@article {pmid41566336,
year = {2026},
author = {Götze, K and Vrillon, A and Sanchez, M and Petit-Damico, I and Bouaziz-Amar, E and Lacaille, S and Hourrègue, C and Cognat, E and Hugon, J and Decaix, T and Dumurgier, J and Raynaud-Simon, A and Lilamand, M and Paquet, C},
title = {Association of Alzheimer's disease biomarkers with malnutrition and altered body composition in cognitively impaired patients: a cross-sectional memory clinic study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01965-1},
pmid = {41566336},
issn = {1758-9193},
}

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

@article {pmid41565970,
year = {2026},
author = {Agrawal, R and Dhule, C and Shukla, G and Singh, S and Agrawal, U and Allabun, S and Othman, M and Bayisenge, L},
title = {Iterative multiblock framework for high frequency EEG based neurological disorder detection.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-37126-5},
pmid = {41565970},
issn = {2045-2322},
abstract = {It has become pertinent to develop early and accurate diagnosis tools for these neurological diseases, such as Alzheimer's and Parkinson's. The diagnosis may be high frequency electroencephalogram (EEG) signal based. These techniques promise good results but fail to obtain the desired clinically relevant features because of the intrinsically non-stationary and noisy nature of high frequency EEG components. Limitations of existing methods include suboptimal signal processing, ineffective strategies for feature selection, lack of robustness in feature fusion mechanisms, and limited explainability for clinical adoptions. This work, therefore, proposes a holistic framework in the context of clinical detection of neurological disorders using high frequency EEG signals which are enhanced as a pipeline of multi-blocks. The combination of Hilbert-Huang transform (HHT) with a modified empirical mode decomposition ensures that the decomposition is adaptive in nature and effective noise reduction leads to preprocessing of the data. Wavelet Packets transform (WPT) in conjunction with shannon entropy-based feature selection reduces the dimensions of the data without information loss, which aids in meaningful extraction of temporal and frequency domain features. Canonical correlation analysis with multi-view representation learning allows integration of EEG features along with clinical metadata as auxiliary information to create a common feature space for increased sensitivity in diagnosis. A new multi-scale convolutional recurrent neural network (MS-CRNN) uses an attention mechanism to process the combined features and find spatiotemporal dependencies while focusing on patterns that are important for diagnosis. The method is demonstrated through grad-cam and integrated gradient techniques that help in visualizing and quantitatively attributing feature extraction. This method was 94% accurate; 92% sensitive; and 93% specific when identifying issues early on. The high accuracy in making clinical interpretation and diagnosis has set a new bar for clinicians and has encouraged public policy to support early intervention.},
}

@article {pmid41565539,
year = {2026},
author = {Zhang, J and Zhao, X and Xu, H and Liu, X and He, Y and Tan, X and Gu, J},
title = {Corrigendum to "NMN synbiotics intervention modulates gut microbiota and metabolism in APP/PS1 Alzheimer's disease mouse models" [Biochem. Biophys. Res. Commun. 726 (2024) 150-274].},
journal = {Biochemical and biophysical research communications},
volume = {},
number = {},
pages = {153298},
doi = {10.1016/j.bbrc.2026.153298},
pmid = {41565539},
issn = {1090-2104},
}

@article {pmid41565513,
year = {2026},
author = {Liu, X and Li, Y and Yu, Q and Su, Y},
title = {Mapping the future of Alzheimer's disease research: Insights from global clinical trial data.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100185},
doi = {10.1016/j.inpsyc.2026.100185},
pmid = {41565513},
issn = {1741-203X},
}

@article {pmid41565509,
year = {2026},
author = {Lee, NC and Lin, CH and Chien, YH and Hwu, WL},
title = {Genetic testing for adult-onset neurodegenerative diseases: A clinical perspective.},
journal = {Journal of the Formosan Medical Association = Taiwan yi zhi},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jfma.2026.01.021},
pmid = {41565509},
issn = {0929-6646},
abstract = {Adult-onset neurodegenerative diseases (AOND), such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, severely affect patients' quality of life. Pathogenic single-nucleotide variations (SNVs) and small insertions and deletions (indels) can disrupt genes involving ANOD, and expansion of short tandem repeats such as trinucleotide repeats is an important etiology of hereditary ataxia. Variations in more than one gene combined to create polygenic risk scores (PRS) for multifactorial types of AOND. Recently, genome structural variations (SVs) like copy number variations (CNVs) and expansion of long repeats are increasingly identified as the etiologies of AOND. Tools for molecular diagnosis of AOND have evolved from Sanger sequencing to next-generation sequencing (NGS) such as short-read whole-exome sequencing (WES) and whole-genome sequencing (WGS), and long-read sequencing is especially helpful in solving SVs and expansions of long repeats. Patients might have affected and/or at-risk family members at the time of diagnosis, so genetic counseling for risk handling and birth planning need to be conducted with caution. This review will help readers to better understand the genetic testing for AOND.},
}

@article {pmid41565476,
year = {2026},
author = {Li, X and Xie, M and Ibáñez, CF},
title = {Amelioration of symptomatic Alzheimer's Disease after selective impairment of p75[NTR] function in adult forebrain excitatory neurons.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.1939-25.2026},
pmid = {41565476},
issn = {1529-2401},
abstract = {The p75 neurotrophin receptor (p75[NTR]) contributes to the development of Alzheimer's Disease (AD) pathology by enhancing amyloid precursor protein (APP) cleavage and amyloid plaque formation. However, the cell type-specific and temporal roles of p75[NTR] in AD progression remain unclear. Here, we report that conditional knock-in of functionally impaired p75[NTR] variants lacking the death domain (ΔDD) or transmembrane Cys[259] (C259A) specifically in forebrain excitatory neurons of male and female 5xFAD mice significantly attenuated multiple AD-associated pathologies, including amyloid plaque accumulation, gliosis, neurite dystrophy, as well as learning and memory deficits. Hippocampal amyloid plaque burden was reduced to levels comparable to those found in whole-body knock-in mice. Strikingly, delaying introduction of p75[NTR] variants until advanced disease stages produced comparable beneficial effects, and rescued behavior performance in cognitively impaired animals. These findings suggest that blunting p75[NTR] function can have beneficial effects even during symptomatic stages of AD, offering a potential therapeutic approach complementary to passive vaccination.Significance Statement Inactivation of p75[NTR] has been reported to show various degrees of neuroprotection in Aβ-based mouse models of AD. As p75[NTR] is expressed in several different cell types in the brain, it has been unclear whether the beneficial effects afforded arose from all cell types or only one. For therapeutic approaches to be viable in AD patients, any form of interference with its activity needs to demonstrate beneficial effects during symptomatic stages of the disease. Here, we show that replacement of native p75[NTR] with signaling-impaired variants in forebrain excitatory neurons is sufficient to significantly alleviate neuropathological and behavioral outcomes in 5xFAD mice. Moreover, significant amelioration of neuropathology and cognitive deficits were achieved after acute disruption of p75[NTR] during symptomatic AD stages.},
}

@article {pmid41565468,
year = {2026},
author = {Ren, Y and Hu, M and Li, YE and Pieper, AA and Cummings, J and Cheng, F},
title = {Cell type-specific gene regulatory atlas prioritizes drug targets and repurposable medicines in Alzheimer's disease.},
journal = {Genome research},
volume = {},
number = {},
pages = {},
doi = {10.1101/gr.280436.125},
pmid = {41565468},
issn = {1549-5469},
abstract = {Alzheimer's disease (AD) is a complex and poorly understood neurodegenerative disorder that lacks sufficiently effective treatments. Computational and integrative analyses that leverage multiomics data provide a promising strategy to uncover disease mechanisms and identify therapeutic opportunities. Here, we develop a cell type-specific regulatory atlas of the human middle temporal gyrus via leveraging single-nucleus RNA-seq (1,197,032 nuclei) and ATAC-seq (740,875 nuclei) datasets from 84 donors across four stages of AD neuropathological change (ADNC). We observe differential gene expression for six major cell types intensified at severe ADNC. Integrating peak-to-gene linkages and motif enrichment analyses, we reconstruct transcription factor (TF)-target gene networks across six major brain cell types. By integrating genome-wide association study (GWAS) loci with cell type-specific cis-regulatory DNA elements (CREs), we pinpoint 141 ADNC-associated genes. Using gene set enrichment analysis (GSEA) and network proximity analysis, we further identify nine candidate repurposable drugs that were associated with these ADNC-related genes. In summary, this cell type-specific multiomics atlas provides a comprehensive resource for mechanistic understanding, target prioritization, and therapeutic hypothesis generation in AD and AD-related dementia if broadly applied.},
}

@article {pmid41565461,
year = {2026},
author = {Murakami, R and Chiba, Y and Miyai, Y and Matsumoto, K and Wakamatsu, K and Saito, Y and Hara, M and Murayama, S and Ueno, M},
title = {Immunohistochemical Analysis of Tom20 in Choroid Plexus Epithelial Cells From Elderly Brains With Neurodegenerative Diseases.},
journal = {Neuropathology : official journal of the Japanese Society of Neuropathology},
volume = {46},
number = {1},
pages = {e70042},
doi = {10.1111/neup.70042},
pmid = {41565461},
issn = {1440-1789},
support = {24K17847//Japan Society for the Promotion of Science/ ; 23K10827//Japan Society for the Promotion of Science/ ; 24K10554//Japan Society for the Promotion of Science/ ; 22H04923//Japan Society for the Promotion of Science/ ; JP21wm0425019//Japan Agency for Medical Research and Development/ ; JP24dk0207074h0001//Japan Agency for Medical Research and Development/ ; JPMH23FC1008//Ministry of Health, Labour and Welfare/ ; //Integrated Research Initiative for Living Well with Dementia (IRIDE) of the Tokyo Metropolitan Institute for Geriatrics and Gerontology/ ; },
mesh = {Humans ; *Choroid Plexus/pathology/metabolism ; Aged ; *Epithelial Cells/pathology/metabolism ; Male ; Female ; Mitochondrial Precursor Protein Import Complex Proteins ; *Neurodegenerative Diseases/pathology/metabolism ; Aged, 80 and over ; Immunohistochemistry ; Middle Aged ; *Membrane Transport Proteins/metabolism ; Mitochondria/pathology/metabolism ; Brain/pathology/metabolism ; *Receptors, Cell Surface/metabolism ; },
abstract = {The choroid plexus (CP) contributes to cerebrospinal fluid (CSF) production and regulation of circadian rhythm. Recently, many neuroimaging studies have reported enlarged CP volumes in patients with neurodegenerative diseases, including Alzheimer's disease (AD). While previous morphometric analysis revealed age-related enlargement of CP epithelial cells, the metabolic significance of such morphological changes including eosinophilic enlarged changes remains unclear. In this study, we investigated mitochondrial alterations in CP epithelial cells using immunohistochemistry for Tom20, a marker of the mitochondrial outer membrane. Temporal lobes, including CP, in patients with AD, vascular dementia, Parkinson's disease, and multiple system atrophy, and neuropathologically unremarkable controls were examined. Quantitative image analysis was performed using AI-assisted segmentation (cellpose) and Python-based processing (OpenCV, NumPy, and Pandas). Cell area and the proportion of Tom20-positive pixels (brown ratio) were measured in 13 090 epithelial cells from 20 cases, and data were analyzed using Spearman's rank correlation. The brown ratio was positively correlated with cell area. Enlarged epithelial cells frequently exhibited strong Tom20 immunoreactivity. These findings suggest that cellular enlargement in the CP epithelium is accompanied by increased mitochondrial content, highlighting a potential metabolic response in neurodegenerative brains.},
}

Humans
*Choroid Plexus/pathology/metabolism
Aged
*Epithelial Cells/pathology/metabolism
Male
Female
Mitochondrial Precursor Protein Import Complex Proteins
*Neurodegenerative Diseases/pathology/metabolism
Aged, 80 and over
Immunohistochemistry
Middle Aged
*Membrane Transport Proteins/metabolism
Mitochondria/pathology/metabolism
Brain/pathology/metabolism
*Receptors, Cell Surface/metabolism

@article {pmid41565312,
year = {2026},
author = {Lepoittevin, M and Greig, J and Erol, O and Benani, A and Bauvin, P and Azzolini, C and Donati, S and Dubois, B and Boscher, C and Bodard, S},
title = {Retinal biomarkers for early Alzheimer's detection: a systematic review of optical coherence tomography (OCT) findings.},
journal = {BMJ open ophthalmology},
volume = {11},
number = {1},
pages = {},
doi = {10.1136/bmjophth-2025-002328},
pmid = {41565312},
issn = {2397-3269},
mesh = {*Alzheimer Disease/diagnosis ; *Tomography, Optical Coherence/methods ; Humans ; Biomarkers ; Early Diagnosis ; Retinal Ganglion Cells/pathology ; *Retina/diagnostic imaging ; Nerve Fibers/pathology ; },
abstract = {OBJECTIVE: Retinal biomarkers accessible via non-invasive optical coherence tomography (OCT) could facilitate early detection of Alzheimer's disease (AD), complementing current invasive or costly diagnostic methods. This review evaluates the evidence for spectral-domain OCT (SD-OCT) and OCT angiography (OCT-A) in identifying retinal changes associated with preclinical and early AD.

METHODS AND ANALYSIS: We conducted a systematic review registered in PROSPERO and aligned with Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. PubMed/MEDLINE was searched up to April 2025, complemented by reference list screening and citation tracking. Eligible studies assessed SD-OCT and/or OCT-A in biomarker-defined preclinical or early AD, mild cognitive impairment or mild AD. Data were synthesised narratively by disease stage, and methodological quality was appraised with the Newcastle-Ottawa Scale.

RESULTS: 22 studies met inclusion criteria. Reported alterations included thinning of the peripapillary retinal nerve fibre layer and retinal ganglion cell layer, macular and choroidal thickness changes and microvascular alterations on OCT-A. However, findings were heterogeneous: some studies observed early thickening or increased vascular density, possibly reflecting inflammatory or compensatory mechanisms, while others reported thinning and rarefaction more consistent with neurodegeneration. Most studies were of moderate quality, limited by small sample sizes, cross-sectional designs and incomplete control for ocular/systemic confounders.

CONCLUSION: SD-OCT and OCT-A hold promise as candidate biomarkers of early AD, but current evidence remains variable, non-specific and methodologically constrained. Further research is needed to standardise imaging protocols, validate findings in biomarker-confirmed longitudinal cohorts and compare OCT-based measures across dementia subtypes. Integration with other biomarkers (eg, plasma or metabolomics) may improve diagnostic specificity and support translation of OCT/OCT-A into clinical practice.

PROSPERO REGISTRATION NUMBER: CRD42024600456.},
}

*Alzheimer Disease/diagnosis
*Tomography, Optical Coherence/methods
Humans
Biomarkers
Early Diagnosis
Retinal Ganglion Cells/pathology
*Retina/diagnostic imaging
Nerve Fibers/pathology

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

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

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

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

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

@article {pmid41564825,
year = {2026},
author = {Kim, S and Chen, W and Sun-Mitchell, S},
title = {Caregiver facilitative communication and dementia care recipient patterns: Insights from in-home care video analysis.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {69},
number = {},
pages = {103881},
doi = {10.1016/j.gerinurse.2026.103881},
pmid = {41564825},
issn = {1528-3984},
abstract = {BACKGROUND: This study focuses on how family caregivers can use supportive communication strategies to better engage and interact with persons living with dementia (care recipient). This study aimed to examine how caregiver facilitative communication followed by the responses of care recipient during 75 video home care interactions.

METHODS: Secondary analysis of video observations from the parent study (blinded for review) was conducted focusing on how caregiver facilitative communication followed by care recipient responses over short time window (5 to 60 s). Care recipient responses were categorized as engaging (responsive and collaborative responses), challenging (nonresponsive, resistive, withdrawing, and critical responses), or neutral (either engaging or challenging depending on the context). Odds ratio, 95% confidence intervals, p-values, and Yule's Q statistics were used.

RESULTS: The results showed that care recipients responded differently to caregiver facilitative communication depending on the time window (range: Odds ratio = 0.37 - 2.23, p < 0.001 - 0.049, Yule's Q = |0.060 - 0.463|). Following caregiver facilitative communication, care recipients used more engaging nonverbal communication immediately and more engaging verbal communication later. Care recipients used less challenging and neutral communication following caregiver facilitative communication.

CONCLUSION: Family caregivers should be encouraged to use facilitative communication techniques, as they promote more positive interactions. Healthcare providers can educate family caregivers about the communication abilities of persons living with dementia and how to incorporate facilitative communication in daily care. Using a balanced combination of verbal and nonverbal facilitative communication can create a more supportive and engaging environment for persons living with dementia.},
}

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

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

DESIGN: Retrospective cohort study.

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

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

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

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

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

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

@article {pmid41564813,
year = {2026},
author = {Boons, JHC and Nguyen Ho, PT and van Houwelingen, A and Ikram, MA and Dingemanse, G and Kremer, B and Vernooij, MW and Goedegebure, A and Neitzel, J},
title = {No longitudinal association between hearing loss and Alzheimer's disease pathology.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {3},
pages = {100481},
doi = {10.1016/j.tjpad.2026.100481},
pmid = {41564813},
issn = {2426-0266},
abstract = {INTRODUCTION: Hearing loss (HL) is a potential risk factor for Alzheimer's disease (AD), with animal studies suggesting a bidirectional relationship. This study examines whether HL links to changes in AD pathology and, whether AD biomarkers relate to subsequent HL progression.

METHODS: Baseline Aβ42/Aβ40 and p-tau217 were measured using single-molecule arrays in 474 participants of the Rotterdam Study (mean age=62.37) between 2010-2016. HL was defined as the better-ear's pure-tone threshold average. After seven years, participants underwent amyloid PET; HL and p-tau217 were reassessed two years after PET.

RESULTS: Baseline HL was not associated with amyloid PET positivity, Aβ42/Aβ40, or longitudinally with p-tau217. Likewise, HL progression did not predict PET outcomes. APOE4 carriership did not modify associations with Aβ PET. Similarly, baseline plasma biomarkers were also unrelated to longitudinal HL changes.

CONCLUSION: No bidirectional association was observed between HL and AD pathology, suggesting that HL may contribute to dementia through other pathways.},
}

@article {pmid41564643,
year = {2026},
author = {Demi̇r, ES and Atlıhan Gündoğdu, E and Özgenç, E},
title = {Development and quality control studies of radiolabelled nanostructured lipid formulations with Ga-68.},
journal = {Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine},
volume = {230},
number = {},
pages = {112453},
doi = {10.1016/j.apradiso.2026.112453},
pmid = {41564643},
issn = {1872-9800},
abstract = {OBJECTIVE: This study aims to radiolabel a nanoparticle formulation containing donepezil with Ga-68 radionuclide with high efficiency for diagnosing Alzheimer's disease. In order to develop lipid carrier systems with biocompatible contents in nanoparticle structures, extensive formulation studies were conducted. These systems were subsequently radiolabeled with Ga-68 radionuclide to evaluate their radiolabeling efficiencies. The results are highly encouraging, suggesting that effective radiolabeling is indeed possible. These findings are particularly significant as they open up a range of applications for targeted drug delivery, medical imaging, and diagnostics. Overall, this study represents a valuable contribution to the expanding body of knowledge on lipid carrier systems in healthcare.

MATERIAL AND METHOD: Nanocarrier formulations were prepared. The radiolabeling parameters of the prepared formulations were studied comparatively. A Ga-68 radionuclide with a half-life of 68 min was used for this. Incubation time, amount of radioactivity, and pH parameters were studied.

