic-speaking Australians in stigma studies, educational interventions, and clinical settings.},
}

@article {pmid41696319,
year = {2026},
author = {Sánchez-Mendoza, AV and Vázquez-García, RA and Castaño, V and Torres-Ramos, MA and Juárez-Solano, AH and Camarillo-López, RH and Rosales-Hernández, MC},
title = {Design and Evaluation of Quinoline-derived Fluorophores for Labeling Amyloid Beta 1-42 in Alzheimer's Disease.},
journal = {ACS omega},
volume = {11},
number = {5},
pages = {7343-7358},
pmid = {41696319},
issn = {2470-1343},
abstract = {Amyloid beta (Aβ) is a key biomarker in Alzheimer's disease, driving the formation of senile plaques that contribute to neuronal death within a complex etiology. Typically, most treatments begin at advanced stages, when irreversible brain atrophy has already occurred; therefore, early diagnosis is essential for effective intervention. Several probes based on the conventional donor-π-acceptor (D-π-A) structural motif have been developed as diagnostic tools, yet few have reached clinical trials. Alternatively, quinoline-based fluorescent compounds with push-pull structures and aggregation-induced emission properties show enhanced fluorescence in the aggregated state due to restricted intramolecular motion (RIM). Accordingly, four quinoline derivatives(?)2QnCN, 3QnCN, 3QnB, and 4QnBB(?)were synthesized using standard methods, including benzoxazole segments and a cyano (-CN) group. They were chemically and optically characterized, and their photophysical properties were calculated. Theoretical analyses include band gap estimation and visualization of intramolecular charge transfer. Molecular docking was also performed to assess binding with the Aβ1-42 pentamer (PDB: 2BEG), identifying 3QnCN as the most promising candidate with a binding energy of-11.9 kcal/mol. Cytotoxicity was tested using the MTT assay to determine the optimal working concentration. The fluorescence intensity of 3QnCN in PC12 cells was quantified, and confocal microscopy confirmed its effectiveness in labeling Aβ1-42.},
}

@article {pmid41696300,
year = {2026},
author = {Bajaj, S and Mahesh, R},
title = {Galantamine-Escitalopram Combination Therapy in Alzheimer's Comorbid Depression Model in Mice: Role of BDNF/KYN Pathways, Neuroinflammation, and Oxidative Stress.},
journal = {ACS omega},
volume = {11},
number = {5},
pages = {7396-7414},
pmid = {41696300},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia, accounting for more than two-thirds of cases in older adults. AD is associated with neuropsychiatric symptoms such as depression, anxiety, and sleep disturbances. The coexistence of AD with depression, in particular, poses serious challenges and often results in suboptimal outcomes with conventional therapies. The present study therefore aimed to investigate the therapeutic potential of escitalopram (ESC; SSRI) in combination with galantamine (GAL; AChE inhibitor) on key pathological pathways, including the neurotrophic system, hypothalamic-pituitary-adrenal (HPA) axis, kynurenine pathway, inflammation, and oxidative stress, in an animal model of AD comorbid with depression. Swiss albino mice were subjected to chronic mild stress (CMS) for 21 days and received intrahippocampal administration of amyloid-β peptide to mimic AD-depression comorbidity. Subsequently, ESC (10 mg/kg) combined with GAL (5 mg/kg) was administered orally for 20 days alongside the CMS protocol, followed by behavioral, biochemical, and histopathological assessments. The combined GAL + ESC treatment significantly alleviated depressive symptoms and improved working and spatial memory in CMS and amyloid-β-exposed mice. Furthermore, the therapy normalized hippocampal levels of BDNF, proinflammatory cytokines (IL-6, TNF-α), kynurenine metabolites (3-HK, QUIN), and oxidative stress markers toward those observed in the sham group. Histopathological analysis further confirmed the preservation of hippocampal integrity with combined therapy. Overall, the findings highlight the potential of ESC as an adjunct to GAL in ameliorating depressive symptoms and cognitive deficits, underscoring its promise for further clinical evaluation in the management of AD comorbid with depression.},
}

@article {pmid41696228,
year = {2026},
author = {de Araújo, AB and S Azul, FVC and Carneiro, YC and de Sousa, CNS and de Vasconcelos, SMM and Rios, FJ and Leal, LKAM},
title = {Neuroinflammation and Oxidative Stress in Parkinson's Disease, Alzheimer's Disease, and COVID-19: Microglia-Neutrophil Interaction.},
journal = {ACS omega},
volume = {11},
number = {5},
pages = {6922-6938},
pmid = {41696228},
issn = {2470-1343},
abstract = {Abnormal activation of the immune system and oxidative stress are crucial factors in neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease. Microglia, neutrophils, oxidative stress mediators such as reactive oxygen species (ROS), lipid peroxidation products (e.g., malondialdehyde), and nitrosative stress markers (e.g., nitrite and nitrate) play important roles in neuroinflammatory mechanisms. Microglial cells acquire a proinflammatory phenotype through interactions with endogenous or exogenous compounds, including cell debris, abnormally modified proteins (including Aβ species and alpha-synuclein), and pathogens (e.g., SARS-CoV-2). They produce many inflammatory mediators and promote the activation of adjacent brain cells and leukocyte infiltration, including polymorphonuclear neutrophils. Accumulation of neutrophils in the central nervous system (CNS) leads to the secretion of more proinflammatory mediators, such as cytokines, proteases, and oxidants, and the formation of neutrophil extracellular traps (NETs). These processes are associated with the pathological activation of microglial cells, cell death, consequent influence on neuronal functions, or even neuronal death, which is a hallmark of CNS disorders. In this review, we address the importance of inflammatory mechanisms and oxidative stress in the CNS associated with Parkinson's disease, Alzheimer's disease, and the neuronal effects observed in coronavirus disease 2019 (COVID-19), as observed by the abnormal activation of central and peripheral immune cells, such as microglia and neutrophils. We also discuss emerging evidence linking SARS-CoV-2 infection to neuroinflammatory mechanisms that could contribute to neurodegenerative complications.},
}

@article {pmid41696149,
year = {2026},
author = {Fang, W and Zhao, J and Li, L and Wang, Y and Xu, ZP and Zhang, L},
title = {An anti-inflammatory neuroenhancer mitigates amyloid-β pathology to improve Alzheimer's disease therapy.},
journal = {Materials today. Bio},
volume = {37},
number = {},
pages = {102874},
pmid = {41696149},
issn = {2590-0064},
abstract = {β-amyloid (Aβ) inhibition significantly attenuates the early-stage Alzheimer's disease (AD) progression, but the improvement in cognitive function remains limited by neuroinflammation. Here, we developed a bioinspired neuroenhancer that concurrently targets both Aβ aggregation and neuroinflammation. Rutin and small interfering RNA targeting beta-site amyloid precursor protein cleaving enzyme 1 (siBACE1) were co-loaded into the calcium phosphate core, which was further coated with lipid bilayers and Angiopep-2/rabies virus glycoprotein 29 peptides to form the multifunctional neuroenhancer (RB@LCP-AR). RB@LCP-AR not only releases siBACE1 to silence BACE1 expression and block Aβ production from the cleavage of amyloid precursor protein, but also releases Rutin to suppress the Aβ aggregation. Moreover, the released Rutin of RB@LCP-AR directly alleviates Aβ-induced mitochondria dysfunction and intracellular ROS production in neuronal cells. Notably, the targeting of RB@LCP-AR to neurons and the inhibition of Aβ reduce the microgliosis and astrogliosis, further alleviating neuroinflammation and synapse loss. Consequently, AD mice receiving RB@LCP-AR treatment efficiently recovered their memory and cognition. Our study thus provides a coordinated targeting of Aβ and neuroinflammation inhibition, holding considerable potential to promote the recovery of memory and cognition in AD.},
}

@article {pmid41696081,
year = {2026},
author = {Muhammad Saqib, S and A Alkhattabi, M and Khan, MA and Mazhar, T and Iqbal, M and Saudagar, AKJ and Tariq Paracha, W and Hamam, H},
title = {Explainable bidirectional encoder representations from image transformers for Alzheimer's disease prediction.},
journal = {Digital health},
volume = {12},
number = {},
pages = {20552076261416823},
pmid = {41696081},
issn = {2055-2076},
abstract = {BACKGROUND: People who have Alzheimer's disease (AD) experience a progressive decline in their neurological function, which leads to mental deterioration and diminished memory abilities, and altered behaviors that affect both patients and their care providers severely. Diagnosis of the disease at an early stage and with precision helps ensure appropriate intervention strategies.

OBJECTIVES: Modern artificial intelligence (AI) technology is promising in medical use for imaging and diagnostic work, specifically involving AD detection and classification. This study aims to develop and evaluate an explainable transformer-based framework that leverages Bidirectional-Encoder representations from Image Transformers (BEiT) to automatically classify AD stages from magnetic resonance imaging (MRI) brain scans.

METHOD: The proposed framework employs BEiT as a feature extractor on a dataset of 8511 MRI brain images categorized into three diagnostic groups (mild, moderate, and no impairment). Class imbalance is addressed through a Wasserstein generative adversarial network with gradient penalty-based oversampling strategy that generates synthetic MRI images for minority classes, and these images are combined with the original scans to form a balanced training set.

RESULTS: The experiments showed outstanding accuracy levels reaching 96%, while the F1-scores indicated 0.94, 1.00, and 0.95 for mild, moderate, and no AD group classifications. Performance evaluation metrics from the study demonstrate strong outcomes with a mean absolute error reaching 0.0727 and Cohen's kappa equaling 0.9451, while Matthews correlation coefficient reached 0.9455 and Hamming loss remained at 0.0365.},
}

@article {pmid41695973,
year = {2026},
author = {Zhang, Q and Ma, L and Zhao, L and Zhu, S and Qi, H and Pan, Z and Zhou, J},
title = {Network analysis of optimal deep or machine learning strategies for classification and detection of Alzheimer's disease based on MRI scanning.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1644480},
pmid = {41695973},
issn = {1662-4548},
abstract = {BACKGROUND: Alzheimer's disease (AD) presents a significant global health challenge, with its prevalence projected to increase substantially by 2050. Despite its widespread impact, the underlying causes and mechanisms remain incompletely understood, complicating efforts toward effective diagnosis and treatment. Pathologically, AD is marked by the accumulation of senile plaques and neurofibrillary tangles, but the relationship between these factors and disease progression is complex and heterogeneous.

OBJECTIVE: The present study aimed to compare the efficacy of different deep/machine learning models based on MRI scanning.

METHODS: The study follows rigorous systematic review protocols, adhering to the Cochrane Handbook of Systematic Reviews and Interventions and the PRISMA guidelines. A comprehensive search strategy was employed across multiple databases, including PubMed, Web of Science, Cochrane, Medline, and EMBASE. Advanced statistical methods were used for data synthesis and analysis, incorporating network meta-analysis and machine learning techniques to evaluate the accuracy and efficacy of different diagnostic models.

RESULTS: The meta-analysis included 11 studies that met the predefined inclusion criteria. The studies employed various machine learning algorithms, including CNN, ResNet, and DenseNet, to classify AD and distinguish it from mild cognitive impairment (MCI) and healthy controls. The results indicate that CNN and ResNet consistently outperform other models in terms of classification accuracy. Additionally, the integration of nanotechnology and AI-driven diagnostics demonstrates significant potential in enhancing the diagnostic process.

CONCLUSION: Despite challenges such as data heterogeneity and the interpretability of AI-driven models, the study highlights the transformative potential of computational techniques and advanced imaging technologies in AD diagnosis and management. The integration of network-based analyses and machine learning approaches offers promising avenues for future research, aiming to revolutionize the understanding and approach to Alzheimer's disease.},
}

@article {pmid41695753,
year = {2026},
author = {Salvadores, N},
title = {Biomedical research in Alzheimer's disease in a Latin American developing country: challenges in the informed consent process.},
journal = {Brain communications},
volume = {8},
number = {1},
pages = {fcag011},
pmid = {41695753},
issn = {2632-1297},
abstract = {Alzheimer's disease (AD) is a significant global health issue, impacting 50 million individuals with dementia worldwide, a number projected to triple by 2050. Although research has been conducted for decades, there is no effective prevention, treatment, or early diagnostic method for AD. Research on AD in Latin America (LatAm) faces unique challenges compared to developed countries due to socioeconomic, cultural, and infrastructural factors. While the prevalence of dementia is rapidly increasing in LatAm due to demographic shifts, the region is underrepresented in research, diagnostics and care. The informed consent process, a critical aspect of research, becomes particularly complex with individuals who have cognitive impairments. It requires a balance between protecting vulnerable individuals and advancing research for their benefit. By developing and implementing best practices, ethical research can be conducted with this population, ensuring they receive appropriate care. This review provides an update on informed consent for AD research in Chile.},
}

@article {pmid41695624,
year = {2026},
author = {Sun, Y and Liu, B and Tong, J and Shi, D and Zhu, X and Jiang, T and Yang, Y and Sun, X},
title = {Analysis of comorbid characteristics, molecular mechanisms between mild cognitive impairment and Alzheimer's disease with interventions in a community-based population in Shanghai.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1765285},
pmid = {41695624},
issn = {1664-2295},
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a critical early stage of Alzheimer's disease (AD). Elucidating the comorbidity characteristics, influencing factors, and molecular mechanisms between MCI and AD in community-based populations is crucial for early intervention in cognitive impairment.

METHODS: 2,234 elderly individuals aged 50 years or older from 14 communities in Pudong New District, Shanghai, were enrolled in this study. The Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR) were used to divide individuals into a control group (n = 1,160) and an MCI group (n = 1,074). The associations of demographic characteristics, lifestyle, and psychological status with MCI were analyzed. Transcriptome data from GSE140829 (training set) and GSE63060 (validation set) were obtained from the GEO database. Weighted gene co-expression network analysis (WGCNA) was used to identify MCI signature genes. KEGG pathway analysis was combined with the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway to elucidate mechanisms of comorbidity. Targeted intervention agents were screened based on the DSigDB database. Molecular docking (MD) was used to evaluate the binding ability between small molecules and target proteins.

RESULTS: The prevalence of AD in the MCI group (30.17%) was significantly higher than that in the control group (p < 0.001), and MCI and AD were significantly positively correlated. Age, gender, smoking, living arrangements, mobile phone use, pet ownership, stress, anxiety, and depression were key influencing factors for MCI (p < 0.05). The proportion of individuals living with children and grandchildren (57.45%) in the MCI group was significantly higher than that in the control group (16.29%) (p < 0.001). WGCNA identified 273 MCI signature genes. KEGG pathway analysis showed that these genes were significantly enriched in neurodegenerative disease pathways, including AD pathways (with the AD pathway ranking first in the "Human Diseases" category). Targeted intervention screening identified the natural compounds boldine (comprehensive score 961.58) and piceatannol (comprehensive score 358.46) as potential drug candidates (p < 0.05), both of which have strong binding ability to target proteins.

CONCLUSION: MCI patients in the community are at high risk of AD, and their comorbidity characteristics are affected by multidimensional lifestyle and psychological factors. Boldine and piceatannol may be potential natural compounds for the intervention of cognitive impairment. The results of this study can provide a theoretical basis for the early prevention and precise intervention of cognitive impairment in the community.},
}

@article {pmid41695614,
year = {2026},
author = {Kara, B and Kelly, IM and Beck, JS and Kuhn, N and Mufson, EJ and Vega, IE and Kanaan, NM and Counts, SE},
title = {Pretangle tau pathology accrual in the default mode network during the progression of Alzheimer's disease.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {13},
pmid = {41695614},
issn = {3059-4944},
abstract = {UNLABELLED: Alzheimer's disease (AD) is a secondary tauopathy characterized by the accumulation of aggregated amyloid-beta (Aβ) peptides as extracellular neuritic and diffuse plaques, alongside hyperphosphorylated tau aggregates forming intracellular neurofibrillary tangles (NFTs). Although NFT pathology is strongly linked to neurodegeneration and cognitive decline in AD, growing evidence suggests that soluble "pretangle" aggregates of tau, formed prior to NFT development, are the primary neurotoxic species driving disease progression and cognitive impairment. We quantified pretangle tau moieties in postmortem tissues of the default mode network (DMN), a resting state connectome that mediates episodic memory and falters early in AD, to determine the association between DMN tau pathology and antemortem cognitive status. To accomplish this, we assayed postmortem fixed and frozen tissue from frontal cortex (FC), posterior cingulate cortex (PCC), and precuneus (PreC) DMN hubs obtained from participants of the Rush Religious Orders Study (RROS). Immunohistochemical and biochemical quantification was performed using site-specific tau antibodies recognizing pathological pretangle epitopes pS422 (phosphorylation at tau residue serine 422), TOC1 (tau oligomers), and TNT2 (N-terminal tau misfolding), as well as the mid-stage NFT marker TauC3 (C-terminal tau truncation). Pretangle tau profiles included neuropil threads and neuronal inclusions as early as Braak stage III, with significant increases from Braak stage IV to V across the DMN hubs. There was a step-wise increase in the pretangle markers in subjects who died with no cognitive impairment (NCI) to mild cognitive impairment (MCI) to AD. The increase in pretangle tau pathology accrual correlated with poorer antemortem neuropsychological tests, including episodic memory, semantic memory, and a global cognitive z score calculated for each RROS participant. Pretangle tau accrual also correlated with postmortem neuropathological diagnostic measures of AD severity. In addition, we found that the PCC displayed greater tau pathology compared to the PreC, suggesting selective vulnerability within DMN hubs. Collectively, our findings are a first of its kind cellular and protein quantitative analysis to demonstrate neurotoxic pre-tangle tau accumulation within the DMN connectome that highly correlated with cognitive decline in MCI and AD, underscoring pretangle tau as a potential early driver of disease progression and a target for therapeutic intervention.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s44477-026-00019-y.},
}

@article {pmid41695579,
year = {2026},
author = {Fu, Y and Pan, Q and van Dijl, JM},
title = {Fimbriae potentiate Aggregatibacter actinomycetemcomitans for periodontal disease.},
journal = {Current research in microbial sciences},
volume = {10},
number = {},
pages = {100566},
pmid = {41695579},
issn = {2666-5174},
abstract = {Aggregatibacter actinomycetemcomitans is a major contributor to aggressive periodontitis and has been increasingly implicated in systemic conditions, such as rheumatoid arthritis and Alzheimer's disease. Among its diverse virulence mechanisms, fimbriae have emerged as central factors driving colonization, immune evasion, and pathogenicity. This review highlights recent findings showing that fimbriae not only facilitate adhesion and biofilm formation, but also contribute to maintaining bacterial cell envelope integrity. The transition from rough (fimbriated) to smooth (non-fimbriated) colony phenotypes upon in vitro culturing is associated with significant changes in virulence, including increased release of outer membrane vesicles (OMVs) and extracellular cytoplasmic proteins (ECPs). These changes suggest a trade-off between surface structure expression and secretion-based virulence. Importantly, fimbriae-rich strains are clinically relevant and more virulent in host models. The combined evidence implies that fimbriae and key virulence factors, such as leukotoxin A, act cooperatively in pathogenesis, as fimbriae-mediated adhesion and persistence will enhance local toxin delivery, killing of immune cells and immune evasion. Together, these insights point to fimbriae as key targets for novel therapeutic and vaccination strategies aimed at controlling periodontal and related systemic diseases.},
}

