@article {pmid41957344,
year = {2026},
author = {Zhang, Z and Huang, P and Yang, Y and Wu, H and Yao, X and Wang, Y and Yi, H and Ning, K and Chen, Y and Wu, Y and Chen, Z and Shen, P and Hong, D and Huang, X and Zou, WQ},
title = {Astrocyte-related proteins mediate the association of YWHAG with Alzheimer's pathology and enhance its diagnostic value.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04020-7},
pmid = {41957344},
issn = {2158-3188},
abstract = {Recent advances have identified YWHAG as a promising synaptic biomarker, with evidence showing that the YWHAG:NPTX2 ratio strongly predicts cognitive decline and Alzheimer's disease (AD) progression independent of amyloid and tau pathology. However, the links between YWHAG and astrocytic processes-key regulators of amyloid clearance, tau phosphorylation, and neuroinflammation-remain poorly understood. A total of 530 participants were included. Levels of YWHAG and a panel of biologically relevant astrocyte-derived proteins were measured using a proximity extension assay and validated immunoassay platforms. Associations with AD biomarkers and cognition were examined using multivariable regression, longitudinal mixed-effects models, and mediation analyses. Path analysis was performed to explore the potential pathways from YWHAG through astrocytic proteins to AD pathology and cognition. We evaluated whether combining YWHAG with astrocyte-related proteins improves its predictive performance, by comparing the area under the curve (AUC) of the combined model with that of YWHAG alone. YWHAG was positively associated with glial fibrillary acidic protein (GFAP, β = 0.558, p < 0.001), vimentin (β = 0.329, p < 0.001), aquaporin-4 (AQP4, β = 0.097, p = 0.044), thrombospondin (THBS) -1 (β = 0.470, p < 0.001), and THBS2 (β = 0.285, p < 0.001), while showing negative associations with gap junction alpha-1 protein (GJα1, β = -0.161, p < 0.001) and serpin family A member 3 (SERPINA3, β = -0.350, p < 0.001). Mediation analysis indicated that certain astrocyte-related proteins may be involved in the association between YWHAG and AD pathology. Additionally, path analysis suggested a potential pathway involving YWHAG, GJα1, Aβ42, and cognitive function. The combination of YWHAG with SERPINA3 and THBS1 achieved an AUC of 0.981, outperforming YWHAG alone (AUC = 0.885). YWHAG is associated with astrocyte-related proteins, and combining them enhances its predictive accuracy for AD, highlighting its potential utility in early clinical screening.},
}

@article {pmid41957377,
year = {2026},
author = {Collij, LE and Salvadó, G and Horie, K and Barthélemy, NR and Betthauser, TJ and Strandberg, O and Smith, R and Palmqvist, S and Schindler, SE and Ossenkoppele, R and Janelidze, S and Mattsson-Carlgren, N and Bateman, RJ and Hansson, O},
title = {Trajectories of plasma and CSF MTBR-tau243 and phosphorylated-tau species across the Alzheimer's disease continuum.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {41957377},
issn = {2041-1723},
mesh = {Humans ; *Alzheimer Disease/blood/cerebrospinal fluid/diagnostic imaging/pathology ; *tau Proteins/blood/cerebrospinal fluid/metabolism ; Phosphorylation ; Biomarkers/blood/cerebrospinal fluid ; Male ; Female ; Aged ; Disease Progression ; Middle Aged ; Positron-Emission Tomography ; Sweden ; Amyloid beta-Peptides/cerebrospinal fluid/metabolism ; Aged, 80 and over ; },
abstract = {To efficiently implement plasma and cerebrospinal fluid (CSF) biomarkers for staging and prognosis of Alzheimer disease (AD), we must understand their dynamics across disease progression. We analyzed participants from the Swedish BioFINDER-2 study with mass spectrometry measurements of plasma and CSF tau species, including eMTBR-tau243/MTBR-tau243 and phosphorylation occupancies (%p-tau). Disease duration was estimated using Aβ-PET and tau-PET with the SILA algorithm. Bootstrapped LOESS models showed that %p-tau217 changes earliest, increasing just before Aβ-PET positivity. Other p-tau species changed later, with smaller dynamic ranges and earlier ceiling effects. %p-tau205 and MTBR-tau243 changes aligned with tau-PET positivity onset, while MTBR-tau243-especially plasma eMTBR-tau243-tracked cortical tau burden in later stages. Non-phosphorylated mid-region tau may serve as a late-stage biomarker. Taken together, concurrent assessments of plasma or CSF %p-tau217, %p-tau205, and (e)MTBR-tau243 provides information about different biological events in the disease cascade, which can benefit clinical trials and patient management in clinical practice.},
}

Humans
*Alzheimer Disease/blood/cerebrospinal fluid/diagnostic imaging/pathology
*tau Proteins/blood/cerebrospinal fluid/metabolism
Phosphorylation
Biomarkers/blood/cerebrospinal fluid
Male
Female
Aged
Disease Progression
Middle Aged
Positron-Emission Tomography
Sweden
Amyloid beta-Peptides/cerebrospinal fluid/metabolism
Aged, 80 and over

@article {pmid41957486,
year = {2026},
author = {Milicevic, KD and Abreu, AC and Chandran, G and Zhu, YMD and Hu, X and Ivanova, VO and Jami, M and Simon, B and Fernández, I and Yan, R and Antic, SD},
title = {Prodromal changes in cortical neuron physiology before amyloid pathology in a mild model of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-47370-4},
pmid = {41957486},
issn = {2045-2322},
support = {778405//UConn IBACS Seed Grant/ ; 65539//Cure Alzheimer's Fund/ ; NS138991/NS/NINDS NIH HHS/United States ; 4242 "NIMOCHIP"//Science Fund RS/ ; },
}

@article {pmid41957539,
year = {2026},
author = {Ferguson, SJ and Choi, YD and Walker, AE},
title = {Contributions of vascular ageing to late-onset Alzheimer's disease.},
journal = {Experimental physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/EP092909},
pmid = {41957539},
issn = {1469-445X},
support = {ALZDISCOVERY-1049110/ALZ/Alzheimer's Association/United States ; AG064016/AG/NIA NIH HHS/United States ; },
abstract = {Late-onset Alzheimer's disease (LOAD) is an age-related disease that is strongly associated with vascular risk factors and cerebrovascular impairments. As such, changes in the vasculature with advancing age likely contribute to LOAD, but the mechanisms underlying these contributions remain incompletely understood. With advancing age, there is dysregulation of cerebral blood flow, impairment of neurovascular coupling, and increased blood-brain barrier permeability, which may initiate or contribute to the neuropathology associated with LOAD. Changes to the vasculature outside of the brain, including increases in blood pressure and arterial stiffness, may initiate age-related cerebrovascular impairments. Age-related increases in oxidative stress and inflammatory signalling, as well as contributions to LOAD-related neuropathology, such as amyloid-β and hyperphosphorylated tau, impair cerebrovascular cells. In this review, we summarize the evidence for the role of vascular ageing in LOAD, describing age-related cerebrovascular impairments and their causes.},
}