RESULTS AND DISCUSSION: The radiolabeling incubation time, pH of the experimental medium, and amount of radioactivity were tested, and the optimal parameters were identified. According to the results of the radiolabeling studies, optimal radiolabeling with Ga-68 radionuclide was obtained in an acid medium (pH: 5), with a 60 min incubation time, and using 5 mCi of activity in the DOTA-functionalized nanolipid formulations, achieving 89.17 % efficiency. Furthermore, quantitative in vivo PET/CT imaging in nude mice (n = 3/group) demonstrated that the optimized Ga-68-DNP-NLC formulation achieved statistically significant and higher brain uptake compared to the free Ga-68 control, confirming its ability to cross the blood-brain barrier.},
}

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

@article {pmid41564480,
year = {2026},
author = {Wang, FY and Wei, L and Wang, P and Chen, WC and Chen, ZJ and Zhou, ZQ and Zhu, GH and Gong, Q and Qin, LP and Yang, L and Ge, GB and Wang, P},
title = {A dual-emission near-infrared fluorogenic probe for sensing Catechol-O- methyltransferase activity from in vitro to in vivo.},
journal = {Biosensors & bioelectronics},
volume = {298},
number = {},
pages = {118409},
doi = {10.1016/j.bios.2026.118409},
pmid = {41564480},
issn = {1873-4235},
abstract = {Human catechol-O-methyltransferase (COMT, EC 2.1.1.6) plays a key role in neurotransmitter signaling and metabolism in the central nervous system. Optical sensing of COMT activity provides a powerful approach to study its biological functions, however, existing fluorescent probes are limited by short emission wavelengths and low sensitivity. Herein, we present TCFC, the first dual-emission near-infrared (NIR) fluorogenic substrate for COMT, rationally designed via a structure-modulated strategy. Under physiological conditions, TCFC was rapidly O-methylated by COMT to yield product 8-MTCFC, which exhibited strong fluorescence at 620 nm and 695 nm upon excitation at 470 nm and 610 nm, respectively. The dual-emission property of TCFC enhanced detection sensitivity and versatility, enabling accurate assessment of COMT activity across individuals and species while supporting high-throughput screening of potential COMT inhibitors. Moreover, the NIR emission of TCFC allowed in situ visualization of COMT activity in living cells and various brain regions of rats with high spatiotemporal resolution, and revealed a reduction of COMT activity in the hippocampal region of a mouse model of Alzheimer's disease, offering insights into its role in neurodegeneration. Collectively, TCFC proved to be a powerful NIR fluorogenic substrate for monitoring COMT activity in complex biological systems, enabling mechanistic studies and high-throughput screening of potential inhibitors.},
}

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

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

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

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

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

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

@article {pmid41564179,
year = {2026},
author = {Becker, S and L'Ecuyer Morison, Z and Allen, J and Saeid, S and Sturgis, L and Adderley, A and Koskelainen, A and Vinberg, F},
title = {Healing of ischemic injury in the retina.},
journal = {Science advances},
volume = {12},
number = {4},
pages = {eadx7204},
doi = {10.1126/sciadv.adx7204},
pmid = {41564179},
issn = {2375-2548},
mesh = {Animals ; Humans ; *Retina/pathology/drug effects/metabolism ; *Reperfusion Injury/pathology ; Mice ; *Ischemia/pathology ; Disease Models, Animal ; Oxidative Stress ; Neuroprotective Agents/pharmacology ; },
abstract = {Neuro- and retinal degenerative diseases, including Alzheimer's, stroke, age-related macular degeneration, and central retinal artery occlusion, rob millions of their independence. Studying these diseases in human retinas has been hindered by the rapid loss of neuronal activity after death. While some CNS activity has been restored postmortem, synchronized neuronal transmission beyond 30 min has remained elusive. We overcome this barrier by reviving and sustaining light signal transmission in human retinas recovered up to 4 hours after death and stored for up to 48 hours. We also introduce infrared-based ex vivo imaging for precise sampling, a closed perfusion system for drug testing, and an ex vivo ischemia-reperfusion model in mouse and human retina. This platform enables testing of neuroprotective and neurotoxic effects of drugs targeting oxidative stress and glutamate excitotoxicity. Our advances question the irreversibility of ischemic injury, support preclinical studies in vision restoration, offer insights into treating CNS ischemia, and pave the way for human donor eye transplantation.},
}

Animals
Humans
*Retina/pathology/drug effects/metabolism
*Reperfusion Injury/pathology
Mice
*Ischemia/pathology
Disease Models, Animal
Oxidative Stress
Neuroprotective Agents/pharmacology

@article {pmid41563787,
year = {2026},
author = {Bray, MJC and Shaw, JS and Morrow, CB and Onyike, CU and , },
title = {Alzheimer Disease-Relevant Biomarker Elevations in Psychosis and Broad Neuropsychiatric Impairment.},
journal = {JAMA psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamapsychiatry.2025.4347},
pmid = {41563787},
issn = {2168-6238},
}

@article {pmid41563783,
year = {2026},
author = {Dabas, A and Priyadarshi, N and Goyal, D and Singhal, NK and Goyal, B},
title = {Mutations in the Aβ42 Recognition Sequence KLVFF Afford New Pentapeptide Inhibitors of Aβ42 Fibrillation: Computation-Driven Rational Design and Experimental Validation.},
journal = {The journal of physical chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jpcb.5c06148},
pmid = {41563783},
issn = {1520-5207},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, marked by the accumulation of amyloid-β (Aβ) plaques in the brain, excessive tau protein phosphorylation, and cholinergic neuron degeneration. In this work, a library of computationally designed peptides based on the Aβ42 recognition sequence KLVFF has been generated, which is further evaluated for its ability to effectively attenuate Aβ42 fibrillation. Notably, molecular mechanics Poisson-Boltzmann surface area analysis identified three new peptides, RPPWF (ΔGbinding = -58.08 ± 9.02 kcal/mol), RPPWY (ΔGbinding = -46.13 ± 3.62 kcal/mol), and KPPWW (ΔGbinding = -44.27 ± 4.08 kcal/mol), displaying significantly higher binding affinity to the Aβ42 monomer (Aβ42m) compared to KLVFF (ΔGbinding = -38.70 ± 17.17 kcal/mol). Importantly, among the designed peptides, RPPWF induces the helix conformation in Aβ42m to the maximum extent and prevents the conformational transitions in Aβ42m to aggregation-competent β-sheet structures. Furthermore, the thioflavin T (ThT) fluorescence assay depicted no self-fibrillation of RPPWF and a maximum inhibitory effect among the synthesized peptides (IC50 = 8.90 ± 0.98 μM) against Aβ42 fibrillation, consistent with the computational results. Notably, DLS and TEM analyses confirmed the RPPWF-induced modulation in Aβ42 fibrillation. RPPWF efficiently rescued PC12 cells from Aβ42 aggregate-induced neurotoxicity by notably enhancing cell viability to 89.6% as compared to 42.2% (Aβ42 alone). Remarkably, this study highlights the synergistic effect of multiple substitutions (K → R, L → P, V → P, and F → W) in the amyloidogenic KLVFF sequence of Aβ42 and depicts the importance of arginine, proline, and tryptophan residues in the RPPWF sequence in affording an efficient new potent inhibitor, RPPWF, of Aβ42 fibrillation. Furthermore, RPPWF has the potential for conjugation or further modifications to afford more effective and clinically relevant multifunctional agents against Aβ42 fibrillation in AD.},
}

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

@article {pmid41563653,
year = {2026},
author = {Ahuja, R and Shaban, A and Chawla, J and Parmar, MS},
title = {Borrelia burgdorferi-Induced Neuroinflammation in Lyme Disease: A Potential Driver of Alzheimer's Disease Pathology?.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {381},
pmid = {41563653},
issn = {1559-1182},
mesh = {*Alzheimer Disease/pathology/microbiology ; Humans ; *Borrelia burgdorferi/pathogenicity ; Animals ; *Neuroinflammatory Diseases/pathology/microbiology/complications ; *Lyme Disease/pathology/complications/microbiology ; Lyme Neuroborreliosis/pathology ; Amyloid beta-Peptides/metabolism ; },
abstract = {Emerging evidence suggests that chronic infections may contribute to neurodegenerative diseases such as Alzheimer's disease (AD). One such infection is caused by Borrelia burgdorferi sensu lato (Bbsl), the spirochete complex responsible for Lyme disease, which can invade the central nervous system (CNS) and trigger Lyme neuroborreliosis (LNB). Bbsl infection is associated with persistent neuroinflammatory responses and immune evasion mechanisms, which may contribute to long-term neurological sequelae in a subset of patients. Neuroinflammation is increasingly recognized as a contributing factor in AD pathogenesis. This review examines proposed mechanistic overlaps between LNB and AD, focusing on the role of Bbsl-induced neuroinflammation driving amyloid-beta (Aβ) accumulation and tau pathology. We summarize evidence from in vitro, in vivo, and postmortem studies reporting assay-dependent co-localization of Borrelia with hallmark AD pathology in selected cases, alongside epidemiological studies that yield mixed results. While some studies suggest an association between Bbsl exposure and neurodegenerative risk, others report no clear correlation. Overall, current evidence indicates only an association, and a causal relationship between Bbsl infection and AD has not been established. Understanding this potential link may inform future mechanistic studies, biomarker development, and preventive strategies targeting chronic infection-driven neuroinflammation to address the hypothesis.},
}

*Alzheimer Disease/pathology/microbiology
Humans
*Borrelia burgdorferi/pathogenicity
Animals
*Neuroinflammatory Diseases/pathology/microbiology/complications
*Lyme Disease/pathology/complications/microbiology
Lyme Neuroborreliosis/pathology
Amyloid beta-Peptides/metabolism

@article {pmid41563627,
year = {2026},
author = {Kashif, M and Chandrabose, K and Pandurangan, AK},
title = {Exploring the Therapeutic Potential of N-(3,4-dimethoxy phenyl)-6,7-dimethoxyquinazoline-4-amine (TKM01) in Aluminium-Induced Alzheimer's Disease-Like Model of Zebrafish.},
journal = {Neurochemical research},
volume = {51},
number = {1},
pages = {56},
pmid = {41563627},
issn = {1573-6903},
mesh = {Animals ; Zebrafish ; *Alzheimer Disease/chemically induced/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; Aluminum Chloride/toxicity ; Disease Models, Animal ; *Quinazolines/therapeutic use/pharmacology ; Maze Learning/drug effects ; Oxidative Stress/drug effects ; Acetylcholinesterase/metabolism ; Male ; },
abstract = {Aluminum (Al), a pervasive environmental neurotoxicant, has been strongly implicated in the onset and progression of Alzheimer's disease (AD)-like pathology. Chronic and sub-chronic exposure to aluminum chloride (AlCl3) induces cognitive deficits, oxidative stress, cholinergic dysfunction, neuroinflammation, and neuronal damage, making it a widely used agent for modeling AD in preclinical research. This study aimed to evaluate the neuroprotective efficacy of TKM01, a novel 4-anilinoquinazoline derivative, in an AlCl3-induced AD-like zebrafish model. Adult zebrafish were exposed to AlCl3 (11 mg/L for 15 days) and pre-treated with TKM01 at two concentrations (240 and 480 µg/mL). Behavioral assessments, including the T-maze, novel object recognition (NOR), and open field test (OFT), demonstrated significant improvements in spatial learning, recognition memory, and reduced anxiety-like behavior in TKM01-treated groups. Biochemical analyses revealed decreased acetylcholinesterase (AChE) activity and lipid peroxidation (LPO), alongside elevated antioxidant enzyme activities, including superoxide dismutase (SOD) and catalase (CAT). ELISA showed a reduction in pro-inflammatory cytokines (TNF-α and IL-1β), and RT-PCR analysis confirmed downregulation of NLRP3, ASC, and caspase A gene expression. Furthermore, histopathological examination revealed that TKM01 mitigated AlCl3-induced neuronal degeneration, edema, and cellular disorganization in brain telencephalon. Additionally, molecular docking and 200 ns molecular dynamics simulations supported stable and favorable binding interactions between TKM01 and IL-1β/ASC. Collectively, these findings suggest that TKM01 attenuates AlCl3-induced neurotoxicity via antioxidant, anti-inflammatory, anticholinesterase, and neuroprotective mechanisms. TKM01 emerges as a promising multifunctional therapeutic candidate for AD, warranting further investigation in mammalian models.},
}

Animals
Zebrafish
*Alzheimer Disease/chemically induced/drug therapy/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology
Aluminum Chloride/toxicity
Disease Models, Animal
*Quinazolines/therapeutic use/pharmacology
Maze Learning/drug effects
Oxidative Stress/drug effects
Acetylcholinesterase/metabolism
Male

@article {pmid41563514,
year = {2026},
author = {Li, M and Xie, H and Li, J and Shen, Y and Cai, L and Lu, M and Wu, X},
title = {The pineal gland in ageing and alzheimer's disease: age-related molecular changes.},
journal = {Brain structure & function},
volume = {231},
number = {2},
pages = {14},
pmid = {41563514},
issn = {1863-2661},
support = {2023AH053430//Grant from Anhui Natural science research project/ ; 2023AH053430//Grant from Anhui Natural science research project/ ; 2023AH053430//Grant from Anhui Natural science research project/ ; 2023AH053430//Grant from Anhui Natural science research project/ ; 2023AH053430//Grant from Anhui Natural science research project/ ; 2023AH053430//Grant from Anhui Natural science research project/ ; 2023AH053430//Grant from Anhui Natural science research project/ ; S202310366065//National Undergraduate Innovation Project, Anhui province/ ; S202310366065//National Undergraduate Innovation Project, Anhui province/ ; S202310366065//National Undergraduate Innovation Project, Anhui province/ ; S202310366065//National Undergraduate Innovation Project, Anhui province/ ; S202310366065//National Undergraduate Innovation Project, Anhui province/ ; S202310366065//National Undergraduate Innovation Project, Anhui province/ ; S202310366065//National Undergraduate Innovation Project, Anhui province/ ; },
mesh = {Humans ; *Pineal Gland/pathology/metabolism ; *Alzheimer Disease/pathology/metabolism/cerebrospinal fluid ; Male ; Female ; *Aging/pathology/metabolism ; Aged ; Middle Aged ; Aged, 80 and over ; Adult ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Glial Fibrillary Acidic Protein/metabolism ; Young Adult ; Melatonin/cerebrospinal fluid/metabolism ; Adolescent ; Child ; Sex Characteristics ; },
abstract = {The pineal gland is an organ that undergoes significant degeneration with age, and these degenerative changes lead to numerous physiological alterations. This study investigated age-related molecular changes and Alzheimer's disease (AD)-associated pathology in the human pineal gland using histopathological analyses. This study collected a total of 54 human pineal gland specimens. Of these, 47 were categorised into five age groups: 0-20, 21-40, 41-60, 61-80, and 81-100 years. A further 7 cases with confirmed AD-related neuropathological changes were assigned to the AD group, while matched to 7 controls. Our findings revealed that pineal calcification was initiated as early as age 3, with progressive accumulation of calcification and accompanying cellular loss during the ageing process. A remarkable degree of sexual dimorphism was observed: female-predominant patterns included lipofuscin deposition and pineal cysts, whereas male-predominant characteristics included glial fibrillary acidic protein (GFAP) immunoreactivity and connective tissue expression. Significantly, phosphorylated Tau (P-Tau) and amyloid-beta (Aβ) have recently been detected within the pineal gland. Aβ deposition was positively correlated with age and was markedly elevated in individuals with AD. Furthermore, individuals with AD exhibited marked pineal cellular depletion compared with controls, alongside elevated GFAP expression. Cerebro-spinal fluid analysis further revealed significantly reduced melatonin levels in the AD cohort. Overall, this study systematically elucidated the multidimensional pathological features of the pineal gland during ageing and AD progression, and these findings may open new avenues for mechanistic exploration and precision medicine in AD.},
}

Humans
*Pineal Gland/pathology/metabolism
*Alzheimer Disease/pathology/metabolism/cerebrospinal fluid
Male
Female
*Aging/pathology/metabolism
Aged
Middle Aged
Aged, 80 and over
Adult
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Glial Fibrillary Acidic Protein/metabolism
Young Adult
Melatonin/cerebrospinal fluid/metabolism
Adolescent
Child
Sex Characteristics

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

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

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

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

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

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

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

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

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

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

@article {pmid41562832,
year = {2026},
author = {Aranda-Abreu, GE and Rojas-Durán, F and Hernández-Aguilar, ME and Herrera-Covarrubias, D and Tlapa-Monge, LR and Mestizo-Gutiérrez, SL},
title = {The Molecular Architecture of Neurodegeneration: An Integrative Overview of Convergent Mechanisms.},
journal = {NeuroSci},
volume = {7},
number = {1},
pages = {},
doi = {10.3390/neurosci7010007},
pmid = {41562832},
issn = {2673-4087},
abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's disease represent a major challenge in neuroscience due to their complex, multifactorial nature and the absence of curative treatments. These disorders share common molecular mechanisms, including oxidative stress, mitochondrial dysfunction, proteostasis collapse, calcium dyshomeostasis, chronic neuroinflammation, and the prion-like propagation of misfolded proteins. Together, these processes trigger a cascade of cellular damage that culminates in synaptic dysfunction and programmed neuronal death. This review integrates current evidence on the sequential stages of neurodegeneration, emphasizing the convergence of oxidative, inflammatory, and proteotoxic pathways that drive neuronal vulnerability. Moreover, it explores emerging therapeutic strategies aimed at restoring cellular homeostasis, such as Nrf2 activation, modulation of the unfolded protein response (UPR), enhancement of autophagy, immunotherapy against pathological proteins, and gene therapy approaches. The dynamic interplay among mitochondria, endoplasmic reticulum, and glial cells is highlighted as a central element in disease progression. Understanding these interconnected mechanisms provides a foundation for developing multi-targeted interventions capable of halting or delaying neuronal loss and improving clinical outcomes in neurodegenerative disorders. This work provides an integrative and introductory overview of the convergent mechanisms underlying neurodegeneration rather than an exhaustive mechanistic analysis.},
}

@article {pmid41562774,
year = {2025},
author = {Godugu, D and Gattu, K and Suri, P and Daartey, AB and Jadhav, K and Rojekar, S},
title = {Nanobody Therapeutics in Alzheimer's Disease: From Molecular Mechanisms to Translational Approaches.},
journal = {Antibodies (Basel, Switzerland)},
volume = {15},
number = {1},
pages = {},
doi = {10.3390/antib15010001},
pmid = {41562774},
issn = {2073-4468},
abstract = {Nanobodies (single-domain antibodies, VHHs) have emerged as versatile tools for evaluating and treating Alzheimer's disease (AD). They offer distinct engineering benefits compared with traditional antibodies and small molecules, including small size, stability, and specificity. In AD, nanobodies have been shown in preclinical models to neutralize toxic amyloid-β oligomers, inhibit tau generation and aggregation, and modulate neuroinflammation, thereby demonstrating significant therapeutic potential. However, all nanobody applications in AD are discussed strictly as preclinical therapeutic potential rather than established clinical therapies, and direct clinical evidence in patients with AD is still lacking. Advanced engineering strategies, including intranasal and intrathecal routes, receptor-mediated transport, plasma protein binding with albumin, and focused ultrasound to facilitate brain penetration. Additionally, to improve nanobody delivery precision, half-life, and efficacy, strategies such as integrating nanobodies with nanoparticles, dendrimers, liposomes, and viral vectors are being employed. In fact, nanobodies are applied beyond monotherapy across multiple technological platforms to optimize brain delivery and target multiple targets. Nanobodies have been used on bispecific and trispecific antibody platforms, as well as in CRISPR/Cas9 editing and AI-driven technologies, to expand their applications. Recently, preclinical evidence has been mounting on the efficacy of nanobodies in clearing Aβ and tau, preserving synapses, and normalizing biomarkers. Comparison with FDA-approved anti-Aβ monoclonal antibodies (aducanumab, lecanemab, and donanemab) highlights opportunities and current translational gaps, including safety testing, half-life extension, and delivery optimization. This review critically delineates the current molecular mechanisms, emerging strategies, and delivery platforms, and emphasizes the potential of nanobodies as promising therapeutic and diagnostic molecules in AD therapeutics.},
}

@article {pmid41562566,
year = {2026},
author = {Sawada, Y and Satoh, T and Saba, H and Kato, Y and Kuwada, T and Shima, S and Murakami, K and Sasaki, M and Abe, Y and Harano, K},
title = {Advanced measurement modeling of the Clock Drawing Test: A confirmatory factor analysis and item response theory-based validation of CDT-14.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251410947},
doi = {10.1177/13872877251410947},
pmid = {41562566},
issn = {1875-8908},
abstract = {BackgroundEarly detection of cognitive impairment is vital for dementia management, especially in Alzheimer's disease. The Clock Drawing Test (CDT) is a widely used screening tool; however, many existing scoring methods lack comprehensive statistical validation and consistent factor structures.ObjectiveWe aimed to evaluate the validity and reliability of a novel scoring method, CDT-14, developed from items predictive of cognitive decline, and to compare its performance with three conventional scoring systems.MethodsWe enrolled 1100 outpatients undergoing cognitive assessments in a cross-sectional study. Scores from CDT-14 and the three conventional methods (Rouleau, Sunderland, Freedman) were compared. Structural validity was examined using confirmatory factor analysis (CFA), and item characteristics were analyzed via item response theory (IRT). Internal consistency was assessed with McDonald's omega. Construct validity and discriminative ability were evaluated through correlations and receiver operating characteristic (ROC) analyses. Participants were classified by Mini-Mental State Examination scores into Normal Cognition, Mild Cognitive Impairment, and Moderate-to-severe Cognitive Impairment.ResultsThe CFA results supported a three-factor model (Circle, Numbering, Hands) with good fit. The IRT analysis indicated high measurement precision in the mild cognitive decline range (θ = -1 to 0). The CDT-14 score exhibited strong internal consistency (ω = 0.835). ROC analyses showed that the CDT-14 score had comparable or superior discriminative accuracy to conventional methods, with practical cut-offs and enhanced performance when adjusted for age and education.ConclusionsThe CDT-14 is a psychometrically robust scoring method providing standardized, sensitive assessment for cognitive screening and longitudinal monitoring in dementia clinical settings.},
}

@article {pmid41562423,
year = {2025},
author = {Han, C and Bae, H and Lee, SH and Kim, J and Chon, MW},
title = {Association Between Serum Levels of Glial Cell Line- Derived Neurotrophic Factor and Cognitive Function in Patients with Methamphetamine Dependence.},
journal = {Psychiatry and clinical psychopharmacology},
volume = {},
number = {},
pages = {},
doi = {10.5152/pcp.2025.24911},
pmid = {41562423},
issn = {2475-0581},
abstract = {BACKGROUND: Methamphetamine causes cognitive impairment. Glial cell line derived neurotrophic factor (GDNF), a survival factor of dopaminergic and motor neurons, has been studied not only for its protective role against neurodegenerative diseases but also for its role in cognitive function. This study examined the relationship between methamphetamine-induced cognitive dysfunction and serum GDNF levels.