@article {pmid41695490,
year = {2026},
author = {Lai, R and Shie, F and Chung, R and Hsu, PW and Chen, Y and Lam, K and Juang, J},
title = {Why 11β-HSD1 inhibitors show variable efficacy in Alzheimer's therapy: an APOE4-dependent HSD11B1 mechanism.},
journal = {Theranostics},
volume = {16},
number = {8},
pages = {4113-4127},
pmid = {41695490},
issn = {1838-7640},
mesh = {*11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors/genetics/metabolism ; Humans ; *Alzheimer Disease/drug therapy/genetics/pathology/metabolism ; *Apolipoprotein E4/metabolism/genetics ; Animals ; Mice ; Hydrocortisone/blood/metabolism ; Male ; Female ; Brain/pathology/metabolism ; Aged ; },
abstract = {Rationale: Clinical trials for Alzheimer's disease (AD) often yield inconsistent results despite promising preclinical findings. Inhibition of 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1), a cortisone reductase, has demonstrated neuroprotective effects in preclinical models. However, clinical outcomes have varied. A potential explanation is the limited representation of apolipoprotein E ε4 (APOE4) carriers in preclinical studies, despite evidence that APOE4 alters stress responses and glucocorticoid regulation. We hypothesized that APOE4 status modulates the efficacy of HSD11B1 inhibition by influencing cortisol metabolism and AD pathology. Methods: We conducted a genetic association study to test whether HSD11B1 variants are linked to plasma cortisol levels, brain atrophy, and AD risk, stratified by APOE4 status. Postmortem human brain tissues and wild-type mice were analyzed for HSD11B1 expression, with emphasis on the entorhinal cortex (EC). Neuroimaging data were examined to assess correlations between cortisol levels and brain volume. In cell models, recombinant APOE4 protein was tested for regulation of HSD11B1 expression via the transcription factor C/EBPβ and its effect on neuronal cortisol production. Results: We identified a functional HSD11B1 variant associated with elevated cortisol, increased AD risk, and accelerated EC atrophy, specifically in APOE4 carriers. HSD11B1 was significantly upregulated in the EC of APOE4-positive brains. Mechanistic studies demonstrated that APOE4, but not APOE3, upregulates HSD11B1 via C/EBPβ, thereby increasing neuronal cortisol. Conclusions: These findings explain the inconsistent efficacy of 11β-HSD1 inhibitors in AD patients by revealing an APOE4-dependent activation of HSD11B1 that promotes early EC pathology. They also support genotype-guided therapeutic strategies targeting local cortisol metabolism.},
}

*11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors/genetics/metabolism
Humans
*Alzheimer Disease/drug therapy/genetics/pathology/metabolism
*Apolipoprotein E4/metabolism/genetics
Animals
Mice
Hydrocortisone/blood/metabolism
Male
Female
Brain/pathology/metabolism
Aged

@article {pmid41695418,
year = {2026},
author = {Zareen, W and Ahmed, N and Tokali, FS and Islam, T and Al-Rashida, M and Senol, AM and Ulucay, O and Tawfeek, AM and Taslimi, P and Shafiq, Z and Islam, MS},
title = {Synthesis, multi-target evaluation and DFT analysis of 6-hydroxychromone derived hydrazones with carbonic anhydrase I-II/acetylcholinesterase inhibition and antioxidant activity.},
journal = {RSC advances},
volume = {16},
number = {10},
pages = {8807-8827},
pmid = {41695418},
issn = {2046-2069},
abstract = {Alzheimer's disease seems to be the result of several tumultuous processes such as cholinergic deficits associated with the abnormal metabolic status and oxidative stress that cannot be controlled effectively by single-target molecules. A complex group of agents capable of combining specific enzyme inhibition with antioxidant protection may be seen as an approach toward neuroprotection. The partial synthesis method led to the creation of a new series of chromone hydrazones (3a-p) from substituted hydrazones and 6-hydroxy-chromone. All the newly obtained hydrazones were assayed for their inhibitory activity against acetylcholinesterase (AchE) and human carbonic anhydrases (CA I and II), and their antioxidant potentials were also studied. The chromone-substituted hydrazones 3c, 3e, and 3f exhibited good inhibitory activity against AChE with IC50 values of 0.82 µM, 0.20 µM, and 1.11 µM, respectively. Compound 3e was found to be highly selective for AChE and about six hundred fold more potent as compared to the standard inhibitor, tacrine. Also, these novel chromone derivatives were tested against CA I and II isoenzymes and exhibited IC50 values within the range of 3.16 µM-19.28 µM against CA I and 1.21 µM-14.90 µM against CA II. In addition, in vitro antioxidant assays revealed that compounds 3c, 3e, and 3m exhibited notable radical-scavenging activity, with compound 3e showing superior antioxidant performance (IC50 = 4.17 µg mL[-1] for DPPH and 2.46 µg mL[-1] for ABTS) compared to the reference standard trolox. Furthermore, cytotoxicity studies on HUVEC cells demonstrated that compounds 3c, 3e, and 3m exhibited IC50 values ranging from 52.36 to 60.84 µM. Molecular docking studies described the nature of binding affinities between the synthesized compounds and enzyme targets. DFT-based FMO, MEP, and reactivity analyses demonstrated that the chromone-hydrazone derivatives exhibit narrow HOMO-LUMO gaps and well-defined electrostatic surfaces, supporting their suitability for efficient charge transfer and biological interaction. Moreover, computational simulations and ADME analysis proved that all of the synthesized molecules were druggable with good inhibitory potential.},
}

@article {pmid41695272,
year = {2026},
author = {Xiang, F and Liu, X and Chen, G},
title = {Dynamic trends, spatial clustering, and multi-model projections of the global burden of Alzheimer's disease and other dementias: an analysis of GBD 1990-2021 data to 2050.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1661370},
pmid = {41695272},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease and other dementias (ADOD) are a leading causes of disability and mortality among older adults worldwide. While the rising burden is recognized, comprehensive analyses of its dynamic growth rates, spatial clustering patterns, and comparative long-term forecasts remain limited, hindering targeted policy response.

METHODS: Using data from the Global Burden of Disease (GBD) 2021 study for individuals aged ≥60 years across 204 countries (1990-2021), we analyzed six burden indicators. We calculated age-standardized rates (ASR) and estimated annual percentage changes (EAPC) to quantify trends. Spatial clustering of EAPC patterns was performed using hierarchical clustering. Future burden to 2050 was projected using both exponential smoothing (ES) and autoregressive integrated moving average (ARIMA) models, with comparative analysis across sex, age, and Socio-demographic Index (SDI).

RESULTS: From 1990 to 2021, global ADOD burden increased markedly in absolute terms. EAPC analysis revealed accelerated annual growth (>1%) in East Asia and Eastern Europe, surpassing the global average. Spatial clustering identified four distinct geographic archetypes, with rapid-growth clusters spanning middle-income regions in Latin America and Southeast Asia. Women and adults aged ≥80 years, especially those ≥95, bore a disproportionately high and increasing burden. Both ES and ARIMA models projected a continued rise in absolute burden to 2050, forecasting a near-doubling of the disease burden (DALYs) among women.

CONCLUSION: The global ADOD burden is escalating with pronounced dynamic heterogeneity in growth velocity and distinct spatial patterns. Our multi-model projections warn of a mounting crisis, disproportionately impacting women, the oldest-old, and rapidly aging middle-income regions. Public health strategies must evolve from static assessments to dynamic surveillance and geographically tailored interventions, with urgent investment in prevention and care systems in high-growth clusters.},
}

@article {pmid41694909,
year = {2026},
author = {Altuna, M and Rodríguez, E and Núñez, M and Trueba-Saiz, Á and Lizan, L and Díaz-Cerezo, S},
title = {A Systematic Literature Review of the Epidemiological, Diagnostic Workup, Humanistic, and Economic Burden of Alzheimer's Disease in Spain.},
journal = {Cureus},
volume = {18},
number = {1},
pages = {e101581},
pmid = {41694909},
issn = {2168-8184},
abstract = {INTRODUCTION: Alzheimer's disease (AD), the leading cause of dementia, affects over 700,000 individuals in Spain, with prevalence expected to rise due to population aging and improved diagnostic accuracy. Around 40,000 new cases are diagnosed annually, yet early-stage AD dementia remains underdiagnosed, limiting understanding of its full epidemiological, clinical, humanistic, and economic burden in Spain.

METHODS: A systematic literature review (SLR) was conducted on the burden of AD dementia in Spain, focusing on observational studies published from January 2019 to January 2024. Searches were performed in PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE), Medicina en Español (MEDES), and Índice Bibliográfico Español en Ciencias de la Salud (IBECS), following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

RESULTS: Twenty-six publications were included, mainly addressing moderate-to-severe AD dementia, with limited evidence on mild cognitive impairment (MCI) due to AD. Commonly used tools included the Mini-Mental State Examination (MMSE), Barthel Index, and Global Deterioration Scale (GDS). Neurologists were the primary clinicians involved in diagnosis (78.6%), though etiological diagnosis often lacked core AD biomarkers. Most caregivers were informal (mainly women), experiencing significant declines in health-related quality of life (HRQoL). Non-healthcare costs accounted for 84.6%-90.7% of total expenditures, followed by direct healthcare (6.1%-10.0%) and social care costs (2.8%-4.6%). Indirect costs, mostly from reduced working hours, represented 0.5%-0.8%.

CONCLUSIONS: This study highlights the need to improve early diagnosis of AD dementia and to establish reliable health registries to measure its burden. The lack of evidence on practice heterogeneity hinders standardized care strategies. Addressing these gaps is essential to improve patient management, ensure equitable access to timely and accurate diagnosis, and facilitate access to emerging disease-modifying treatments for AD dementia.},
}

@article {pmid41694525,
year = {2026},
author = {Jiang, X and Lv, G and Mendes, ME and Wu, J and Yuan, J and Lu, ZK},
title = {Lifetime cost-effectiveness of lecanemab for early Alzheimer's disease.},
journal = {Frontiers in public health},
volume = {14},
number = {},
pages = {1692508},
pmid = {41694525},
issn = {2296-2565},
mesh = {*Alzheimer Disease/drug therapy/economics ; Humans ; *Cost-Benefit Analysis ; *Antibodies, Monoclonal, Humanized/economics/therapeutic use ; Quality-Adjusted Life Years ; United States ; Markov Chains ; Aged ; Male ; Female ; },
abstract = {INTRODUCTION: Lecanemab is the second anti-amyloid-β monoclonal antibody to receive FDA approval for the treatment of early Alzheimer's disease (AD), following aducanumab. Unlike aducanumab, which faced restricted Medicare coverage, lecanemab received traditional approval in 2023, resulting in broader access through Medicare. Despite these developments, the comparative cost-effectiveness of lecanemab and aducanumab has not been fully established. This study aimed to assess whether lecanemab is more cost-effective than aducanumab in the management of early AD.

METHODS: An indirect comparison of cost-effectiveness was performed due to the absence of head-to-head randomized controlled trials. A five-state Markov model was constructed from the perspective of the US healthcare system with a lifetime horizon and a 1-year cycle length. Model outcomes included life-years (LYs), quality-adjusted life-years (QALYs), and costs, all discounted at an annual rate of 3%. Incremental cost-effectiveness ratios (ICERs) were calculated and compared with established willingness-to-pay (WTP) thresholds. One-way sensitivity analyses identified key drivers of model uncertainty, and a probabilistic sensitivity analysis (PSA) with 1,000 Monte Carlo simulations tested the robustness of the findings.

RESULTS: The incremental cost of the lecanemab group compared to the aducanumab group was $30,018.97, with an increase in quality-adjusted life-years (QALYs) of 0.25, resulting in an ICER of $121,678.49 per QALY gained. The result of the one-way sensitivity analysis showed that the utility of the state of mild dementia due to AD had the most important effects on the ICER of the lecanemab group compared to the aducanumab group. The probabilistic sensitivity analysis showed that lecanemab was more cost-effective than aducanumab across various WTP thresholds.

CONCLUSION: Our findings suggest that lecanemab provides greater value than aducanumab; however, at current list prices, neither drug is cost-effective compared with the standard of care. Price reductions are necessary to improve affordability, particularly for lecanemab, which is more widely covered by Medicare. Policy implications remain significant, as under the Inflation Reduction Act (IRA), biologics such as lecanemab are exempt from Medicare price negotiations for 13 years post-approval, limiting short-term opportunities for cost adjustment.},
}

*Alzheimer Disease/drug therapy/economics
Humans
*Cost-Benefit Analysis
*Antibodies, Monoclonal, Humanized/economics/therapeutic use
Quality-Adjusted Life Years
United States
Markov Chains
Aged
Male
Female

@article {pmid41694459,
year = {2025},
author = {Liu, S and Wu, G and Ma, X and Xu, K and Lan, X and Wang, L and Li, H and Gu, D and Wang, M and Liu, J},
title = {Trends and cross-country inequalities in the global burden of Alzheimer's disease and other dementias among adults aged 65+ years, 1990-2021: a population based study with projections into 2050.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1683158},
pmid = {41694459},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease and other dementias (ADOD) pose a significant global health challenge, with projected annual increases. The growing elderly population exacerbates burdens, underscoring the need for interventions.

METHODS: Using data from the Global Burden of Disease Study 2021, we analysed global ADOD trends from 1990 to 2021 among adults aged 65+ and projected to 2050. Average annual percentage change (AAPC) in the age-standardised prevalence, mortality and disability-adjusted life years (DALYs) rates of ADOD were calculated to quantify the temporal trends.

RESULTS: Globally, the number of adults aged 65 years or older living with ADOD increased from 18.1 (95% uncertainty interval [UI] 14.4-22.5) million in 1990 to 49.1 (38.7-61.3) million in 2021 (AAPC 0.09%). While mortality rates remained relatively stable (AAPC 0%), DALYs increased by 176% (AAPC 0.02%). Females consistently exhibited a higher age-standardised prevalence (7,603 [95% UI 6,023-9,469] cases per 100,000 population) vs. 5,744 [4,486-7,205]) and mortality (304 [78 to 782] vs. 225 [54-626]) rate compared to males, with notable regional variations. From 1990 to 2021, the age-standardised prevalence of ADOD increased only in East Asia and High-income Asia Pacific (AAPC 0.79% and 0.16%). High fasting plasma glucose, high body-mass index, and smoking were identified as primary risk factors. Projections indicate a 50.1% increase in age-standardised prevalence by 2050, with an estimated 191 (52-330) million cases, and a predicted death toll of 6.8 (2.4-11.3) million.

CONCLUSION: The global number of people living with dementia nearly tripled from 1990 to 2021, mainly due to increases in population ageing and growth. The findings emphasize the need for comprehensive strategies to address ADOD, including prevention, early diagnosis, and effective management, with a focus on gender and regional disparities.},
}

@article {pmid41694229,
year = {2026},
author = {Kushnir, CN and Taylor-Bateman, V and Davies, NM and Anderson, EL},
title = {Assessing the repurposing potential of disease-modifying antirheumatic drug targets to reduce Alzheimer's disease risk: a Mendelian randomization study.},
journal = {Brain, behavior, & immunity - health},
volume = {52},
number = {},
pages = {101185},
pmid = {41694229},
issn = {2666-3546},
abstract = {BACKGROUND: Systemic inflammation plays a key role in the development and progression of Alzheimer's disease (AD). However, the repurposing potential of select anti-inflammatory drug targets for AD treatment remains unclear.

METHODS: Two-sample Mendelian randomization (MR) and colocalization analyses were conducted to estimate the effects of select disease-modifying antirheumatic (DMARD) targets on AD risk. We investigated 9 DMARD targets, using blood protein quantitative trait loci (pQTLs) from the UK Biobank Pharma Proteomics Project (n = 54,219). Outcome associations were extracted from the International Genomics of Alzheimer's Project (ncases = 21,982, ncontrols = 41,944).

RESULTS: Our MR estimates suggest that higher levels of FCGR3B, an etanercept target, increased the risk of AD (OR: 1.10; 95% CI [1.02, 1.19]; p = 0.01). We found little evidence that the remaining DMARD targets affected AD risk. Colocalization analysis provided little evidence that target pQTLs, including FCGR3B, colocalized with AD.

CONCLUSIONS: Our findings suggest a causal effect of FCGR3B on AD risk, but not for the remainder of the analyzed DMARD targets. Further research is recommended to elucidate the causal role of FCGR3B in AD and build upon the current literature on viable AD therapeutic targets.},
}

@article {pmid41693955,
year = {2026},
author = {Fang, L and Zhuang, Y and Zhang, M and Yang, D and Zhang, R and Peng, J and Wang, C},
title = {Dietary and metabolic reprogramming alleviates neurodegeneration: a review of mechanisms and clinical implications.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1706597},
pmid = {41693955},
issn = {2296-861X},
abstract = {Neurodegenerative diseases, characterized by their insidious onset and progressive neuronal degeneration, present significant challenges in the fields of neuroscience and medicine. We elucidate the critical role of nutrition and cellular metabolism in the pathogenesis and progression of these disorders, with a particular focus on Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). We demonstrate that fundamental nutrients such as glucose, lipids, and amino acids are crucial for neuronal bioenergetics, oxidative stress mitigation, and neuroprotective functions. Furthermore, we emphasize the concept of metabolic reprogramming as a key driver in neurodegeneration; this process entails alterations in energy metabolism, mitochondrial dysfunctions, and shifts in nutrient utilization that exacerbate neuroinflammation and oxidative stress. We emphasize the potential advantages of nutritional strategies, especially those involving the Mediterranean dietary pattern, characterized by high antioxidant and omega-3 fatty acid content, to optimize cellular metabolic pathways and attenuate disease manifestations. However, clinical application of nutritional strategies faces several challenges including complexities surrounding nutrient mechanisms, patient adherence issues, and concerns regarding long-term efficacy. To address these obstacles, we advocate for personalized nutrition approaches that integrate metabolomics, genomics, and epigenetics to tailor interventions according to individual metabolic profiles. Additionally, emerging strategies such as probiotics along with synergistic combinations of nutrients and pharmaceuticals offer promising avenues for enhancing therapeutic outcomes. In conclusion, understanding the intricate interplay between nutrition and cellular metabolism is crucial for developing effective treatments for neurodegenerative diseases. Future research should prioritize mechanistic studies alongside precise assessment tools as well as high-quality clinical trials to validate the efficacy of these interventions.},
}

@article {pmid41693920,
year = {2026},
author = {Ebdah, W and Thomas, SD and Eissa, N and Jayaprakash, P and Łażewska, D and Kieć-Kononowicz, K and Sadek, B},
title = {Simultaneous inhibition of cholinesterase and antagonism of histamine H3 receptors alleviates cognitive deficits and mitigates apoptosis in scopolamine-induced amnesia in mice.},
journal = {Frontiers in behavioral neuroscience},
volume = {20},
number = {},
pages = {1722019},
pmid = {41693920},
issn = {1662-5153},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory deficits. Mounting evidence highlights the role of cholinergic and histaminergic neurotransmissions in the pathophysiology of AD. Hence, developing agents that target multiple neurotransmitter systems may provide improved therapeutic benefits.