@article {pmid41957813,
year = {2026},
author = {Avilés-Granados, C and Gea-González, A and Sáez-Leyva, J and Perez, SE and Mufson, EJ and Granholm, AC and Carmona-Iragui, M and Zetterberg, H and Blennow, K and Fortea, J and García-Ayllón, MS and Sáez-Valero, J},
title = {Cerebrospinal fluid and frontal cortex TMPRSS2 and ACE2 protein levels differ in Down syndrome and Alzheimer's disease.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02289-9},
pmid = {41957813},
issn = {2051-5960},
support = {PRE2022-104182//Agencia Estatal de Investigación/ ; CIACIF/2021/426//Generalitat Valenciana/ ; PO1AG014449, RF1AG081286, R01AG061566/AG/NIA NIH HHS/United States ; PO1AG014449, RF1AG081286, R01AG061566/AG/NIA NIH HHS/United States ; CA2018010//BrightFocus Foundation/ ; CA2018010//BrightFocus Foundation/ ; 5 R01 AG071228-02, R01AG070153, 1U24AG092191-01, and 5 R01 AG061566//NIH grants/ ; GRT-2023b/2277//Foundation Lejeune grant to the DSBC brain bank consortium/ ; (#2023-00356, #2022-01018 and #2019-02397//Swedish Research Council/ ; #2017-00915 and #2022-00732//Swedish Research Council/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; #201809-2016862//Alzheimer's Drug Discovery Foundation/ ; #ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C//AD Strategic Fund and the Alzheimer's Association/ ; NEuroBioStand, #22HLT07//European Partnership on Metrology/ ; FO2022-0270//the Bluefield Project, Cure Alzheimer's Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Familjen Rönströms Stiftelse, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden/ ; No 860197 (MIRIADE)//H2020 Marie Skłodowska-Curie Actions/ ; JPND2021-00694//European Union Joint Programme - Neurodegenerative Disease Research/ ; UKDRI-1003//National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, the UK Dementia Research Institute at UCL/ ; #AF-930351, #AF-939721, #AF-968270, and #AF-994551//Swedish Alzheimer Foundation/ ; #ALZ2022-0006, #FO2024-0048-TK-130 and FO2024-0048-HK-24//Hjärnfonden, Sweden/ ; #ALFGBG-965240 and #ALFGBG-1006418//ALF-agreement. Swedish state/ ; JPND2019-466-236//European Union Joint Program for Neurodegenerative Disorders/ ; ZEN-21-848495//Alzheimer's Association 2021 Zenith Award/ ; SG-23-1038904 QC//Alzheimer's Association 2022-2025 Grant/ ; PI22/01329//Instituto de Salud Carlos III/ ; AICO/2021/308//Conselleria de Cultura, Educación y Ciencia, Generalitat Valenciana/ ; },
}

@article {pmid41958080,
year = {2026},
author = {Caniceiro, AB and Agostinho, SP and Piochi, LF and Rosário-Ferreira, N and Moreira, IS},
title = {The GPCR Connection: Linking Alzheimer's Disease and Glioblastoma.},
journal = {Journal of cellular and molecular medicine},
volume = {30},
number = {7},
pages = {e71131},
doi = {10.1111/jcmm.71131},
pmid = {41958080},
issn = {1582-4934},
support = {MPr-2023-09//COMPETE2030-FEDER-01475900 SI I&DT Individual/ ; 10.54499/UID/PRR/04539/2025//Fundação para a Ciência e a Tecnologia/ ; LA/P/0058/2020//Fundação para a Ciência e a Tecnologia/ ; 2024.07255.IACDC//Fundação para a Ciência e a Tecnologia/ ; 2022.12479.BD//Fundação para a Ciência e a Tecnologia/ ; 2024.03713.BDANA//Fundação para a Ciência e a Tecnologia/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Glioblastoma/metabolism/pathology ; *Receptors, G-Protein-Coupled/metabolism ; Signal Transduction ; Animals ; *Brain Neoplasms/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) and glioblastoma multiforme (GBM) are biologically distinct age-related brain disorders with opposing clinical phenotypes. AD is characterised by progressive neurodegeneration and cognitive decline, whereas GBM is characterised by aggressive cellular proliferation and a poor prognosis. Despite these differences, converging evidence indicates that both conditions share molecular pathways and network-level dysfunction that emerge during brain ageing. Central to this convergence are G protein-coupled receptors (GPCRs), which act as integrative signalling hubs that regulate inflammation, metabolism, calcium (CA[2+]) homeostasis, and cell survival. In AD, GPCR signalling modulates amyloid-β production and clearance, Tau phosphorylation, intracellular CA[2+] dynamics, and glial-driven neuroinflammation. In contrast, the same receptor families promote tumour growth, angiogenesis, immune evasion, and therapeutic resistance in patients with GBM. Core intracellular cascades, such as PI3K-AKT-mTOR and MAPK-ERK, are dysregulated in both diseases and function as shared signalling backbones, with outcomes dictated by cellular context rather than receptor identity. CXCR4, LPA1, and FPR1 exemplify this duality, driving either oncogenic proliferation or neuronal dysfunction, depending on the biological environment. Recent advances in integrative multiomics, computational modelling, artificial intelligence, and organoid systems have revealed GPCR-centred regulatory nodes and accelerated the identification of druggable targets. Collectively, these findings suggest that AD and GBM, although pathologically antithetical, share a molecular fingerprint shaped by ageing-associated inflammation, metabolic disruption, cellular senescence and dysregulated GPCR networks. Deciphering this context-dependent duality may enable precision therapeutic strategies to either restore neuronal integrity in AD or suppress malignant programmes in GBM while fostering cross-fertilisation between neurodegeneration and neuro-oncology research.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Glioblastoma/metabolism/pathology
*Receptors, G-Protein-Coupled/metabolism
Signal Transduction
Animals
*Brain Neoplasms/metabolism/pathology