METHODS: Thirty-eight male outpatients dependent on methamphetamine completed a clinical and neuropsychological battery, the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease, and were tested using an enzyme-linked immunosorbent assay.

RESULTS: Sociodemographic data, including years of methamphetamine use and abstinence period, showed no correlation with serum levels of GDNF. Additionally, among the neurocognitive tests, only the performance on the trail making test B was significantly inversely correlated with serum GDNF levels.

CONCLUSION: Unlike the reports on cerebrospinal fluid GDNF concentration, previous reports on the relationship between serum GDNF levels and cognitive function in neurodegenerative and psychiatric diseases have demonstrated mixed results. This study is significant, as it is the first study on the relationship between serum GDNF and cognitive function in patients with methamphetamine dependence.},
}

@article {pmid41562409,
year = {2026},
author = {Benina, N and Buitrago, L and De Simone, FI and Radwan, RR and Miller, MC and Martin, K and Dickson, D and Ho, S and Moghekar, A and Albert, M and Mattsson-Carlgren, N and Palmqvist, S and Ossenkoppele, R and Jonsson, MF and Hansson, O and Stomrud, E and Sachdev, P and Niu, H and Verbel, D and Hawkins, DM},
title = {Plasma pTau 217:β-amyloid 1-42 ratio for enhanced accuracy and reduced uncertainty in detecting amyloid pathology.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag001},
pmid = {41562409},
issn = {1460-2156},
abstract = {Blood biomarkers have the potential to revolutionize Alzheimer's disease (AD) diagnosis, offering advantages over cerebrospinal fluid (CSF) and positron emission tomography (PET) due to their accessibility, scalability, and cost-effectiveness. This study evaluated the effectiveness of individual plasma biomarkers, such as phosphorylated Tau (pTau) 217, as well as biomarker combinations, with a focus on the pTau 217/β-Amyloid (Aβ) 1-42 ratio to predict amyloid positivity. To improve clinical utility, a dual threshold approach was applied to maximize predictive values and positive likelihood ratios while minimizing the proportion of indeterminate results. Plasma samples from two hundred eight (208) participants (including 7 with Subjective Cognitive Decline, 150 with Mild Cognitive Impairment, 12 with Alzheimer's disease dementia, and 39 with other cognitive conditions) from three cohorts (BioFINDER2, BIOCARD, and MissionAD) were analyzed to measure Aβ 1-42, Aβ 1-40, and pTau 217 levels using the Fujirebio LUMIPULSE® G1200 platform. Amyloid status was determined by FDA-cleared PET imaging and/or CSF biomarker ratios. Logistic regression modelling evaluated biomarkers either individually or in combination to identify those that best distinguished amyloid positivity. Clinically applicable thresholds were established through likelihood ratio analysis and further evaluated based on predictive values. When assessing the ability of individual plasma biomarkers to differentiate between amyloid-positive and amyloid-negative participants, plasma pTau 217 (p < 0.001) and plasma Aβ 1-42 (p = 0.0056) demonstrated significant discriminative power, whereas Aβ 1-40 (p = 0.30) did not. Notably, the integration of these biomarkers into the plasma pTau 217/Aβ 1-42 ratio, demonstrated enhanced classification performance (p < 0.001). Using a two-threshold approach based on positive and negative likelihood ratios (PLR/NLR) targets of 14/20, respectively, the plasma pTau 217/Aβ 1-42 ratio achieved a PPV of 94.44% and NPV of 94.28%, in the parametric model, comparable to plasma pTau 217 alone (PPV: 94.44%, NPV: 94.28%), but yielded fewer indeterminate results (26.5% vs. 38.6%). Using a non-parametric model, the plasma ratio achieved a PPV and NPV of 94.62% and 91.78%, respectively, while plasma pTau 217 alone achieved 92.41% and 92.86%; the ratio once again reduced the proportion of indeterminate results (20.2% vs. 35.1%). The plasma pTau 217/Aβ 1-42 ratio demonstrated superior performance in identifying amyloid pathology and reduced the frequency of indeterminate results compared to plasma pTau 217 alone. These findings support the evaluation of the clinical utility of the plasma pTau 217/Aβ 1-42 ratio as a tool for identifying amyloid pathology in patients presenting with cognitive complaints.},
}

@article {pmid41562366,
year = {2026},
author = {Li, C and Li, WX and Liu, ZY and Zhai, FF and Han, F and Li, ML and Zhou, LX and Ni, J and Yao, M and Zhang, SY and Cui, LY and Jin, ZY and Peng, B and Zhu, YC},
title = {Glymphatic system dysfunction as a predictor of cognitive decline and incident dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411493},
doi = {10.1177/13872877251411493},
pmid = {41562366},
issn = {1875-8908},
abstract = {BackgroundCognitive decline and incident dementia in ageing populations have been linked to brain parenchymal injury and the ALPS index (ALPS-I).ObjectiveThis investigation aimed to elucidate whether the baseline ALPS-I could predict incident dementia and cognitive decline in this population.MethodsIn total, 973 dementia-free participants from the Shunyi Study (mean age, 57 years; 37% male) received MRI between 2013 and 2016 to quantify the ALPS-I. The longitudinal relationships between the ALPS-I and cognitive deterioration in various cognitive areas were evaluated via linear mixed models. Cox proportional hazard models were utilized to explore the link between the index and incident dementia. Mediation assessments were carried out to identify the potential mediating effects of brain parenchymal injury on the link between the ALPS-I and cognition.ResultsThe baseline ALPS-I predicted longitudinal changes in global cognition (Montreal Cognitive Assessment), language (verbal fluency test), visuospatial perception (block design subtest of Wechsler intelligence scale), and executive function (Trail Making Test). A lower score was markedly associated with a higher incident dementia risk. Mediation analysis revealed that fractional anisotropy mediated the associations between the ALPS-I and executive function (mediation effect: 21.9%) and visuospatial perception (mediation effect: 68.8%). The white matter hyperintensity fraction was found to mediate the link between the ALPS-I and global cognition (mediation effect: 55.0%).ConclusionsThis longitudinal evidence supports a link between the ALPS-I and cognitive degeneration. Furthermore, the link is mediated by subcortical parenchymal injury.},
}

@article {pmid41562363,
year = {2026},
author = {Sinnamon, CJ and Hughes, CM and Cardwell, CR and Barry, HE},
title = {Antidepressant and anxiolytic medications and risk of mortality in people with dementia: A nested case-control study in Northern Ireland.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251414888},
doi = {10.1177/13872877251414888},
pmid = {41562363},
issn = {1875-8908},
abstract = {BackgroundAntidepressant and anxiolytic medication use in people with dementia (PwD) may contribute to potentially inappropriate prescribing and be associated with mortality.ObjectiveTo investigate trends in prescribing of these medications and their association with mortality risk among PwD.MethodsA nested case-control study was conducted in Northern Ireland (NI) using linkage of five administrative population-based data sources within a cohort of dementia patients (identified if a medication indicated for dementia was prescribed). Dementia patients who died were matched to one control who lived at least as long as their matched case after dementia diagnosis (matched on age, sex and year of dementia). Exposure to antidepressant and anxiolytic medications was assessed from two years prior to study entry. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression after adjusting for demographic factors and comorbidities.ResultsThe study included 14,420 dementia cases. Antidepressants were prescribed to 59.2% of cases and 54.7% of controls while 44.8% of cases and 36.0% of controls were prescribed anxiolytics. There was evidence of a weak increased risk of mortality in PwD prescribed antidepressants (fully adjusted OR = 1.08; 95% CI 1.02-1.14) and a strong increased risk in those prescribed anxiolytics (fully adjusted OR =1.26; 95% CI 1.19-1.33) compared to nonusers.ConclusionsIn this large NI population-based cohort of PwD, elevated levels of antidepressant and anxiolytic prescribing were observed. The use of anxiolytic medications was strongly associated with mortality in PwD.},
}

@article {pmid41562354,
year = {2026},
author = {Castellani, RJ and Bharadwaj, RA and Fisher-Hubbard, AO and Deep-Soboslay, A and Hyde, TM and Kleinman, JE and Hazrati, LN and Iverson, GL},
title = {Hyperphosphorylated tau and amyloid-β proteinopathy in people over age 50: Findings from the Lieber Institute for Brain Development Brain Donation Repository.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411332},
doi = {10.1177/13872877251411332},
pmid = {41562354},
issn = {1875-8908},
abstract = {BackgroundThe Lieber Institute for Brain Development (LIBD) has one of the largest postmortem human brain banks for the study of neuropsychiatric disorders in the world. The postmortem evaluation involves neuropathological assessment for age-related protein accumulations, specifically phosphorylated tau (p-tau) and amyloid-β (Aβ).ObjectivePresent the LIBD semiquantitative assessment methodology for p-tau and Aβ by comparing proteinopathy by age and by apolipoprotein E (APOE) genotype.MethodsPostmortem brain tissue samples were from 1509 people aged 50 or greater (median age at death = 63 years; range = 50-102). Seven brain regions (four neocortical areas, hippocampal formation, midbrain, and cerebellum) were examined by routine histopathology, p-tau immunohistochemistry (AT8; hippocampus and four neocortical samples), and Aβ immunohistochemistry (BAM01; four neocortical samples). APOE genotyping was performed in a subgroup. Semiquantitative assessments include modified CERAD (Consortium to Establish a Registry for Alzheimer's Disease) and modified Braak approaches.ResultsThere were 63.8% rated as B1 (modified Braak I or II), 30.4% rated as B2 (modified Braak III or IV), and 5.8% rated as B3 (modified Braak V or VI). For those in their early 70 s, half had modified Braak stage III-IV ratings. For decedents in their 80 s, approximately 1 in 4 had modified Braak stage V-VI ratings. Aβ was present in 48.8% (C0 = 51.2%, C1 = 17.2%, C2 = 24.5%, and C3 = 7.1%). Age and APOE genotype were significant predictors of Aβ plaques.ConclusionsThe LIBD protocol assessing p-tau and Aβ burden identified significant associations with age and APOE genotype. More research is needed to understand the spectrum of age-related proteinopathy versus neurodegenerative disease neuropathology.},
}

@article {pmid41562040,
year = {2026},
author = {Li, C and Wang, S and Chen, X and Dongye, C and Zhao, Y and Chan, TD and Chen, X},
title = {Multiomics Reveals Mitochondrial and Metabolic Perturbations Underlying Cyclotriphosphazene-Induced Lung Injury.},
journal = {Environment & health (Washington, D.C.)},
volume = {4},
number = {1},
pages = {74-87},
pmid = {41562040},
issn = {2833-8278},
abstract = {Cyclotriphosphazenes (CTPs), widely used as flame-retardant electrolyte additives in lithium batteries, have raised significant environmental and health concerns due to their potential release and human exposure. However, the toxicological effects of CTPs, particularly on pulmonary health, remain poorly understood. This study investigates the impact of long-term CTPs exposure at environmentally relevant doses on lung cells and animal models. In vitro experiments revealed that CTPs exposure impaired mitochondrial function in BEAS-2B cells in a time-dependent manner. Proteomic analysis demonstrated significant alterations in oxidative phosphorylation-related proteins, disrupting the electron transport chain (ETC). Untargeted metabolomics further revealed disruptions in the tricarboxylic acid (TCA) cycle, glutathione metabolism, and purine metabolism, with notably decreased levels of key metabolites. Multiomics integration suggested potential associations between high-dose CTPs exposure and diseases including lipoyltransferase 1 deficiency, Alzheimer's disease, and schizophrenia. In vivo studies confirmed pathological lung damage in mice, including alveolar destruction and pulmonary fibrosis. Additionally, downregulation of N-lauroylsphingosine (NLDP) was identified as a potential metabolic biomarker for CTPs-induced lung injury, offering novel insights for mitigating CTPs' adverse effects. These findings highlight the pulmonary toxicity of CTPs and provide a foundation for future risk assessment and preventive strategies.},
}

@article {pmid41561843,
year = {2025},
author = {Roberts, SS and Sohmer, D and White, N and Potts, JM and Goldberger, R and Lewis, M and Kline, C and Madrigal, L and Roberts, R and Rider, NL},
title = {Assessing the ECHO[®] model's role in strengthening health department responses to dementia risk.},
journal = {Frontiers in public health},
volume = {13},
number = {},
pages = {1686733},
pmid = {41561843},
issn = {2296-2565},
mesh = {Humans ; *Dementia/prevention & control ; Tennessee ; Male ; Female ; *Risk Reduction Behavior ; Focus Groups ; *Health Knowledge, Attitudes, Practice ; Surveys and Questionnaires ; Middle Aged ; *Public Health ; },
abstract = {INTRODUCTION: The Alzheimer's and Dementia Care ECHO Program was adapted for Public Health Professionals and a pilot was conducted among professionals from state and local health departments in Tennessee. The series aimed to increase knowledge, confidence, and public health action around dementia risk reduction across six virtual sessions, which featured a brief presentation followed by a case discussion.

METHODS: The evaluation sought to understand the ECHO's impact on public health professional practice and knowledge change regarding dementia risk reduction using a mixed-methods approach. Data were collected through pre and post-series surveys, surveys following each session, and focus groups.

RESULTS AND DISCUSSION: Participants reported high levels of satisfaction with the ECHO series, increased recognition of dementia risk reduction as a public health issue, and increased knowledge and confidence about reducing dementia risk. Overall, 70% of respondents said they would implement something they learned immediately or in the next 30 days. Increased recognition of and confidence to implement dementia risk reduction strategies can lead to improved health outcomes and more proactive measures being integrated into public health strategies.},
}

Humans
*Dementia/prevention & control
Tennessee
Male
Female
*Risk Reduction Behavior
Focus Groups
*Health Knowledge, Attitudes, Practice
Surveys and Questionnaires
Middle Aged
*Public Health

@article {pmid41561816,
year = {2025},
author = {Grammenos, G and Vrahatis, AG and Lazaros, K and Exarchos, TP and Vlamos, P and Krokidis, MG},
title = {AI agents in Alzheimer's disease management: challenges and future directions.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1735892},
pmid = {41561816},
issn = {1663-4365},
abstract = {Neurodegenerative diseases such as Alzheimer's and Parkinson's disease pose a major global healthcare challenge, with cases projected to rise sharply as populations age and effective treatments remain limited. AI has shown promise in supporting diagnostics, predicting disease progression, and exploring biomarkers, yet most current tools are narrowly focused, unimodal, and lack longitudinal reasoning or interpretability. By enabling context-aware analysis across imaging, genomics, cognitive, and behavioral data, agentic AI can track disease progression, identify therapeutic targets, and support clinical decision-making. Over time, these systems may detect gaps in their own information and request targeted data, moving closer to real clinical reasoning while keeping clinicians in control. The next frontier in medical AI lies in developing autonomous, multimodal agents capable of integrating diverse data, adapting through experience, supporting decision-making, and collaborating with clinicians. Furthermore, ethical, patient-centered AI requires close technical-clinical collaboration to support clinicians and improve patient outcomes. This perspective examines AI's current role in Alzheimer's care, identifies key challenges in integration, interpretability, and regulation, and explores pathways for safely deploying these agentic systems in clinical practice.},
}

@article {pmid41561789,
year = {2025},
author = {Simoni, Z and Hilfiker, V},
title = {The social construction of Aduhelm in the context of pharmaceutical ambiguity: exploring narratives from informal caregivers, medical professionals, and redditors on r/Alzheimers.},
journal = {Frontiers in sociology},
volume = {10},
number = {},
pages = {1636160},
pmid = {41561789},
issn = {2297-7775},
abstract = {INTRODUCTION: In 2021, the Food and Drug Administration approved Aduhelm (Aducanumab), a pharmaceutical developed to treat Alzheimer's disease. At first, many in the advocacy and caregiving community responded with jubilation as there are currently few effective treatments to reduce or eliminate the symptoms of Alzheimer's disease. However, suspicions about the approval process quickly arose as well as concern from the medical community, which led to controversy about the drug. With this context in mind, our study aims to analyze the viewpoints of caregivers, medical professionals, and Redditors on a popular subreddit for caregivers, as the controversy unfolded. Understanding caregivers' perspectives is vital, as they play an important role in medical compliance and Aduhelm's reception may impact adherence to future treatments. We aim to address two research questions: (a) What are the attitudes towards Aduhelm of caregivers, medical professionals, and members of an online forum associated with caregiving for Alzheimer's patients (r/Alzheimers) and (b) How does the controversy surrounding Aduhelm influence attitudes about the health system and medical practice?

METHODS: We conducted a grounded theory analysis of 23 semi-structured interviews with caregivers and five medical professionals, alongside an online discourse analysis of r/Alzheimers.

RESULTS: Our findings reveal various concerns about Aduhelm involving efficacy, safety, and affordability. Most notably, we find these narratives increased a sense of medical mistrust from participants, which may be problematic for adherence and the doctor/patient interaction.

DISCUSSION: Drawing on sociological literature, we introduce the concept of pharmaceutical ambiguity, a theoretical framework for understanding these social phenomena. This study highlights how controversies like that surrounding Aduhelm can deeply erode trust in medical systems.},
}

@article {pmid41561734,
year = {2026},
author = {Clina, JG and Helsel, BC and Hartley, SL and White, DA and Fleming-Batayneh, VL and Handen, B and Christian, B and Head, E and Mapstone, M and Hom, CL and Ances, B and Burns, J and Rosas, HD and Lai, F and McHale, SK and Lee, JH and Schmitt, FA and Harp, J and Lott, IT and Zaman, S and Ptomey, LT and , },
title = {The impact of congenital heart disease on the timing of Alzheimer's disease in Down syndrome.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70257},
pmid = {41561734},
issn = {2352-8729},
abstract = {INTRODUCTION: The incidence of Alzheimer's disease (AD) in Down syndrome (DS) exceeds 90%. Approximately 50% of people with DS have congenital heart disease (CHD). Having CHD increases risk for early-onset AD in populations without DS, but it is unclear if CHD influences AD in DS.

METHODS: Data from the Alzheimer Biomarker Consortium-Down Syndrome (ABC-DS) were used. Participants with CHD (n = 82, mean age = 39.9 ± 8.5 years, 97.6% White race) were age- and sex-matched to participants without CHD (n = 82, mean age = 40.5 ± 8.1 years, 98.8% White race). Cognitive assessments and Centiloid load (CL) (positron emission tomography) were compared by CHD status.

RESULTS: People with CHD scored lower for visuospatial ability (β = -3.515, p = 0.022) but had higher CL (29.8 ± 12.8 vs. 39.8 ± 12.8, β = 8.00, p = 0.036) and were projected to hit Aβ positivity at a younger age (37.6 and 42.1 years).

DISCUSSION: Presence of CHD may influence AD progression in DS.