METHODS: This study investigated the effects of acute systemic administration of E100, a dual-active cholinesterase inhibitor (ChEI) and histamine H3 receptor (H3R) antagonist, on scopolamine (SCO)-induced memory impairment in male C57BL/6 mice. Behavioral assessments, including the Novel Object Recognition Test (NORT), Y-Maze test (YMT), Three-Chamber Test (TCT), Fear Conditioning test (FCT), and Elevated Plus Maze (EPM), were conducted to assess cognitive performance while biochemical analyses assessed apoptotic markers, oxidative stress, neuroinflammation and acetylcholinesterase activity.

RESULTS: Systemic administration of E100 (10 mg/kg, i.p.) significantly improved memory function in SCO-induced amnesia, as evidenced by enhanced short-term memory (STM) (p < 0.001) and long-term memory (LTM) (p < 0.01) performance in the NORT, as well as improved spatial memory in YMT (p < 0.001) and FCT (p < 0.001; for cued fear memory) and (p < 0.001; for contextual fear memory). Additionally, E100 treatment in the TCT, improved social memory (p < 0.001) and alleviated SCO-induced anxiety-related deficits in the EPM (p < 0.001). Moreover, treatment with E100 (10 mg/kg, i.p.) attenuated SCO-induced neuroinflammation by reducing TNF-α and IL-1β levels and mitigated oxidative stress by increasing GSH and SOD while decreasing MDA levels in the hippocampus and cerebellum (p's < 0.001). E100 also reduced caspase-1 activity (p < 0.001), suggesting its anti-apoptotic effect. Furthermore, E100 attenuated the elevated AChE activity observed in SCO-induced amnesic mice (p < 0.01), providing effects comparable to those of the reference drug Donepezil.

DISCUSSION: These findings provide extensive in vivo evidence of the neuroprotective effects of E100, demonstrating its ability to ameliorate memory deficits, mitigate neuroinflammation and restore oxidative as well as AChE activity balance. By targeting both cholinergic and histaminergic dysfunction in the brain, E100 offers a promising therapeutic strategy for AD and related neurodegenerative disorders. This study highlights the potential role of dual-active ChEIs and H3R antagonists in memory impairment, and addressing multiple neuropathological mechanisms underlying AD.},
}

@article {pmid41693868,
year = {2025},
author = {do Nascimento, ACL and da Paz, EP and Freire, GRLB and Almendra, SCCGE and Almendra, MCCGE and de Lima, LFF and da Silva, LBR and Dos Santos, JFB and de Paiva, BA and Novaes, LESS and de Melo, MM and Sobral, AIGDP},
title = {Assessment of cognitive function in individuals with Down syndrome and dementia: a systematic review.},
journal = {Dementia & neuropsychologia},
volume = {19},
number = {Suppl 1},
pages = {e20250308},
pmid = {41693868},
issn = {1980-5764},
abstract = {UNLABELLED: Individuals with Down syndrome (DS) face a high risk of dementia, particularly Alzheimer's disease (AD). Early diagnosis is complex due to pre-existing cognitive deficits, underscoring the need for specific diagnostic criteria.

OBJECTIVE: To present cognitive and behavioral features of dementia in DS and examine cognitive assessment tools.

METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the databases United States National Library of Medicine (PubMed), Scopus, Web of Science, and Virtual Health Library (BVS) were searched for studies (2014-2024) in English, Portuguese, or Spanish. The quality of the included articles was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria.

RESULTS: Of 254 records screened, 28 studies met the inclusion criteria. Early dementia in DS presents with declines in executive functions, memory, language, attention, and behavioral changes. Behavioral symptoms, including agitation, hallucinations, and apathy, were prominent in AD-DS and prodromal dementia, and may serve as early indicators.

CONCLUSION: Early dementia in individuals with DS is characterized by cognitive and behavioral declines, with behavioral symptoms potentially serving as early diagnostic markers.},
}

@article {pmid41693755,
year = {2026},
author = {Zhai, T and Zhang, W and Ma, C and Ni, L and Paulus, YM and Su, EJ and Murphy, GG and Lawrence, DA and Wang, X},
title = {Multi-parametric longitudinal imaging of cerebral biomarkers in a rodent model of Alzheimer's disease.},
journal = {Photoacoustics},
volume = {48},
number = {},
pages = {100808},
pmid = {41693755},
issn = {2213-5979},
abstract = {This study introduces a method for longitudinally monitoring Alzheimer's disease (AD)-related biomarkers in a rodent model utilizing a dual-modality imaging system combining photoacoustic microscopy (PAM) and confocal fluorescence microscopy (CFM). Using a cranial window transparent to both light and ultrasound, we examined cerebral vasculature, blood flow speed, oxygen saturation (sO2), and amyloid-β (Aβ) deposition with single capillary resolution in genetically modified AD mice longitudinally over three months. Empowered by the high-resolution multimodal imaging, the analysis showed consistent changes of small vessel density decrease and Aβ deposition increase in AD mice compared to the control group. Meanwhile, a decrease in sO2 was observed in AD group near the end of the observation period, highlighting the potential importance of functional imaging of hemodynamics that PAM facilitates. This multimodal system, with its longitudinal imaging capability, could provide valuable insight into the temporal dynamics and interrelationships of multiple biomarkers in neurodegenerative diseases.},
}

@article {pmid41693715,
year = {2026},
author = {Jang, SI and Gomez, CL and Becker, A and Thibault, E and Price, JC and Johnson, KA and El Fakhri, G and Gong, K},
title = {A Cross-modality Transformer Network for MR-guided Low-dose Tau PET Image Denoising.},
journal = {IEEE transactions on radiation and plasma medical sciences},
volume = {10},
number = {2},
pages = {249-257},
pmid = {41693715},
issn = {2469-7311},
abstract = {Tau PET imaging is an essential imaging modality for the diagnosis and monitoring of Alzheimer's disease and related dementias. To enable tau PET imaging-based longitudinal monitoring of disease progression, further reducing the injected dose during each scan is important. In this work, we developed a novel deep learning approach that incorporated cross-modality transformer blocks to integrate both PET and MR prior information to further improve low-dose tau PET imaging. Both spatial and channel information were utilized during the calculation of cross-modality self-attention maps. Performance of the proposed method was evaluated based on the early-frame and late-frame images from 139 dynamic [18]F-MK-6240 tau PET datasets. Results showed that the proposed network can outperform other reference networks which concatenated PET and MR images together as the network input.},
}

@article {pmid41693543,
year = {2026},
author = {Tábuas-Pereira, M and Mano, F and Bernardes, C and Durães, J and Lima, M and DenHaan, K and Paquette, K and Kun-Rodrigues, C and Carmona, S and Tábuas, T and Faustino, P and Coelho, MR and Silva-Spínola, A and Duro, D and Almeida, MR and Malva, J and Baldeiras, I and Brás, J and Guerreiro, R and Santana, I},
title = {Maternal Longevity is Associated With Reduced Risk but an Earlier Onset of Alzheimer's Disease in Offspring.},
journal = {Journal of geriatric psychiatry and neurology},
volume = {},
number = {},
pages = {8919887261424534},
doi = {10.1177/08919887261424534},
pmid = {41693543},
issn = {1552-5708},
abstract = {IntroductionWhile human longevity has increased significantly over the last 2 centuries, the time spent in good physical and cognitive health has not risen proportionately. The incidence of Alzheimer's disease (AD) increases with age, but parental longevity is often associated with better offspring health and lower AD risk. This study aimed to investigate the relationship between parental longevity and AD.MethodsWe included patients with AD and cognitively healthy subjects (over 75 years), collecting family history data, namely maternal and paternal age at death. We performed a logistic regression to evaluate the association of parental longevity and AD risk and linear regression models for the association with age of onset and CSF biomarkers, adjusting for confounders.ResultsWe analyzed 3069 participants from a Portuguese cohort, including 893 AD patients and 2176 cognitively healthy controls. Maternal longevity was inversely associated with AD risk (OR: 0.989, 95%CI = [0.982, 0.997], P = 0.005). In AD patients, higher maternal age of death was associated with an earlier disease onset (β = -0.081, 95%CI = [-0.148, -0.013], P = 0.019). No associations were found between parental longevity and CSF biomarkers.DiscussionMaternal longevity appears protective against AD risk but is linked to an earlier onset in patients. This may indicate that protective factors for AD could become detrimental once AD is triggered. These findings highlight the complex interplay of genetic, environmental, and potentially epigenetic influences on AD.},
}

@article {pmid41693429,
year = {2026},
author = {Shabbir, U and McNulty, H and Hughes, C and Ward, M and Dooley, J and Hoey, L},
title = {B-vitamins, immune function and the ageing brain: A critical review of the evidence, mechanisms and potential role of the gut microbiome.},
journal = {The Proceedings of the Nutrition Society},
volume = {},
number = {},
pages = {1-33},
doi = {10.1017/S0029665126102249},
pmid = {41693429},
issn = {1475-2719},
abstract = {This review aims to explore the potential role of folate and related B-vitamins (B12, B6, and riboflavin) in maintaining cognitive health in ageing, focussing particularly on their interactions with the gut microbiota and inflammation. Low B-vitamin status, common in older adults, is associated with poorer cognitive function and dementia. Furthermore, people with dementia are observed to have increased abundance of pro-inflammatory microbes and concomitant higher concentrations of cytokines in their circulation. Therefore, gut dysbiosis and chronic inflammation have been proposed as contributors of cognitive dysfunction. Although many observational studies report that low B-vitamin status, especially vitamin B6, is associated with a worse inflammatory state, the role of the gut microbiota is much less investigated. Pre-clinical evidence suggests higher B-vitamin intakes may beneficially modulate the gut bacterial profile and its metabolic activity, positively influencing inflammation. The evidence however is inconsistent and the few human intervention studies available are confined to clinical populations, or are limited by small sample size or to a single B-vitamin at high supplementation doses. Of note, one study in rats with Alzheimer's type dementia reported an association of folate and vitamin B12 deficiency with disturbed gut bacterial composition, neuroinflammation and impaired memory. In conclusion, optimising B-vitamin status may help promote cognitive health during ageing through modulation of the gut microbiota and immune function. Well-designed human studies are however required to confirm these relationships and inform evidence-based nutritional strategies for healthy ageing.},
}

@article {pmid41693397,
year = {2026},
author = {Zhang, H and Li, W and Xiao, P and Lu, Z and Tian, Y and Xu, Y},
title = {The immune-metabolism interactome in efferocytosis: a new paradigm for the central nervous system diseases revealed by single-cell sequencing analysis.},
journal = {The Journal of pathology},
volume = {},
number = {},
pages = {},
doi = {10.1002/path.70031},
pmid = {41693397},
issn = {1096-9896},
support = {M1427//345 Talent Project of Shengjing Hospital of China Medical University/ ; 82271294//National Natural Science Foundation of China/ ; 82470923//National Natural Science Foundation of China/ ; },
abstract = {Efferocytosis is a process that maintains tissue homeostasis by removing apoptotic cells (ACs) by professional or non-professional phagocytes. The intricate process can be categorized into recognition of ACs, engulfment of ACs, and degradation of efferosomes. Aberrations in efferocytosis result in inadequate clearance of ACs, leading to prolonged inflammation that is implicated in the development and progression of various human diseases. Most central nervous system (CNS) diseases are associated with dysregulation of inflammatory homeostasis. Microglia, the resident immune cells of the CNS, play a primary role in efferocytosis in the brain, which is essential for maintaining the homeostasis of the internal environment. In this review, we summarize the current knowledge of the basic processes of efferocytosis and its indispensable role in the developing and aging brain. Additionally, we discuss the regulatory role of immune-metabolism crosstalk and the insights from single-cell sequencing analysis in dissecting microglial heterogeneity during efferocytosis. We also focus on recent discoveries regarding the critical role of efferocytosis in several CNS diseases, including cerebral ischemia, intracerebral hemorrhage, traumatic brain injury, major depressive disorder, glioblastoma multiforme, Alzheimer's disease, and Parkinson's disease. Finally, we outline potential therapeutic strategies and existing challenges, emphasizing the need for context-specific targeting to improve CNS disease outcomes. © 2026 The Pathological Society of Great Britain and Ireland.},
}

@article {pmid41693339,
year = {2026},
author = {Tanriverdi, İ and Bilgic, İ and Pasin, O and Oren, C and Irmak, HS and Smith, L and Hajek, A and Soysal, P},
title = {Alzheimer disease knowledge among gerontologists in Turkiye.},
journal = {Gerontology & geriatrics education},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/02701960.2026.2630669},
pmid = {41693339},
issn = {1545-3847},
abstract = {This study aimed to evaluate the level of knowledge about Alzheimer's disease (AD) among graduates of gerontology undergraduate programs in Turkiye and to identify factors associated with their knowledge levels. A cross-sectional study was conducted with 100 gerontology graduates recruited via alumni networks and professional platforms. Data were collected using an online survey including a demographic form and the Turkish version of the Alzheimer's Disease Knowledge Scale (ADKS-TR). Descriptive statistics, Mann-Whitney U, and Kruskal-Wallis tests were used to examine differences in AD knowledge scores across participant characteristics, with significance set at p < .05. The overall mean ADKS-TR score was 22.04 ± 3.44 (IQR:11-29), indicating a moderate level of knowledge. Female graduates scored significantly higher than males (p = .007). Employed participants and those who perceived themselves as knowledgeable also had higher scores (p < .001 and p = .017, respectively). No significant differences were observed based on age, time since graduation, prior AD-specific training, or personal/familial exposure to AD. Participants demonstrated the highest knowledge in the "Assessment and Diagnosis," "Life Impact," and "Symptoms" domains, while "Caregiving" scored lowest. The most common misconceptions concerned functional impairments, prevention strategies, and decision-making abilities, whereas general disease characteristics were correctly identified by most participants. Gerontology graduates in Turkiye possess moderate AD knowledge, with gender, employment status, and self-perceived competence as key correlates. Persistent gaps in practical caregiving and prevention highlight the need for continuous, practice-oriented, and targeted educational programs to improve professional competence in AD care.},
}

@article {pmid41693328,
year = {2026},
author = {Evans, M and Ritchie, C and Trepel, D and Hahn-Pedersen, JH and Kettle, J and Chan, MS and Bray, BD and Clark, A and Ivkovic, M and Wichmann, CA and Edwards, S},
title = {Estimating the Future Health and Social Care Costs of Alzheimer's Disease Dementia in the UK: Impact of Disease Modifying Therapy Efficacy, Uptake, and Care Model - A Scenario Modelling Study.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {2},
pages = {e70185},
doi = {10.1002/gps.70185},
pmid = {41693328},
issn = {1099-1166},
support = {//Novo Nordisk/ ; },
mesh = {Humans ; *Alzheimer Disease/economics/therapy/epidemiology ; United Kingdom/epidemiology ; *Health Care Costs/trends ; Aged ; Markov Chains ; Male ; Female ; Aged, 80 and over ; },
abstract = {BACKGROUND: To model scenarios exploring potential impacts of disease-modifying therapies (DMTs) for Alzheimer's disease (AD) dementia on future health and social care costs in the United Kingdom.

METHODS: A cohort Markov model was developed using population projections and published AD epidemiological data. Stage-specific transition rates (mild cognitive impairment due to AD and mild, moderate, severe AD dementia) and health and social care cost data were applied to estimate cost outcomes over 2020-2040. Potential proportion of eligible population receiving treatment (uptake) and follow-up care models (primary vs. specialist care) were elicited from expert opinion. Scenarios combined ranges of DMT efficacy estimates, uptake, and care model. DMT price was excluded due to no UK precedent.

RESULTS: Without DMT access, 1,038,405 people (1.5%) were projected to have AD dementia by 2040. Under the various DMT treatment scenarios, the prevalence of AD dementia by 2040 was projected to be 34,000-98,000 cases lower. Associated cumulative cost offsets were higher, £4.4-12.9billion over 2020-2040, in scenarios where most individuals received primary care follow-up, compared with majority specialist care follow-up (-£2.3billion to +£3.2billion). Assuming DMT efficacy of 25%, 58% uptake and majority primary care follow-up cumulative cost offsets increased from £4.4billion to £10.1billion by 2040 but the UK Health Service would need to diagnose and provide DMT for over a million individuals by 2030 and two million by 2040 to achieve this.