@article {pmid41958117,
year = {2026},
author = {Lv, Y and Han, K and Xie, D and Zhao, P and Xie, S and Jiang, Q and Zou, L and Zhu, G and Zhang, Y and Li, J and Yang, X},
title = {Study on Cholinesterase Inhibitory Activities and AChE Inhibition Mechanism of Gastrodin Compounds Based on Molecular Docking and Kinetic Simulation.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {4},
pages = {e03705},
doi = {10.1002/cbdv.202503705},
pmid = {41958117},
issn = {1612-1880},
support = {202205AC160049//Young and Middle-Aged Academic and Technological Leaders of Yunnan Province/ ; 22267018//the National Natural Science Foundation of China/ ; 32060107//the National Natural Science Foundation of China/ ; 32060327//the National Natural Science Foundation of China/ ; 202501BD070001-027//Yunnan Fundamental Research Projects/ ; 202401AT070295//Yunnan Fundamental Research Projects/ ; 202401BD070001-103//Yunnan Fundamental Research Projects/ ; 202503AC100002//Yunnan Fundamental Research Projects/ ; 202205AF150068//Zhang Xia Expert Workstation of the Yunnan Province/ ; },
mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; *Molecular Docking Simulation ; *Benzyl Alcohols/chemistry/pharmacology/chemical synthesis ; *Acetylcholinesterase/metabolism ; *Glucosides/chemistry/pharmacology/chemical synthesis ; Kinetics ; Butyrylcholinesterase/metabolism ; Structure-Activity Relationship ; Humans ; Molecular Structure ; Dose-Response Relationship, Drug ; },
abstract = {Alzheimer's disease (AD) is characterized by cholinergic neurotransmission dysfunction, and inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) represents a key therapeutic strategy. Gastrodin exhibits broad biological activity. In vitro enzyme inhibition assays, enzyme kinetic analysis, fluorescence spectroscopy, and molecular docking simulations validated the inhibitory effects of gastrodin and its analogues on acetylcholinesterase. All compounds exhibited concentration-dependent inhibition curve inhibition against AChE, with compound 3 demonstrating significant inhibitory activity, yielding an AChE IC50 value of 25.64 ± 4.59 µM. The inhibitory activity against AChE was ranked as follows: 2-hydroxymethylphenyl-β-D-glucopyranoside (compound 3) > 4-hydroxymethylphenyl-β-D-glucopyranoside (compound 2) > 4-methoxyphenyl-β-D-glucopyranoside (compound 4) > phenyl-β-D-glucopyranoside (compound 1). Enzyme kinetics revealed that compounds 1-4 exhibit reversible mixed-site inhibition mechanisms, simultaneously binding to both the catalytic active site (CAS) and peripheral anion site (PAS) of acetylcholinesterase. Fluorescence spectroscopy indicated that compounds 1-3, except compound 4, form stable complexes with acetylcholinesterase via static quenching. Molecular docking studies revealed multiple bond interactions between the compounds and AChE, with compound 3 exhibiting the lowest binding free energy. Subsequent investigation of the compounds' inhibitory activity against BChE demonstrated that they also possess significant inhibitory effects on BChE. This study elucidates the inhibitory mechanism of gastrodin-derived compounds against AChE and their structure-activity relationship, providing a theoretical basis for developing anti-Alzheimer's disease drug candidates based on these compounds.},
}

*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis
*Molecular Docking Simulation
*Benzyl Alcohols/chemistry/pharmacology/chemical synthesis
*Acetylcholinesterase/metabolism
*Glucosides/chemistry/pharmacology/chemical synthesis
Kinetics
Butyrylcholinesterase/metabolism
Structure-Activity Relationship
Humans
Molecular Structure
Dose-Response Relationship, Drug

@article {pmid41958244,
year = {2026},
author = {Zhou, CH and Han, F and Gao, F and Zhou, LX and Yao, M and Ni, J and Cui, LY and Li, ML and Jin, ZY and Zhang, SY and Shen, Y and Zhang, DD and Zhu, YC},
title = {Cerebral small vessel disease burden relates to cognitive decline via impaired amyloid clearance in the general population.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261437577},
doi = {10.1177/0271678X261437577},
pmid = {41958244},
issn = {1559-7016},
abstract = {Our aim is to examine the interplay between cerebral small vessel disease (CSVD) pathology, Alzheimer's disease (AD) related amyloid-β (Aβ) clearance, and cognition in general population. Cross-sectional structural equation modeling (SEM) was conducted to evaluate CSVD burden, cognition, and plasma Aβ42/40 ratios in 1026 participants without dementia from a prospective community-based cohort. CSVD burden was quantified using five established MRI markers, while cognition was assessed with the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), verbal fluency test, and reverse digit span. Models were adjusted for age, sex, education, body mass index, vascular risk factors (hypertension, diabetes mellitus, hyperlipidemia, and smoking), antihypertensive medication use, and APOE4 carrier status. Greater CSVD burden was significantly associated with poorer cognition (B = -2.607 ± 1.016, β = -0.167, p = 0.010), with white matter hyperintensity volume (∆R[2] = 0.3%, p = 0.016) and brain parenchymal fraction (∆R[2] = 0.4%, p = 0.019) contributing most strongly. CSVD burden was also negatively correlated with plasma Aβ42/40 ratios (B = -0.280 ± 0.074, β = -0.140, p < 0.001), which partially mediated the CSVD-cognition association (B = -0.241 ± 0.087, β = -0.015, p = 0.006). These findings underscore potential CSVD involvement in AD-related pathology across aging.},
}

@article {pmid41958409,
year = {2026},
author = {Lu, WC and Tsai, MS and Huang, SH and Lee, HH and Hsu, JL and Chang, YL},
title = {A normative study of the free and cued selective reminding test in Mandarin-speaking adults in Taiwan.},
journal = {Journal of the International Neuropsychological Society : JINS},
volume = {},
number = {},
pages = {1-12},
doi = {10.1017/S1355617726101957},
pmid = {41958409},
issn = {1469-7661},
abstract = {OBJECTIVE: Episodic memory decline is among the earliest and most prominent cognitive changes observed in both normal aging and Alzheimer's disease. The Free and Cued Selective Reminding Test (FCSRT) enhances differentiation of memory deficits through controlled semantic encoding and cue-based retrieval. However, culturally appropriate normative data for Mandarin-speaking adult populations have been lacking. This study aimed to establish normative data for the Taiwan version of the FCSRT (T-FCSRT), examine demographic effects on test performance, and evaluate its psychometric properties and clinical applicability.

METHOD: A total of 372 cognitively healthy adults aged 45-86 years were recruited using stratified sampling to reflect the Taiwanese population across sex, age, and education levels. Participants completed the T-FCSRT, and regression-based analyses were used to adjust for demographic effects. Reliability and validity were assessed using test-retest data and correlations with established neuropsychological measures.

RESULTS: All T-FCSRT core indices were significantly influenced by age and education level, whereas sex effects were confined to immediate and delayed free-recall measures. The T-FCSRT demonstrated good test-retest reliability, criterion-related and construct validity, and regression-based percentile norms that provide population-representative benchmarks.

CONCLUSION: The T-FCSRT demonstrates strong psychometric properties and provides culturally appropriate normative data for Mandarin-speaking adults in Taiwan. These findings support its utility for clinical assessment and research on episodic memory, enabling more accurate differentiation between normal and pathological aging.},
}

@article {pmid41958469,
year = {2026},
author = {Voigt, RM and Chaudhary, A and Naqib, A and Engen, PA and Adnan, D and Dhana, K and Green, SJ and Villanueva, M and Agarwal, P and Barnes, LL and Sacks, F and Keshavarzian, A},
title = {Weight loss and metabolic improvements dominate the microbiome response in the MIND diet intervention: a randomized controlled trial.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {2},
pages = {e70239},
pmid = {41958469},
issn = {2352-8737},
abstract = {INTRODUCTION: Observational studies link the MIND diet to reduced risk of Alzheimer's disease (AD) and slower cognitive decline. However, a recent randomized controlled trial found no differential cognitive benefit of the MIND diet over a control diet in the context of shared caloric restriction. Given that both groups achieved significant weight loss and metabolic improvements, this study aimed to disentangle the impact of the MIND diet and host metabolic improvements on the intestinal microbiome.