HIGHLIGHTS: In adults with Down syndrome (DS), those with congenital heart disease (CHD) had higher amyloid beta and reached the threshold for an amyloid positivity at a younger age than those without CHDNo differences in cognition were seen in the age- and sex-matched sample based on CHD status; however, the average age of the sample may be too young to see cognitive changesCHDs may influence the timing of Alzheimer's disease (AD) in adults with DS.},
}

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

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

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

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

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

@article {pmid41561476,
year = {2026},
author = {Dai, CL and Song, Y and Chen, Y and Tung, YC and Huang, WC and Gong, CX and Lovell, JF},
title = {Therapeutic nanoliposome vaccine targeting multiple Aβ and tau epitopes reduces AD-like brain pathologies and rescues cognitive deficits in 3xTg-AD mice.},
journal = {Brain, behavior, & immunity - health},
volume = {51},
number = {},
pages = {101167},
pmid = {41561476},
issn = {2666-3546},
abstract = {Amyloid beta (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles (NFTs) are the histopathological hallmarks of Alzheimer's disease (AD) and targets for AD therapeutics. Since Aβ and tau pathologies both drive AD pathogenesis and progression, immunotherapies singularly targeting either Aβ or tau may be limited, and simultaneously targeting multiple epitopes of both Aβ and tau may be an efficacious approach. We developed a novel vaccine including three his-tagged tau peptides, tau1-22, mid-region tau171-191 (taupT181), and tau388-407 (taupS396/S404), as well as two his-tagged Aβ fragments (N-terminal Aβ1-14 and N-terminal pyroglutamate AβpE3-14) with the spontaneous nanoliposome antigen particle (SNAP) system, termed SNAP-AD5. Intramuscular vaccination of nine to ten months old of 3xTg-AD mice and age-matched wild-type control animals with SNAP-AD5 or adjuvant only, once every three weeks for a total of 5 immunizations, simultaneously produced IgG titers of antibody against their specific antigens, significantly decreased Aβ and tau pathologies, and effectively improved cognitive function. SNAP-AD5 was well tolerated without any detectable adverse side effects, including inflammatory responses in the peripheral circulation and in the brain, and hemorrhages in the mouse brain. These results support that SNAP-AD5 simultaneously targeting both Aβ and tau is potentially a promising new approach for treating AD. Further optimization and development of the SNAP-AD5 vaccine for treating AD is warranted.},
}

@article {pmid41561336,
year = {2025},
author = {Dai, X and Zhang, J and Li, X and Chen, Y and Qiao, Y and Zhang, S and Chen, K and Ai, L and Peng, D and Zhang, Z},
title = {Neuropsychological and neuroimaging characteristics of patients with mild cognitive impairment and negative-amyloid deposition.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1658712},
pmid = {41561336},
issn = {1664-2295},
abstract = {OBJECTIVES: Accumulating studies have reported that some mild cognitive impairment (MCI) patients without significant β-amyloid (Aβ) deposition on amyloid positron emission tomography (PET) can later develop Alzheimer's disease (AD). Therefore, this study profiled the cognitive and neural characteristics of MCI patients with negative Aβ deposition to better understand potential features associated with an increased risk of AD progression.

METHODS: Thirty-seven MCI patients and 32 normal controls (NCs) underwent neuropsychological assessments, structural magnetic resonance imaging, and diffusion tensor imaging scans. MCI patients were stratified into amyloid-positive (Aβpos; n = 18) and amyloid-negative (Aβneg; n = 19) groups based on [18]F-florbetapir PET. We compared cognitive performance, white matter (WM) integrity, and gray matter volume (GMV) across the three groups and further examined the interplay among brain structural alterations and cognitive changes.

RESULTS: Cognitively, relative to NCs, participants in Aβneg MCI group showed significant deficits in multiple cognitive domains including episodic memory, attention, and executive function, as those in Aβpos MCI group did. Both MCI subgroups exhibited extensive disruptions of WM integrity. Direct comparisons between the Aβneg and Aβpos groups revealed that Aβ-related structural changes were predominantly localized to the left hippocampus and adjacent regions. The increased Aβ deposition was closely associated with elevated mean diffusivity in the left hippocampal portion of the cingulum and reduced GMV of the left hippocampus. Moreover, the GMV of hippocampus could mediate the impact of WM disruption on episodic memory performance.

CONCLUSION: Aβneg MCI patients who exhibit AD-like cognitive and structural abnormalities, particularly involving the hippocampus, may be associated with advanced cognitive decline or dementia progression. These results may help identify high-risk individuals within the heterogeneous Aβneg MCI population.},
}

@article {pmid41561144,
year = {2026},
author = {Rezaei, M and Mohammadikhaveh, S and Faraji, H and Ardalani, R and Rezaei, M and Shirazinodeh, A},
title = {Early diagnosis of Alzheimer's disease based on brain morphological changes: A comprehensive approach combining voxel-based morphometry and deep learning.},
journal = {Neuroimage. Reports},
volume = {6},
number = {1},
pages = {100315},
pmid = {41561144},
issn = {2666-9560},
abstract = {Deep learning algorithms optimize data by enhancing resolution and suppressing noise associated with biological knowledge. The root issue is that, for example, CNNs learning mathematical patterns from statistical correlations in the data without regard to biological cues whatsoever, and merely apply filters such as max pooling, never grasping what the biological cues they are supposed to investigate are. This blind procedure can indeed be in technical language; however, it does not help to identify meaningful insights into neuroimaging, where interpretability is essential, and such inadequacies pose a grave challenge. In our research, rather than depending on the CNNs and FCNs only for the feature extractions, we have integrated biologically motivated features into voxel-based morphometry as well as deep learning. Our goal is to analyze T1-weighted MRI scans and T2-Flair images to investigate the characteristics of gray matter, white matter, cerebrospinal fluid, and white matter Hyperintensity in patients with mild cognitive impairment (MCI) who lie on the spectrum between normal aging and Alzheimer's disease (AD). So we extracted critical structural features such as white matter Hyperintensity, gray matter volume, white matter volume, cerebrospinal fluid (CSF) volume, and cortical thickness. These are biologically meaningful biomarkers that reflect the neurodegenerative alterations directly. To validate our method, after the detection of biological features, we have converted them into 3-bit, 4-bit, 8-bit, and 16-bit images. These images were used as inputs for both FCN and CNN models to investigate the early symptoms of AD from classified intracranial features.},
}

@article {pmid41561142,
year = {2026},
author = {Aoki, Y and Takahashi, R and Pascual-Marqui, RD and Hata, M and Takahashi, S and Ishii, R and Iwase, M and Maenishi, M and Kim, YO and Yamamoto, Y and Hikida, S and Maruyama, K and Mori, E and Ikeda, M},
title = {PyCaret machine learning library with three preprocessing steps after eLORETA source estimation predicts Alzheimer's disease.},
journal = {Neuroimage. Reports},
volume = {6},
number = {1},
pages = {100317},
pmid = {41561142},
issn = {2666-9560},
abstract = {Alzheimer's disease (AD) -the most common form of dementia- begins with mild memory loss and gradually progresses, eventually resulting in a generalized loss of brain function. The pathological changes of AD in the brain cortex begin decades before the onset of symptoms. Improvements in lifestyle habits and disease-modifying treatments before the onset of the disease have been shown to help prevent or delay the onset of AD. However, diagnosis of AD is difficult at the early stage -or even at the prodromal stage [i.e., mild cognitive impairment due to AD (MCIAD)]- since normal aging and other types of dementia also involve memory impairment. Therefore, there is an urgent need to identify markers for the detection of AD at the early stage or pre-onset stage. In this study, we applied exact low-resolution brain electromagnetic tomography (eLORETA) as the source estimation method to electroencephalography (EEG) data. We obtained cortical electrical activity in 96 drug-free AD patients and 147 healthy subjects to train the final model, in addition to activity for 21 MCIAD patients and seven healthy subjects for the purpose of its evaluation. We then applied the low-code machine learning library of PyCaret, with three preprocessing steps (subject-wise normalization, age-difference correction, and log-transformation) to the eLORETA data of AD and healthy subjects. Of the many machine learning classification models used, the linear discriminant analysis (LDA) model showed the highest accuracy, identifying 10 AD patients and 15 healthy subjects with an accuracy of 100.0 %. The LDA model of eLORETA has high transparency and we visualized the discriminant function of the LDA final model using Viewer in eLORETA. Cortical electrical activities in the delta, theta and alpha frequency bands increased in the right dorsolateral prefrontal cortex (DLPFC) regions, as the degree of AD increased (Figs. 2-4). Cortical electrical activity in the beta frequency band decreased in the posterior cingulate cortex (PCC) regions, as the degree of AD increased (Fig. 5) Furthermore, the LDA final model correctly identified 21 MCIAD patients and seven healthy subjects with an accuracy of 96.4 %. Our findings indicate that the LDA final model of eLORETA had the capacity to detect physiological features of AD in EEG data, even before the onset of the disease. Overall, PyCaret with three preprocessing steps after eLORETA source estimation can create an accurate EEG classification model, which makes a significant contribution to the early detection of AD among the many individuals in the general population who remain undiagnosed.},
}

@article {pmid41561087,
year = {2025},
author = {Lee, CK and Woodward, M and Hohenberg, MI and Tang, JW},
title = {Charting the research frontier for viral infections, immunomodulation, and dementia: a perspective on synaptic biomarkers as essential clinical trial endpoints.},
journal = {Frontiers in cellular and infection microbiology},
volume = {15},
number = {},
pages = {1701760},
pmid = {41561087},
issn = {2235-2988},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; *Dementia/cerebrospinal fluid ; *Immunomodulation ; Antiviral Agents/therapeutic use ; Alzheimer Disease/cerebrospinal fluid ; *Synapses/metabolism ; *Virus Diseases/cerebrospinal fluid/drug therapy ; Clinical Trials as Topic ; COVID-19 ; SARS-CoV-2 ; },
abstract = {The viral-inflammatory hypothesis of Alzheimer's disease offers a new paradigm, yet interventions like antivirals and vaccination present a paradox that challenge therapeutic development. This perspective examines the critical research gap concerning cerebrospinal fluid (CSF) synaptic biomarkers in immunomodulatory therapy trials. Following decades of partially successful amyloid-centric trials, focus has shifted to upstream triggers including viral infections like Herpes Simplex Virus Type 1, Varicella Zoster Virus, and Severe Acute Respiratory Syndrome Coronavirus 2. While large observational and quasi-experimental studies suggest antivirals and vaccines reduce long-term dementia risk, the first major antiviral randomized controlled trial (Valacyclovir for Alzheimer's Disease) was negative. This perspective posits that this paradox arises from a fundamental flaw in trial design: the absence of synaptic integrity biomarkers. Synaptic loss, not amyloid or tau burden, is the strongest correlate of cognitive decline. Therefore, CSF synaptic protein biomarkers such as the prognostic YWHAG: NPTX2 ratio, postsynaptic Neurogranin (Ng), and presynaptic Growth-Associated Protein 43 (GAP-43) are the most clinically relevant endpoints. The paradoxical trial results may arise from omitting these synaptic measures, creating a mechanistic "black box" obscuring their true biological effects. A strategic framework is proposed, centered on the mandatory inclusion of CSF synaptic biomarkers and relevant co-pathology markers like TAR DNA-Binding Protein 43 (TDP-43; a proteinopathy linked to viral triggers) in all antiviral and vaccine trials. This approach is critical to resolve existing paradoxes, elucidate mechanisms of neuroprotection, and accelerate developing effective therapies that preserve synaptic integrity to prevent and treat dementia.},
}

Humans
*Biomarkers/cerebrospinal fluid
*Dementia/cerebrospinal fluid
*Immunomodulation
Antiviral Agents/therapeutic use
Alzheimer Disease/cerebrospinal fluid
*Synapses/metabolism
*Virus Diseases/cerebrospinal fluid/drug therapy
Clinical Trials as Topic
COVID-19
SARS-CoV-2

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

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

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

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

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

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

@article {pmid41560711,
year = {2026},
author = {Fujita, K and Kaneda, D and Sakurai, K and Matsubara, T and Harada, M and Izumi, Y},
title = {A gray matter volume network in pathologically confirmed cases of argyrophilic grain disease: An exploratory analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411404},
doi = {10.1177/13872877251411404},
pmid = {41560711},
issn = {1875-8908},
abstract = {BackgroundArgyrophilic grain disease (AGD) is a common yet underrecognized tauopathy that often mimics Alzheimer's disease (AD) in clinical and imaging presentations. While regional atrophy in AGD has been reported on magnetic resonance imaging (MRI), network-level structural changes remain poorly understood.ObjectiveWe aimed to explore a gray matter volume network related to AGD.MethodsStructural MRI data were collected from 12 patients with pathologically confirmed AGD (age at MRI, 87.7 ± 5.5 years; male, 4), 12 patients with pathologically confirmed AD (83.4 ± 10.0 years; male, 4), and 9 healthy controls (HCs; 82.4 ± 1.9 years; male, 2) at Fukushimura Hospital in Japan. Scaled Subprofile Model with principal component analysis was applied to preprocessed gray matter volume data of AGD and HCs to identify an AGD-related network.ResultsAn AGD-related network involving relative reduction in the ambient gyrus, entorhinal cortex, hippocampus, amygdala, and thalamus was identified. Represented by principal components 1, 2, and 3, this network showed significantly higher expression in patients with AGD than HCs (p < 0.0001, permutation test). The expression of the network was also higher in patients with AD than HCs (p < 0.0001, t-test).ConclusionsThis exploratory study identified a gray matter volume network related to AGD, providing a basis for future research of network-based imaging approaches.},
}

@article {pmid41560705,
year = {2026},
author = {Patel, PJ and Yan, Z},
title = {Epigenomic aberrations of histone methylation in prefrontal cortex of humans with mild cognitive impairment and Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251414887},
doi = {10.1177/13872877251414887},
pmid = {41560705},
issn = {1875-8908},
abstract = {BackgroundEpigenetic mechanisms, particularly histone modifications at gene promoters, are crucial for controlling gene transcription.ObjectiveWe aim to find out epigenomic aberrations during the progression of neurodegenerative disorders.MethodsWe employed a multifaceted approach to investigate how the two key histone methylation marks, H3K4me3 (linked to gene activation) and H3K27me3 (linked to gene suppression), are altered in postmortem prefrontal cortex of humans with mild cognitive impairment (MCI) or Alzheimer's disease (AD).ResultsCompared to controls, MCI and AD exhibited pronounced losses of permissive H3K4me3 peaks at promoters of genes enriched in synaptic plasticity and neurotransmission, and significant gains of H3K4me3 peaks at promoters of genes enriched in transcriptional regulation. AD displayed more substantial H3K4me3 losses on synaptic genes than MCI. Conversely, significant gains of repressive H3K27me3 peaks were observed at synaptic gene promoters in both disease groups, with MCI exhibiting more pronounced H3K27me3 gains on synaptic genes than AD. Weighted Gene Correlation Network Analysis (WGCNA) revealed multiple modules characterizing distinct patterns of gains and losses of H3K4me3 and H3K27me3 during the transition from MCI to AD. Integrative analysis of epigenomic and transcriptomic data indicated that these histone mark alterations were well correlated with the downregulation of synaptic genes and upregulation of transcriptional regulators in AD.ConclusionsThis comprehensive profiling uncovers a stage-dependent reorganization of histone modifications at critical gene loci, implicating these events in the molecular cascade of AD pathogenesis. Targeting dysregulated chromatin states may offer novel therapeutic avenues for early intervention of AD.},
}

@article {pmid41560704,
year = {2026},
author = {Thai, QM and Ngo, ST},
title = {Aβ42 Adopts a Stronger Binding Affinity to the Gold Surface than Aβ40.},
journal = {The journal of physical chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jpcb.5c07335},
pmid = {41560704},
issn = {1520-5207},
abstract = {Soluble Aβ oligomers are categorized as major agents of Alzheimer's disease progression, instead of insoluble fibrils. The binding affinity of Aβ peptides on the gold surface is associated with the biocorona due to the Vroman effect. This phenomenon can be used to screen and/or remove highly toxic amyloid pieces using gold nanoparticles. In this context, the binding process of Aβ40 and Aβ42 dimers to the gold nanosurface was investigated via atomistic simulations, including molecular dynamics (MD) and steered-MD (SMD) simulations. In particular, the obtained results indicate that the Aβ17-42 dimer exhibits a stronger binding affinity to the gold surface than the Aβ17-40 dimer in terms of the rupture force, pulling work, and Jarzynski's free energy analyses. During this process, the van der Waals (vdW) interaction energy plays an important role, and Aβ17-42 adopts a significantly larger value compared with Aβ17-40. The enlarged interaction is caused by the additional hydrophobic residues at the C-terminus, including Ile41 and Ala42. Furthermore, free energy landscape outcomes demonstrate that Aβ17-42 maintains a rigid β-hairpin during the dissociation process, while Aβ17-40 becomes a random coil.},
}

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

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

@article {pmid41560652,
year = {2026},
author = {Bayattork, M and Rahman, M and Hossain, MI and Zhang, Y and Haque, ANMA and Kim, B and Naebe, M},
title = {Impact of Textile-Derived Micro- and Nanoplastics on Brain Health: An Emerging Environmental Risk.},
journal = {Environmental science & technology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.est.5c10338},
pmid = {41560652},
issn = {1520-5851},
abstract = {Textile-derived micro- and nanoplastics (MNPs), primarily shed from synthetic fibers, such as polyester, acrylic, polyethylene, and nylon, constitute a widespread yet underexplored class of environmental pollutants. Despite their pervasive presence in indoor air, household dust, and the human body, these fibrous MNPs have received considerably less attention than polystyrene-based particles, resulting in a critical gap in our understanding of their potential health impacts. This review examines the growing evidence that textile-derived MNPs can translocate across biological barriers following inhalation or ingestion, reaching the brain via both direct olfactory pathways and systemic circulation through the blood-brain barrier. Experimental studies increasingly implicate MNPs in oxidative stress, neuroinflammation, and protein aggregation, processes central to the pathogenesis of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. We also explore the therapeutic potential of natural bioactive compounds, including polyphenols and omega-3 fatty acids, in mitigating MNP-induced neurotoxicity. By consolidating current findings, this review highlights the urgency of advancing mechanistic studies, exposure assessment, and regulatory oversight to address the emerging threat of textile-derived MNPs to neurological health.},
}

@article {pmid41560403,
year = {2026},
author = {Sánchez-Sánchez, JL and Rolland, Y and Lucas, A and Guyonnet, S and Vellas, B and de Souto Barreto, P and , },
title = {Associations Between Growth Differentiating Factor-15 and Frailty in Older Adults From the MAPT Study.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {17},
number = {1},
pages = {e70182},
doi = {10.1002/jcsm.70182},
pmid = {41560403},
issn = {2190-6009},
support = {ANR-23-IAHU-0011//Agence Nationale de la Recherche/ ; //Gérontopôle of Toulouse/ ; PHRC 2008//French Ministry of Health/ ; PHRC 2009//French Ministry of Health/ ; //Pierre Fabre Research Institute/ ; //ExonHit Therapeutics SA/ ; //Avid Radiopharmaceuticals Inc./ ; //Association Monegasque pour la Recherche sur la maladie d'Alzheimer/ ; //INSERM-University of Toulouse III UMR 1295 Unit/ ; 1901175//Region Occitanie/Pyrénées-Méditerranée/ ; MP0022856//European Regional Development Fund/ ; //Alzheimer Prevention in Occitania and Catalonia (APOC Chair of Excellence-Inspire Program)/ ; },
mesh = {Humans ; *Growth Differentiation Factor 15/blood ; Female ; Aged ; Male ; *Frailty/blood/diagnosis ; Biomarkers/blood ; Aged, 80 and over ; Cross-Sectional Studies ; },
abstract = {BACKGROUND: Frailty is a prevalent syndrome in older adults and is associated with increased vulnerability to adverse health outcomes. Growth differentiation factor 15 (GDF-15), a cytokine involved in mitochondrial dysfunction and inflammation, has been proposed as a potential biomarker for age-related conditions. Evidence on the association between GDF-15 and frailty in older adults is limited. This study explores the relationship between plasma GDF-15 levels and frailty onset in community-dwelling older adults.

METHODS: A secondary analysis was performed on 1096 participants (mean age = 75.2 ± 4.5 years; 64.5% women) from the Multidomain Alzheimer Prevention Trial (MAPT). Plasma GDF-15 levels were measured at year 1. Frailty was assessed using the Fried phenotype. Logistic regression was used to examine cross-sectional associations between GDF-15 and frailty, while mixed effects logistic regression or Cox proportional hazards models assessed longitudinal associations over a 4-year follow-up.

RESULTS: Higher plasma GDF-15 levels (both as continuous and categorical) were cross-sectionally associated with frailty (high vs. low GDF-15: OR = 3.56, 95% CI = 1.58-8.03). Longitudinally, very high GDF-15 levels predicted an increased risk of incident frailty (HR = 1.69, 95% CI = 1.03-2.78).