CONCLUSIONS: Potential cost offset from DMT are large but highly dependent on the model of healthcare delivery and the ability of healthcare systems to scale up diagnosis and treatment services.},
}

Humans
*Alzheimer Disease/economics/therapy/epidemiology
United Kingdom/epidemiology
*Health Care Costs/trends
Aged
Markov Chains
Male
Female
Aged, 80 and over

@article {pmid41693320,
year = {2026},
author = {Dey, C and Pratap Singh, P and Chakraborty, S},
title = {In-silico investigation of the molecular disruption of Aβ42 protofibril by stilbenoids.},
journal = {Journal of biomolecular structure & dynamics},
volume = {},
number = {},
pages = {1-27},
doi = {10.1080/07391102.2026.2621265},
pmid = {41693320},
issn = {1538-0254},
abstract = {Amyloid-β aggregation into protofibrillar and fibrillar assemblies is a central hallmark of Alzheimer's disease (AD), making disruption of A β42 protofibrils a promising therapeutic strategy. Here, we assessed the destabilization potential of five naturally occurring biphenolic stilbenoids - Resveratrol, Piceid, Astringin, Piceatannol, and Rhapontigenin - through an integrated in silico approach. Molecular docking, 500 ns all-atom molecular dynamics simulations, MM-PBSA binding free energy calculations, and structural analyses (RMSD, RMSF, radius of gyration, hydrogen-bond and salt-bridge dynamics, intersheet contacts, and principal component analysis) were employed to capture ligand-induced perturbations in fibril stability. Docking revealed preferential binding at β-sheet-forming hotspots (PHE19, PHE20, VAL36, GLY38) along the interchain interface. Among the studied compound, Rhapontigenin exhibited the most favorable binding free energy (ΔGbfe = -16.732±5.807 kcal/mol) and induced pronounced disruption of hydrogen-bond networks, salt-bridge integrity, and fibrillar compactness. Structural descriptors further indicated chain-terminal deformation, elevated RMSD and Rg, and broadened conformational sampling, reflecting loss of fibril rigidity. Piceatannol and Piceid exerted moderate destabilization effects, whereas Astringin and Resveratrol showed minimal impact. These findings identify Rhapontigenin as a potent destabilizer of A β42 protofibrils and highlight naturally derived stilbenoids as promising scaffolds for anti-amyloid drug design, while underscoring the value of simulation-driven strategies for targeting protein aggregates.},
}

@article {pmid41693141,
year = {2026},
author = {Jiang, Z and Wang, H and Yu, J and Gu, S and Yan, J and Ran, C},
title = {Molecular Probes: From Aβ Imaging to Phototherapy in Alzheimer's Disease.},
journal = {Accounts of chemical research},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.accounts.5c00860},
pmid = {41693141},
issn = {1520-4898},
abstract = {ConspectusAlzheimer's disease (AD) is a common neurodegenerative disease, one of whose pathological characteristics is the abnormal deposition of amyloid beta (Aβ). The development of highly sensitive and specific Aβ imaging probes is of great significance for diagnosis, therapeutic discovery, and pathological mechanism studies of AD. In recent years, small molecule-based optical probes have shown significant potential for in vivo whole-brain imaging in small animals and high-resolution microscopic imaging of biological processes, advancing Aβ imaging from detection to molecular mechanisms study and drug discovery. Therefore, the rational design and efficient application of these small molecular probes in Aβ imaging and therapy remain active areas of research. In this regard, a comprehensive understanding of the design strategy of the Aβ probes is highly desirable for advancing and guiding future research directions.Over the past decade, our research has been focused on a trilogy of developing Aβ-based small molecules as imaging probes and therapeutics. In episode I, we invented a brand-new family of near-infrared fluorescent (NIRF) probes CRANAD-Xs, for in vivo selective imaging of Aβ species in AD mice. Considering that different Aβ species exhibit distinct neurotoxicities─with soluble oligomers regarded as the most toxic and insoluble plaques representing a less toxic, late stage of amyloidosis, we rationally designed the CRANAD-X series to cover the full spectrum of amyloid pathology, from low-toxicity plaques to highly toxic oligomers. Importantly, unlike most studies in this field that focus solely on probe characterization, we demonstrated that CRANAD-Xs can longitudinally monitor therapeutic efficacy in real time, supporting their use in drug discovery.Although in vivo NIRF imaging with CRANAD-Xs shows great promise, it remains severely limited by shallow tissue penetration, largely due to autofluorescence interference and a low signal-to-noise ratio (SNR). Consequently, achieving sufficient imaging depth in vivo continues to be a major challenge. In episode II, we pioneered the exploration of chemiluminescence probes (ADLumin-Xs) for detecting Aβ species to meet the needs of deep imaging. Due to high SNR and deep imaging with ADLumin-Xs, we demonstrate the first in vivo 3D whole-brain imaging using chemiluminescence probes, enabling precise localization of Aβ deposits. In addition, using chemiluminescence resonance energy transfer (CRET) with dual nonconjugated probes, we achieve dual-amplification of the Aβ signal in vivo whole-brain imaging.In episode III, we focus on molecularly produced light ("molecular light") for AD therapeutics. Molecular light, primarily including chemiluminescence and bioluminescence, owns a dual nature as both a deliverable molecule and intrinsic light source that enables limitless tissue penetration unattainable with naturally/physically produced light. This dual nature supports theranostic applications including imaging, photodynamic therapy, photooxidation, and photobiomodulation. Leveraging phototherapy that employs the synergistic effect of a photolabile Aβ ligand and molecular light could effectively slow Aβ accumulation in vivo in AD mice. Our studies support the feasibility of molecular light therapy. Overall, we believe that our research offers valuable scientific inspiration for researchers in the fields of chemistry, chemical biology, and biomedicine, particularly for neurodegenerative diseases.},
}

@article {pmid41693057,
year = {2026},
author = {Powell, KR and Isnainy, M and Lee, S and Farmer, MS and Amewudah, P and Popescu, M and Woods, A and Alexander, GL and Mehr, DR},
title = {Using novel natural language processing approaches to examine age-friendly communication about nursing Nome residents with dementia.},
journal = {The Gerontologist},
volume = {66},
number = {3},
pages = {},
doi = {10.1093/geront/gnaf285},
pmid = {41693057},
issn = {1758-5341},
support = {R01AG078281//National Institute on Aging of the National Institutes of Health/ ; },
mesh = {Humans ; *Nursing Homes ; Aged ; *Dementia/nursing ; *Natural Language Processing ; Male ; Female ; Aged, 80 and over ; *Text Messaging ; *Communication ; United States ; *Patient Transfer/statistics & numerical data ; },
abstract = {BACKGROUND AND OBJECTIVES: The Age-Friendly Health Systems model has emerged as a geriatric care model focusing on the 4Ms: what matters, mobility, mentation, and medications. Representation of the 4Ms in interdisciplinary communication could have implications for outcomes including avoidable nursing home-to-hospital transfers. The objective of this article was to explore the association between the 4Ms found in text messages and avoidable transfer of residents with and without Alzheimer's Disease and Related Dementias (ADRD).

RESEARCH DESIGN AND METHODS: The researchers merged data from two primary datasets: (a) text messages (n = 30,066) between nursing home (NH) healthcare workers from an HIPAA-compliant messaging platform and (b) resident transfer data (n = 3,687) from NHs (n = 16) that participated in a 5-year (2016-2020) Centers for Medicare and Medicaid Services demonstration project. They used natural language processing to extract 4M terms from text messages and fit generalized linear mixed models to estimate avoidable NH-to-hospital transfer, controlling for resident characteristics, NH characteristics, and the 4Ms.

RESULTS: Merged data contained 1,031 observations grouped by temporal proximity to the transfer date. Cardiopulmonary resuscitation status, late-stage ADRD, NH bed size, and location were associated with avoidable NH-to-hospital transfer of residents. Text messages containing terms representing mentation and mobility were also associated with avoidable NH-to-hospital transfers.

DISCUSSION AND IMPLICATIONS: These results suggest that natural language processing can be used to identify components of age-friendly care in unstructured data. Association between resident level and nursing home factors and avoidable transfers should be considered as nursing homes implement strategies to reduce avoidable transfer of residents with ADRD.},
}

Humans
*Nursing Homes
Aged
*Dementia/nursing
*Natural Language Processing
Male
Female
Aged, 80 and over
*Text Messaging
*Communication
United States
*Patient Transfer/statistics & numerical data

@article {pmid41692982,
year = {2026},
author = {Zhang, L and Ji, T and Bi, J and Long, A and Long, YF and Zhang, L and Chen, N and Ma, Y and Chen, C and Wang, S and Jiang, H and Chen, Y and Zhou, G and Cao, F and Hu, Y and Ma, L and Cheung, WH and Kang, L and Duque, G and Zhang, C},
title = {Moving Geroscience Forward in China: Proceedings of the First International Exchange Forum of the Chinese Geriatrics Society.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag042},
pmid = {41692982},
issn = {1758-535X},
abstract = {Held on 17 August 2025 in Guangzhou, the inaugural International Exchange Forum of the Chinese Geriatrics Society marked a significant milestone in advancing geroscience and fostering global collaboration in China. The forum brought together leading international experts and emerging Chinese researchers to present the latest advances in aging research. Presentations covered various topics, such as musculoskeletal aging (mitochondrial dysfunction, muscle-bone communication, and exosome-mediated mechanisms in sarcopenia and osteoporosis), cardiovascular aging (TKI- and anthracycline-induced cardiotoxicity), metabolic regulation (sarcopenic obesity and the gut-muscle axis), neurodegenerative interfaces (androgen-mediated monocyte-microglia interactions in Alzheimer's disease), and geriatric assessment (muscle-specific strength, intrinsic capacity, and gait biomarkers). There was a particular focus on novel mechanistic insights, such as RNA epitranscriptomics, mitochondrial homeostasis, and inter-organ communication, as well as on strategies for early risk prediction, intervention, and personalized management. The forum also emphasized the importance of addressing sex-specific differences and translating basic discoveries into clinical applications. As a platform designed to promote academic dialogue and collaboration, the forum successfully brought together the Chinese and global geroscience communities. It emphasized the necessity of multidisciplinary and international efforts to address the challenges posed by population aging. Moving forward, sustained partnerships, data sharing and capacity-building initiatives will be essential to accelerating the development of evidence-based, scalable solutions for healthy aging in China and beyond. This event sets a precedent for future exchanges that integrate scientific innovation with clinical practice to improve the health and quality of life of aging populations worldwide.},
}

@article {pmid37988027,
year = {2026},
author = {O'Donnell, MG and Baker, ZG},
title = {"I Have Accepted My Father's Death; I was not Sad but Relieved." Adaptive Grief Responses for Bereaved Dementia Family Caregivers: A Scoping Review.},
journal = {Omega},
volume = {92},
number = {4},
pages = {1958-1988},
doi = {10.1177/00302228231217334},
pmid = {37988027},
issn = {1541-3764},
support = {R00 AG073463/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Caregivers/psychology ; *Dementia/nursing/psychology ; *Grief ; *Adaptation, Psychological ; *Bereavement ; *Attitude to Death ; Male ; },
abstract = {This scoping review explores findings from the psychological and medical literature on the adaptive grieving experiences of bereaved dementia family caregivers and integrates what healthcare professionals can do to support bereaved dementia family caregivers transition into a post-death role. Bereaved dementia family caregivers are particularly susceptible to prolonged grief disorder post-death due to the protracted caregiving demands and progressive course of the illness. The mention of caregiver grief while the person with dementia is living is quite common in the literature; however, limited research focuses on the bereaved dementia family caregiver and the methods they use to grieve adaptively. Three overarching adaptive grieving themes emerged from the review: 1) social health, 2) emotional and spiritual fitness, and 3) reclaiming activities. Given the growing prevalence of bereaved family dementia caregivers, understanding how they might most adaptively grieve and experience the greatest possible well-being should be a top focus for research.},
}

Humans
*Caregivers/psychology
*Dementia/nursing/psychology
*Grief
*Adaptation, Psychological
*Bereavement
*Attitude to Death
Male

@article {pmid41692954,
year = {2026},
author = {Zhu, S and Resnick, B and Boltz, M and Galik, E and Mcpherson, R and Kuzmik, A and Wells, C and Lee, E and Shim, S},
title = {Bidirectional Associations Between Physical Function and Physical Activity Among Older Adults Living with Dementia.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag027},
pmid = {41692954},
issn = {1758-535X},
abstract = {BACKGROUND: Previous research has suggested a likely reciprocal relationship between physical function and physical activity among older adults, but few assessed those living with dementia. This study examined the bidirectional relationship between physical function and physical activity among older adults living with dementia during hospitalization and post discharge periods, and whether the relationship differs by severity of dementia.

METHODS: This secondary analysis included 455 older adult patients aged 55 years and older living with dementia from a randomized clinical trial, assessed during admission, discharge, 1-, 6-, and 12-month post-discharge periods. Random intercept cross-lagged panel models were used to assess the bidirectional relations, controlling for age, comorbidities, admission location, length of stay, discharge location, and intervention status.

RESULTS: Average age was 82.47 (SD = 8.49) and majority were female (62.6%) and White (65.3%). The average SLUMS score was 7.51 (SD = 5.90) with 77% (n = 351) having a severe level of cognitive impairment. Antecedent physical function at admission, discharge, and 1-month predicted physical activity at corresponding cross-lagged timepoint separately (range of unstandardized coefficients b's: .037-.043, p's<.05); physical activity at discharge predicted physical function at 1-month (b=.708, p=.016). This bi-directional relationship varied by severity of dementia, appearing at the first two cross-lagged time points in patients with severe dementia (b's: .039-.049 and .464-.848, all p's <.05), but not in those with moderate dementia.

CONCLUSIONS: Physical activity and physical function commonly co-occur among older adults with dementia. Intervention studies promoting both physical function and physical activity among older adults with dementia may achieve greater effectiveness when tailored to differences in dementia severity.},
}

@article {pmid41692891,
year = {2026},
author = {More, SA and Mundke, R and Sikkalgar, A and Tarwani, RS and Siddique, MUM and Goyal, SN and Agrawal, YO and Nakhate, KT and Rathod, SS},
title = {Neuroprotective efficacy of hentriacontane against rotenone-induced apoptosis in SH-SY5Y cells: In silico and in vitro evidence of GSK3β association.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41692891},
issn = {1432-1912},
abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), are marked by gradual neuronal loss, frequently associated with mitochondrial dysfunction. Hentriacontane is a naturally occurring long-chain saturated hydrocarbon found in beeswax and certain herbal plants, and has antioxidant, anti-inflammatory and cytoprotective properties, suggesting its therapeutic potential in oxidative stress-associated neurodegeneration. Rotenone, a mitochondrial complex I inhibitor, induces oxidative stress and apoptosis, making it a widely used neurotoxic agent for investigating neurodegenerative disorders like AD. We initially performed in silico molecular docking, molecular dynamics, MM/GBSA, and ADMET pharmacokinetic analyses of hentriacontane against GSK3β to evaluate binding affinities and energies and assess the stability and dynamics of protein-ligand complexes. An in vitro drug safety assay was conducted using the MTT assay in SH-SY5Y cells. The cells were pretreated with 100 μM rotenone two hours before the assay. A 96-well tissue culture-grade microplate was prepared with 100 μL of cell suspension (1 × 10[4] cells/mL), and test compounds were added at concentrations of 20, 40, 60, 80, and 100 μg/mL. Biochemical assays were conducted on cell supernatant to evaluate oxidative stress, proinflammatory, and apoptotic markers. Hentriacontane exhibited a significant binding affinity, with lower RMSD, RMSF, and a more negative ΔG_bind. ADMET analyses indicated favorable pharmacokinetic features. In vitro studies demonstrated that hentriacontane significantly enhanced cell viability, reduced oxidative stress markers, suppressed apoptotic and pro-inflammatory markers, and GSK3β protein levels. The collaborative significance of in silico and in vitro investigations suggests that hentriacontane may serve as a promising therapeutic candidate for mitigating oxidative stress-induced neurotoxicity via modulation of the GSK3β pathway.},
}

@article {pmid41692872,
year = {2026},
author = {Zhang, L and Li, X and Luo, H and Huo, Y and Zhou, G and Wang, P and Wu, S and Lin, X and Dai, K and Shi, J and Wang, Z and Xu, J and Li, R and Chen, S and Sun, Z and Zhao, C and Zhou, Z and Wang, Z and Liang, C and Zhu, J and Chen, X and Luo, J and Yu, Y and Zhang, Z and Wang, G},
title = {Mitochondrial double-stranded RNA drives aging-associated cognitive decline.},
journal = {Cell research},
volume = {},
number = {},
pages = {},
pmid = {41692872},
issn = {1748-7838},
support = {32450418, 91949103, 32071159//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2017YFA0504600//Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)/ ; },
abstract = {Aging is the primary cause of cognitive decline. Despite extensive study, the molecular mechanisms driving aging-associated cognitive decline remain unclear. Here, we describe a proteostasis-independent function of SEC61A1 and its involvement in aging-associated cognitive decline. SEC61A1 regulates ER-mitochondria contact sites, affecting mitochondrial DNA and RNA synthesis and subsequently leading to changes in innate immune signaling mediated by mitochondrial double-stranded RNA (mt-dsRNA). This pathway is activated in aged wild-type mice, Alzheimer's disease patients, and 5×FAD mice. Tissue-specific overexpression of Sec61a1 in the mouse cortex (Sec61a1[Tg]) is sufficient to induce cognitive decline without affecting motor activity. Knockdown of Sec61a1 or Mavs ablates mt-dsRNA-mediated innate immune signaling and alleviates cognitive decline in naturally aging wild-type mice. These results reveal a molecular mechanism of aging- and disease-associated cognitive decline and provide a potential therapeutic tool for intervention.},
}

@article {pmid41692846,
year = {2026},
author = {Nguyen, VTD and Pham, P and Hy, TS},
title = {Enabling multi-target drug discovery through latent evolutionary optimization and synthesis-aware prioritization (EVOSYNTH).},
journal = {Communications chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42004-026-01945-4},
pmid = {41692846},
issn = {2399-3669},
abstract = {Complex diseases, such as cancer and neurodegeneration, feature interconnected pathways, making single-target therapies ineffective due to pathway redundancy and compensatory mechanisms. Polypharmacy, which combines multiple drugs to target distinct proteins, addresses this but often leads to drug-drug interactions, cumulative toxicity, and complex pharmacokinetics. To overcome these challenges, we introduce EVOSYNTH, a modular framework for multi-target drug discovery that combines latent evolution and synthesis-aware prioritization to generate and prioritize candidates with high translational potential. Latent evolution navigates a chemically and functionally informed latent space to identify candidates with strong predicted affinity across multiple targets. Synthesis-aware prioritization evaluates both retrosynthetic feasibility and the trade-off between synthetic cost and therapeutic reward, enabling practical and efficient candidate selection. Applied to dual inhibition of JNK3 and GSK3β in Alzheimer's disease and PI3K and PARP1 in ovarian cancer, EVOSYNTH consistently outperforms baseline generative models, achieving higher predicted affinities, improved scaffold diversity, and lower synthesis costs. These findings highlight EVOSYNTH's ability to integrate target-driven generation with practical synthesizability, establishing a scalable framework for multi-target and polypharmacological drug discovery. Our source code and data to reproduce all experiments are publicly available on GitHub at: https://github.com/HySonLab/EvoSynth.},
}