METHODS: A subset of participants (n = 213) from the MIND trial were analyzed in this study. Clinical data and stool samples were collected at baseline, Year 1, Year 2, and Year 3, and longitudinal changes in microbiome composition were assessed via shotgun metagenomics.

RESULTS: Both groups exhibited significant, transient microbiome remodeling at Year 1 (the period of most active weight loss). The control group demonstrated a broad range of altered metabolic pathways, whereas the MIND diet group showed only one, suggesting a functional buffering effect of the MIND diet. Prospective modeling independent of diet group revealed that a poorer cognitive trajectory was significantly associated with increased inositol degradation (PWY-7237) and purine nucleotide salvage (PWY66-409); conversely, a better cognitive trajectory was associated with increased degradation of deoxy sugars (FUC-RHAMCAT-PWY).

DISCUSSION: Caloric restriction, weight loss, and host metabolic improvement are the dominant factors shaping the intestinal microbiome, overshadowing diet-specific taxonomic shifts. The MIND diet appeared to provide a modest stabilizing effect on the microbial functional profile against perturbations during active weight loss; however, these dietary associations did not persist in covariate-adjusted models, suggesting that host metabolic improvements remained the primary driver of functional shifts.},
}

@article {pmid41958476,
year = {2026},
author = {Nguyen, TD and Tran, TK and Truong, CK and Can, DC and Nguyen, BT and Chén, OY},
title = {High-dimensional Many-to-many-to-many Mediation Analysis.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {41958476},
issn = {2331-8422},
abstract = {We study high-dimensional mediation analysis in which exposures, mediators, and outcomes are all multivariate, and both exposures and mediators may be high-dimensional. We formalize this as a many (exposures)-to-many (mediators)-to-many (outcomes) (MMM) mediation analysis problem. Methodologically, MMM mediation analysis simultaneously performs variable selection for high-dimensional exposures and mediators, estimates the indirect effect matrix (i.e., the coefficient matrices linking exposure-to-mediator and mediator-to-outcome pathways), and enables prediction of multivariate outcomes. Theoretically, we show that the estimated indirect effect matrices are consistent and element-wise asymptotically normal, and we derive error bounds for the estimators. To evaluate the efficacy of the MMM mediation framework, we first investigate its finite-sample performance, including convergence properties, the behavior of the asymptotic approximations, and robustness to noise, via simulation studies. We then apply MMM mediation analysis to data from the Alzheimer's Disease Neuroimaging Initiative to study how cortical thickness of 202 brain regions may mediate the effects of 688 genome-wide significant single nucleotide polymorphisms (SNPs) (selected from approximately 1.5 million SNPs) on eleven cognitive-behavioral and diagnostic outcomes. The MMM mediation framework identifies biologically interpretable, many-to-many-to-many genetic-neural-cognitive pathways and improves downstream out-of-sample classification and prediction performance. Taken together, our results demonstrate the potential of MMM mediation analysis and highlight the value of statistical methodology for investigating complex, high-dimensional multi-layer pathways in science. The MMM package is available at https://github.com/THELabTop/MMM-Mediation.},
}

@article {pmid41958504,
year = {2026},
author = {Laslo, A and Laslo, L and Brinzaniuc, K},
title = {Intrahippocampal injection in mice used for experimental studies in Alzheimer's disease: a challenging procedure for neuroscience purposes.},
journal = {Journal of medicine and life},
volume = {19},
number = {2},
pages = {136-141},
pmid = {41958504},
issn = {1844-3117},
mesh = {Animals ; *Alzheimer Disease/pathology ; Mice ; *Hippocampus/pathology/surgery ; Disease Models, Animal ; Microinjections/methods ; *Neurosciences/methods ; Stereotaxic Techniques ; Male ; },
abstract = {Neuroscience has advanced over the years largely due to animal experiments, particularly in mice. These experiments are generally challenging and require thorough preparation to be successfully carried out. The training required to perform procedures on mice must be rigorous to minimize the risk of errors that could lead to experimental failure and, equally important, to prevent unnecessary suffering of the animals involved. In this study, we present a detailed description of the surgical procedure for intrahippocampal injection in mice using a motorized stereotaxic system equipped with synchronized drilling and microinjection modules. The protocol emphasizes precise anatomical targeting, controlled infusion parameters, and standardized procedural steps designed to enhance reproducibility and minimize tissue trauma. Key aspects of the technique include stereotaxic atlas alignment, skull reference acquisition, controlled drilling to the dura mater, and microinjection of small tracer volumes under physiologically relevant conditions. This methodological framework provides a reliable platform for investigating brain parenchymal transport mechanisms, including intramural periarterial drainage pathways implicated in neurodegenerative disorders such as Alzheimer's disease.},
}

Animals
*Alzheimer Disease/pathology
Mice
*Hippocampus/pathology/surgery
Disease Models, Animal
Microinjections/methods
*Neurosciences/methods
Stereotaxic Techniques
Male

@article {pmid41958631,
year = {2026},
author = {Kransberg, J and Sjøli Bråthen, AC and Falch, ES and Øverbye, KEØ and Garrido, PF and Fjell, AM and Stangl, M and Wolbers, T and Sneve, MH and Walhovd, KB},
title = {Failure to detect entorhinal grid-like signals in a passive navigation human fMRI study.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
pmid = {41958631},
issn = {2837-6056},
abstract = {Grid cells in the human entorhinal cortex (EC) play a critical role in spatial navigation and memory. The EC is also one of the first regions affected by ageing and Alzheimer's disease. This pre-registered functional magnetic resonance imaging (fMRI) study aimed to detect grid-cell-like signals (GLS) in a passive virtual navigation task. Contrary to our hypotheses and previous findings, we did not observe significant GLS at a population level, even in younger participants. Further exploratory analyses investigated the impact of task-engagement, as inferred from object-location memory performance, and showed no relationship with GLS magnitude. We also examined potential influences of a confounding one-fold directional signal and various data-processing choices but observed no consistent patterns. Our findings, consistent with recent null results from similar studies, suggest that passive navigation paradigms may be insufficient for reliably eliciting grid-like signals in human fMRI.},
}