CONCLUSIONS: Elevated plasma GDF-15 levels were associated with frailty in older adults, suggesting its potential as a biomarker for increased vulnerability and an indicator of increased risk over time. Our results support a pleiotropic role of GDF-15, with low physiological levels not contributing to frailty development.},
}

Humans
*Growth Differentiation Factor 15/blood
Female
Aged
Male
*Frailty/blood/diagnosis
Biomarkers/blood
Aged, 80 and over
Cross-Sectional Studies

@article {pmid41560352,
year = {2026},
author = {Wang, D and Abbruzzese, S and Heard-Costa, N and Rampersaud, A and Martin, E and Naj, A and Akgun, B and Kunkle, B and Seshadri, S and Peloso, G and , and , and DeStefano, AL and Li, Z and Li, X and Choi, SH},
title = {Application of the STAAR Framework in Detecting Rare Variant Associations with Alzheimer's Disease and Related Dementias: Insights and Implications.},
journal = {HGG advances},
volume = {},
number = {},
pages = {100574},
doi = {10.1016/j.xhgg.2026.100574},
pmid = {41560352},
issn = {2666-2477},
abstract = {Rare genetic variation is considered a potential source of heritability in individuals with sporadic Alzheimer's Disease and related dementias (ADRD). The STAAR framework leverages multiple functional annotations of genetic variants and combines association statistics from multiple variant aggregation-based methods, including burden, SKAT, and ACAT-V, into a single measure of significance. Using whole genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP), we comprehensively examined the association of rare genetic variation with ADRD in 23,454 individuals (37% ADRD cases) and with cognitively healthy elder status in 13,292 individuals (13% cognitively healthy elders) from diverse populations via the STAAR framework. We identified several genes significantly associated with ADRD or cognitively healthy status. However, our analysis revealed several limitations within the STAAR framework incorporating ultra-rare variants with dichotomous outcomes. To enhance the robustness of the framework, we proposed several computational refinements, including creating a burden of ultra-rare variants and employing more precise annotations to match with expected mechanism. After implementing the proposed modifications, the association with ADRD for ZNF200 was no longer statistically significant (α=1x10[-7]), while TBX19, PLXNB2, CARD11, and LINC01880 remained significantly associated with cognitively healthy status. We identified and addressed the computational limitations in the STAAR framework that could lead to potential spurious results for ultra-rare variant aggregates with an extremely low cumulative minor allele count. Our proposed refinements produced more robust results for associations with rare variants in the context of dichotomous outcomes.},
}

@article {pmid41560134,
year = {2025},
author = {Chen, C and Chen, H and Yu, Y and Tan, R},
title = {Effects of different organic solvents on the structure of Aβ_{1-42}
monomer.},
journal = {Physical review. E},
volume = {112},
number = {6-1},
pages = {064409},
doi = {10.1103/6c4s-bgyx},
pmid = {41560134},
issn = {2470-0053},
mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; *Solvents/chemistry/pharmacology ; Molecular Dynamics Simulation ; *Peptide Fragments/chemistry/metabolism ; Dimethyl Sulfoxide/chemistry/pharmacology ; Acetonitriles/chemistry/pharmacology ; Ethanol/chemistry/pharmacology ; Hydrogen Bonding ; Protein Aggregates/drug effects ; },
abstract = {The aggregation of amyloid-β42 (Aβ42) peptide, a key pathological event in Alzheimer's disease, is strongly influenced by its solvent environment. While cosolvents are often used in experimental studies, their specific role in modulating the conformational stability and aggregation propensity of Aβ42 remains poorly understood. We perform molecular dynamics simulations to investigate the effects of three organic solvents-ethanol (EtOH), dimethyl sulfoxide (DMSO), and acetonitrile (ACN)-on the structural dynamics of Aβ42. Our results reveal a distinct dichotomy: EtOH and DMSO exert a stabilizing effect by promoting the α-helical content, reducing Coil formation, and extending the lifetime of intramolecular hydrogen bonds. In contrast, ACN destabilizes the native state and accelerates the formation of aggregation-prone β-sheet structures. We attribute these opposing effects to the solvents' differential disruption of the peptide's hydrophobic core and their specific interactions with the protein backbone. This work elucidates the microscopic mechanisms by which solvent environment directs Aβ42 conformational sampling, with implications for understanding aggregation pathways and designing modulating agents.},
}

*Amyloid beta-Peptides/chemistry/metabolism
*Solvents/chemistry/pharmacology
Molecular Dynamics Simulation
*Peptide Fragments/chemistry/metabolism
Dimethyl Sulfoxide/chemistry/pharmacology
Acetonitriles/chemistry/pharmacology
Ethanol/chemistry/pharmacology
Hydrogen Bonding
Protein Aggregates/drug effects

@article {pmid41363728,
year = {2026},
author = {Zhang, W and Huang, H and Wang, L and Lehmann, BD and Chen, XS},
title = {An integrative multiomics random forest framework for robust biomarker discovery.},
journal = {GigaScience},
volume = {15},
number = {},
pages = {},
doi = {10.1093/gigascience/giaf148},
pmid = {41363728},
issn = {2047-217X},
support = {R01CA200987/NH/NIH HHS/United States ; P50CA098131/NH/NIH HHS/United States ; P30CA240139/NH/NIH HHS/United States ; R01AG062634/NH/NIH HHS/United States ; R61NS135587/NH/NIH HHS/United States ; RF1NS128145/NH/NIH HHS/United States ; BC201286//Department of Defense Breast Cancer Research/ ; },
mesh = {Humans ; *Genomics/methods ; *Biomarkers ; *Biomarkers, Tumor/genetics ; *Computational Biology/methods ; Algorithms ; Breast Neoplasms/genetics ; Random Forest ; Multiomics ; },
abstract = {BACKGROUND: High-throughput technologies now produce a wide array of omics data, from genomic and transcriptomic profiles to epigenomic and proteomic measurements. Integrating multiple omics layers measured on the same samples can reveal cross-layer molecular hubs that single-layer analyses miss. However, many existing integrative methods rely on linear assumptions or univariate feature importance, limiting their ability to capture nonlinear and interaction-driven dependencies across data modalities.

RESULTS: We present an unsupervised, multivariate random forest (MRF) framework with an inverse minimal depth (IMD) importance to prioritize shared biomarkers across omics. In each forest, one layer serves as a multivariate response and the other as predictors; IMD summarizes how early a predictor (or response maximal splitting response variable) appears across trees, yielding interpretable, cross-layer feature rankings. We provide two IMD-based selection strategies and introduce an optional IMD power transform to enhance sensitivity to interaction signals. In extensive simulations spanning linear, nonlinear, and interaction regimes, our method matches sparse partial least squares/canonical correlation analysis under linear settings and outperforms them as nonlinearity increases, while adapted univariate ensemble learners (random forest, gradient boosting machine, XGBoost) underperform in the multivariate, unsupervised context. Applied to breast invasive carcinoma and colon adenocarcinoma in The Cancer Genome Atlas (TCGA), MRF-IMD identifies genes, CpGs, and microRNAs enriched for cancer-relevant pathways and yields more robust survival stratification than linear integrators with matched model sizes. In a TCGA pan-cancer analysis, MRF-IMD features achieve a higher Adjusted Rand Index than alternatives and recover coherent tumor-type clusters; in the Alzheimer's Disease Neuroimaging Initiative (ADNI), the integrative signature improves dementia progression stratification over a published methylation risk score.

CONCLUSIONS: MRF-IMD provides a scalable and interpretable framework for multiomics integration that reliably identifies cross-layer biomarkers when nonlinear and interaction-driven dependencies are present. This approach advances robust biomarker discovery beyond the limits of linear integrative methods.},
}

Humans
*Genomics/methods
*Biomarkers
*Biomarkers, Tumor/genetics
*Computational Biology/methods
Algorithms
Breast Neoplasms/genetics
Random Forest
Multiomics

@article {pmid41122776,
year = {2025},
author = {Suen, D and Chen, YC},
title = {Modeling Missing at Random Neuropsychological Test Scores Using a Mixture of Binomial Product Experts.},
journal = {Psychometrika},
volume = {},
number = {},
pages = {1-24},
doi = {10.1017/psy.2025.10053},
pmid = {41122776},
issn = {1860-0980},
support = {U24-AG072122/AG/NIA NIH HHS/United States ; DGE-2140004//National Science Foundation Graduate Research Fellowship Program/ ; DMS-195278,DMS-2112907,DMS-2141808//Division of Mathematical Sciences/ ; },
abstract = {Multivariate bounded discrete data arises in many fields. In the setting of dementia studies, such data are collected when individuals complete neuropsychological tests. We outline a modeling and inference procedure that can model the joint distribution conditional on baseline covariates, leveraging previous work on mixtures of experts and latent class models. Furthermore, we illustrate how the work can be extended when the outcome data are missing at random using a nested EM algorithm. The proposed model can incorporate covariate information and perform imputation and clustering. We apply our model to simulated data and an Alzheimer's disease data set.},
}

@article {pmid41559842,
year = {2026},
author = {Sánchez Milán, JA and Mulet, M and Molet, I and Lisa-Molina, J and Font-Alberich, M and Lorca, C and Gea-Sánchez, M and Bellon, F and Batalla, I and Meana, JJ and Callado, LF and Morentin, B and Ramos-Miguel, A and Kalaria, RN and Serra, A and Gallart-Palau, X},
title = {Brain and circulating EV proteome signatures in schizophrenia as prognostic markers for age-related dementia.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02223-z},
pmid = {41559842},
issn = {2051-5960},
support = {IT1512/22//Eusko Jaurlaritza/ ; PID2020-114885RB-C21//Agencia Estatal de Investigación/ ; 2022 DI 100//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; 2023 LLAV 00056//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; PIRS23/02//Diputació de Lleida, Spain/ ; PIRS22/03//Diputació de Lleida, Spain/ ; X25022//Universitat de Lleida/ ; PI22/00443//Instituto de Salud Carlos III/ ; PRTR-C17.I1//NextGenerationEU/ ; },
abstract = {Schizophrenia (SZ) is epidemiologically linked to an increased risk of developing age-related dementias (ARD) predominantly characterized by Alzheimer's disease and vascular dementia. However, the molecular mechanisms underlying this association remain insufficiently elucidated. Extracellular vesicles (EVs) play a critical role in neuropathological processes and offer a promising avenue for identifying shared disease mechanisms and potential circulating markers for patient stratification. Here we used a two-phase systems biology approach integrating discovery-driven proteomics with a targeted validation strategy using data-independent acquisition mass spectrometry (DIA-MS) in a large, independent SZ cohort. First, we analyzed brain-derived EVs (bEVs) from post-mortem SZ and ARD subjects to identify shared molecular signatures. Next, we validated the presence and circulation of these bEV markers in circulating plasma EVs (pEVs) using DIA-MS data. Remarkably, SZ and ARD bEV proteome and peptidome showed overlapping alterations in neuronal connectivity, synaptic integrity, neuroinflammation, and metabolism. Unsupervised clustering analysis of correlated bEV/pEV markers stratified SZ patients into two clusters: high dementia risk and control-like profiles. Collectively, these data emphasize the significance of bEVs as crucial mediators of shared neuropathogenic mechanisms in SZ, and ARD. Furthermore, we identified a set of pEVs markers, including proteins and specific peptides, with a robust and promising bench-to-bedside trajectory that may facilitate the stratification of SZ patients at risk for ARD.},
}

@article {pmid41559829,
year = {2026},
author = {Ma, C and Ye, Y and Shi, X and Li, N and Mu, Z and Tan, T and Yin, H and Dai, J and Liu, Y and Chen, H},
title = {Correction: Photobiomodulation mitigates blood-brain barrier disruption in APP/PS1 mouse model of Alzheimer's disease by activating the AMPK pathway.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {16},
pmid = {41559829},
issn = {1758-9193},
}

@article {pmid41559471,
year = {2026},
author = {Liu, T and Chen, D and Liu, F and Sun, Y},
title = {ZFP36-mediated ZBP1 degradation inhibits microglia pro-inflammatory and NLRP3 inflammasome activation in Alzheimer's disease.},
journal = {Cell biology and toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10565-026-10139-6},
pmid = {41559471},
issn = {1573-6822},
abstract = {Alzheimer's disease (AD) is a heterogeneous disease with limited treatment efficacy. Identifying novel molecular targets and mechanisms is therefore crucial for developing therapeutic strategies. Zinc finger protein 36 (ZFP36) has not been reported in AD. This study found that the hippocampus of APP/PS1 mice showed ZFP36 upregulation. Using recombinant adeno-associated virus to overexpress ZFP36 improved the cognitive function of APP/PS1 mice, as assessed by Morris maze and Y maze tests. Furthermore, ZFP36 overexpression reduced Aβ deposition, expression of pro-inflammatory markers, and inhibited NLRP3 inflammasome activation in the hippocampus. These inhibitory effects of ZFP36 overexpression on the aforementioned proteins were also observed in Aβ1-42-treated BV-2 cells. mRNA sequencing identified Z-DNA Binding Protein 1 (ZBP1) as a target of ZFP36. After ZFP36 overexpression, ZBP1 was downregulated in the hippocampus and Aβ1-42-treated BV-2 cells. The interaction between ZFP36 and ZBP1 RNA was verified by RIP-PCR, and ZFP36 was shown to promote the degradation of ZBP1 mRNA. The inhibitory effects of ZFP36 on the NLRP3 inflammasome activation and microglial pro-inflammatory activation was reversed by ZBP1 overexpression. In summary, ZFP36 inhibits microglia pro-inflammatory and NLRP3 inflammasome activation through promoting the degradation of ZBP1 mRNA, thereby ameliorating cognitive deficits of APP/PS1 mice.},
}

@article {pmid41559358,
year = {2026},
author = {Wang, K and Shao, B and Zeng, Q and Liu, X and Li, K and Luo, X},
title = {Trajectory of stratum radiatum, lacunosum and moleculare integrity in Alzheimer's disease continuum.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-35610-6},
pmid = {41559358},
issn = {2045-2322},
support = {82202090//National Natural Science Foundation of China/ ; 82271936//National Natural Science Foundation of China/ ; },
abstract = {The atrophy of the hippocampus and its subfields represents a critical hallmark of neurodegeneration in Alzheimer's Disease (AD). However, the trajectories of stratum radiatum, lacunosum, and moleculare (SRLM) integrity along the AD continuum are still unclear. This study encompassed 178 amyloid-negative cognitively unimpaired controls (CU A-), 91 amyloid-positive cognitively unimpaired individuals (CU A+), 90 amyloid-positive patients with mild cognitive impairment (MCI A+), and 14 amyloid-positive AD patients (AD A+), to model the AD continuum. T1-weighted images facilitated the hippocampal volume segmentation, while T2-weighted images enabled both visual hippocampal atrophy and SRLM assessments. Furthermore, the associations between hippocampal metrics and cognitive function were evaluated. Across the AD continuum, CU A+ individuals exhibited lower visual SRLM integrity score compared to their CU A- counterparts. Both MCI A+ and AD A+ groups displayed reduced SRLM integrity score, increased visual hippocampal atrophy score, and decreased hippocampal volume compared to CU A-. Correlational analyses revealed significant associations between hippocampal metrics and cognitive function. Hippocampal atrophy progresseses along the AD continuum, with visual SRLM integrity score declining in the early stages of AD. These results suggest that SRLM integrity may serve as a sensitive marker for early detection of AD.},
}

@article {pmid41559192,
year = {2026},
author = {Hu, EY and Oleshko, S and Firmani, S and Cheng, H and Zhu, Z and Ulmer, M and Arnold, M and Colomé-Tatché, M and Tang, J and Xhonneux, S and Marsico, A},
title = {Enhancing link prediction in biomedical knowledge graphs with BioPathNet.},
journal = {Nature biomedical engineering},
volume = {},
number = {},
pages = {},
pmid = {41559192},
issn = {2157-846X},
abstract = {Understanding complex interactions in biomedical networks is crucial for advancements in biomedicine, but traditional link prediction (LP) methods are limited in capturing this complexity. We present BioPathNet, a graph neural network framework based on the neural Bellman-Ford network (NBFNet), addressing limitations of traditional representation-based learning methods through path-based reasoning for LP in biomedical knowledge graphs. Unlike node-embedding frameworks, BioPathNet learns representations between node pairs by considering all relations along paths, enhancing prediction accuracy and interpretability, and allowing visualization of influential paths and biological validation. BioPathNet leverages a background regulatory graph for enhanced message passing and uses stringent negative sampling to improve precision and scalability. BioPathNet outperforms or matches existing methods across diverse tasks including gene function annotation, drug-disease indication, synthetic lethality and lncRNA-target interaction prediction. Our study identifies promising additional drug indications for diseases such as acute lymphoblastic leukaemia and Alzheimer's disease, validated by medical experts and clinical trials. In addition, we prioritize putative synthetic lethal gene pairs and regulatory lncRNA-target interactions. BioPathNet's interpretability will enable researchers to trace prediction paths and gain molecular insights.},
}

@article {pmid41559153,
year = {2026},
author = {Peter, Q and Taylor, C and Lapinska, U and Wei, J and Michaels, TCT and Arosio, P and Linse, S and Knowles, TPJ},
title = {Oligomers mediate the spatial transmission of Aβ peptide aggregation.},
journal = {Communications chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42004-025-01837-z},
pmid = {41559153},
issn = {2399-3669},
support = {674979//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; },
abstract = {Alzheimer's disease (AD) is marked by the abnormal aggregation of amyloid-beta peptides within the central nervous system. The formation of amyloid fibrils from amyloid-beta peptides is a hallmark of AD Here, we demonstrate that the aggregation of amyloid-beta 42 spreads both spatially and temporally. By measuring the spatial propagation of amyloid-beta in macroscopic capillaries and performing Monte Carlo simulations, we show that this spreading occurs through a diffusion mechanism involving oligomers in solution. These species, catalytically produced through spontaneous secondary nucleation, significantly accelerate the propagation velocity of the reaction wavefront. Our findings suggest that, in addition to their potential role in toxicity, these oligomers in solution are key drivers of the spatial spreading of aggregation and can therefore be considered key targets for therapeutic intervention.},
}

@article {pmid41558999,
year = {2026},
author = {Hiransuthikul, A and Thanapornsangsuth, P and Luechaipanit, W and Haethaisong, T and Ubolyam, S and Apornpong, T and Han, WM and Kerr, S and Avihingsanon, A and , },
title = {Blood-based Alzheimer's disease biomarkers and cognitive trajectories in older people with HIV with undetectable viral loads.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71101},
doi = {10.1002/alz.71101},
pmid = {41558999},
issn = {1552-5279},
support = {//U.S. National Institutes of Health's (NIH)/ ; },
mesh = {Humans ; Biomarkers/blood ; Male ; Female ; *Alzheimer Disease/blood/diagnosis ; *HIV Infections/blood/complications ; *tau Proteins/blood ; *Viral Load ; *Cognitive Dysfunction/blood ; Middle Aged ; Neurofilament Proteins/blood ; *Glial Fibrillary Acidic Protein/blood ; Aged ; Mental Status and Dementia Tests/statistics & numerical data ; Thailand ; },
abstract = {INTRODUCTION: Cognitive impairment among people with HIV (PWH) remains common, yet underlying mechanisms remain unclear. Alzheimer's disease (AD) is the leading cause of dementia, and blood-based biomarkers offer a promising diagnostic alternative. We evaluated phosphorylated-tau 217 (p-tau217), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) as predictors of cognitive decline among virologically suppressed older PWH.

METHODS: Thai PWH aged ≥50 years with plasma viral loads <50 copies/mL completed the Montreal Cognitive Assessment (MoCA) at baseline (2015-2017) and a follow-up visit (2021-2024). Associations between each biomarker and cognitive trajectories were assessed using multivariate mixed-effects models.

RESULTS: Among 255 participants followed for a median of 5.9 years, those in Q4 of p-tau217 and GFAP had greater MoCA decline than Q1-3 (p-tau217: -3.3 vs. -1.4, p-interaction = 0.02; GFAP: -2.9 vs. -1.3, p-interaction = 0.03).