@article {pmid41692408,
year = {2026},
author = {Saeed, S and Khan, S and Noor, A and Zerr, I and Zafar, S},
title = {Therapeutic Potential of Amyloid-β Interactors in Rapidly Progressive Alzheimer's Disease-An In Silico Study.},
journal = {Molecular informatics},
volume = {45},
number = {2},
pages = {e70024},
doi = {10.1002/minf.70024},
pmid = {41692408},
issn = {1868-1751},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism/chemistry ; Humans ; Molecular Docking Simulation ; Computer Simulation ; Protein Interaction Maps ; },
abstract = {Rapidly progressive Alzheimer's disease (rpAD) is a rare but severe form of Alzheimer's disease characterized by accelerated cognitive decline and limited therapeutic options. Conventional anti-amyloid-β interventions have shown little success due to poor target specificity, neurotoxicity, and lack of efficacy, underscoring the need for novel therapeutic strategies. This study aimed to identify and prioritize molecular targets associated with rpAD by investigating the protein interactome of amyloid-β (Aβ42) using integrative computational approaches. Functional enrichment, protein-protein interaction network analysis, and community clustering revealed that rpAD-specific Aβ42 interactors were predominantly involved in mitochondrial bioenergetics, redox regulation, and cytoskeletal stability, pathways central to neuronal survival and synaptic function. Molecular docking identified fumarate hydratase, carbonyl reductase 1, and the F-actin capping protein as high-affinity interactors of Aβ42, linking these proteins to energy failure, oxidative stress, and synaptic dysfunction. Virtual screening of a therapeutic drug library against fumarate hydratase identified several compounds with strong binding affinities, among which quinestrol, estradiol benzoate, norethindrone, tamibarotene, drospirenone, and ketanserin emerged as lead candidates. Pharmacokinetic profiling, including ADMET modeling, confirmed their blood-brain barrier permeability and drug-likeness, supporting their potential as central nervous system active agents. Together, this work highlights key molecular targets in rpAD and proposes repurposed, pharmacologically diverse compounds with multitarget neuroprotective potential. By utilizing in silico analysis, the study provides a rational framework for target discovery and drug prioritization in rpAD, offering a foundation for future experimental validation and the development of translational research.},
}

*Alzheimer Disease/drug therapy/metabolism
*Amyloid beta-Peptides/metabolism/chemistry
Humans
Molecular Docking Simulation
Computer Simulation
Protein Interaction Maps

@article {pmid41692246,
year = {2026},
author = {Strickland, MR and Wang, Z and Golden, LR and Wang, H and Lu, P and Ren, Y and Tabor, GT and Zhao, N and Ulrich, JD and Han, X and Peng, J and Holtzman, DM},
title = {Lipidome and Proteome of Astrocyte and Microglia ApoE Lipoprotein Reveal Differences Based on Cell Type and ApoE Isoform.},
journal = {Journal of lipid research},
volume = {},
number = {},
pages = {101000},
doi = {10.1016/j.jlr.2026.101000},
pmid = {41692246},
issn = {1539-7262},
abstract = {Apolipoprotein E (ApoE) is the primary, most abundant apolipoprotein of the central nervous system (CNS) and plays an important role in brain metabolism and lipid homeostasis. In the CNS, ApoE is primarily secreted by astrocytes under homeostatic conditions and by microglia in certain disease-related conditions. APOE has three major alleles: APOE2, APOE3, and APOE4. APOE4 is the strongest genetic risk factor for late onset Alzheimer's disease (AD) and APOE2 results in decreased risk relative to APOE3. ApoE derived from astrocytes and microglia have been hypothesized to play different roles in the disease pathogenesis of Alzheimer's disease. In this study, we profiled the lipidome and proteome of ApoE lipoproteins secreted by astrocytes or microglia and found that they differed according to the cellular source of ApoE and ApoE isoform. Lipidomics revealed microglia-derived ApoE lipoproteins were enriched in cholesterol esters whereas astrocyte ApoE lipoproteins were enriched in sphingomyelin. Proteomics revealed astrocyte ApoE lipoproteins were enriched in proteins involved in glucose metabolism and acute phase response. Microglia-secreted lipoproteins were enriched in proteins involved in complement activation, synapse pruning, proteolysis, and the innate immune response. Further comparison of ApoE lipoproteins from APOE4 microglia revealed that ApoE4 lipoproteins were enriched in C1q and Lpl compared to ApoE2 and ApoE3 microglial lipoproteins which were enriched in Ankk1 and ApoC1. These results provide the molecular foundation for better understanding of how ApoE functions as an apolipoprotein with the lipoprotein cargo being dependent on the cellular source and ApoE isoform, ultimately contributing to CNS homeostasis and disease pathogenesis.},
}

@article {pmid41692216,
year = {2026},
author = {Roland, NJ and Zigmond, JW and Manganaro, JE and Daniel Estrella, L and Stauch, KL},
title = {APOE4 induces sex-dependent synaptic mitochondrial cholesterol, proteome, and respiratory function alterations in mice.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106125},
doi = {10.1016/j.neuint.2026.106125},
pmid = {41692216},
issn = {1872-9754},
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is characterized by synapse damage and loss, correlating strongly with cognitive decline. APOE4, the strongest genetic risk factor for AD, impairs synapses with the mechanisms remaining unclear. APOE, the central nervous system's primary lipid and cholesterol carrier, is critical for axonal growth, synapse formation, and spine remodeling. To investigate how APOE4 affects cholesterol and synaptic dysfunction, we studied male and female human APOE3 and APOE4 knock-in mice. Cholesterol levels were measured in brain homogenates, synaptosomes, and mitochondria using bioluminescent assays, and APOE protein expression was analyzed via immunoblotting. Proteomics of synaptosomes and mitochondrial respiratory function assessments were performed using mass spectrometry and the Seahorse XF Analyzer, respectively. We found that cholesterol levels did not differ between APOE3 and APOE4 mice in brain homogenates or synaptosomes. However, male APOE4 mice exhibited lower cholesterol levels in synaptic mitochondria than APOE3 mice, with no changes in non-synaptic mitochondria or female mice. APOE protein was present in synaptosomes and mitochondrial fractions without changes due to APOE4 expression. Synaptosomal proteomics uncovered synaptic mitochondrial membrane proteins were differentially expressed in APOE4 versus APOE3 mice. Proteomic analysis also revealed altered neurotransmitter signaling and metabolic pathways in the APOE4 mice, predominantly in males. Notably, proteins involved in synaptic vesicle endocytosis and aerobic respiration were differentially expressed. Mitochondrial respiratory function was disrupted in female APOE4 mice, which displayed increased maximal respiration and spare respiratory capacity at the synapse. These findings identify a role for APOE in regulating synaptic mitochondrial cholesterol, protein expression, and respiratory function in a sex-dependent manner, contributing to synaptic dysfunction in AD.},
}

@article {pmid41692211,
year = {2026},
author = {Yue, S and Xing, H and Du, X and Wang, Y and Qin, R and He, J and Yu, J and Zhangsun, D and Craik, DJ and McIntosh, JM and Wu, Y and Zhu, X and Luo, S},
title = {α-Conotoxin LvID, an antagonist of α7 nicotinic acetylcholine receptor, mitigates Alzheimer-associated phenotypes by inhibiting Aβ deposition and reactive astrogliosis.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {150933},
doi = {10.1016/j.ijbiomac.2026.150933},
pmid = {41692211},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is the most common form of dementia in older adults. Neuritic plaques and reactive astrogliosis are neuropathological hallmarks of AD. Amyloid beta (Aβ), the major component of neuritic plaques, is derived from amyloid precursor protein (APP) by sequential cleavages by β-secretase and γ-secretase. The dysregulation of α7 nicotinic acetylcholine receptors (α7 nAChRs) is associated with both reactive astrogliosis and Aβ deposition. However, the role of nAChR antagonists in AD pathogenesis and underlying mechanisms remains elusive. In this study, we explored the effect of α-conotoxin LvID, a marine-derived peptide from Conus lividus, acts as a selective antagonist of α7 nAChRs, on AD pathogenesis. We found that LvID rescues learning and memory deficits in AD model mice in Morrios water maze, This led to a doubling of the memory of the AD model mice. Moreover, LvID treatment can reduce it by 50% in Aβ levels and also inhibited the proliferation of reactive astrocytes in AD model mice compared to non-treated AD model mice. Furthermore, the effect of LvID on learning and memory deficits and Aβ generation is mediated by an α7 nAChR‑calcium-CaMKII signaling pathway. These findings suggest that LvID may offer therapeutic potential for AD treatment by modulating α7 nAChR-mediated pathways involved in Aβ production. The work demonstrates that LvID is a potential drug template for AD treatment.},
}

@article {pmid41692182,
year = {2026},
author = {Dos Santos, JR and Pedrazzi, JF and Alberici, LC and Catalão, CHR},
title = {Enhanced avoidance learning associated with elevated anxiety in the 3xTg-AD mouse model of Alzheimer's disease.},
journal = {Physiology & behavior},
volume = {},
number = {},
pages = {115269},
doi = {10.1016/j.physbeh.2026.115269},
pmid = {41692182},
issn = {1873-507X},
abstract = {Alzheimer's disease (AD) is the world's most prevalent degenerative neurological disease, characterized by extracellular accumulation of misfolded Aβ peptide and intracellular formation of neurofibrillary tangles. In addition to cognitive deficits, psychological and behavioral manifestations such as fear, anxiety, and depression are present in patients with AD. The relationship between these noncognitive symptoms and memory and learning deficits remains unknown. Using a genetic mouse model of the disease, we assessed fear-based learning and anxiety through the active avoidance test (AAT) and elevated plus maze (EPM) in middle-aged 3xTg-AD mice. Animals were tested in four consecutive daily sessions, and measures of avoidance rate, avoidance latency, escape rate, and escape latency were performed. After seven days, the mice were placed in the EPM, and the number of entries and time spent on the open arms were quantified. The AAT revealed that 3xTg-AD animals exhibited a higher avoidance rate in sessions 3 (p < 0.001) and 4 (p < 0.01), a shorter escape rate in sessions 3 (p < 0.01) and 4 (p < 0.05), and a shorter escape latency in session 3 (p < 0.05). Furthermore, 3xTg-AD mice had a lower percentage of entries (p < 0.001) and a shorter time spent (p < 0.001) in the open arms of the EPM compared to the control group. These results suggest that the high performance of transgenic animals in learning to avoid shocks may be related to an intrinsic state of alertness, making the 3xTg-AD mouse a reliable model for investigating the neurobiological and pathological mechanisms of anxiety and fear in AD.},
}

@article {pmid41692179,
year = {2026},
author = {Khangura, MS and Spratt, MA and Gao, A and Manhapra, A and Siegel, NH and Chen, X and Poulaki, V and Ness, S and Stein, T and Subramanian, ML},
title = {The Association Between Diabetic Retinopathy Severity and Dementia Risk: A TriNetX Longitudinal Cohort Study.},
journal = {American journal of ophthalmology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajo.2026.02.014},
pmid = {41692179},
issn = {1879-1891},
abstract = {PURPOSE: Diabetes mellitus (DM) and diabetic retinopathy (DR) have been associated with higher incidence of dementia and may serve as clinical indicators for underlying cognitive disease. This study investigated whether severity of DR is linked to increased risk of dementia.

DESIGN: Retrospective cohort study.

PARTICIPANTS: Participants were categorized into four groups: proliferative diabetic retinopathy (PDR), nonproliferative DR (NPDR), type 2 DM (DM2) without DR, and no DM. Individuals under age 65 and those with macular edema were excluded.

METHODS: Groups were propensity score matched 1:1 for demographic and clinical covariates. Outcomes included incidence of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD), assessed using Cox proportional hazard ratios (HR) with 95% confidence intervals (CIs). Kaplan-Meier analysis evaluated time to dementia onset.

MAIN OUTCOME MEASURES: Incidence and hazard ratios of all-cause dementia, AD, and VD.

RESULTS: The TriNetX database identified 14,034 individuals with PDR, 29,188 individuals with NPDR, 208,640 with DM2 without DR, and 447,054 without DM. Compared to non-diabetics, all three diabetic groups (PDR, NPDR, and DM2 without DR) had a higher risk of all-cause dementia (HR 1.583, p<0.0001 PDR; 1.405, p<0.0001 NPDR; 1.262, p<0.0001 DM2 without DR), AD (HR 1.175, p=0.0419 PDR; 1.233, p<0.0001 NPDR; 1.117, p<0.0001 DM2 without DR), and VD (HR 2.077, p<0.0001 PDR; 1.917, p<0.0001 NPDR; 1.384, p<0.0001 DM2 without DR). Compared to participants with DM2 without DR, those with PDR and NPDR had higher risk for all-cause dementia (HR 1.202, p<0.0001 PDR; 1.113, p<0.0001 NPDR) and VD (HR 1.504, p<0.0001 PDR; 1.322, p<0.0001 NPDR), but not AD. When stratified by DR severity, PDR was associated with a higher risk of all-cause dementia (HR 1.121, p=0.0003 PDR) and VD (HR 1.177, p=0.0126 PDR), but not AD, compared to NPDR.

CONCLUSION: Greater severity of DR is associated with an increased risk of all-cause dementia and VD in individuals with DM2 without DR, whereas AD risk appears elevated only when compared to nondiabetic participants. These findings suggest that progressive DR reflect systemic microvascular injury that parallels cerebral small vessel disease. Routine ophthalmologic screening in patients with DM may provide an opportunity for early identification of individuals at higher risk of cognitive decline.},
}

@article {pmid41692154,
year = {2026},
author = {Chen, YC and Chiu, TJ and Wu, YY and Wang, YT and Wu, KH and Yeh, TH and Hsieh, YJ and Chen, WS and Chiu, CC},
title = {ALDH2 activation protects against mutant TOMM40-mediated mitochondrial dysfunction and neurodegeneration in Alzheimer's disease.},
journal = {Life sciences},
volume = {},
number = {},
pages = {124274},
doi = {10.1016/j.lfs.2026.124274},
pmid = {41692154},
issn = {1879-0631},
abstract = {AIMS: TOMM40 (translocase of outer mitochondrial membrane 40) is crucial for mitochondrial protein import. Mutations in TOMM40 increase the risk of Alzheimer's disease (AD) and trigger neuroinflammation. ALDH2 (aldehyde dehydrogenase 2) has neuroprotective effects, but the therapeutic role of ALDH2 activation in targeting neuroinflammation-induced AD remains unclear.

MATERIALS AND METHODS: In this study, it was hypothesized that TOMM40 mutations cause BV2 microglial activation and neuronal loss by impairing mitochondrial functions and that ALDH2 activation by small-molecule activator Alda-1 exerts anti-neuroinflammatory effect on HT22 hippocampal neurons.

KEY FINDINGS: Expression of mutant TOMM40 (F113L or F131L) induced BV2 microglial activation, reduced ALDH2 activity, and impaired mitochondrial function in BV2 microglia. ALDH2 activation by Alad-1 attenuated mutant TOMM40-induced microglial activation, mitochondrial dysfunction, ROS production, and lipid droplet accumulation. Alda-1 also suppressed mutant TOMM40-induced ROS/NF-κB/NLRP3 inflammasome axis and reduced the secretion of IL-1β, IL-6, and TNF-α. Conditioned medium from mutant TOMM40-expressing microglia induced apoptosis, neurite degeneration, and neuronal death in HT22 hippocampal neurons, which were alleviated by Alda-1 treatment.

SIGNIFICANCE: These findings suggest that ALDH2 activation prevents neuroinflammation-induced hippocampal neuronal death by downregulating NLRP3 inflammasome pathway, reducing lipid droplet accumulation, and enhancing mitochondrial function and neurite outgrowth.},
}

@article {pmid41692031,
year = {2026},
author = {Hobday, JV and Rosopa, PJ and Rosopa, EB and Hobday, A and Gaugler, JE},
title = {An Online Training Program to Reduce Antipsychotic Medication Use in Nursing Homes: The CARES Method.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {106122},
doi = {10.1016/j.jamda.2026.106122},
pmid = {41692031},
issn = {1538-9375},
abstract = {The objective of this Pragmatic Innovation article is to present a case study examining whether an online, asynchronous staff dementia care training program (CARES) was associated with reductions in the use of antipsychotic medications and improved staff perceptions in a New Mexico residential long-term care setting. Staff at Lakeview Christian nursing home began using the CARES Dementia 5-Step Method-Complete Catalog online training and certification program in 2019. The asynchronous, scalable CARES online dementia care modules were implemented successfully and sustained at Lakeview Christian as a core strategy to reduce antipsychotic medication use. The reductions in antipsychotic medication use at Lakeview Christian were more pronounced than those in peer nursing homes in New Mexico during the CARES implementation period (2019-2024). Various elements of CARES appeared to drive its implementation success, including its flexibility and self-paced module delivery, its comprehensive focus on behaviors, and its alignment with Lakeview Christian's culture and its focus on reducing antipsychotic medication use. The implementation process of CARES also highlighted the need for person-centered dementia care education, training, and principles for prescribing physicians.},
}

@article {pmid41691984,
year = {2026},
author = {Zhang, X and Cao, K and Wan, J and Liu, Z and Ren, Z and Wang, W and Wang, H},
title = {Neuroprotective effects and mechanism of ginseng aqueous extract against Alzheimer's disease.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {153},
number = {},
pages = {157943},
doi = {10.1016/j.phymed.2026.157943},
pmid = {41691984},
issn = {1618-095X},
abstract = {Limitations of current Alzheimer's disease (AD) therapies necessitate novel neuroprotective strategies. This study elucidated the multi-target mechanisms of ginseng aqueous extract (GAE) using complementary in vitro and in vivo AD models. Structural characterization indicated that the active ingredients of GAE included total saponins (19.64 ± 0.89%), total flavonoids (0.04±0.03%) and total polyphenols (6.41±0.15%). The primary active components in GAE are total saponins, which account for its highest compositional proportion. In vitro, GAE (0.8 mg/ml) exhibited potent antioxidant activity, evidenced by DPPH scavenging (27.14%), ABTS[+] reduction (59.49%), and ·OH quenching (28.08%). It restored neuronal homeostasis by normalizing intracellular Ca[2+] levels, reinstating mitochondrial membrane potential, and reducing ROS production. In transgenic Drosophila, GAE conferred multi-mechanistic neuroprotection via upregulation of antioxidant genes, autophagy activation, and enhanced insulin signaling. These actions translated to functional improvements, including reduced Aβ deposition, decreased neuronal apoptosis, preserved gut barrier integrity, extended lifespan, and improved locomotion-stress tolerance. Collectively, GAE represents a promising multi-target therapeutic candidate for AD by synergistically modulating oxidative stress, protein homeostasis and metabolic pathways.},
}

@article {pmid41691953,
year = {2026},
author = {Sandoval-Diez, N and Loizeau, N and Huss, A and Röösli, M and Vienneau, D},
title = {Long-term residential magnetic field exposure and neurodegenerative disease mortality: An 18-year nationwide cohort study in Switzerland.},
journal = {Environment international},
volume = {208},
number = {},
pages = {110145},
doi = {10.1016/j.envint.2026.110145},
pmid = {41691953},
issn = {1873-6750},
abstract = {BACKGROUND: Epidemiological evidence on the association between extremely low-frequency magnetic fields (ELF-MF) exposure and neurodegenerative diseases (NDD) remains inconsistent. Few population-based studies using exposure from high-voltage power lines (HVPL) have found mixed findings, and none have yet considered exposure from railway lines.