@article {pmid41958634,
year = {2026},
author = {Ayyıldız, N and Mueller, K and Hardikar, S and Beyer, F and Enzenbach, C and Baber, R and Wirkner, K and Zachariae, S and Girbardt, J and Hassett, JD and Anwander, A and Elze, T and Wang, M and Witte, AV and Rauscher, FG and Villringer, A},
title = {Retinal nerve fibre layer thickness reflects characteristics of brain grey and white matter.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
pmid = {41958634},
issn = {2837-6056},
abstract = {The retina is an optically accessible part of the central nervous system. Using high-resolution optical coherence tomography, we explored the relationship between retinal thickness and structural features of the brain obtained with magnetic resonance imaging. We hypothesized that there are associations between circumpapillary (i.e., around optic disc) retinal nerve fibre layer thickness and structural features of (i) brain areas and pathways related to visual information processing and (ii) more widespread brain areas affected by the consequences of cardiovascular risk factors and/or age-related neurodegeneration. In a population-based sample of over 500 subjects, in support of the first hypothesis, we showed associations of circumpapillary retinal nerve fibre layer thickness with visual cortex grey matter density and with optic radiation fractional anisotropy. These correlations were stronger for the right eye, possibly reflecting right ocular dominancy. Regarding the second hypothesis, while we confirmed the broad impact of cardiovascular risk factors such as body mass index, diabetes, and hypertension on brain structure, we did not find (adequate) significant partial correlations between circumpapillary retinal nerve fibre layer thickness and cardiovascular risk factors. Consequently, we were unable to confirm an association between circumpapillary retinal nerve fibre layer thickness and the impact of cardiovascular risk factors on brain structure especially on grey matter rather than white matter. However, even when the effects of cardiovascular risk factors were accounted for statistically, circumpapillary retinal nerve fibre layer thickness (particularly on the right side) was associated with fractional anisotropy of limbic system tracts, that is, the fornix and stria terminalis including hippocampus and amygdala, areas which are commonly affected by Alzheimer's disease. To further explore the structural associations between eye and brain, in terms of a possible common underlying pathology related to cardiovascular risk factors and progressive neurodegenerative diseases on the central nervous system, longitudinal and interventional studies are necessary.},
}

@article {pmid41958871,
year = {2026},
author = {Leung, SK and Walker, EM and Policicchio, S and Dahir, A and Vellame, DS and Smith, AR and Swarbrick, R and Lunnon, K and Dempster, EL and Ahmed, Z and Hannon, E and Castanho, I and Mill, J},
title = {Methylomic signatures of tau and amyloid-beta in transgenic mouse models of Alzheimer's disease neuropathology.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {23},
pmid = {41958871},
issn = {3005-1940},
abstract = {Alzheimer's disease (AD) is characterized by progressive neurodegeneration driven by tau and amyloid-β (Aβ) pathology, although the underlying molecular mechanisms remain incompletely understood. Emerging evidence implicates altered DNA methylation (DNAm) in AD but comprehensive analyses in experimental models are limited. Here, we profile DNAm dynamics in two widely used transgenic mouse models of tau (rTg4510) and Aβ (J20) neuropathology, focusing on the entorhinal cortex and hippocampus. Using reduced representation bisulfite sequencing (RRBS) and methylation arrays across multiple disease stages, we identified widespread pathology-associated DNAm alterations in both models. Tau pathology in rTg4510 mice was associated with extensive DNAm remodeling at genes involved in neuronal plasticity, apoptosis, and lipid metabolism, including Dcaf5, Creb3l4, and As3mt. In contrast, J20 mice exhibited more modest changes, primarily at immune-related loci such as Grk2, Ncam2, and Prmt8. Tau-associated DNAm changes were more consistent across brain areas than those associated with Aβ pathology. Comparison with human AD DNAm datasets revealed overlapping DNAm differences, including hypermethylation at Ank1 and Prdm16 in rTg4510 mice. These findings provide robust evidence for early, pathology-associated epigenetic alterations in AD and highlight the utility of epigenomic profiling in transgenic models for identifying novel targets for early intervention in AD.},
}

@article {pmid41958924,
year = {2026},
author = {Xiao, J and Li, B and Li, B and Wang, J and Tang, R and Gao, C and Che, X and Xu, X and Chen, S and Ren, R and Wang, G},
title = {A prospective real-world study of the efficacy and safety of aducanumab in China: Focus on early-onset and autosomal dominant Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70328},
pmid = {41958924},
issn = {2352-8729},
abstract = {INTRODUCTION: Aducanumab is the first anti-amyloid therapy used for Alzheimer's disease (AD) in China.

METHODS: This 12-month, single-center, real-world study enrolled 12 participants with early AD receiving aducanumab 10 mg/kg every 4 weeks (ChiCTR2200066153). The primary outcomes were changes in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores at 12 months. Secondary outcomes included amyloid clearance, brain structure measures, and biomarker assessments.

RESULTS: No amyloid-related imaging abnormalities occurred. The mean CDR-SB score increased by 0.88 at 12 months, with cortical and hippocampal atrophy, enlarged choroid plexus, and ventricular volumes. Two autosomal dominant AD patients exhibited transient amyloid burden elevation at 6 months and subsequent reduction at 12 months, alongside increased serum glial fibrillary acidic protein (GFAP) levels. In the remaining 10 patients, the mean amyloid clearance reached -34.93 Centiloids, alongside decreased serum GFAP levels.

DISCUSSION: Aducanumab showed good tolerability and favorable biological outcomes, with different responses in autosomal dominant mutation carriers.},
}

@article {pmid41958981,
year = {2026},
author = {Daniel, SF and Lee, C and Mollenkopf, T and Lee, M and Arbuckle, J and Fiabane, E and Gabitto, MI and Johansen, N and Kapen, I and Kraft, AW and Lai, J and Li, SY and McGinty, R and Miller, JA and Welch-Moosman, S and Otto, S and Sawyer, L and Shepard, N and Thompson, CL and Tjärnberg, A and Waters, J and Zhen, X and Macosko, E and Lein, ES and Ng, L and Zeng, H and Mufti, S and Yao, Z and Hawrylycz, MJ},
title = {MapMyCells: High-performance mapping of unlabeled cell-by-gene data to reference brain taxonomies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.06.710160},
pmid = {41958981},
issn = {2692-8205},
abstract = {Single-cell mapping methods convert raw, heterogeneous single-cell datasets into interpretable and comparable representations of biological identity. As reference cell-type taxonomies mature, mapping new datasets to shared references has become a central strategy for enabling cross-study integration, reproducible annotation, and cumulative biological knowledge. Here we present MapMyCells , an open-source framework designed to align diverse single-cell omics datasets to hierarchical reference taxonomies with minimal preprocessing. MapMyCells provides out-of-the-box support for an expanding set of high-quality brain cell-type references generated by the Allen Institute for Brain Science, the BRAIN Initiative, and the Seattle Alzheimer's Disease Brain Cell Atlas, including whole-brain mouse and human atlases, aging and Alzheimer's disease cohorts, and a cross-species consensus taxonomy initially focused on the basal ganglia. MapMyCells enables efficient mapping of hundreds of thousands of cells on standard workstations without specialized hardware, providing a deterministic, scalable, and modality-agnostic approach that is robust across species and molecular assays. The framework produces interpretable confidence metrics and quantitative summaries of mapping performance, allowing users to evaluate assignment precision and accuracy. We demonstrate the mapping of unlabeled transcriptomic, epigenomic, and spatial datasets to reference taxonomies and describe a general workflow for preparing arbitrary hierarchical taxonomies for reference-based mapping. As the ecosystem of single-cell reference atlases expands, MapMyCells offers a practical and reproducible solution for community-scale cell-type annotation and cross-dataset integration, supporting the development of unified and extensible brain cell atlases.},
}