DISCUSSION: Elevated p-tau217 and GFAP predict cognitive decline in PWH, underscoring AD and inflammatory biomarker relevance.},
}

Humans
Biomarkers/blood
Male
Female
*Alzheimer Disease/blood/diagnosis
*HIV Infections/blood/complications
*tau Proteins/blood
*Viral Load
*Cognitive Dysfunction/blood
Middle Aged
Neurofilament Proteins/blood
*Glial Fibrillary Acidic Protein/blood
Aged
Mental Status and Dementia Tests/statistics & numerical data
Thailand

@article {pmid41558820,
year = {2026},
author = {Nishioka, K and Ikezaki, M and Iwahashi, N and Arakawa, M and Fukushima, M and Mori, N and Mizoguchi, M and Horiuchi-Tanizaki, Y and Fujino, M and Tomiyama, T and Ihara, Y and Uchimura, K and Ino, K and Nishitsuji, K},
title = {Amyloid-β fibrils accumulated in preeclamptic placentas suppress cytotrophoblast syncytialization.},
journal = {Life science alliance},
volume = {9},
number = {4},
pages = {},
doi = {10.26508/lsa.202503453},
pmid = {41558820},
issn = {2575-1077},
mesh = {Humans ; *Pre-Eclampsia/metabolism/pathology ; Pregnancy ; Female ; *Trophoblasts/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; *Placenta/metabolism/pathology ; Amyloid Precursor Protein Secretases/metabolism ; Aspartic Acid Endopeptidases/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Peptide Fragments/metabolism ; Adult ; Amyloid/metabolism ; },
abstract = {Cerebral deposition of fibrillar amyloid-β (Aβ) is a pathological hallmark of Alzheimer's disease. Although Aβ is present in human placentas and accumulates in preeclamptic placentas characterized by poor placentation, the production and role of Aβ in the human placenta remain unclear. Because hypoxia in mid-to-late pregnancy is a risk for preeclampsia, we found that levels of hypoxia-inducible factor 1-α and β-secretase (BACE-1) increased concurrently with placental Aβ deposition in late-stage preeclamptic placentas. We also found that a human cytotrophoblast (CTB) model, BeWo cells, actually produced Aβ species and that hypoxia increased Aβ production and BACE-1 protein levels. Aβ42 fibrils inhibited CTB syncytialization, a critical step in maintaining pregnancy, by inducing loss of membrane localization of cell-cell adhesion molecules. Primary human CTBs confirmed these observations. Taken together, our results suggest that increased Aβ production in CTBs by hypoxia may lead to the formation of Aβ fibrils, which inhibit syncytiotrophoblast formation and are detrimental to pregnancy. Thus, our results reveal the novel role of Aβ fibrils in the pathogenesis of preeclampsia.},
}

Humans
*Pre-Eclampsia/metabolism/pathology
Pregnancy
Female
*Trophoblasts/metabolism/pathology
*Amyloid beta-Peptides/metabolism
*Placenta/metabolism/pathology
Amyloid Precursor Protein Secretases/metabolism
Aspartic Acid Endopeptidases/metabolism
Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
Peptide Fragments/metabolism
Adult
Amyloid/metabolism

@article {pmid41558720,
year = {2026},
author = {Zhou, R and Li, J and Liu, W and Zheng, R and Han, J and Liao, Z and Ning, W and Tang, C},
title = {[Systematic review and mechanistic exploration of "intelligence three-needling" in treatment of Alzheimer's disease].},
journal = {Zhongguo zhen jiu = Chinese acupuncture & moxibustion},
volume = {46},
number = {1},
pages = {153-160},
doi = {10.13703/j.0255-2930.20250723-k0001},
pmid = {41558720},
issn = {0255-2930},
mesh = {*Alzheimer Disease/therapy/metabolism/genetics ; Humans ; Animals ; *Acupuncture Therapy ; Acupuncture Points ; Brain/metabolism ; },
abstract = {The "intelligence three-needling" therapy, developed by Professor JIN Rui, the eminent acupuncture- moxibustion master in the south of Five Ridges, is effective on cognitive dysfunction in practice. The paper reviews the animal experiment researches of Alzheimer's disease (AD) treated with this therapy, aiming to explain its core mechanism and effect characteristics for AD. The results showed that the "intelligence three-needling" therapy exerts its effect through multiple targets and diverse pathways. It improves cholinergic system function, enhances glucose metabolism in brain regions, reduces oxidative stress damage, suppresses neuroinflammation, regulates the Wnt/β-catenin signaling pathway, promotes autophagy-lysosomal clearance of pathological proteins, activates the transmembrane receptor protein (Notch) pathway to strengthen synaptic plasticity, demonstrates neuroprotective and anti-apoptotic effects, and modulates gut microbiota. In experiments, this therapy demonstrated specific effect in brain regions of 5xFAD mouse models. Compared with the single application at "Benshen" (GB13) or "Shenting" (GV24), the acupoint combination in this therapy displayed the synergistic advantages, regulating more comprehensively adenosine monophosphate activated protein kinase (AMPK)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) kinase network. This review provides the theoretical basis for optimizing the protocol of acupuncture and moxibustion for AD, and is conducive to promoting the deep integration of traditional acupuncture-moxibustion therapy with modern neuroscience.},
}

*Alzheimer Disease/therapy/metabolism/genetics
Humans
Animals
*Acupuncture Therapy
Acupuncture Points
Brain/metabolism

@article {pmid41558522,
year = {2026},
author = {Shimizu, T and Mizushima, N},
title = {[Autophagy and Neurological Diseases].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {78},
number = {1},
pages = {65-72},
doi = {10.11477/mf.188160960780010065},
pmid = {41558522},
issn = {1881-6096},
mesh = {Humans ; *Autophagy/genetics/physiology ; *Nervous System Diseases/genetics ; Animals ; Neurodegenerative Diseases ; },
abstract = {Autophagy is an essential degradation mechanism that maintains intracellular homeostasis. In recent years, an increasing number of cases with mutations in autophagy-related genes, such as ATG7, have been reported. These findings highlight the crucial role of autophagy in human neurodevelopment. However, the severity of clinical symptoms does not always correlate with the degree of autophagy impairment observed in patient-derived cells, and phenotypic manifestations can vary widely. These findings indicate that autophagy dysfunction alone does not fully explain disease mechanisms, even in neurological disorders directly associated with mutations in autophagy-related genes. Currently, no established methods exist to quantitatively assess autophagy activity in vivo, making it challenging to determine whether autophagy dysfunction serves as a primary driver of disease pathogenesis in adult-onset neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Although several lines of indirect evidence indicate impaired autophagy in these conditions, it remains uncertain whether such changes are causative or secondary to the disease process. Further research is warranted to elucidate the precise role of autophagy in both developmental and degenerative neurological disorders and to determine whether targeting autophagy holds promise as a therapeutic strategy.},
}

Humans
*Autophagy/genetics/physiology
*Nervous System Diseases/genetics
Animals
Neurodegenerative Diseases

@article {pmid41558515,
year = {2026},
author = {Nishio, Y},
title = {[Dementia in the Lewy Body Disease Spectrum].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {78},
number = {1},
pages = {5-12},
doi = {10.11477/mf.188160960780010005},
pmid = {41558515},
issn = {1881-6096},
mesh = {Humans ; *Lewy Body Disease/complications/pathology ; *Dementia/etiology ; Parkinson Disease/complications ; },
abstract = {The timing of dementia onset in patients with Parkinson's disease varies significantly. Predictors of the early development of dementia include postural instability, gait disturbance, REM sleep behavior disorder, and visuo-spatial impairment. The main neuropathological basis of dementia in Parkinson's disease involves the co-occurrence of α-synuclein pathology in the cerebral cortex and Alzheimer's disease co-pathology. Cholinergic system degeneration significantly affects symptom expression, making cholinesterase inhibitors effective for alleviating visual hallucinations and cognitive deficits.},
}

Humans
*Lewy Body Disease/complications/pathology
*Dementia/etiology
Parkinson Disease/complications

@article {pmid41558401,
year = {2026},
author = {Zhao, X and Zhu, Z and Wang, Y and Sun, M and Li, N and Su, Z and Huang, W},
title = {A sulfur-atom-enhanced strategy for NIR imaging of soluble and insoluble amyloid-β species.},
journal = {Talanta},
volume = {302},
number = {},
pages = {129417},
doi = {10.1016/j.talanta.2026.129417},
pmid = {41558401},
issn = {1873-3573},
abstract = {Soluble Aβ oligomers, more neurotoxic than monomers and plaques, are the predominant drivers of Alzheimer's disease in its earliest phase. However, the severe scarcity of effective molecular design principles for constructing soluble Aβ oligomer-targeted imaging probes severely hampers early-stage Alzheimer's diagnosis and pathological mechanistic dissection. Herein, we propose a sulfur-atom hybridization enhancement strategy to boost the binding ability of probes towards Aβ species, especially soluble Aβ oligomers and successfully engineer a fluorescence (FL) intensity amplifying (91-fold) D-π-A probe F-BSTH-NM for Aβ oligomers. Specifically, we initially develop a novel non-planar chromophore by changing the CC of quinoline into C-S to improve the interaction towards Aβ species. Then, optimizing the π-bridge to improve sulfur content and integrating electron donor group to extend the emission into near-infrared (NIR) window and simultaneously enhance desirable targetability and binding affinity. The rational designed F-BSTH-NM exhibits larger FL turn-on ratios as well as NIR emissions after binding to Aβ species, especially Aβ oligomers. Moreover, the proper lipophilicity (cLogP = 2.61) enable itself with desirable BBB penetration ability, and in vivo NIR fluorescent imaging reveals that probe F-BSTH-NM is capable of differentiating transgenic (Tg) AD mice from normal controls. The ex vivo histology experiment demonstrate that F-BSTH-NM could co-localization with both plaque cores and oligomer-enriched peripheries, suggesting that F-BSTH-NM could serve as a potential imaging tool for the early diagnosis of AD.},
}

@article {pmid41558396,
year = {2026},
author = {Hsieh, PH and Chen, YF and Chen, TF and Wu, WC and , },
title = {Association between cognitive status and structural brain changes in Alzheimer's disease: Clinical implication of lightweight deep learning-aided diagnosis.},
journal = {European journal of radiology},
volume = {196},
number = {},
pages = {112678},
doi = {10.1016/j.ejrad.2026.112678},
pmid = {41558396},
issn = {1872-7727},
abstract = {BACKGROUND: The complex brain changes involved in Alzheimer's disease (AD) development constitute a high-dimensional nonlinear feature space where deep learning (DL) classification/diagnosis may be advantageous over classical non-learning methods. However, the practicality of DL remains under debate among healthcare professionals, largely because many models are computationally expensive and operate without explicit interpretability. This study aimed to construct a lightweight DL model to disclose the association between cognitive status and structural brain changes in AD.

METHODS: By using the data obtained from the Alzheimer's Disease Neuroimaging Initiative database, 418 AD patients and 418 age-matched cognitively normal (CN) subjects were included for DL model construction based on their T1-weighted magnetic resonance images at baseline visit. A lightweight design was achieved by incorporating group convolution, global pooling, and efficient channel attention.

RESULTS: The accuracy rate of our model was 90.6 %, competitive with previous models built with up-to-ten times more parameters. The occlusion maps showed that the medial temporal area and thalamus accounted the most for our model's differentiation between AD and CN, in line with current knowledge of the pathological trajectory. Hierarchical regression further revealed that the logit of the DL model output explained a significant amount of variance in the mini mental state examination score, above and beyond the clinical indices including age, sex, and education duration (R[2] change = 0.341, F(1, 91) = 57.623, p < 0.001).

CONCLUSIONS: Lightweight DL can be clinically practicable for AD diagnosis by focusing on pathologically interpretable structural changes and offering image-based assessment of cognitive status.},
}

@article {pmid41558095,
year = {2026},
author = {Santos, LTR and Costa, FL and Rosa, ID and Frota, AF and Bezerra, JR and Soares, MVR and Barbosa, CSN and Farias, JWF and da Silva, LRAM and Gonçalves, PVS and Coelho Filho, JM and Lôbo, RR and Teixeira, AL and Diniz, BS and Peixoto Junior, AA and Macedo, DS},
title = {Plasma but not salivary p-Tau181 reflects Alzheimer's disease in a Latin American Cohort.},
journal = {Journal of the neurological sciences},
volume = {481},
number = {},
pages = {125762},
doi = {10.1016/j.jns.2026.125762},
pmid = {41558095},
issn = {1878-5883},
abstract = {Identifying accessible and reliable biomarkers for Alzheimer's disease (AD) remains a major challenge, particularly in low- and middle-income countries. Phosphorylated tau at threonine 181 (p-tau181) measured in plasma has shown strong diagnostic performance, but its potential in saliva, a truly noninvasive biofluid, remains uncertain. This study compared plasma and salivary p-tau181 levels, assessed their agreement, and evaluated their diagnostic accuracy in a Latin American cohort. Eighty participants were clinically classified as cognitively unimpaired (CU, n = 25), mild cognitive impairment (MCI, n = 22), or Alzheimer's dementia (AD, n = 33). Plasma and salivary p-tau181 concentrations were quantified using Single Molecule Array (Simoa) assays. Salivary p-tau181 levels were markedly higher than plasma levels (900.26 vs. 26.67 pg/mL; p < 0.001) but showed no correlation. Bland-Altman analysis revealed a mean bias of -1.56 with significant proportional bias (β = 0.73; p < 0.001), and Passing-Bablok regression confirmed the absence of a linear relationship between matrices. Plasma p-tau181 showed a numerical increase across the cognitive continuum, reaching statistically significant differences only when AD was compared with CU and MCI (AUC = 0.82; 95% CI 0.73-0.92), whereas salivary p-tau181 failed to discriminate clinical groups (AUC = 0.55, ns). These results demonstrate that plasma and salivary p-tau181 are not interchangeable and that current saliva-based quantification methods lack clinical reliability. This study provides the first evidence from Latin America supporting the diagnostic validity of plasma, but not salivary, p-tau181, and highlights the need for further investigation into pre-analytical and biological determinants of salivary biomarker variability.},
}

@article {pmid41558007,
year = {2026},
author = {Muthui, R and Paun, O and Inventor, B and Ruppar, T and Hickman, S and Zaman, A},
title = {Process of Addressing Advance Care Planning With African American Family Caregivers of Nursing Home Residents Diagnosed With Alzheimer's Disease and Related Dementias.},
journal = {Research in gerontological nursing},
volume = {19},
number = {1},
pages = {17-24},
doi = {10.3928/19404921-20260105-01},
pmid = {41558007},
issn = {1938-2464},
mesh = {Humans ; *Nursing Homes ; *Black or African American ; *Caregivers/psychology ; *Advance Care Planning ; *Alzheimer Disease/nursing/ethnology ; Female ; Male ; *Dementia/nursing/ethnology ; Aged ; Middle Aged ; Decision Making ; Aged, 80 and over ; Terminal Care ; White ; },
abstract = {PURPOSE: To explore advance care planning (ACP) and end-of-life (EOL) communication and decision-making experiences of African American family caregivers of nursing home residents with Alzheimer's disease and related dementias (ADRD).

METHOD: The study used a descriptive qualitative design with semi-structured interviews. African American family caregivers of nursing home residents diagnosed with ADRD with documented POLST were interviewed. Sixteen participants were recruited from eight nursing homes in a large Midwestern city.

RESULTS: Three major themes were developed and highlighted that ACP and EOL conversations occurred at different points within the health care system and were facilitated by family caregivers' knowledge of residents' wishes for EOL care and the faith/spirituality of the family caregiver/resident. Conversations were challenged by caregivers' lack of understanding of medical terminology and lack of providers available to educate them.

CONCLUSION: ACP and EOL decision-making with African American family caregivers of nursing home residents with ADRD is a process that is affected by nursing home challenges, such as physician shortage. In making ACP and EOL decisions, African American family caregivers relied on their faith as well as their knowledge of wishes the resident with ADRD had verbalized or documented.},
}

Humans
*Nursing Homes
*Black or African American
*Caregivers/psychology
*Advance Care Planning
*Alzheimer Disease/nursing/ethnology
Female
Male
*Dementia/nursing/ethnology
Aged
Middle Aged
Decision Making
Aged, 80 and over
Terminal Care
White

@article {pmid41557840,
year = {2026},
author = {Smirnova, D and Ustinova, A and Chukanov, V and Pchitskaya, E},
title = {3D dendritic spines shape descriptors for efficient classification and morphology analysis in control and alzheimer`s disease modeling neurons.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btag025},
pmid = {41557840},
issn = {1367-4811},
abstract = {MOTIVATION: Dendritic spines, postsynaptic structures characterized by their complex shapes, provide the essential structural foundation for synaptic function. Their shape is dynamic, undergoing alterations in various conditions, notably during neurodegenerative disorders like Alzheimer's disease. The dramatically increasing prevalence of such diseases highlights an urgent need for effective treatments. A key strategy in developing these treatments involves evaluating how dendritic spine morphology responds to potential therapeutic compounds. Although a link between spine shape and function is recognized, its precise nature is still not fully elucidated. Consequently, advancing our understanding of dendritic spines in both health and disease necessitates the urgent development of more effective methods for assessing their morphology.

RESULTS: This study introduces qualitatively new 3D dendritic shape descriptors based on spherical harmonics and Zernike moments and proposes a bases on them clustering approach for grouping dendritic spines with similar shapes applied to three-dimensional polygonal spines meshes acquired from Z-stack dendrite images. By integrating these methods, we achieve improved differentiation between normal and pathological spines represented by the Alzheimer's disease in vitro model, offering a more precise representation of morphological diversity. Additionally, the proposed spherical harmonics approach enables dendritic spine reconstruction from vector-based shape representations, providing a novel tool for studying structural changes associated with neurodegeneration and possibilities for synthetic dendritic spines dataset generation.

AVAILABILITY: The software used for experiments is public and available at https://github.com/Biomed-imaging-lab/SpineTool with the DOI: 10.5281/zenodo.17359066. Descriptors codebase is available at https://github.com/Biomed-imaging-lab/Spine-Shape-Descriptors with the DOI: 10.5281/zenodo.17302859.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}

@article {pmid41557715,
year = {2026},
author = {Rosal, AE and Torres-Carmona, E and Martin, SL and Boileau, I and Graff-Guerrero, A and Strafella, AP},
title = {The effect of Apolipoprotein E4 on cognitive function in Parkinson's disease: A structural MRI study in the PPMI cohort.},
journal = {PloS one},
volume = {21},
number = {1},
pages = {e0341240},
doi = {10.1371/journal.pone.0341240},
pmid = {41557715},
issn = {1932-6203},
mesh = {Humans ; *Parkinson Disease/genetics/diagnostic imaging/pathology/complications/physiopathology ; *Apolipoprotein E4/genetics ; Male ; Magnetic Resonance Imaging ; Female ; Aged ; *Cognition/physiology ; Middle Aged ; Gray Matter/diagnostic imaging/pathology ; *Cognitive Dysfunction/genetics ; Cohort Studies ; Heterozygote ; },
abstract = {BACKGROUND: Cognitive impairment is a common non-motor symptom of Parkinson's disease (PD), yet its underlying mechanisms remain poorly understood. Apolipoprotein E4 (APOE4), a genetic risk factor of Alzheimer's Disease, has been associated with PD-related cognitive impairment. However, findings are inconsistent, highlighting the need for further investigation. Neuroimaging studies have found gray matter abnormalities, mainly reductions in gray matter volume (GMV) and cortical thickness (CTh), in both cognitively impaired PD patients and APOE4 carriers. Yet, APOE4's role in these structural changes and their cognitive impact in PD is underexplored.

AIM: This study aimed to determine whether APOE4 influences early structural brain differences in terms of GMV and CTh in PD prior to the emergence of cognitive dysfunction.

METHODS: A total of 51 PD APOE4 carriers and 120 non-carriers who were cognitively unimpaired from the Parkinson's Progression Markers Initiative (PPMI) database were included. T1-weighted MRI scans were used to calculate GMV and CTh in regions previously associated with PD-related cognitive impairment, including hippocampal subregions. Cognitive scores assessing global cognition and specific cognitive domains were used to examine associations between regions showing significant GMV or CTh group differences and cognitive performance.

RESULTS: PD APOE4 carriers showed increased GMV in the left angular gyrus (AnG) and decreased GMV in the left nucleus accumbens (NAcc) compared to non-carriers, though neither survived multiple comparison correction. Left AnG GMV correlated with visuospatial function in both groups but did not remain significant after co-variate adjustment. Left NAcc GMV correlated with visuospatial function and working memory, but only in non-carriers even after co-variate adjustment. No group differences were observed in CTh measures and hippocampal subregion GMVs.

CONCLUSIONS: This study suggests that APOE4 may not influence cognitive function in PD by affecting GMV and CTh. However, longitudinal analyses must confirm these observations.},
}

Humans
*Parkinson Disease/genetics/diagnostic imaging/pathology/complications/physiopathology
*Apolipoprotein E4/genetics
Male
Magnetic Resonance Imaging
Female
Aged
*Cognition/physiology
Middle Aged
Gray Matter/diagnostic imaging/pathology
*Cognitive Dysfunction/genetics
Cohort Studies
Heterozygote

@article {pmid41557600,
year = {2026},
author = {Fisher, DW and Borisovskaya, A and Lindley, E and Domoto-Reilly, K},
title = {Somatic Symptom Disorder as a Prodrome of Alzheimer Disease and Successful Treatment of Pain and Agitation With Electroconvulsive Therapy: A Case Report.},
journal = {The journal of ECT},
volume = {},
number = {},
pages = {},
doi = {10.1097/YCT.0000000000001229},
pmid = {41557600},
issn = {1533-4112},
support = {T32AG052354//National Institute of Aging/ ; },
abstract = {Neuropsychiatric symptoms in dementia can be heterogeneous and hard to treat, though electroconvulsive therapy (ECT) is becoming more widely accepted as a viable treatment option. Here, we describe a patient with Alzheimer disease (AD) who developed Somatic Symptom Disorder as a prodrome to cognitive and functional decline, though atypical, primary affective disorder in AD was also on the differential. This patient further developed debilitating anxiety and agitation that was refractory to multiple behavioral and pharmacological interventions. ECT was able to treat the patient's neuropsychiatric symptoms, resulting in sustained, full remission with minimal transient, cognitive side effects. This case depicts a rare presentation of AD and further adds to the growing body of literature that suggests ECT is safe and effective for treating neuropsychiatric symptoms in dementia.},
}

@article {pmid41557594,
year = {2026},
author = {Alves, F and Ayton, S},
title = {Missing tissue, missing data: Resolving brain volume loss caused by anti-amyloid therapies.},
journal = {PLoS medicine},
volume = {23},
number = {1},
pages = {e1004880},
doi = {10.1371/journal.pmed.1004880},
pmid = {41557594},
issn = {1549-1676},
mesh = {Humans ; *Alzheimer Disease/drug therapy/pathology ; *Brain/pathology/drug effects ; Organ Size/drug effects ; *Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Disease Progression ; Clinical Trials as Topic ; },
abstract = {Anti-amyloid drugs modestly slow Alzheimer's disease progression, albeit with uncertainty of sustained benefit, particularly as they cause paradoxical acceleration of brain volume changes. Here, we examine explanations for these volume changes and argue for transparent release of clinical trial data.},
}

Humans
*Alzheimer Disease/drug therapy/pathology
*Brain/pathology/drug effects
Organ Size/drug effects
*Amyloid beta-Peptides/antagonists & inhibitors/metabolism
Disease Progression
Clinical Trials as Topic

@article {pmid41557565,
year = {2026},
author = {Erickson, P and Borgh Skillbäck, T and Kern, S and Skoog, I and Jönsson, L and Andreasson, U and Blennow, K and Eriksdotter, M and Zetterberg, H},
title = {Limited diagnostic performance of cerebrospinal fluid glial fibrillary acidic protein in dementia.},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1-17},
doi = {10.1159/000550601},
pmid = {41557565},
issn = {1421-9824},
abstract = {INTRODUCTION: Cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) is a neuroinflammatory marker reflecting reactive astrogliosis and is measured regularly in clinical practice. However, its diagnostic utility in differentiating dementia subtypes remains unclear. This study aimed to evaluate differences in CSF GFAP concentrations and its associations with markers of disease severity and amyloid pathology.