METHODS: We followed 3,555,064 adults from the Swiss National Cohort (2001-2018), contributing 55.4 million person-years. Long-term ELF-MF exposure from HVPL (50 Hz) and railway lines (16.7 Hz) was modelled using validated proximity models and updated over four intervals (2001-2005, 2006-2010, 2011-2015, 2016-2018). Long-term ELF-MF exposure was calculated as a time-weighted average exposure over 10-year windows preceding each interval. Cox proportional hazards models estimated hazard ratios (HRs) for mortality from Alzheimer's disease (AD), other types of dementia (OTD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS), adjusting for sociodemographic and environmental co-exposures.

RESULTS: During follow-up, 146,655 NDD deaths occurred. Less than 1% of the population was exposed to long-term ELF-MF ≥ 0.3 µT from HVPL and 2.4% from railway lines. HVPL exposure was positively associated with mortality from AD (HR per 1 µT increase in exposure = 1.54; 95% CI: 1.23-1.92) and OTD (HR = 1.31; 95% CI: 1.13-1.52). Associations for railway exposure were weaker and attenuated after adjusting for environmental co-exposures. No associations were observed for ALS, PD, or MS.

CONCLUSIONS: Long-term ELF-MF exposure was associated with higher dementia mortality risk in the general population, but not with ALS, PD, or MS. Causal inference remains limited by the absence of established biological mechanisms.},
}

@article {pmid41691754,
year = {2026},
author = {Emam, NE and Refaey, RH and El-Ashrey, MK and Mahmoud, WR and Nissan, YM and Seif, EM},
title = {Development of coumarin-based acetylcholinesterase inhibitors: Synthesis, biological assessment and computational simulations.},
journal = {Bioorganic chemistry},
volume = {173},
number = {},
pages = {109630},
doi = {10.1016/j.bioorg.2026.109630},
pmid = {41691754},
issn = {1090-2120},
abstract = {Novel coumarin-based derivatives (5, 6a-c and 10a-j) have been designed, synthesized and biologically assessed as multimodal anti-Alzheimer agents targeting acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and glycogen synthase kinase-3β (GSK-3β). The synthesized derivatives have been afforded in a good yield and the structures confirmed by the spectral analysis. Among these derivatives, four derivatives (10c, 10d, 10 f and 10i) exhibited remarkable inhibitory activity against the acetylcholinesterase enzyme in nanomolar concentration (IC50 = 5.93 ± 0.06, 3.97 ± 0.15, 3 ± 0.1, and 4.97 ± 0.06 nM, respectively), surpassing the reference donepezil drug (IC50 = 7.03 ± 0.15 nM). Moreover, derivative 10 f demonstrated a significant BuChE inhibitory activity (IC50 = 303 ± 0.03 nM), about 2-fold the donepezil activity. Consequently, derivative 10 f was selected for the GSK-3β inhibition assay and displayed a greater inhibitory activity in nanomolar range (7.58 ± 0.83 nM) than the reference broad-spectrum kinase inhibitor staurosporine (8.63 ± 0.94 nM). Additionally, derivative 10 f was assayed for the iron chelating capacity and showed significant activity compared to the iron chelator EDTA. The molecular docking of derivatives 10c, 10d, 10 f, and 10i utilizing the AChE enzyme as a target protein (PDB: 4EY7) was evaluated and highlighted 10 f as a promising lead candidate with favorable interactions and high affinity. The key hydrogen bonds, hydrophobic contacts, and π-π stacking interactions support the observed bioactivity. Furthermore, molecular dynamics simulations indicated the stability of the compound-enzyme complexes, with low RMSD fluctuations and favorable binding free energies. Collectively, these findings emerge as derivative 10 f, a promising lead scaffold for Alzheimer's disease with multimodal activity.},
}

@article {pmid41691696,
year = {2026},
author = {Baniasadipour, B and Bagheri, F and Hendudari, F and Koopaee, S and Amini, SM and Kamalabadi, MA and Fatemidokht, A},
title = {Molecular and Microstructural MRI of Neuroinflammation in Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050420458251115070244},
pmid = {41691696},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a leading cause of cognitive decline in older adults, often diagnosed late when pathology and symptoms are established, reducing treatment effectiveness. Both AD and mild cognitive impairment (MCI) trigger neuroinflammation, leading to molecular and microstructural changes, including oxidative stress, mitochondrial dysfunction, glial activation, synaptic and neurotransmitter disturbances, myelin degradation, and white matter dysfunction. The blood-brain barrier (BBB) is also compromised.

METHODS: Advanced magnetic resonance imaging (MRI) techniques, such as magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), magnetization- transfer imaging (MTI), chemical exchange saturation transfer (CEST), contrast-enhanced MRI (CE-MRI), and arterial spin labeling (ASL), offer promise for the early detection of Alzheimer's disease (AD)-related molecular and microstructural changes.

RESULTS: Based on recent studies, advanced MRI modalities-including magnetic resonance spectroscopy, diffusion imaging, contrast-enhanced imaging, and chemical shift imaging-can highlight metabolic dysfunction, white matter degradation, microstructural disruption, blood-brain barrier dysfunction, cerebral hypoperfusion, vascular dysfunction, and pH alterations caused by neuroinflammation in Alzheimer's patients.

DISCUSSION: The integration of advanced MRI modalities into clinical practice could improve the diagnosis and management of Alzheimer's disease (AD). Magnetic resonance spectroscopy and diffusion imaging can identify metabolic and microstructural changes years before brain atrophy occurs, aiding professionals in the early detection of AD. Additionally, perfusion imaging and magnetization transfer imaging can help distinguish between Alzheimer's disease, frontotemporal dementia (FTD), and vascular dementia. Finally, contrast-enhanced MRI can monitor the integrity of the blood-brain barrier to evaluate responses to drug treatments.

CONCLUSION: Despite challenges, such as longer scan times and limited specificity, advanced MRIbased approaches are at the forefront of identifying reliable biomarkers for early detection of Alzheimer's disease and determining optimal management and treatment strategies.},
}

@article {pmid41691694,
year = {2026},
author = {Yang, Z and Tangli, M and Tan, Y and Chen, H and Shu, N and Ke, Z and Hu, Z and Ye, Q and Meng, H and Chen, H and Xu, Y},
title = {Repetitive Transcranial Magnetic Stimulation Alters Brain Communication Networks to Improve the Cognitive Function in Patients with Amnestic Mild Cognitive Impairment - A Clinical Trial.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X389814251019160424},
pmid = {41691694},
issn = {1875-6190},
abstract = {INTRODUCTION: Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive intervention that could effectively enhance the cognitive function in patients with amnestic mild cognitive impairment (aMCI). However, the mechanism and predictive biomarkers for therapeutic response remain poorly understood.

METHODS: Fifty-three aMCI patients underwent either neuro-navigated rTMS (n=28) or sham stimulation (n=25) targeting the left angular gyrus over four weeks (registered in 2021: ChiCTR2100050496). Multimodal MRI and comprehensive neuropsychological assessments were conducted pre- and post-intervention. Changes in brain communication networks and their correlation with cognitive improvements were analysed, with random forest models applied to predict treatment efficacy.

RESULTS: Episodic memory (p<0.001) and general cognitive function (p<0.05) of aMCI patients were significantly improved after intervention. Novel alterations in brain communications networks were identified in 5 sensorimotor areas, executive control regions, and emotion-cognition processing hubs. Communication alterations between the right precentral gyrus and right angular gyrus were positively correlated with the improvements in episodic memory (r=0.38, p=0.046), while the alterations between right precentral gyrus and right angular gyrus were negatively correlated with improvements in general cognitive function (MMSE, r=-0.44, p=0.019; MoCA, r=-0.43, p=0.024). Notably, the random forest model integrating communication network patterns with baseline demographic and neuropsychological data showed strong power in predicting rTMS effects.

DISCUSSION: These findings advance understanding of rTMS mechanisms by linking network plasticity to cognitive gains, addressing critical knowledge gaps.

CONCLUSION: Neuro-navigated rTMS targeting the left angular gyrus may enhance cognitive function in aMCI patients by improving inter-brain regions communication. Baseline communication patterns hold promise as predictive biomarkers, facilitating personalized treatment strategies.},
}

@article {pmid41691677,
year = {2026},
author = {Xinyang, L and Yuling, L and Shuai, M and Jing, H and Jianjun, C and Yang, G and Caixia, L and Ke, H and Yazhen, S},
title = {Network Pharmacology and Experimental Approaches Reveal the Effects of Scutellaria barbata Flavonoids Against Alzheimer's Diseasevia CREB Phosphorylation in Rats.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673417632251125054314},
pmid = {41691677},
issn = {1875-533X},
abstract = {INTRODUCTION: In this study, we investigated the effects and molecular mechanisms by which Scutellaria barbata flavonoids (SBFs) enhance neurogenesis and ameliorate memory impairment mediated by CREB phosphorylation in rats, using a network pharmacology approach.

METHODS: The active ingredients of SBFs and their targets were identified using the Traditional Chinese Medicine Systems Pharmacology platform. An Alzheimer's disease (AD) model was established by intracerebroventricular injection of Aβ25-35 combined with AlCl₃ and RHTGF-β1 (composited Aβ) in rats. The Morris water maze was used to confirm the successful establishment of the AD rat model. Successfully modeled rats were randomly divided into three groups: a model group and two treatment groups receiving either 140 mg/kg SBFs or 0.5 mg/kg Rolipram (positive control). After 38 days, the Morris water maze test was performed to assess learning and memory abilities. Hematoxylin-eosin (HE) staining, immunohistochemistry, quantitative PCR (qPCR), and Western blotting (WB) were conducted to evaluate neuronal morphology, NeuN protein expression, the mRNA levels of TrkB, RSK, CREB, and BDNF, and the protein expression of NeuN, TrkB, RSK, P-CREB-Ser133, and BDNF in the hippocampus and cerebral cortex of the rats.

DISCUSSION: These results indicate that SBFs and Rolipram ameliorate learning and memory impairment, reduce neuropathological changes, promote neurogenesis, and upregulate the BDNF- RSK-CREB signaling pathway through the activation of CREB phosphorylation. The findings suggest that the effects of SBFs are similar to those of Rolipram and that SBFs may also act as activators of CREB phosphorylation. Overall, SBFs promote neurogenesis and improve learning and memory deficits, possibly by enhancing CREB phosphorylation. This study identified the key targets and signaling pathways of SBFs in AD, indicating that SBFs represent a promising multitarget therapeutic candidate for the treatment of AD. However, our research has some limitations. Further studies are needed to determine the absorption route, major active components, and metabolic forms of the bioactive substances in SBFs. In future work, we aim to clarify the potential mechanisms of SBFs in AD by integrating multiple omics approaches and to evaluate the safety and efficacy of SBFs in AD treatment.

RESULTS: Thirty-seven targets were identified based on the intersection between AD-related targets and the components of SBFs. SBFs were involved in anti-AD activity through the MAPK signaling pathway, including the BDNF-RSK-CREB pathway. SBFs attenuated memory impairment, ameliorated neuropathological changes, increased NeuN protein expression, and regulated the mRNA expression of TrkB, RSK, CREB, and BDNF, as well as the protein expression of NeuN, TrkB, RSK, P-CREB-Ser133, and BDNF. Rolipram produced similar effects to SBFs.

CONCLUSION: Network pharmacology analysis and animal experiments confirmed that SBFs promote neurogenesis and ameliorate learning and memory impairment in AD model rats, primarily by facilitating CREB phosphorylation, similar to Rolipram. This study indicates that SBFs may be a promising therapeutic candidate for the treatment of AD.},
}

@article {pmid41691604,
year = {2026},
author = {Zhong, P and Shaker, T and Li, P and Yan, Z},
title = {Compromised synaptic signal from prefrontal cortex to mediodorsal thalamus in Alzheimer's disease models and its rescue by kinase inhibitors.},
journal = {The Journal of physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/JP289018},
pmid = {41691604},
issn = {1469-7793},
support = {AG064656/NH/NIH HHS/United States ; AG067597/NH/NIH HHS/United States ; },
abstract = {One of the most important neural circuits controlling cognitive processes is the projection from prefrontal cortex (PFC) to thalamus. To determine the strength of PFC projections to different thalamic nuclei, we performed optogenetic experiments by injecting channelrhodopsin-2 (ChR2) to medial PFC and recording synaptic responses evoked by light stimulation of ChR2-expressing terminals in thalamic neurons. The mediodorsal thalamus (MD) had markedly larger synaptic currents than neighbouring areas, suggesting that PFC sends prominent signals to MD. To determine whether the PFC to MD pathway is altered at early stages of Alzheimer's disease (AD), we used two mouse models (∼4 months old), transgenic mice carrying the human P301S mutation of microtubule-associated protein tau (Tau), and familial AD mice carrying five mutations on APP and PS1 (5xFAD). Both AD mouse models exhibited a more significant decline in short-term depression (STD) of synaptic responses in response to repeated light stimulation of MD ChR2 signals. Optogenetic imaging showed that Tau mice had significantly reduced ChR2 expression in MD axon terminals innervated by PFC. Next, we inhibited two kinases, serum and glucocorticoid-regulated kinase 1 (SGK1) and glycogen synthase kinase-3 beta (GSK3β), both of which can induce tau hyperphosphorylation and the ensuing disruption of microtubule-based transport in AD. Treatment with SGK1 or GSK3β inhibitor normalized STD of PFC to MD synaptic responses in Tau mice, but not in 5xFAD mice. These results suggest that the synaptic connectivity in the PFC-to-MD pathway is compromised in AD, which may be due to tau kinase-induced disruption of axonal transport. KEY POINTS: Optogenetic recordings reveal the strong connection from prefrontal cortex (PFC) to mediodorsal thalamus (MD). Short-term depression (STD) of PFC to MD synaptic responses is altered in P301S Tau and 5xFAD mouse models of Alzheimer's disease (AD). Optogenetic imaging uncovers the significantly reduced PFC to MD projection in Tau mice. Inhibition of tau kinase SGK1 or GSK3β normalizes STD of PFC to MD synaptic responses in Tau mice, but not 5xFAD mice. These results suggest that the synaptic information transfer from PFC to MD pathway is compromised in AD, probably via tau kinase-induced disruption of axonal transport.},
}

@article {pmid41691336,
year = {2026},
author = {Wang, X and Pan, T and Chen, S and Webb, GI and Jiang, Y and Rozowsky, J and Gerstein, M and Song, J},
title = {Predicting disease-specific histone modifications and functional effects of non-coding variants by leveraging DNA language models.},
journal = {Genome biology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13059-026-04003-3},
pmid = {41691336},
issn = {1474-760X},
support = {APP1127948, APP1144652, APP2036864//National Health and Medical Research Council of Australia/ ; },
abstract = {BACKGROUND: Epigenetic modifications play a vital role in the pathogenesis of human diseases, particularly neurodegenerative disorders such as Alzheimer's disease, where dysregulated histone modifications are strongly implicated in disease mechanisms. While recent advances underscore the importance of accurately identifying these modifications to elucidate their contribution to Alzheimer's disease pathology, existing computational methods remain limited by their generic approaches that overlook disease-specific epigenetic signatures.

RESULTS: To bridge this gap, we develop a novel large language model-based deep learning framework tailored for disease-contextual prediction of histone modifications and variant effects. Focusing on Alzheimer's disease as a case study, we integrate epigenomic data from multiple patient samples to construct a comprehensive, disease-specific histone modification dataset, enabling our model to learn Alzheimer's disease -associated molecular signatures. A key innovation of our approach is the incorporation of a Mixture of Experts architecture, which effectively distinguishes between disease and healthy epigenetic states, allowing for precise identification of Alzheimer's disease -relevant epigenetic modification patterns. Our model demonstrates robust performance in disease-specific histone modification prediction, significantly outperforming existing state-of-the-art methods that lack disease context. Beyond accurate modification site prediction, our framework provides important biological insights by successfully prioritizing Alzheimer's disease-associated genetic variants, which show significant enrichment in disease-relevant pathways.

CONCLUSIONS: Our framework establishes a powerful new paradigm for epigenetic research that can be extended to other complex diseases, offering both a valuable tool for variant effect interpretation and a promising strategy for uncovering novel disease mechanisms through epigenetic profiling.},
}

@article {pmid41566378,
year = {2026},
author = {Wu, Q and Ding, J and He, R and Hui, L and Liu, J and Li, Y},
title = {Exploring phenotype-related single-cells through attention-enhanced representation learning.},
journal = {Genome medicine},
volume = {18},
number = {1},
pages = {21},
pmid = {41566378},
issn = {1756-994X},
support = {2025ZD01901900//Prevention and Control of Emerging and Major Infectious Diseases-National Science and Technology Major Project/ ; 2023YFF1204701//National Key Research and Development Program of China/ ; SRPG22007//the Self-supporting Program of Guangzhou Laboratory/ ; 2023B1515130008//Guangdong Basic and Applied Basic Research Foundation/ ; GZNL2025C01013//the Major Project of Guangzhou National Laboratory/ ; No.12371485 and No.82400622//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: Atlas-level single-cell investigations elucidate disease pathogenesis and progression. Accurate interpretation of phenotype-related single-cell data necessitates pre-defining cell subtypes and identifying their abundance variations. However, batch correction and clustering resolution biases can impact this interpretation. To overcome these challenges, an end-to-end integrative approach that combines both cell- and gene-level information is needed to more accurately connect single-cell characteristics to clinical phenotypes.

METHODS: We developed scPhase, a deep learning framework using attention-based multiple instance learning (AMIL). It treats each patient sample as a bag of single cells, learning a comprehensive representation from their gene expression profiles. By incorporating a Mixture-of-Experts (MoE) aggregation layer, it predicts clinical phenotypes that generalize across patient cohorts. Furthermore, it includes an interpretability framework that uses cellular attention and gene attribution scores to pinpoint the key cell profiles that drive its predictions.

RESULTS: We evaluated scPhase across diverse single-cell disease atlases, covering COVID-19 infection, aging, neurodegeneration, and oncology, using single-cell data from peripheral blood mononuclear cells (PBMCs), brain, and tumor tissues. The model consistently outperforms baselines in classifying diverse clinical phenotypes, achieving area under the curve (AUC) scores of 0.895 for COVID-19, 0.840 for Alzheimer’s disease, and 0.951 and 0.962 for lung and colorectal cancers. It shows robust performance in age regression with a Pearson correlation coefficient (PCC) of 0.87. The model’s interpretability framework effectively pinpointed clinically relevant cell populations, enhancing its utility in identifying disease-specific cellular signatures.