@article {pmid41959011,
year = {2026},
author = {Mallick, A and Du, Y and Haynes, C},
title = {Impaired Endosomal Recycling of Signaling Receptors Activates an Extracellular UPR.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.12.711310},
pmid = {41959011},
issn = {2692-8205},
abstract = {Mitochondrial dysfunction and extracellular protein aggregation occur in neurodegenerative diseases such as Alzheimer's disease (AD). However, it remains unclear if these processes are functionally linked. Here, we identify a signaling pathway that is activated upon accumulation of aggregation-prone proteins in the extracellular space. We find that the transcription factor ATFS-1, which regulates the mitochondrial unfolded protein response, also regulates transcripts required for endosomal recycling, multiple plasma membrane-localized signaling receptors, and secreted proteins that bind aggregation-prone proteins in the extracellular space, including transthyretin and Aβ, and promote their degradation. Interestingly, Aβ(1-42) aggregation induces atfs-1 -dependent transcription by promoting degradation of the bZIP protein ZIP-3, which antagonizes ATFS-1. ZIP-3 accumulates in the cytosol when it is phosphorylated by kinases that function downstream of plasma membrane-localized signaling receptors, including the WNT and glutamate receptors. Upon ligand binding, the signaling receptors stimulate the cognate kinase, many of which we found phosphorylate ZIP-3, impeding ZIP-3 degradation, allowing it to antagonize atfs-1 -dependent transcription. However, accumulation of aggregation-prone proteins such as Aβ(1-42) causes endosomal swelling, which impairs endosomal recycling, instead diverting signaling receptors to lysosomes for degradation. In turn, the depletion of signaling receptors reduces the level of ZIP-3 phosphorylation, resulting in ZIP-3 degradation and activation of atfs-1 -dependent transcription, which promotes extracellular proteostasis. Our findings uncover an unexpected coupling between endocytic quality control and mitochondrial signaling, revealing a circuit that preserves extracellular proteostasis and promotes organismal resilience.},
}

@article {pmid41959017,
year = {2026},
author = {Levine, CM and Caggiano, C and Anderson, T and Kelberman, MA and Weinshenker, D and Lail, HL and Wanders, D and Bangasser, DA and Kanoski, SE and Parent, MB},
title = {Hypothalamus amyloid levels are associated with early sex-dependent alterations in energy homeostasis in TgF344-AD rats.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.08.710398},
pmid = {41959017},
issn = {2692-8205},
abstract = {We reported previously that diet-induced obesity exacerbates early-stage Alzheimer's disease (AD)-like pathology in TgF344-AD rats. Our findings also suggested that TgF344-AD rats may be prone to weight gain during early AD development, which we assessed here. Energy intake, body composition, and the impact of glucose administration on blood glucose were also assessed. Body temperature, intrascapular brown adipose tissue (iBAT) mass, and iBAT uncoupling protein-1 (UCP1) expression were used as indicators of thermogenic function. Soluble amyloid β 40 (Aβ 40) and Aβ 42 were quantified in hypothalamus. Male TgF344-AD rats began to outweigh wildtype (WT) littermates by 5 weeks of age; this increase emerged later in female TgF344-AD rats (~5 months). Female TgF344-AD rats ingested more energy from chow and a high fat, high sugar (HFHS) diet, gained more weight on the HFHS diet, and had lower UCP1 than WT rats, effects not observed in male TgF344-AD rats. Surprisingly, male and female TgF344-AD rats had increased body temperatures. This was restricted to the dark phase in females, which is when they ingest excess calories. Finally, the HFHS diet disrupted glucose regulation in male but not female TgF344-AD rats. These findings suggest that increases in energy intake and decreases in UCP1 may contribute to the additional weight gain in female TgF344-AD rats. The causes for these increases in males remain unclear. Hypothalamic Aβ 42 correlated with glucose dysregulation in male TgF344-AD rats and BAT mass in female TgF344-AD rats, raising the possibility that increases in Aβ 42 in hypothalamus produce sex-specific disruptions in energy homeostasis.},
}

@article {pmid41959086,
year = {2026},
author = {Pereira, FL and Lew, C and Li, SH and Rizzi, L and Soloviev, AV and Paes, V and Brooks, SD and Spina, S and Rexach, JE and Newell, KL and Leite, REP and Seeley, WW and Suemoto, CK and Ghetti, B and Murray, ME and Grinberg, LT},
title = {Single-nucleus transcriptomics identifies a shared vulnerable excitatory neuronal population across typical and atypical Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.30.715299},
pmid = {41959086},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) presents with substantial clinical and anatomical heterogeneity, including both typical amnestic and atypical variants such as posterior cortical atrophy and logopenic primary progressive aphasia. Although neurofibrillary tangle (NFT) burden is a defining pathological feature of AD, its regional distribution varies across clinical phenotypes, suggesting that selective neuronal vulnerability may shape disease presentation. However, the cellular and molecular determinants underlying this vulnerability remain incompletely understood. Here, we profiled single-nucleus transcriptomes across multiple brain regions, including hippocampal (CA1) and neocortical (superior temporal gyrus and occipital cortex) regions, from individuals with typical and atypical AD and healthy controls. Integrative analysis identified major cell classes and resolved diverse excitatory and inhibitory neuronal subpopulations that were reproducibly observed across regions and individuals. Using quasi-binomial regression models to assess compositional changes, we quantified subtype-specific vulnerability associated with AD pathology. We identified a distinct excitatory neuronal subpopulation characterized by NRGN and BEX1 expression, which showed reproducible depletion across multiple regions, with the strongest evidence in amnestic AD and in neocortical regions in lvPPA. This vulnerable population showed concordance with previously reported AD-associated excitatory neuron signatures, supporting a conserved transcriptional program of susceptibility. Genes enriched in this population were associated with chemical synaptic transmission and regulation of synaptic plasticity and formed interconnected networks in protein-protein interaction analyses. These findings suggest that intrinsic properties related to synaptic function may predispose specific neuronal populations to degeneration in AD. Together, our results define a conserved, transcriptionally distinct excitatory neuron subpopulation that is selectively vulnerable across AD phenotypes and brain regions. This work provides a framework for linking regional pathology to cell-type-specific susceptibility and highlights synaptic regulatory pathways as potential contributors to neuronal degeneration in Alzheimer's disease.},
}

@article {pmid41959105,
year = {2026},
author = {Burberry, A and Benchek, P and Lowe, M and Shin, W and McCourt, B and Beamon, Q and Chakrabarti, S and Ramaiah, S and Woidke, E and Khrestian, M and Maecker, H and Bekris, LM and Rao, S and Ontaneda, D and Leverenz, JB and Bush, W and Pillai, JA},
title = {Early peripheral immune signaling precedes tau elevation and blood-brain barrier disruption in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.02.716122},
pmid = {41959105},
issn = {2692-8205},
abstract = {Neuroinflammation, along with amyloid beta (Aβ) deposition, phospho-tau (ptau) accumulation, blood-brain barrier (BBB) disruption, and cognitive decline are recognized components of Alzheimer's disease (AD). However, the timing and nature of peripheral immune changes across AD biological and clinical stages remain poorly understood. Here we performed mass cytometry profiling of whole blood and cerebrospinal fluid (CSF) immune cells from 351 human samples across two independent clinical cohorts spanning the AD continuum. We identify coordinated peripheral immune signaling signatures that emerge during preclinical stage of AD and precede significant elevation of plasma ptau217, CSF ptau181 and BBB disruption measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). AD-enriched immune features, including increased phospho-Akt signaling in naï ve T killer cells and phospho-PLCγ2 signaling in granulocytes, were not observed in patients with Frontotemporal lobar degeneration or treatment-naï ve multiple sclerosis. Furthermore, these immune signaling states could be induced in healthy donor immune cells following exposure to plasma or CSF from individuals with AD, indicating that circulating factors can drive these peripheral immune alterations. Together, our findings demonstrate that dynamic peripheral immune state changes arise early in AD and precede canonical biomarker and vascular changes, highlighting immune signaling pathways as potential targets for early therapeutic intervention.},
}