METHODS: We conducted a retrospective cohort study using three datasets encompassing a broad range of dementia diagnoses. Included variables were CSF GFAP, β-amyloid 42 (Aβ42), the Aβ42/Aβ40 ratio, mini-mental state exam (MMSE) scores, and time from sampling to death.

RESULTS: A total of 1345 individuals were included. In Parkinson's disease dementia (PDD) and Lewy body dementia (LBD), GFAP levels were similar (p>.05). Lower levels were observed in PDD compared to early-onset Alzheimer's disease (AD), late-onset AD (LAD), and vascular dementia (VaD) (all p<.05); however, the discriminative performance was low-to-moderate: PDD versus LAD (AUROC=.74, CI=.64-.84, p<.001), VaD (AUROC=.71, CI =.61-.81, p<.001) and EAD (AUROC=.59, CI=.47-.71, p=.13). Associations were seen with MMSE in mixed AD and VaD (MIX) (p=.027), but not in the other diagnostic categories. GFAP levels did not differ between subjects grouped according to Aβ42/Aβ40 status (p>.05).

CONCLUSION: CSF GFAP did not exhibit clinically relevant diagnostic or prognostic value in dementia. Further studies are needed to clarify its role in PDD.},
}

@article {pmid41557197,
year = {2026},
author = {Dos Santos, JFM and Mello, IS and da Cruz, ILS and Soares, MA},
title = {Non-Saccharomyces yeasts contribute to longevity, mitigated protein toxicity, and protection against abiotic stress in Caenorhabditis elegans.},
journal = {Archives of microbiology},
volume = {208},
number = {3},
pages = {128},
pmid = {41557197},
issn = {1432-072X},
support = {445388/2024-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; },
mesh = {Animals ; *Caenorhabditis elegans/microbiology/physiology/genetics ; *Longevity ; Caenorhabditis elegans Proteins/genetics/metabolism ; Oxidative Stress ; Probiotics ; *Stress, Physiological ; *Cryptococcus/physiology/isolation & purification ; Amyloid beta-Peptides/toxicity ; *Yeasts/physiology/isolation & purification ; Saccharomyces/physiology/isolation & purification ; DNA-Binding Proteins ; Receptor, Insulin ; Transcription Factors ; },
abstract = {The search for probiotic microorganisms that can be applied beyond gut health has advanced into areas that seek to promote longevity and to prevent neurodegenerative diseases. In this study, we have investigated non-Saccharomyces strains isolated from the Amazon, Cerrado, and Pantanal biomes and evaluated how they affect Caenorhabditis elegans. During our initial screening, based on increased body size and population, we selected eight yeast strains and characterized their cells. Then, we selected three of these strains for in vivo testing. Cryptococcus sp._T038 and Cryptococcus sp._T248 prolonged longevity and reduced the effects of thermal and oxidative stress in C. elegans. Hanseniaspora opuntiae_W164 and Saccharomyces boulardii_SB delayed beta-amyloid-induced paralysis in C. elegans CL4176. The antioxidant genes of the DAF-2/SKN-1 pathway were activated by Cryptococcus_T038 and _T248 and H. opuntiae_W164 in C. elegans strain LD1171 (GCS-1p::GFP) and by Cryptococcus_T038, H. opuntiae_W164, and S. boulardii_SB in C. elegans strain CF1553 (SOD-3p::GFP). These data reinforce that wild yeasts are potential functional probiotics.},
}

Animals
*Caenorhabditis elegans/microbiology/physiology/genetics
*Longevity
Caenorhabditis elegans Proteins/genetics/metabolism
Oxidative Stress
Probiotics
*Stress, Physiological
*Cryptococcus/physiology/isolation & purification
Amyloid beta-Peptides/toxicity
*Yeasts/physiology/isolation & purification
Saccharomyces/physiology/isolation & purification
DNA-Binding Proteins
Receptor, Insulin
Transcription Factors

@article {pmid41557069,
year = {2026},
author = {Yıldırım, M and Ünver, H and Necip, A and Hord, B and Ersatir, M},
title = {Novel triphenylphosphonium-hydrazone salts: ıntegrated experimental and computational ınsights into AChE ınhibition and resistance-overcoming antimicrobial and antibiofilm potential.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41557069},
issn = {1432-1912},
abstract = {Neurodegenerative disorders and multidrug-resistant (MDR) bacterial infections represent two major and interconnected global health challenges. However, current therapeutic strategies are largely limited by single-target approaches, insufficient efficacy against biofilm-forming MDR pathogens, and the lack of multifunctional small molecules capable of addressing both neurodegeneration and bacterial resistance simultaneously. These limitations constitute a critical technical bottleneck in contemporary drug discovery and underscore the urgent need for innovative, dual-action therapeutic scaffolds. In this study, five novel triphenylphosphonium-hydrazone derivatives (1a-1e) were rationally designed, synthesized, and fully characterized by FT-IR, 1H/13C NMR, and HR-MS/MS analyses to overcome these challenges by integrating neuroprotective and antimicrobial functionalities within a single molecular framework. All synthesized compounds exhibited potent acetylcholinesterase (AChE) inhibitory activity, with IC50 values ranging from 8.66 to 13.9 µM, highlighting their strong neuroactive profiles. Notably, compound 1b emerged as the most effective AChE inhibitor (IC50 = 8.66 µM), underscoring its promise as a lead scaffold for the development of next-generation anti-Alzheimer agents. Beyond enzyme inhibition, the compounds demonstrated significant antibacterial efficacy against clinically relevant carbapenem-resistant pathogens. In particular, compound 1d showed the strongest activity against Acinetobacter baumannii and Klebsiella pneumoniae, with MIC values of 32 µg/mL and 64 µg/mL, respectively. Importantly, all derivatives (1a-1e) exhibited dose-dependent antibiofilm activity, achieving up to 83.4% biofilm disruption in Acinetobacter baumannii and 72.8% in Escherichia coli at 1024 µg/mL, directly addressing a major resistance-associated bottleneck in antibacterial therapy. Molecular docking studies provided mechanistic validation of this multifunctional design, revealing a strong binding affinity of compound 1d toward PBP1A (PDB: 6OWS) and the AcrB efflux pump protein (PDB: 6PT1), suggesting a previously unexplored dual antibacterial mechanism involving simultaneous inhibition of cell-wall biosynthesis and efflux-mediated drug resistance. Overall, this study introduces a novel triphenylphosphonium-hydrazone platform, establishes a clear structure-activity relationship, and highlights its potential as a multifunctional therapeutic strategy against both neurodegenerative disorders and MDR bacterial infections.},
}

@article {pmid41557057,
year = {2026},
author = {Xu, Z and Dai, S and Wu, Y and Zhu, Y and Qiu, P and Xu, S and Qiu, F and Peng, X and Liu, W and Wang, H},
title = {Atractylenolide III Attenuated Neurotoxicity in Alzheimer's Disease via AMPK/GSK3β/Nrf2/HO-1 Signaling Pathway.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {377},
pmid = {41557057},
issn = {1559-1182},
mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Animals ; *NF-E2-Related Factor 2/metabolism ; *Sesquiterpenes/pharmacology/therapeutic use ; *Signal Transduction/drug effects ; *Glycogen Synthase Kinase 3 beta/metabolism ; *Lactones/pharmacology/therapeutic use ; *Heme Oxygenase-1/metabolism ; Mice ; *AMP-Activated Protein Kinases/metabolism ; Humans ; Male ; Neuroprotective Agents/pharmacology/therapeutic use ; Cell Line, Tumor ; Amyloid beta-Peptides/metabolism ; Hippocampus/drug effects/pathology ; Apoptosis/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques and widespread neuroinflammation. Atractylenolide III (AT-III), the primary active compound in Atractylodes macrocephala Koidz, has shown various health-promoting effects, including antioxidant properties and neuroprotection. However, the anti-AD molecular mechanism of AT-III remains to be further investigated. FAD[4T] mice were treated with AT-III for 4 weeks, and the neuroprotective effect of AT-III was subsequently evaluated by cognitive performance, histopathology, transcriptomic profiling, and 16S rRNA sequencing. SH-SY5Y cells were also used to verify the roles of AT-III on the AMPK/GSK3β/Nrf2/HO-1 pathway. AT-III significantly improved cognitive function, evidenced by a decreased escape latency and increased number of platform crossings in the Morris water maze (MWM) test and an increased alternation ratio in the Y-maze test. Histological analysis revealed that AT-III alleviated neuronal loss, reduced apoptosis and glial activation, and reduced Aβ deposition in the hippocampus. Biochemical assessments indicated that AT-III decreased oxidative stress and reduced neuroinflammation. Additionally, AT-III improved the diversity of the gut microbiota, including an increase in Ileibacterium and a decrease in Candidatus_Saccharimonas. Mechanistically, AT-III activated the AMPK/GSK3β/Nrf2/HO-1 signaling pathway both in vivo and in vitro. We further confirmed that AT-III significantly ameliorates Aβ1-42-induced cytotoxicity, excessive ROS production, and apoptosis in SH-SY5Y cells. However, the protective effects of AT-III were partially abolished by Compound C (an AMPK inhibitor). Our study demonstrates that AT-III mitigated neurodegenerative damage in AD by suppressing microglial activation and neuroinflammation through the AMPK/GSK3β/Nrf2/HO-1 signaling, which suggests that AT-III might be a novel therapeutic strategy for the inhibition of AD.},
}

*Alzheimer Disease/drug therapy/metabolism/pathology
Animals
*NF-E2-Related Factor 2/metabolism
*Sesquiterpenes/pharmacology/therapeutic use
*Signal Transduction/drug effects
*Glycogen Synthase Kinase 3 beta/metabolism
*Lactones/pharmacology/therapeutic use
*Heme Oxygenase-1/metabolism
Mice
*AMP-Activated Protein Kinases/metabolism
Humans
Male
Neuroprotective Agents/pharmacology/therapeutic use
Cell Line, Tumor
Amyloid beta-Peptides/metabolism
Hippocampus/drug effects/pathology
Apoptosis/drug effects

@article {pmid41556772,
year = {2026},
author = {Lin, H and Macaden, L and Chandler, C},
title = {The Impact of Inappropriate Sexual Behaviors in People With Dementia on Family Caregivers: A Scoping Review.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261418909},
doi = {10.1177/15333175261418909},
pmid = {41556772},
issn = {1938-2731},
mesh = {Humans ; *Caregivers/psychology ; *Dementia/nursing/psychology ; *Sexual Behavior/psychology ; Psychological Distress ; },
abstract = {This scoping review examines the impact of inappropriate sexual behaviors (ISBs) in people with dementia on their family caregivers. Through synthesizing 15 studies from 8 countries, 6 themes were identified: complex emotional responses, psychological distress, increased caregiver burden, practical caregiving challenges, impaired marital relationships, and social isolation. Findings reveal caregivers frequently experience helplessness, embarrassment, anger, anxiety, depression, and social withdrawal, exacerbated by societal taboos surrounding sexuality and limited professional support. Spousal caregivers are particularly affected, reporting increased emotional strain and marital distress. Practical caregiving difficulties, including safety and privacy concerns, limited access to care services, and challenging institutionalization decisions, further intensify caregiver burden. The review highlights significant research gaps, including the need for specialized assessment tools, broader and culturally diverse studies, and exploration of ISBs as distinct phenomena. Addressing these gaps is crucial for developing targeted interventions and adequately supporting caregivers, particularly within home-based and culturally sensitive dementia care services.},
}

Humans
*Caregivers/psychology
*Dementia/nursing/psychology
*Sexual Behavior/psychology
Psychological Distress

@article {pmid41556651,
year = {2026},
author = {Nguyen, VTT and König, S and Formes, H and Al Taleb, Z and Steinert, F and Bufe, B and Eggert, S and Stegmüller, S and Schermer, Y and Richling, E and Kins, S and Reinhardt, C and Endres, K},
title = {Monocolonization with Bacteroides thetaiotaomicron exerts region-specific effects on Alzheimer's disease-related traits in the murine brain.},
journal = {Microbiology spectrum},
volume = {},
number = {},
pages = {e0074425},
doi = {10.1128/spectrum.00744-25},
pmid = {41556651},
issn = {2165-0497},
abstract = {UNLABELLED: Bacteroides thetaiotaomicron (B. theta) dominates the gut microbiome of most mammals. This strictly anaerobic gut symbiont colonizes the mucus layer of host intestinal epithelial cells in both healthy and diseased conditions. Reduced neuronal and vagal afferent innervation observed in germ-free mice was found to be normalized by colonization with B. theta. In addition to deficits in gut innervation, germ-free mice have been reported to have reduced neuronal number and neurotransmitter levels in the brain. Here, we investigated the hallmarks of Alzheimer's disease (AD) in the brain of germ-free mice compared to mice mono-colonized with B. theta. We analyzed the number of mature neurons, neurotransmitter transporters, amyloid precursor protein processing, and inflammatory status in three brain regions: the hippocampus, prefrontal cortex (PFC), and cerebellum. The hippocampus and the PFC are regions thought to be highly susceptible to pathogenesis, whereas the cerebellum is thought to be only mildly affected. Interestingly, secretion of neuroprotective sAPPα decreased in hippocampus and remained unchanged in PFC, while levels were increased in the cerebellum in response to bacterial colonization. In addition, the number of presynaptic boutons increased in the hippocampus but remained unaffected in the cerebellum.

IMPORTANCE: The gut microbiome has been reported to not only contribute to diseases of the gastrointestinal tract but also to interfere with and potentially even initiate diseases of other organ systems, such as the brain. Interference with the gut microbiome has been shown to elicit cognitive changes, for example, in rodent models of AD. Colonization with the common gut microbe B. theta not only affected the brain per se in our study but also showed specific brain region-dependent effects related to AD. This implies that evaluating the impact the microbiome might have on brain disorders needs a much more detailed investigation in the future with spatial and also potentially time resolution.},
}

@article {pmid41556609,
year = {2026},
author = {Candow, DG and Pratt, J and Fabiano, N and Gordji-Nejad, A and Smith, A and Rawson, ES and Moriarty, T and Forbes, SC and Kerksick, CM},
title = {Creatine Supplementation and the Brain: Have We Put the Cart Before the Horse?.},
journal = {Journal of dietary supplements},
volume = {},
number = {},
pages = {1-30},
doi = {10.1080/19390211.2026.2616440},
pmid = {41556609},
issn = {1939-022X},
abstract = {Creatine is an important regulator of brain bioenergetics, yet the efficacy of creatine supplementation (CrS) in the brain remains largely unknown. Measurement of brain creatine using proton ([1]H) and phosphorus ([3][1]P) magnetic resonance spectroscopy is highly sensitive to voxel placement, signal quality, analysis pipelines, and reporting conventions which can obscure the detection of biological responses to CrS. There is evidence that CrS increases brain creatine, but this response may be dose and/or duration dependent. CrS provides some benefits during acute periods of metabolic stress such as sleep deprivation, mental fatigue, and hypoxia. Emerging clinical data also suggest potential therapeutic effects from CrS for Alzheimer's disease, major depressive disorder, and mild traumatic brain injury (mTBI), although findings across conditions remain preliminary and inconsistent. Further, CrS shows some promise for improving aspects of sleep quality. The purpose of this narrative review is to: (1) outline methodological considerations in the quantification of brain creatine, (2) discuss the divergent effects of CrS on brain creatine levels and measures of brain function, (3) examine the purported mechanistic actions of CrS for improving brain health and function, (4) highlight critical gaps and limitations which should be considered moving forward, and (5) identify future research directions involving CrS and the brain.},
}

@article {pmid41556545,
year = {2026},
author = {Trudel, L and Therriault, J and Macedo, AC and Hosseini, SA and Fernandez-Arias, J and Chan, T and Rahmouni, N and Bezgin, G and Tissot, C and Woo, MS and Aumont, É and Zheng, Y and Hall, B and Oliva-Lopez, D and Mitchell, SW and Hopewell, R and Hsiao, CH and Toga, AW and Braskie, MN and Meeker, KL and Soucy, JP and Guiot, MC and Gauthier, S and Vitali, P and O'Bryant, SE and Pascoal, TA and Rosa-Neto, P},
title = {Clinical-biological Alzheimer's disease stage concordance: insights from cohorts and autopsy data.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag018},
pmid = {41556545},
issn = {1460-2156},
abstract = {Alzheimer's disease (AD) is defined by its characteristic neuropathologic changes, which allow for diagnosis and assessment of severity. Recently, the Alzheimer's Association proposed a framework to stage Alzheimer's disease biologically based on tau-PET. Furthermore, the framework hypothesizes a degree of alignment between biological Alzheimer's disease severity and clinical symptom severity. We aimed to investigate the concordance between clinical and biological stages of Alzheimer's disease and explore factors contributing to discordance using in vivo and postmortem neuropathological data. Data from 768 amyloid-β positive individuals were drawn from four observational cross-sectional in vivo cohorts-TRIAD, ADNI, HABS-HD, and SCAN-as well as a postmortem autopsy dataset from the National Alzheimer's Coordinating Center (NACC; n = 3,188). All in vivo participants had tau-PET imaging, clinical diagnosis, and neurobehavioral assessments. Participants were assigned a biological Alzheimer's disease stage based on their tau-PET scan according to the Alzheimer's Association revised criteria stages. The autopsy dataset included individuals with moderate-to-frequent neuritic plaques (CERAD scores 2-3), along with premortem clinical and neurobehavioral data. Clinical-biological concordance was quantified using squared-weighted Cohen's Kappa. Ordinal and linear regression models assessed associations between biological stage and clinical severity (CDR-Sum of Boxes, MMSE), adjusting for age, sex, and cohort. Postmortem analyses evaluated the impact of comorbid neuropathologies on clinical-biological discordance using adjusted odds ratios and ordinal regression. Overall concordance between clinical and biological Alzheimer's disease staging was moderate (Cohen's Kappa=0.52, p < 0.001). Approximately 70% of individuals classified as cognitively unimpaired or with dementia exhibited biological stages consistent with their clinical diagnoses. In contrast, transitional decline and mild cognitive impairment (MCI) groups were more heterogenous. Notably, 25% of Aβ-positive individuals with MCI demonstrated no detectable tau-PET abnormality. Nonetheless, advanced tau-PET stage was reliably associated with clinical impairment. In the NACC autopsy dataset, nearly all individuals with more severe clinical stage than their proposed biological stage exhibited comorbid neuropathologies, including FTLD-TDP-43, FTLD-tau, Lewy bodies, LATE, and cerebrovascular disease. The number of comorbid pathologies was strongly associated with increased odds of clinical dementia (t = 8.45, p < 0.001). While there is moderate agreement between clinical and biological stages of Alzheimer's disease across the entire disease spectrum, strong agreement is found in clinically unimpaired and dementia stages. Comparison of clinical and biological Alzheimer's disease stages provides a framework for understanding the large contributions of non-AD neurodegenerative diseases to dementia in Aβ-positive individuals. Our results have important implications for clinical trial recruitment strategies and highlight the urgent need for biomarkers for non-AD pathological processes.},
}

@article {pmid41556177,
year = {2026},
author = {Xiao, J and Liu, M and Zhou, M and Deng, G and Yang, Q and Li, Q},
title = {The causal effects of dementia on systemic sclerosis: a two-sample bidirectional Mendelian randomization study.},
journal = {International journal of surgery (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1097/JS9.0000000000004881},
pmid = {41556177},
issn = {1743-9159},
abstract = {BACKGROUND: Recent studies suggest that systemic sclerosis (SSc) may be associated with cognitive impairment and dementia. However, the causal relationship and its direction remain unclear. This study employed a two-sample bidirectional Mendelian randomization (MR) approach to systematically evaluate the genetic causal relationship between five types of dementia and SSc.