CONCLUSIONS: scPhase offers an interpretable supervised learning framework for single-cell data, accurately predicting sample-level clinical phenotypes while uncovering key biological mechanisms. Furthermore, it can be readily adapted for broader atlas-level clinical phenotype analyses.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-026-01598-x.},
}

@article {pmid41691306,
year = {2026},
author = {Orellana, P and Henríquez, F and Cabral-Miranda, F and Hernandez, H and Ferreira, PCL and Bellaver, B and Caviedes, A and Pizarro, M and Gonzalez-Silva, C and Marin-Diaz, N and Riquelme, P and Pozo, N and Damm, F and Court, FA and Gonzalez-Billault, C and Lillo, P and Thumala-Dockendorff, D and Cerda, M and Villagra, R and de la Cruz, R and K Karikari, T and Ibañez, A and Zetterberg, H and A Pascoal, T and Duran-Aniotz, C and Slachevsky, A},
title = {Plasma ATN biomarkers across the alzheimer's disease continuum in a Chilean community- and clinic-based cohort.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01974-0},
pmid = {41691306},
issn = {1758-9193},
abstract = {BACKGROUND: Plasma biomarkers have emerged as robust indicators of Alzheimer's disease (AD) pathology, offering accessible tools for staging and stratification. However, their expression across globally diverse populations remains poorly characterized. The aim of this study was to evaluate whether the combination of plasma biomarkers could distinguish different stages along the AD continuum and assess their clinical associations in a Latin American cohort.

METHODS: We evaluated plasma amyloid, tau, and neurodegeneration (ATN) biomarkers in 318 older adults from a Chilean community- and clinic-based cohort, including individuals with subjective cognitive complaints (SCC), mild cognitive impairment (MCI), and Alzheimer's disease dementia (ADD), alongside cognitively unimpaired (CU) participants. Plasma ATN biomarkers (Aβ42/Aβ40, p-tau217, NfL, and GFAP) were quantified using Simoa technology. Global cognition was assessed with the Addenbrooke's Cognitive Examination (ACE), memory with the Free and Cued Selective Reminding Test (FCSRT), and functional ability with the Technology-Activities of Daily Living Questionnaire (T-ADLQ). Group differences in plasma biomarkers were examined using ANCOVA models adjusted for age, sex, and education, and associations with cognitive performance were evaluated through linear regression analyses. In addition, supervised machine-learning models were implemented to classify participants across diagnostic categories based on plasma biomarker profiles, using cross-validation to evaluate predictive performance.

RESULTS: We observed a progressive decline in the Aβ42/Aβ40 ratio and elevations in p-tau217 and GFAP across the clinical continuum. Additionally, p-tau217 and NfL levels were inversely associated with cognitive, memory, and functional performance. Notably, p-tau217 distinguished ADD from CU with high accuracy (AUC = 0.88), although its performance in earlier stages was limited.

CONCLUSION: These findings support the biological consistency of plasma biomarkers in AD-related neurodegeneration and provide novel evidence from a Latin American population. Further studies are needed to improve early-stage detection and to better understand how genetic, environmental, and health factors shape biomarker expressions in underrepresented regions.},
}

@article {pmid41691301,
year = {2026},
author = {Penny, LK and Arastoo, M and Lofthouse, R and Abdallah, A and Imoesi, PI and Schwab, K and Shiells, H and Melis, V and Riedel, G and Harrington, CR and Wischik, CM and Porter, A and Palliyil, S},
title = {Timing matters: early administration of a high-affinity antibody targeting the tau repeat domain prevents aggregation in a mouse tauopathy model.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01985-x},
pmid = {41691301},
issn = {1758-9193},
}

@article {pmid41691109,
year = {2026},
author = {Zhao, P and El Fadel, O and Le, A and Mangleburg, CG and Dhindsa, J and Wu, T and Zhao, J and Huang, M and Amoh, B and Marella, AS and Li, Y and Seyfried, NT and Levey, AI and Liu, Z and Al-Ramahi, I and Botas, J and Shulman, JM},
title = {Systems genetic dissection of brain gene expression reveals excitotoxic mechanisms of Alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41691109},
issn = {1476-5578},
support = {U01AG061357, R01AG057339, and RF1AG078660//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG10161, P30AG72975, R01AG15819, R01AG17917, U01AG46152, and U01AG61356//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30CA125123, P30CA125123, 1S10OD023469//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; RP200504//Cancer Prevention and Research Institute of Texas (Cancer Prevention Research Institute of Texas)/ ; },
abstract = {Gene expression changes likely mediate the impact of Alzheimer's disease (AD) neuropathology on cognition, but there are challenges to resolve the proximal causal pathways from postmortem brain transcriptome profiles which lack temporal resolution and are further confounded by mixed pathologies. Here, we functionally dissect 30 AD-associated human brain gene co-expression modules using fruit fly (Drosophila melanogaster) models. Integrating longitudinal RNA-sequencing and behavioral phenotyping, we interrogated the consequences of amyloid beta (Aβ) plaques, tau neurofibrillary tangles, and aging, highlighting hundreds of conserved, differentially expressed genes. To pinpoint causal modules and drivers, we manipulated 344 prioritized targets in vivo, identifying 141 modifiers of Aβ- or tau-induced neurodegeneration. We discovered an upregulated immune module enriched for AD risk variants that promotes neurodegeneration based on genetic manipulations in neurons. By contrast, a downregulated human brain synaptic regulatory network includes many loss-of-function suppressors of Aβ/tau and modulates glutamatergic hyperexcitation injury. Additional analyses support a biphasic model in which early AD pathology activates expression of a synaptic transcriptional signature that promotes neuronal injury, followed by a decrease that is compensatory. In sum, our cross-species strategy establishes a causal chain linking AD pathology, transcriptome perturbation, N-Methyl-D-Aspartate receptor excitotoxicity, and neurodegeneration.},
}

@article {pmid41690978,
year = {2026},
author = {Pan, Y and Cho, H and Lou, Q and Zhang, W and Asken, B and Song, Q},
title = {Genetic risk in Alzheimer's disease.},
journal = {NPJ systems biology and applications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41540-026-00665-8},
pmid = {41690978},
issn = {2056-7189},
abstract = {Alzheimer's disease (AD) has a strong genetic predisposition. Genome-wide association studies have identified multiple risk loci, yet many non-coding variants remain uncharacterized. Machine learning-based polygenic risk scores (PRS) enhance prediction by modeling genetic epistasis and sex-specific risks. This review summarizes AD genetic risk factors, PRS methodologies, and ML-based AD risk prediction. It also highlights challenges such as population bias, functional validation, and integrating multi-omics for precision medicine.},
}

@article {pmid41690969,
year = {2026},
author = {Lorincz-Comi, N and Song, W and Chen, X and Paz, IR and Hou, Y and Zhou, Y and Xu, J and Martin, W and Barnard, J and Pieper, AA and Haines, JL and Chung, MK and Cheng, F},
title = {Combining xQTL and genome-wide association studies from diverse populations improves druggable gene discovery.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-69236-z},
pmid = {41690969},
issn = {2041-1723},
support = {R01AG066707//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG084250//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG076448//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG082118//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG092462//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG092591//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1AG082211//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R33AG083003//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P01HL158501//U.S. Department of Health Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; },
abstract = {Repurposing existing medicines to target disease-associated genes represents a promising strategy for developing effective treatments for complex diseases. However, progress has been hindered by a lack of viable candidate drug targets identified through genome-wide association studies. Gene-based association tests provide a more powerful alternative to traditional SNP-based methods, yet current approaches often fail to leverage shared heritability across populations and to effectively integrate functional genomic data. To address these challenges, we develop GenT and its various extensions, comprising a framework of gene-based tests utilizing summary-level data from genome-wide association studies. Using GenT, we identify 16, 15, 35, and 83 candidate genes linked to Alzheimer's disease, amyotrophic lateral sclerosis, major depression, and schizophrenia, respectively, not detected by Genome-Wide Association Studies (GWAS). Additionally, we use our multi-ancestry gene-based test (MuGenT) to identify 28 candidate genes associated with type 2 diabetes. By integrating brain expression and protein quantitative trait loci into our analysis, we identify 43 candidate genes associated with Alzheimer's disease that have supporting xQTL evidence. We also perform experimental assays to demonstrate that the NTRK1 inhibitor GW441756 significantly reduces tau hyper-phosphorylation (including p-tau181 and p-tau217) in Alzheimer's disease patient-derived iPSC neurons, providing mechanistic support for our predictions.},
}

@article {pmid41690817,
year = {2026},
author = {Yang, Y and Bhullar, R and Conde, S and , },
title = {Spatial abilities in aging adults with Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71159},
doi = {10.1002/alz.71159},
pmid = {41690817},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; UO1 AG051406//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; UO1 AG051412//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; },
mesh = {Humans ; *Down Syndrome/psychology/complications/physiopathology ; Male ; Female ; Middle Aged ; *Aging/physiology ; *Cognitive Dysfunction/diagnosis/physiopathology ; Neuropsychological Tests/statistics & numerical data ; Aged ; Adult ; *Space Perception/physiology ; *Alzheimer Disease/diagnosis ; },
abstract = {INTRODUCTION: People with Down syndrome (DS) have a higher likelihood of developing Alzheimer's disease (AD). Deficits in spatial abilities could serve as early indicators of AD. We examined age effects on visuospatial construction and visuomotor integration in DS and whether spatial tasks could distinguish various extents of cognitive decline in DS.

METHODS: We used the Alzheimer's Biomarkers Consortium-Down Syndrome project dataset, where 376 DS participants completed a series of cognitive measures.

RESULTS: Age effects were found in visuomotor integration but not in visuospatial construction. Both abilities declined with AD progression. While both abilities showed relatively poor discrimination between cognitively stable (CS) and mild cognitive impairment (MCI) and between MCI and AD, they showed excellent or acceptable discrimination between CS and AD. Visuospatial construction showed better discrimination than visuomotor integration.

DISCUSSION: Visuomotor integration declines more with aging than visuospatial construction in DS. When used alone, neither may effectively diagnose cognitive decline in DS.

HIGHLIGHTS: We examined two spatial abilities in aging adults with Down syndrome using the ABC-DS project. Age effects were found in visuomotor integration. Age effects were not found in visuospatial construction abilities. Both visuomotor integration and visuospatial construction abilities distinguished between CS and AD in people with DS. Block Design had the highest predictive power in distinguishing cognitive stability from AD.},
}

Humans
*Down Syndrome/psychology/complications/physiopathology
Male
Female
Middle Aged
*Aging/physiology
*Cognitive Dysfunction/diagnosis/physiopathology
Neuropsychological Tests/statistics & numerical data
Aged
Adult
*Space Perception/physiology
*Alzheimer Disease/diagnosis

@article {pmid41690816,
year = {2026},
author = {Shishegar, R and Doecke, JD and Lim, YY and Bourgeat, P and Dore, V and Tallapragada, B and Laws, SM and Porter, T and Burnham, S and Feizpour, A and Gillman, A and Weiner, M and Hassenstab, J and Rowe, CC and Villemagne, VL and Masters, CL and Fripp, J and Sohrabi, H and Maruff, P and , },
title = {Harmonizing neuropsychological test data across prospective studies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71186},
doi = {10.1002/alz.71186},
pmid = {41690816},
issn = {1552-5279},
support = {P50 AG00561/GF/NIH HHS/United States ; P30 NS09857781/GF/NIH HHS/United States ; P01 AG026276/GF/NIH HHS/United States ; P01 AG003991/GF/NIH HHS/United States ; R01 AG043434/GF/NIH HHS/United States ; UL1 TR000448/GF/NIH HHS/United States ; R01 EB009352/GF/NIH HHS/United States ; 5R01AG058676/GF/NIH HHS/United States ; 1156891//NHMRC/ ; 1132604//NHMRC/ ; 1156891//National Health and Medical Research Council/ ; 1132604//National Health and Medical Research Council/ ; 1140853//National Health and Medical Research Council/ ; 1152623//National Health and Medical Research Council/ ; /NH/NIH HHS/United States ; /AG/NIA NIH HHS/United States ; //Department of Defense/ ; //California Department of Public Health/ ; //University of Michigan/ ; //Hillblom Foundation/ ; /ALZ/Alzheimer's Association/United States ; //Johnson & Johnson/ ; //Kevin and Connie Shanahan/ ; //GE/ ; //VUmc/ ; //Australian Catholic University/ ; //Stroke Foundation/ ; //Veterans Administration/ ; },
mesh = {Humans ; *Neuropsychological Tests/statistics & numerical data/standards ; *Alzheimer Disease/diagnosis/psychology ; Male ; Female ; Aged ; Prospective Studies ; Neuroimaging ; Australia ; Machine Learning ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) research relies on large datasets and advanced statistical models. However, individual population studies often lack sufficient sample size for conclusive results. Harmonizing cognitive test data across studies can address this gap, despite differences in testing protocols. This study harmonizes cognitive data from three major AD cohorts to support robust clinical-pathological modelling.

METHODS: Information from the Alzheimer's Disease Neuroimaging Initiative (N = 1446); Australian Imaging, Biomarkers and Lifestyle (N = 1764); and Open Access Series of Imaging Studies-3 (N = 440) were integrated, including cognitive scores, demographics, genetics, and clinical and neuroimaging data. Neuropsychological tests relevant to AD were harmonized using MissForest, a machine learning-based imputation method. Validation involved assessing imputation accuracy and analyzing composite cognitive scores across clinical-pathological groups.

RESULTS: Imputation showed high accuracy (mean absolute error ≤ test-retest variability in cognitively unimpaired participants). Composite scores reflected known disease patterns with significant stratification across clinical-pathological groups.

DISCUSSION: The validated harmonization approach demonstrated reliable imputation, enabling more powerful AD models and supporting future diagnostic and therapeutic advances.},
}

Humans
*Neuropsychological Tests/statistics & numerical data/standards
*Alzheimer Disease/diagnosis/psychology
Male
Female
Aged
Prospective Studies
Neuroimaging
Australia
Machine Learning
Aged, 80 and over

@article {pmid41690814,
year = {2026},
author = {Fung, M and Chai, YL and Cheng, YL and Tabassum, N and Lim, VJT and Kalaria, RN and Jo, DG and Chen, CP and Lai, MKP and Arumugam, TV},
title = {Characterizing TDP-43 involvement in vascular dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71196},
doi = {10.1002/alz.71196},
pmid = {41690814},
issn = {1552-5279},
support = {2019100//National Health and Medical Research Council of Australia/ ; MOH-001086-00//National Medical Research Council of Singapore/ ; },
mesh = {*Dementia, Vascular/metabolism/pathology ; *DNA-Binding Proteins/metabolism ; Humans ; Animals ; *Brain/metabolism/pathology ; Aged ; Female ; Male ; Phosphorylation ; Neurons/metabolism/pathology ; Disease Models, Animal ; Aged, 80 and over ; Carotid Stenosis/complications ; },
abstract = {INTRODUCTION: Vascular dementia (VaD) is a major therapeutic challenge. Tar DNA-binding protein 43 (TDP-43), known for its role in neurodegeneration, may contribute to VaD pathogenesis under chronic cerebral hypoperfusion (CCH). This study investigates TDP-43 dysregulation in VaD.

METHODS: TDP-43 and phosphorylated TDP-43 (pTDP-43) expression and localization were assessed in a VaD animal model, neuronal cells exposed to oxygen-glucose deprivation (OGD), and post mortem human brain tissues.

RESULTS: Bilateral Common Carotid Artery Stenosis (BCAS)-induced CCH led to increased pTDP-43 and aberrant redistribution of both TDP-43 and pTDP-43. In vitro OGD triggered similar mislocalization. Post mortem VaD brains showed no TDP-43 abnormalities, while Alzheimer's and mixed dementia cases exhibited marked pathology.

DISCUSSION: TDP-43 dysregulation appears early in VaD under hypoperfusive stress, distinguishing it from other dementia subtypes. These findings indicate that TDP‑43 may warrant further investigation as a potential early molecular feature of VaD.

HIGHLIGHTS: Tar DNA-binding protein 43 (TDP-43) is dysregulated early in vascular dementia models. Hypoperfusion triggers TDP-43 mislocalization and phosphorylation. TDP-43 pathology is absent in late-stage human vascular dementia. TDP-43 is a transient, novel target for vascular cognitive impairment.},
}

*Dementia, Vascular/metabolism/pathology
*DNA-Binding Proteins/metabolism
Humans
Animals
*Brain/metabolism/pathology
Aged
Female
Male
Phosphorylation
Neurons/metabolism/pathology
Disease Models, Animal
Aged, 80 and over
Carotid Stenosis/complications

@article {pmid41690676,
year = {2026},
author = {Trainum, K and Stuifbergen, A and Becker, H and Morgan, S},
title = {Statewide Examination of Rural-Urban Differences in Assisted Living Facilities.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {106121},
doi = {10.1016/j.jamda.2026.106121},
pmid = {41690676},
issn = {1538-9375},
abstract = {OBJECTIVES: To compare facility characteristics between rural and urban assisted living facilities (ALFs).

DESIGN: A descriptive, cross-sectional study.

SETTING AND PARTICIPANTS: A convenience sample of 517 ALFs (143 rural) that included facilities from all public health regions in Texas.

METHODS: Survey data were collected from administrative staff at each facility. Data were analyzed using descriptive statistics, χ[2] analysis, and Mann-Whitney U tests.

RESULTS: Overall, rural areas had relatively more Type A and fewer Type B facilities (the latter require 24-hour attendants) than did urban areas. Rural facilities (vs urban) also had significantly fewer Alzheimer's disease certifications and licensed beds. Provided services differed significantly between rural and urban facilities: urban facilities more often offered concierge, medical, and nursing services, whereas rural facilities more often provided transportation, wound care, and physical/occupational therapy. Antipsychotic use was high across all facilities (26.6%), but only 38.5% reported initiating gradual dose reductions.