@article {pmid41959110,
year = {2026},
author = {Murtha, K and Chongtham, A and Song, WM and Ilkov, M and Wang, M and Chen, CQ and Sanctis, C and Datta, R and Purohit, D and Lee, EB and Zhang, B and Pereira, AC},
title = {Single-Nuclei Transcriptomic Characterization of APOE4 -Associated Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.03.715591},
pmid = {41959110},
issn = {2692-8205},
abstract = {Apolipoprotein E (APOE) genotype contributes significantly to Alzheimer's disease (AD) risk and pathogenesis. Cell-type specific effects of APOE alleles have been studied. However, due to the variable prevalence of APOE genotypes within human populations, characterization of cell-type specific transcriptomes across APOE genotypes has been challenging. Here, we integrated previous and newly generated single-nuclei sequencing (snRNA-seq) data in the prefrontal cortex (PFC) from individuals across APOE genotypes (2/2 , 2/3 , 3/3 , 3/4 , 4/4). Clustering analysis revealed distinct excitatory and microglial subpopulations that were uniquely enriched or depleted for APOE4/4 AD. Notably, an excitatory neuronal cluster exhibited neurofibrillary tangle (NFT) signatures and was selectively depleted in APOE4/4 AD cases. In addition, several microglial subpopulations were influenced by both APOE4 dosage and disease status. Among these, the putative AD risk gene FRMD4A emerged as APOE4 dose and AD-dependent. These findings were validated by RNAscope in an extended cohort. Together, our findings provide insights into how APOE4 reshapes cellular states and contributes to cell-type-specific vulnerability in AD.},
}

@article {pmid41959118,
year = {2026},
author = {Waghmare, SG and Krishna, MM and Maccoux, EC and Franitza, AL and Link, BA and E, L},
title = {Functional Analysis of Late-Onset Alzheimer's Disease Risk Genes in Caenorhabditis elegans Identifies Regulators of Neuronal Aging.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.26.714531},
pmid = {41959118},
issn = {2692-8205},
abstract = {BACKGROUND: Genome-wide studies in late-onset Alzheimer's disease (LOAD) have uncovered many risk loci, yet identifying the causal genes and clarifying how these genetic signals connect to molecular and cellular mechanisms relevant to AD pathogenesis in vivo remains challenging.

METHODS: Using Caenorhabditis elegans as a model to identify LOAD-associated genes that drive neurodegenerative processes, we focused on 14 understudied genes and their homologs: ABI3/abi-1 , B4GALT3/bre-4 , CCDC6/T09B9.4 , CLPTM1 (two homologs C36B7.6 and R166.2), CNN2/cpn-2 , DMWD/wdr-20 , ECHDC3/ech-2 , MADD/aex-3 , NCK2/nck-1 , RABEP1/rabn-5 , RIN3/rin-1 , SLC39A13/zipt-13 , TRAM1/tram-1 , and USP6NL/tbc-17 . We knocked down these genes by RNAi and quantified lifespan, aging-associated degeneration of two neuron classes, PVD and PLM, and associative learning and short-term memory.

RESULTS: Lifespan was unaffected by most knockdowns, and only nck-1 and tbc-17 shortened lifespan. Across neuronal assays, multiple homologs modulated aging with clear neuron-class selectivity. Knockdown of aex-3 , C36B7.6 , cpn-2 , ech-2 , rabn-5 , rin-1 , T09B9.4 , and zipt-13 attenuated late-life PVD degeneration, whereas R166.2 and tram-1 accelerated early PVD aging. Only two genes affected PLM aging: R166.2 knockdown exacerbated degeneration, while tbc-17 knockdown attenuated it despite its lifespan-shortening effect. In PLM neurons, tbc-17 knockdown, targeting a Rab GTPase-activating protein, also preserved mitochondrial architecture during early aging and shifted heat stress-induced mitochondrial remodeling toward a pattern consistent with improved quality control. In behavioral assays, ech-2 knockdown, targeting an enoyl-CoA-hydratase, enhanced short-term memory during early stages of aging. To further assess how LOAD-linked genes interact with Aβ-driven neurodegeneration, we developed a model that combines the PVD aging assay with a background expressing human Aβ 1-42 panneuronally. In this model, Aβ expression accelerated age-dependent PVD degeneration, whereas ech-2 knockdown abolished this Aβ-induced effect.

CONCLUSIONS: Our findings show that conserved homologs of several understudied LOAD risk genes causally modulate neuronal aging in vivo in a neuron-class-selective manner, often dissociable from organismal longevity. This C. elegans framework translates human genetic associations into quantitative, aging-linked neuronal phenotypes, and our results further emphasize early endosomal and lipid-related processes as key pathways that warrant functional testing in neuronal aging. This study also provides a tractable platform to prioritize targets for cross-species validation and to test synergy with established LOAD risk genes.},
}

@article {pmid41959128,
year = {2026},
author = {Hughes, JB and Sandholm, A and Croll, D and Senchyna, F and Schneider, K and Butterfield, R and McHugh, TLM and Brown, I and Deguchi, H and Hilsabeck, TAU and Mak, S and Wilson, KA and Davtyan, H and Blurton-Jones, M and Herdy, J and Higuchi-Sanabria, R and Gage, FH and Furman, D and Ellerby, LM and Desprez, PY and Campisi, J},
title = {DNA damage drives a unique, Alzheimer's disease-relevant senescent state in neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.02.716205},
pmid = {41959128},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) shares molecular hallmarks with the canonical drivers of cellular senescence. Senescent cells have also been shown to accumulate in the brain with age, yet the mechanisms linking AD pathology to the accumulation of senescent cells in the brain remain unclear. Here, we demonstrate that DNA damage in patient-derived directly induced neurons (iNs) drives a senescent-like cell state with relevance to AD. DNA damage-induced senescent iNs show significant transcriptional concordance with human AD neurons and a weighted gene co-expression network analysis (WGCNA) uncovers candidate regulators associated with the senescent-like state in neurons. Direct comparison of iNs to the original patient fibroblasts reveals striking cell-type specific senescence signatures following DNA damage. iNs adopt a p21-associated senescent-like state characterized by a senescence-associated secretory phenotype (SASP) and predicted activation of NF-κꞴ1. In contrast, fibroblasts develop a p16-associated senescent state lacking a SASP phenotype and show a predicted repression of NF-κꞴ1. Early responses to DNA damage further reveal divergent DNA damage response (DDR), with neurons exhibiting higher accumulation of damage lesions relative to fibroblasts. Together, these findings demonstrate that DNA damage drives a unique senescent-like neuronal state that models molecular features of AD, while also revealing fundamental cell-type specific differences in senescent-like phenotypes and DDR.},
}