METHODS: Based on genome-wide association study (GWAS) summary data, we investigated the relationship between five types of dementia and SSc. The inverse variance weighted (IVW) method served as the primary analytical approach, supplemented by validation using the weighted median method, MR-Egger regression, simple mode, and weighted mode methods. Sensitivity analyses (leave-one-out, funnel plot, MR-PRESSO), pleiotropy tests (Egger intercept), and heterogeneity assessments (Cochran's Q) were conducted to ensure the robustness and reliability of the results. Additionally, reverse MR analysis was performed to further confirm the directionality of the causal relationship.

RESULTS: Forward MR analysis revealed a significant negative association between Alzheimer's disease (AD) and the risk of SSc (IVW OR = 0.530, 95% CI: 0.290-0.969, P = 0.039). In contrast, no significant causal relationships were found between SSc and frontotemporal dementia, vascular dementia, dementia with Lewy bodies, or Parkinson's disease dementia. Reverse MR analysis did not identify any causal effects of SSc on the aforementioned types of dementia, further supporting the directionality of the causal relationship. Sensitivity analyses, pleiotropy tests, and heterogeneity assessments did not reveal significant horizontal pleiotropy or heterogeneity.

CONCLUSION: Our study provides evidence of a potential causal relationship between AD and a reduced risk of SSc, highlighting the need for further research to explore the underlying mechanisms of this complex disease relationship.},
}

@article {pmid41556110,
year = {2026},
author = {Xia, W and Xu, C and Xiao, Z and Zhou, X and Zhao, Q and Ding, D and Deng, W},
title = {Plasma phosphorylated tau 217 and neurofilament light chain on the association between depressive symptoms and cognitive decline: The Shanghai Aging Study.},
journal = {Psychological medicine},
volume = {56},
number = {},
pages = {e25},
doi = {10.1017/S0033291725103115},
pmid = {41556110},
issn = {1469-8978},
support = {82173599, 82473701, 82071200, 82371429//National Natural Science Foundation of China/ ; },
mesh = {Humans ; Male ; Female ; *tau Proteins/blood ; China/epidemiology ; Aged ; *Neurofilament Proteins/blood ; *Cognitive Dysfunction/blood/epidemiology ; *Depression/blood/epidemiology ; Biomarkers/blood ; Aged, 80 and over ; Phosphorylation ; *Alzheimer Disease/epidemiology/blood ; *Aging/blood ; Middle Aged ; *Dementia/epidemiology/blood ; },
abstract = {BACKGROUND: Depressive symptoms are closely associated with cognitive decline and risk of incident dementia, and plasma biomarkers may play a significant role in this relationship. We aimed to investigate the influence of plasma biomarkers and explore the underlying mechanisms.

METHODS: This study included 1,658 dementia-free community residents recruited in 2009-2011 from the Shanghai Aging Study. At baseline, we assayed plasma phosphorylated tau 217 (p-tau217) and neurofilament light chain (NfL), and assessed depressive symptoms using the Center for Epidemiologic Studies Depression scale. Cox regression models were performed to estimate the risks of incident dementia and Alzheimer's disease (AD) during the 5-year follow-up. Parallel and serial mediation models were applied to investigate whether plasma p-tau217 and NfL mediated the relationship between depressive symptoms and cognitive decline.

RESULTS: Older adults with depressive symptoms had higher risks of dementia and AD, especially among those with higher concentrations of baseline plasma p-tau217/NfL. Sex-specific analysis revealed that depressive symptoms combined with high plasma NfL increased AD risk in men (hazard ratio, HR [95% confidence interval, CI] = 5.89 [2.01, 17.27], p = 0.001), whereas women with depressive symptoms and high plasma p-tau217 showed higher AD risk (HR [95%CI] = 6.07 [2.82, 13.09], p < 0.001). Parallel mediation analysis revealed that plasma p-tau217/NfL mediated the relationship between depressive symptoms and cognitive decline, respectively. Additionally, serial mediation analysis found p-tau217 precedes NfL within the mediating pathway (β = 0.403, bootstrap 95% CI: 0.347, 0.452).

CONCLUSIONS: Plasma p-tau217 and NfL could individually or jointly mediate the relationship between depressive symptoms and cognitive decline.},
}

Humans
Male
Female
*tau Proteins/blood
China/epidemiology
Aged
*Neurofilament Proteins/blood
*Cognitive Dysfunction/blood/epidemiology
*Depression/blood/epidemiology
Biomarkers/blood
Aged, 80 and over
Phosphorylation
*Alzheimer Disease/epidemiology/blood
*Aging/blood
Middle Aged
*Dementia/epidemiology/blood

@article {pmid41555829,
year = {2026},
author = {Daly, T},
title = {Nothing about us without us? Using public consensus for priority setting in Alzheimer's disease research.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261415592},
doi = {10.1177/13872877261415592},
pmid = {41555829},
issn = {1875-8908},
abstract = {Getting the public involved upstream in priority setting in the form of consensus-building activities in Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD) research is necessary to make that research more impactful for people affected. AD/ADRD research should focus on questions related to significant truths that society cares about.},
}

@article {pmid41555828,
year = {2026},
author = {Merten, N and Dawes, P and Munro, KJ and Brenowitz, WD},
title = {Hearing impairment and cognitive decline: Alternative explanations to causality.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251410502},
doi = {10.1177/13872877251410502},
pmid = {41555828},
issn = {1875-8908},
abstract = {Despite growing interest in hearing impairment as a potentially modifiable risk factor for dementia, the association is poorly understood. This has implications for whether treating hearing impairment can prevent or delay onset of dementia, as causation is not the only explanation for the association. In this editorial, we highlight how biases in research studies might account for the reported associations. We suggest future research using different study designs and novel biomarkers to help us overcome methodological limitations. This may allow us to determine the strength of the causal pathways linking hearing impairment to dementia, ultimately informing prevention and treatment strategies.},
}

@article {pmid41555826,
year = {2026},
author = {Klusek, J and Gierman, J and Fairchild, AJ and Benitez, AM and Berry-Kravis, E and Mailick, MR},
title = {Cognitive dysfunction in women with the FMR1 premutation during midlife: The LASSI-L reveals curvilinear CGG-dependent risk buffered by college education.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251414950},
doi = {10.1177/13872877251414950},
pmid = {41555826},
issn = {1875-8908},
abstract = {BackgroundThe FMR1 premutation (FXPM) is a common genetic variant (∼1:151 females) linked to increased risk for neurodegenerative disease. Midlife cognitive phenotypes remain poorly defined.ObjectiveTo characterize episodic memory performance in midlife FXPM women and examine potential risk moderation via genetic (i.e., FMR1 CGG repeat expansion size) and environmental (i.e., college degree attainment) influences.MethodsEighty-eight FXPM women and 84 matched controls, aged 30-55, completed the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L), a measure of specific episodic memory processes sensitive to subtle Alzheimer's disease (AD)-related cognitive and neuropathological changes.ResultsFXPM women demonstrated deficits in proactive semantic interference (PSI), recovery from PSI, and intrusion errors relative to controls. College education buffered these effects: college-educated FXPM women performed comparably to controls, while those without a college degree showed deficits. Gene-environment interactions showed patterns consistent with differential susceptibility: LASSI-L performance in women with mid-range CGG repeats (∼80-100) was strongly influenced by educational attainment, whereas education effects were absent in women with lower/higher CGG lengths.ConclusionsMidlife FXPM women showed episodic memory deficits, paralleling LASSI-L deficits seen in prodromal AD. College education offered protective benefits, particularly for women with mid-range CGG expansions. Findings highlight a critical midlife window for cognitive monitoring, identify education as a potential protective factor, and inform personalized risk assessment based on CGG length to promote earlier detection and targeted prevention for FXPM women. Findings suggest potential overlapping mechanisms with AD that merit further study.},
}

@article {pmid41555825,
year = {2026},
author = {Wang, EJ and Oğuztüzün, Ç and Xu, R and Gao, Z},
title = {Comparative evaluation of large language models in retrieving known and predicting novel drug combinations.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261415635},
doi = {10.1177/13872877261415635},
pmid = {41555825},
issn = {1875-8908},
abstract = {BackgroundLarge language models (LLMs) are increasingly used in the biomedical field for information retrieval, information extraction and knowledge discovery. However, their potential in retrieving and discovering drug combinations for diseases remains underexplored.ObjectiveThis study aims to evaluate the effectiveness of LLMs in retrieving known drug combinations and to identify novel drug combinations for treating Alzheimer's disease (AD).MethodsWe developed a series of prompts to guide LLMs in retrieving drug combinations. Their performance was evaluated using both FDA-approved combinations and combinations identified through PubMed literature mining. We then assessed the feasibility of identifying novel drug combination candidates for AD. In collaboration with domain experts, we performed pathway enrichment analyses to evaluate their potential mechanisms of action within the context of AD.ResultsIn a comparative evaluation of multiple LLMs, GPT-5 demonstrated the strongest overall performance, achieving an accuracy of 0.95 and a balanced F1 score of 0.95 in identifying FDA-approved drug combinations. Among the top 10 drug-combination candidates for AD treatment suggested by GPT-5, the combination of donepezil and memantine is already FDA-approved. Three other combinations have been tested in AD clinical trials, and three have supporting evidence in the literature. We also identified 10 off-label drug combinations, with pathway enrichment analyses indicating that several target key AD-related biological pathways.ConclusionsLLMs is effective in retrieving drug combinations for a given disease and the performance varies among different language models with best performance for GPT-5. However, the suggestions from LLM models require further validation to be considered reliable.},
}

@article {pmid41555821,
year = {2026},
author = {Kärkkäinen, V and Saari, T and Rusanen, M and Uusitalo, H and Leinonen, V and Thiede, B and Koivisto, AM and Kaarniranta, K and Utheim, TP},
title = {Altered tear fluid protein expression in persons with mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251413291},
doi = {10.1177/13872877251413291},
pmid = {41555821},
issn = {1875-8908},
abstract = {BackgroundTear fluid (TF) is a protein-rich fluid reported to reflect pathophysiological changes in several neurodegenerative diseases, including Alzheimer's disease. TF proteins are increasingly being considered as putative biomarker candidates to help in the diagnosis of disease. However, little information is available on TF protein changes in persons with mild cognitive impairment (MCI).ObjectiveThis study aimed to determine alterations in the expression of proteins in TF collected from persons with MCI compared with cognitively healthy controls.MethodsWe analyzed data from 54 study participants, including 34 controls (mean age, 71 years; mean Mini-Mental State Examination [MMSE] score ± standard deviation, 28.9 ± 1.4) and 20 persons with MCI (mean age, 71 years; mean MMSE score, 27.1 ± 1.9). All participants underwent cognitive, neurological, and ophthalmological examinations. TF was collected using Schirmer strips and evaluated using mass spectrometry-based proteomics and label-free quantification.ResultsThe expression of 33 TF proteins involved in oxidative stress, clearance mechanism, cytoskeleton stability, and inflammation were altered in persons with MCI compared with controls (p ≤ 0.05).ConclusionsOur findings reveal that numerous cellular stress-related biomarker candidate proteins are upregulated or downregulated in the TF of persons with MCI, a condition that may increase the risk of developing AD or other memory disorder. These data encourage TF protein studies in neurodegenerative diseases and TF provides an additive source of biomarkers for early diagnostics of memory diseases.},
}

@article {pmid41555820,
year = {2026},
author = {Smith, PJ and Blumenthal, JA and Ingle, K and Watkins, LL and Avorgbedor, F and Mabe, SK and Kraus, W and Tyson, C and Hinderliter, A and Sherwood, A},
title = {Lifestyle, sleep quality, and cognitive function in resistant hypertension: One-year follow-up from the TRIUMPH trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251409716},
doi = {10.1177/13872877251409716},
pmid = {41555820},
issn = {1875-8908},
abstract = {BackgroundTreatment resistant hypertension (TRH) is associated with increased risk of cognitive decline, which may be reduced by healthy lifestyle changes.ObjectiveTo examine the effects of a comprehensive, rehabilitation-based lifestyle hprogram on cognitive function during a one-year follow-up of participants from the TRIUMPH clinical trial.MethodsAmong the 140 TRIUMPH participants originally randomized, 91 (65%) were available for one-year assessments prior to the COVID-19 lockdown. Participants were originally randomized to a Cardiac rehabilitation-based LIFEstyle program (C-LIFE) or to a Standardized Education and Physician Advice (SEPA) condition for 4-months. During their one-year follow-up, participants underwent assessments of sleep quality, body mass index, actigraphy-assessed physical activity levels, and cerebrovascular reactivity using functional near infrared spectroscopy (fNIRS). Cognitive function was assessed using a 45-min test battery incorporating tests of Executive Function/Learning, Memory, and Processing Speed. Regression-based models incorporating reliable change indices were used to assess cognitive change.ResultsParticipants included 91 individuals (mean age = 63.6 [SD = 8.6]), evenly distributed in biological sex and race/ethnicity, and tended to be college-educated. The C-LIFE group had more preserved cognitive functioning compared to SEPA (C-LIFE: z = -0.26 [-0.40, -0.12] versus SEPA: -0.60 [-0.81, -0.39]; d = 0.44, p = 0.008), with reduced PSQI sleep symptoms associating with more preserved cognitive function (B = -0.18, p = 0.050 per 3-points). Treatment did not improve fNIRS markers, although changes in weight and physical activity associated with fNIRS outcomes.ConclusionsLifestyle modification may help preserve cognitive functioning among individuals with resistant hypertension.},
}

@article {pmid41555802,
year = {2026},
author = {Lim, EY and Hong, YJ and Jeong, JH and Park, KH and Kim, S and Wang, MJ and Shim, Y and Choi, SH and Yang, DW},
title = {Hand Grip Strength Predicts Cognitive Decline in Subjective Cognitive Decline: 2-Year Follow-up Results.},
journal = {Journal of Korean medical science},
volume = {41},
number = {3},
pages = {e36},
doi = {10.3346/jkms.2026.41.e36},
pmid = {41555802},
issn = {1598-6357},
support = {HI18C0530/MOHW/Ministry of Health and Welfare/Korea ; },
mesh = {Humans ; *Hand Strength/physiology ; Male ; Female ; *Cognitive Dysfunction/diagnosis/pathology ; Aged ; Positron-Emission Tomography ; Follow-Up Studies ; Longitudinal Studies ; Neuropsychological Tests ; Logistic Models ; Odds Ratio ; Middle Aged ; Aged, 80 and over ; Muscle Weakness ; Executive Function ; },
abstract = {BACKGROUND: Hand grip strength (HGS) has been proposed as a potential clinical marker for cognitive decline. However, its association with domain-specific cognitive changes and underlying amyloid pathology remains unclear.

METHODS: This longitudinal study included 107 older adults with subjective cognitive decline (SCD) who completed a 24-month follow-up. Participants were categorized based on the presence of HGS weakness using Asian Working Group of Sarcopenia criteria. Logistic regression analyses were performed to examine the association between baseline HGS and cognitive decline across multiple domains, adjusting for relevant covariates. Repeated measures analysis of variance evaluated longitudinal changes in neuropsychological performance.

RESULTS: Participants with HGS weakness had significantly higher amyloid positron emission tomography (PET) positivity (47.1% vs. 18.9%, P = 0.012). HGS weakness was associated with poorer baseline performance and greater decline in visuospatial and executive function over 24 months. Baseline HGS weakness predicted decline in visuospatial function (odds ratio [OR], 3.517; 95% confidence interval [CI], 1.072-11.535) and verbal memory (OR, 3.503; 95% CI, 1.046-11.729), but these associations lost significance after adjusting for amyloid positivity.

CONCLUSION: HGS weakness is associated with cognitive decline, particularly in visuospatial and executive domains, and may serve as an early indicator of amyloid-related neurodegeneration in older adults with SCD. HGS assessment could be a practical clinical tool for identifying individuals at risk, especially when amyloid PET is not available.},
}

Humans
*Hand Strength/physiology
Male
Female
*Cognitive Dysfunction/diagnosis/pathology
Aged
Positron-Emission Tomography
Follow-Up Studies
Longitudinal Studies
Neuropsychological Tests
Logistic Models
Odds Ratio
Middle Aged
Aged, 80 and over
Muscle Weakness
Executive Function

@article {pmid41555795,
year = {2026},
author = {Roth, S and Yan, J and Patru, MM and Mattke, S and Gustavsson, A and Ortsater, G},
title = {The capacity for Alzheimer's disease confirmatory testing in the United States: The current situation and simulations for future increase.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251406909},
doi = {10.1177/13872877251406909},
pmid = {41555795},
issn = {1875-8908},
abstract = {BackgroundWith recent advances in disease-modifying therapies for Alzheimer's disease (AD), demand for confirmatory biomarker testing such as via cerebrospinal fluid (CSF) analysis or amyloid positron emission tomography (PET) will increase considerably for diagnosis.ObjectiveTo assess the current capacity and estimating the anticipated future need of AD confirmatory testing in the United States (US).MethodsA population-based decision tree model was employed to simulate the AD diagnostic pathway for patients presenting with symptoms of mild cognitive impairment or mild dementia in primary and secondary care in the US. All patients were assumed to be enrolled in Medicare. The study was conducted from the US payer's perspective over a 5-year period. Four scenarios assessed the impact of different utilization patterns: (1) reference scenario (current use in AD diagnostic pathway: < 1% amyloid-PET; 3.5% CSF analysis); (2) increased CSF analysis utilization scenario (50% utilization); (3) amyloid-PET only; and (4) CSF analysis only.ResultsScenario 1 fails to meet the growing demand for AD confirmatory testing (assumed annual care-seeking rate of 50%), with approximately 0.3% of all amyloid-β-positive patients receiving a timely and accurate diagnosis with amyloid-PET, and 1.7% with CSF analysis. Scenarios 2 and 4 resulted in the highest proportion of accurate and timely diagnoses for amyloid-β-positive patients (24.8% and 44.6%, respectively) versus 15.1% of patients in scenario 3.ConclusionsIt is imperative to address capacity issues for AD confirmatory testing to facilitate timely diagnosis and initiation of amyloid-targeting therapies. Increasing CSF analysis utilization has the capacity to meet this growing demand.},
}

@article {pmid41555782,
year = {2026},
author = {Francis, L and Beiser, A and Lu, S and Kujawa, SG and Heard-Costa, N and Kolo, FB and Kamboh, MI and Bernal, R and Welling, DB and Alcabes, RL and Himali, JJ and Seshadri, S},
title = {Hearing loss in the young-old is associated with increased risk for Alzheimer's disease and vascular dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251407211},
doi = {10.1177/13872877251407211},
pmid = {41555782},
issn = {1875-8908},
abstract = {Hearing loss is a risk factor for dementia, but dementia subtypes underlying this association and effect modifiers are unknown. Using data collected from 2000 Framingham Heart Study participants we found that hearing loss increases risk for Alzheimer's disease and vascular dementia in participants aged 60-70 years ("young-old") at time of hearing assessment (Alzheimer's disease: HR 1.46[CI 1.07-2.0] p = 0.017; vascular dementia: HR 2.08[CI 1.22-3.56] p = 0.007). Longer duration of hearing loss determines increased risk for Alzheimer's disease and vascular dementia, and screening and intervention for hearing loss from mid-life may help reduce dementia.},
}

@article {pmid41555553,
year = {2026},
author = {Liu, Z and Li, X and Wang, Q and Liu, K and Zeng, W and Li, D and Zhao, K and Ma, Y and Long, H and Zhang, S and Li, D and Sun, B and Le, W and Wang, C and He, Z and Kang, W and Xiao, W and Liu, C},
title = {Dopamine-Induced Tau Modification Prevents Pathological Phosphorylation and Generates a Distinct Fibril Polymorph.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.5c22156},
pmid = {41555553},
issn = {1520-5126},
abstract = {Amyloid aggregation of tau is the key pathological event in various tauopathies including Alzheimer's and Pick's disease. Recently, dopamination was identified to modify tau on cysteine, which protects against tau pathology, yet its structural and functional consequences remain unclear. Here, we show that dopamination of the three-repeat (3R) tau fragment K19 alleviates disease-associated tau phosphorylation and alters the tau fibril structure. Solution NMR analysis reveals that dopamine modification at Cys322 of tau suppresses phosphorylation at several pathogenic sites across the microtubule-binding region. Dopaminated tau also exhibited greatly diminished fibrillization in vitro and reduced seeding activity in cells. Finally, we determined the cryo-EM structure of dopaminated tau fibrils at 3.55 Å resolution, revealing a unique fibril polymorph with the smallest core region reported to date for tau. The dopaminated fibril core comprises only 11 residues (centered on the VQIVYK motif) and is stabilized by a minimal hydrophobic interface, explaining its decreased stability compared to that of unmodified tau fibrils. Our results provide atomic-level insight into how dopamine modification imparts a protective effect on tau and underscore the profound influence of post-translational modifications in modulating amyloid protein structure and pathology.},
}