CONCLUSIONS AND IMPLICATIONS: Findings highlight rural-urban differences in service availability and dementia care. Combined with high rates of antipsychotic use, these findings suggest a need for policy reforms, especially as resident acuity in ALFs increases. Additional research is needed to improve ALF quality measurement and to better understand factors influencing care quality in rural and urban settings.},
}

@article {pmid41690630,
year = {2026},
author = {Hwang, G and Blair, NO and Claesges, SA and Reynolds, CF and Davatzikos, C and Goveas, JS},
title = {Accelerated brain aging in prolonged grief disorder of later life: Influence of comorbid depression.},
journal = {Journal of affective disorders},
volume = {},
number = {},
pages = {121387},
doi = {10.1016/j.jad.2026.121387},
pmid = {41690630},
issn = {1573-2517},
abstract = {BACKGROUND: Prolonged Grief Disorder (PGD) in later life may involve volumetric patterns indicative of accelerated brain aging. This study examined whether structural brain age differs between individuals with PGD and those with integrated grief (IG), and whether it is associated with clinical severity.

METHODS: Chronically grieving older adults with PGD (n = 36) and IG (n = 56), equated on demographics and time since loss, underwent structural MRI. Machine learning-derived indices were computed for each participant: Brain Age Gap (SPARE-BAG), Alzheimer's disease-like atrophy (SPARE-AD), and five dominant brain aging patterns. Group differences and associations with symptom severity were assessed, along with moderation by age, cognitive status, medical burden, and current and past depression.

RESULTS: Compared to IG, the PGD group showed significantly higher SPARE-BAG (t = 2.61, pcorrected = 0.021), SPARE-AD (t = 2.04, pcorrected = 0.045), and medial temporal lobe atrophy pattern (t = 3.44, pcorrected = 0.005). However, these findings were attenuated and no longer significant after accounting for comorbid depressive symptoms. In the PGD group, both SPARE scores positively correlated with grief and depressive symptom severity (pcorrected < 0.03). The SPARE-BAG-grief symptom association was moderated by younger age (z = -2.92, pFDR = 0.018) and higher depressive symptoms (z = 1.88, p = 0.061); SPARE-AD-depressive symptom correlation was moderated by past depression history (z = 2.64, pcorrected = 0.041).

CONCLUSION: Adults with PGD exhibit structural brain patterns consistent with accelerated and AD-like aging. However, these findings were largely driven by comorbid depressive symptoms. The brain aging indices were associated with both grief and depressive symptom severity, highlighting the cumulative neurobiological burden associated with PGD and co-occurring depression and underscoring the need for integrative clinical approaches addressing both conditions.},
}

@article {pmid41690530,
year = {2026},
author = {Swart, DH and Stevens, J and de Haan, M and Ulu, N and Henning, RH and van der Graaf, AC and Touw, DJ and Mian, P and Krenning, G},
title = {Absorption, distribution, metabolism and excretion of SUL-138 in rats and minipigs.},
journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences},
volume = {},
number = {},
pages = {107469},
doi = {10.1016/j.ejps.2026.107469},
pmid = {41690530},
issn = {1879-0720},
abstract = {SUL-138 is an orally bioavailable 6-chromanol which is in development as therapeutic against Noncommunicable Chronic Diseases (NCDs) including Chronic Heart Failure, Chronic Kidney Disease, Alzheimer's and Parkinson's Disease. The compound improves mitochondrial function by preserving respiration through activation of complex I and IV during disease. Thorough comprehension of preclinical Absorption, Distribution, Metabolism and Excretion (ADME) is pivotal for the safety assessment prior to starting Phase I clinical trials. To this end, a single oral or intravenous dose of [[14]C]-SUL-138 at a therapeutic and near Maximum Tolerated Dose (MTD) dose level were administered to rats and minipigs for characterization of ADME properties. Non-radiolabelled SUL-138 and radiolabelled [[14]C]-SUL-138 were administered as single oral or intravenous dose to intact and bile duct-canulated rats and to minipigs to investigate pharmacokinetics of total radioactivity and SUL-138, tissue distribution by Quantitative Whole-Body Autoradiography (QWBA), excretion and metabolite profiling. The pharmacokinetic profiles of [[14]C]-SUL-138 and SUL-138 indicated rapid absorption, tissue distribution and extensive metabolism in both species. In rats, the QWBA showed that drug-related radioactivity was widely distributed throughout nearly all tissues shortly after dosing. Total radioactivity was completely eliminated; in rats excretion was mainly via the faecal route, whereas in minipigs elimination was equal between the faecal and renal excretory routes. Primary metabolic pathways for clearance of SUL-138 were oxidation, N-dealkylation and glucuronidation. Plasma exposure to the parent was low compared to the main circulating oxidation metabolite M2 and glucuronide conjugate M7 in rats and glucuronide conjugates M7 and M8 in minipigs. In conclusion, ADME properties of SUL-138 are characterized by rapid absorption, wide tissue distribution, extensive metabolism and excretion via the renal and faecal route. Oxidation and glucuronidation are the main metabolic pathways in both nonclinical safety species.},
}

@article {pmid41690259,
year = {2026},
author = {Eckenweber, S and Völter, F and Franzmeier, N and Palleis, C and Wagemann, O and Weidinger, E and Katzdobler, S and Wlasich, E and Sandkühler, K and Böning, G and Gnörich, J and Scheifele, M and Eckenweber, F and Janowitz, D and Kurz, C and Perneczky, R and Bürger, K and Danek, A and Höglinger, G and Levin, J and Brendel, M and Schönecker, S},
title = {Additive value of early-phase β-Amyloid-PET for the differential diagnosis of non-Alzheimer's disease dementia.},
journal = {NeuroImage. Clinical},
volume = {49},
number = {},
pages = {103963},
doi = {10.1016/j.nicl.2026.103963},
pmid = {41690259},
issn = {2213-1582},
abstract = {PURPOSE: Recent studies demonstrated strong agreement between early-phase β-amyloid-PET perfusion imaging and glucose hypometabolism assessed by [[18]F]FDG-PET, indicating the potential of early-phase β-amyloid-PET as a surrogate biomarker of neuronal injury. We therefore aimed to investigate the additive value of early-phase β-amyloid-PET for the differential diagnosis of non-Alzheimer's disease dementia syndromes in clinical routine.

MATERIALS AND METHODS: [[18]F]florbetaben- and [[18]F]flutemetamol-PET scans (n = 379) performed between July 2013 and July 2021 were analyzed for their amyloid status and the presence of a neurodegenerative hypoperfusion pattern using visual assessment and z-score maps. In patients visually rated as amyloid-negative/neurodegeneration-positive (A-N+), the most likely diagnosis based on perfusion patterns was compared to the final clinical diagnosis, i.e. frontotemporal dementia or psychiatric disorders, suspected 4R-tauopathy, and suspected non-Alzheimer pathophysiology. Logistic regression models based on a data-driven selection of cerebral regions of hypoperfusion by principal component analysis were used to predict neurodegenerative disease and clinical diagnoses. Diagnostic accuracy was compared between visual assessment and the regression models.

RESULTS: Neurodegeneration status was correctly identified in 78.8% (119/151) of amyloid-negative patients through visual rating, compared to 67.5% (102/151) using logistic regression. Visual assessment assigned 75.3% (67/89) of A-N+ patients to the correct diagnostic category. In contrast, the regression model classified 69.7% (62/89) of patients.

CONCLUSIONS: The current study demonstrates an additive value of early-phase β-amyloid-PET for the differential diagnosis of dementia syndromes. While visual assessment of early-phase β-amyloid-PET already provides substantial diagnostic accuracy, a data-driven analysis approach could aid in cases of uncertainty.},
}

@article {pmid41690071,
year = {2026},
author = {El-Moaty, HIA and Sameh, A and Saber, S and Hamad, RS and Elmorsy, EA and Alsoqih, NS and Farrag, AA and Eissa, H and El-Kott, AF and Negm, S and AlShehri, MA and Ali, MAM and Hasan, WA and Gaafar, A and Khalifa, HS and Ibrahim, EH and Morsy, K and Elnaghy, F},
title = {Adenosine A2A receptor as a dual-acting molecular switch: Glial morphological changes and neurovascular tissue remodeling in neuroinflammation and neurodegeneration.},
journal = {Tissue & cell},
volume = {100},
number = {},
pages = {103389},
doi = {10.1016/j.tice.2026.103389},
pmid = {41690071},
issn = {1532-3072},
abstract = {Neuroinflammation appears in a variety of neurological disorders, including multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis. The adenosine A2A receptor (A2AR), a Gs protein-coupled receptor that affects cAMP signaling and downstream kinases like PKA, CREB, and NF-κB, is one of the primary regulators of this process. Context-dependent effects of A2AR activation include lowering acute inflammation and promoting neuronal survival when stimulated moderately, but increasing glial activation and cytokine production when overexpressed over an extended period of time. In microglia and astrocytes, A2AR signaling regulates inflammatory pathways mediated by NF-κB and MAPK, affecting oxidative stress, blood-brain barrier (BBB) stability, and excitotoxicity. Acute or transient (short-term) A2AR activation, on the other hand, increases the production of anti-inflammatory cytokines like IL-10 and enhances neurotrophic support through BDNF. A2AR antagonists, including istradefylline and SCH58261, may reduce microglial triggering and have neuroprotective benefits, according to clinical and experimental data. The context-dependent activity of the receptor is shown by the fact that total receptor blockage interferes with adaptive immune control. Therefore, the therapeutic challenge is to carefully modify A2AR signaling in particular cell populations, specifically targeting astrocytic or microglial receptors while maintaining the peripheral immunoregulatory activities. The dual regulatory role of A2AR in neuroinflammation is summarized in this review along with its molecular mechanisms, disease-specific actions, and therapeutic significance. Developing next-generation neuroprotective strategies that reduce A2AR signaling's pro-inflammatory and neurotoxic effects while preserving its beneficial homeostatic effects will require an understanding of the temporal and cell-specific dynamics of this signaling.},
}

@article {pmid41689888,
year = {2026},
author = {Perry, R and Kipps, C and Soto Martín, ME and Bozzali, M and Logroscino, G and Trafford, S and Dhadda, S and Kanekiyo, M and Goodwin, A and Hodgkinson, M and Hersch, S and Irizarry, M and Kramer, L and Froelich, L},
title = {Lecanemab for treatment of individuals with early Alzheimer's Disease (AD) who are apolipoprotein E ε4 (ApoE ε4) non-carriers or heterozygotes.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {4},
pages = {100507},
doi = {10.1016/j.tjpad.2026.100507},
pmid = {41689888},
issn = {2426-0266},
abstract = {BACKGROUND: Lecanemab, an antibody directed at Aβ-protofibrils and plaque, showed meaningful delay in disease progression and biological effects consistent with disease modification in the phase 3 Clarity AD trial.

OBJECTIVE: The objective of this paper is to present efficacy and safety results in ApoE ε4 non-carriers or heterozygotes population of Clarity AD.

DESIGN: Clarity AD is an 18-month, randomized study (core) in participants with early AD, with an open-label extension phase (OLE) phase.

SETTING: Academic and clinical centers.

PARTICIPANTS: All eligible ApoE ε4 participants were randomized 1:1 across 2 treatment groups (placebo and lecanemab 10 mg/kg biweekly); the results presented herein are for the ApoE4 heterozygote or non-carrier participants.

MEASUREMENTS: Endpoints included change from baseline at 18 months in the global cognitive and functional scale, CDR-SB, amyloid positron emission tomography (PET), Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14), Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL), and health-related quality-of-life (HRQoL) assessments. Amyloid imaging related abnormalities (ARIA) occurrence was monitored throughout the study by central reading of magnetic resonance imaging. Following 18 months treatment in the Core, eligible participants transitioned to the OLE where they received open-label lecanemab. Clinical outcomes (CDR-SB, ADAS-Cog14, and ADCS-MCI-ADL) were evaluated by examining 'delayed start' (core:placebo followed by OLE:lecanemab) and 'early start' (core:lecanemab followed by OLE:lecanemab) cohorts as well as natural history cohorts. Time to progression to next stage of AD was also evaluated through 36 months.

RESULTS: 1795 participants with early AD were enrolled in Clarity AD, of which 1521 were ApoE ε4 heterozygotes or non-carriers (85 %). Lecanemab significantly reduced clinical decline on CDR-SB at 18 months compared to placebo in the ApoEε4 heterozygotes or non-carriers subgroup. Amyloid PET, ADAS-Cog14, ADCS-MCI-ADL, and HRQoL results were consistent with the CDR-SB findings. In the analysis subgroup, the most common adverse reactions for lecanemab were infusion-related reactions (26 %), ARIA-H (13 %), fall (11 %), headache (11 %), and ARIA-E (9 %). In the OLE, lecanemab-treated participants continued to accrue benefit in CDR-SB through 36 months, with continued separation through 36 months relative to the ADNI natural history cohort. Delayed start results follow a parallel trajectory relative to early start results, but do not catch up, confirming a disease modifying effect and reflecting importance of early treatment initiation. Results were similar for ADAS-Cog14 and ADCS-MCI-ADL. Lecanemab reduced the risk of progression to next stage of AD by 28 % on lecanemab as compared to the ADNI natural history cohort.

CONCLUSION: In the ApoE ε4 heterozygotes or non-carrier subgroup of Clarity AD, lecanemab slowed decline in disease progression and reduced markers of amyloid, with expanding benefit over time.

GOV IDENTIFIER: Clarity AD NCT03887455.},
}

@article {pmid41689887,
year = {2026},
author = {Lephart, ED and Hedges, DW and Naftolin, F and Draelos, ZD},
title = {The future of HRT/MHT and Alzheimer's disease risk, onset and progression.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {4},
pages = {100508},
doi = {10.1016/j.tjpad.2026.100508},
pmid = {41689887},
issn = {2426-0266},
}

@article {pmid41689882,
year = {2026},
author = {Hanazawa, R and Sato, H and Suzuki, K and Hirakawa, A},
title = {Applying a statistical model-based AI method to identify prognostic factors for long-term cognitive decline in Alzheimer's disease: Evidence from pooled placebo data of four phase III trials.},
journal = {International journal of medical informatics},
volume = {211},
number = {},
pages = {106337},
doi = {10.1016/j.ijmedinf.2026.106337},
pmid = {41689882},
issn = {1872-8243},
abstract = {BACKGROUND: Heterogeneity in the long-term progression of Alzheimer's disease (AD) challenges the efficiency of clinical trials. Identifying long-term prognostic factors is critical for enhancing trial efficiency, although it has been limited by the lack of appropriate statistical approaches. We applied a recently developed statistical model-based AI method to identify the baseline prognostic factors for long-term cognitive decline in a clinical trial population.

METHODS: We analyzed pooled placebo arm data (N = 1,597) from four Phase III trials in patients with mild-to-moderate AD. Long-term trajectories for the Mini-Mental State Examination (MMSE), 11- and 14-item versions of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog11, ADAS-Cog14), and Clinical Dementia Rating-Sum of Boxes (CDR-SB) were predicted from their short-term data (≤80 weeks). Trajectories were compared between subgroups defined by six baseline factors (age, sex, apolipoprotein E ε4 [APOE ε4] status, years of education, years from diagnosis, and years from disease onset) using the area under the curve (AUC).

RESULTS: Longer years of education (≥13 years) was the most robust predictor associated with faster progression across all four outcomes (e.g., for 20-year ADAS-Cog11, AUC ratio, 1.11, p < 0.001). Younger age (<74 years) was associated with a faster decline in MMSE and ADAS-Cog scores, but not in CDR-SB. APOE ε4 status, sex, years from diagnosis, and years from disease onset were not significantly associated with long-term progression.

CONCLUSIONS: Baseline educational level and age were significant prognostic factors of long-term cognitive decline. These findings will help optimize patient stratification in future clinical trials on AD.},
}

@article {pmid41689708,
year = {2026},
author = {Huang, H and Cheng, S and Lu, W and Gao, X and Liu, Z and , },
title = {Elevated branched-chain amino acids linked to hippocampal volumes and cognitive improvement in mild cognitive impairment.},
journal = {Brain imaging and behavior},
volume = {20},
number = {1},
pages = {15},
pmid = {41689708},
issn = {1931-7565},
support = {2022ZDYF22//Key Science & Technologies R&D Program of Lishui City/ ; 2022ZDYF22//Key Science & Technologies R&D Program of Lishui City/ ; 2022ZDYF22//Key Science & Technologies R&D Program of Lishui City/ ; 2022ZDYF22//Key Science & Technologies R&D Program of Lishui City/ ; 2022ZDYF22//Key Science & Technologies R&D Program of Lishui City/ ; },
}

@article {pmid41689668,
year = {2026},
author = {Sui, Y and Zhang, N and Chen, X and Tortorella, MD and He, J},
title = {Entorhinal Cholecystokinin in Alzheimer's Disease: Its Earliest Vulnerability and Rescue Effects Across Different Disease Stages in a Mouse Model.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01689-8},
pmid = {41689668},
issn = {1573-6830},
support = {CityUHK 11103922, CityUHK 11104923, CityUHK 11104524//Hong Kong Research Grants Council, General Research Fund/ ; C1043-21G, C1002-24W//Hong Kong Research Grants Council, Collaborative Research Fund/ ; SRFS2324-1S02//Hong Kong Research Grants Council, Senior Research Fellow Scheme/ ; 09203656//Hong Kong Health Bureau, Health and Medical Research Fund/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. The entorhinal cortex (Ent) is among the earliest affected regions, and its neuropeptide cholecystokinin (CCK) supports neocortical-associated memory. Although our previous work demonstrated that CCK treatment rescues cognition and neuroplasticity in aged AD mice, the correlations among CCK expression, synaptic function, and cognitive decline with aging remain poorly understood. Using 3xTg-AD mice (2-18 months), we performed stereological, histological, and molecular analyses to evaluate brain atrophy, neuronal loss, glial responses, and gene expression. Cognitive function was assessed using the novel object recognition test (NOR), motor learning was evaluated using the rotarod test, and synaptic integrity was measured via electrophysiological recordings. We also investigated the therapeutic potential of CCK-B receptor (CCK-BR) agonists on learning and memory and neuroplasticity across disease stages of AD. In 3xTg-AD mice, the Ent exhibits significant atrophy and excitatory neuronal loss as early as 7 months of age, confirming its role as one of the earliest and most severely affected regions in AD. CCK was downregulated earlier than other synaptic genes in the Ent and other brain regions. Cholecystokinin tetrapeptide (CCK-4) treatment rescued deficits in synaptic plasticity, cognition, and motor learning in 3xTg-AD mice across multiple disease stages. Long-term administration of HT-267, a CCK-BR agonist with a prolonged half-life, in young 3xTg-AD mice delayed cognitive decline, enhanced synaptic scaffolding, and restored long-term potentiation in both the cortex and hippocampus (HPC). Our findings identify CCK downregulation as an early biomarker in AD and demonstrate the therapeutic effects of CCK-BR agonists in mitigating cognitive and synaptic deficits from mild to severe disease stages. The ability of long-term CCK-4 analogue treatment to decelerate AD progression indicates its promise as an early intervention strategy.},
}