@article {pmid41959177,
year = {2026},
author = {Travi, F and Mehta, A and Castro, E and Li, H and Reinen, J and Dhurandhar, A and Meyer, P and Slezak, DF and Cecchi, GA and Polosecki, P},
title = {Alzheimer's Disease Brain Phenotypes are Age-dependent.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.31.715296},
pmid = {41959177},
issn = {2692-8205},
abstract = {A widespread view of neurodegenerative disorders, including Alzheimer's Disease (AD), frames their effects as accelerated aging, with the brain-age gap (BAG, the deviation of predicted 'brain age' from chronological age) as a staple biomarker. However, BAG relies on a fundamental, untested assumption: that AD can be identified via age-invariant brain phenotypes. Using invariant representation learning on brain MRI from 44,178 individuals, we created neural representations that optimally convey age information (age-aware) or conversely remove it (age-invariant) while minimizing reconstruction distortion. We provide the first causal evidence that age information is necessary in brain biomarkers for AD detection: age-aware representations achieve competitive state-of-the-art performance and significantly outperform age-invariant ones (0.84 vs. 0.77 AUC, p < 0.001, with external validation). This necessity reveals a conceptual flaw in BAG: by subtracting chronological age, it discards the very information essential for accurate detection. Using conditional decoders to simulate aging trajectories, we found that healthy aging and AD operate along multiple independent anatomical dimensions (deep gray matter, frontoparietal, temporal). AD patients diverge from rather than accelerate healthy aging, showing pathological temporal shifts alongside, remarkably, relative frontoparietal preservation. Furthermore, representational similarity analysis suggests that even models pretrained on non-age tasks (e.g., sex or BMI) implicitly converge toward age-related features when optimized for AD. Given that the AD phenotype cannot be decoupled from age, our results establish a hard limit for age-independent biomarkers and favor multidimensional models that preserve aging structure over unidimensional summaries like BAG.},
}

@article {pmid41959199,
year = {2026},
author = {Lin, L and Chuang, KH and Dai, C},
title = {c-MYC is an aggregation-prone, amyloidogenic protein.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.12.711438},
pmid = {41959199},
issn = {2692-8205},
abstract = {As a master transcription factor, c-MYC governs a plethora of biological processes. Despite being a prominent oncoprotein, counterintuitively, c-MYC also possesses an intrinsic tumor suppressor activity through induction of apoptosis, a phenomenon known as "the paradox of c-MYC". Serendipitously, we discover that c-MYC is aggregation-prone, becoming detergent-insoluble upon heat shock. Even in the absence of heat shock, c-MYC assembles into soluble oligomers exhibiting characteristics of amyloids in both human cancer tissues and, surprisingly, human Alzheimer's disease brains. In vitro , recombinant c-MYC proteins form amyloid oligomers as well as protofibrils spontaneously. By contrast, its obligate dimerization partner MAX is non-amyloidogenic and, moreover, antagonizes the amyloidogenesis of c-MYC. Screening of the c-MYC synthetic peptide library identifies two intrinsically disordered short linear fragments, which are amyloidogenic in vitro . This amyloidogenesis of c-MYC, importantly, induces apoptosis largely independently of transcription. Thus, our findings unveil a previously unrecognized amyloidogenicity of c-MYC, which may contribute to its tumor-suppressing activity. Upon loss of the stringent control of its expression, conceptually, this amyloidogenesis of c-MYC may serve as a built-in failsafe mechanism to self-destruct its troublesome oncogenic potential.},
}

@article {pmid41959262,
year = {2026},
author = {Uhl, GR and Kannan, B and Hess, E and Henderson, and Schultz, K},
title = {Quercetin and 6-Br-quercetin: antioxidant properties and off target screening results advance glycosylated 6BrQ as developmental candidates for Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.10.710855},
pmid = {41959262},
issn = {2692-8205},
abstract = {Quercetin is an abundant dietary flavonol with interesting in vitro properties that include substrate-selective positive allosteric modulation (PAM) of the activity of the receptor type protein tyrosine phosphatase D (PTPRD) and substantial antioxidant actions. Its in vivo activities include reducing incidence of Alzheimer's disease (AD) and reducing AD neurofibrillary pathology in mouse models. Structure-activity studies have identified quercetin analogs with improved in vitro and in vivo properties, including the improved PTPRD PAM 6-bromoquercetin (6BrQ). However, there is no comparison of the antioxidant properties of 6BrQ to those of quercetin. There is no systematic screening for activities of quercetin or of 6BrQ using a panel of targets for most currently-used drugs. We now report that both quercetin and 6BrQ provide equivalent results in cyclic voltammetric and biochemical antioxidant assays. We also report that neither 10 [-7] M quercetin nor 6BrQ provides any significant (>50%) effects on any of the 104 assays in a Eurofins off-target screening panel. At 10 [-5] M, both quercetin and 6BrQ exert significant effects in assays for glycogen synthase kinase 3 (GSK3β) as well as those for serotonin 5HT2B receptor, adenosine transport, adenosine A2A receptors, cyclooxygenases COX1 and COX2, phosphodiesterases PDE3A and 4D2 and PPAR gamma. These data extend prior characterization of quercetin's biochemical effects, provide novel results for 6BrQ and support the likelihood that both quercetin and 6BrQ can a) directly inhibit GSK3, b) reduce GSK3 activities via enhancement of its dephosphorylation by PTPRD and c) display modest numbers of off target activities at high concentrations, several of which could conceivably contribute to anti-AD activities. These results advance bioavailable glycosylated prodrugs that can be metabolized to 6BrQ as developmental candidates for AD.},
}

@article {pmid41959283,
year = {2026},
author = {Jones, A and Loeffler, T and Wu, E and Varma, VR and Im, HK and Thambisetty, M},
title = {Network pharmacology-based discovery and experimental validation of novel drug repurposing candidates in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.05.709917},
pmid = {41959283},
issn = {2692-8205},
abstract = {Despite a growing body of evidence implicating genetic variants and proteins encoded by them with risk and pathogenesis of Alzheimer's disease (AD), this knowledge has not been successfully translated into effective AD treatments. We integrated current genomic, transcriptomic and proteomic profiles of AD into a network pharmacology framework that leverages comprehensive gene-gene and drug-target interactions. This approach allowed us to screen 2,413 drugs for repurposing opportunities in AD. Computational validation and drug prioritization was followed by experimental validation in 33 cell culture-based phenotypic assays combined with Bayesian hypothesis testing. Our network-based screen rediscovered drugs in clinical trials for AD, providing computational validation. Besides many cancer drugs, the screen identified three drugs previously implicated in AD-related endophenotypes: the primary bile acid chenodiol, arundine (3,3'-diindolylmethane), and cysteamine. In analysis of results from culture-based phenotypic assays, large Bayes factors supported the hypothesized benefits of arundine and the chenodiol derivative, tauroursodeoxycholic acid (TUDCA), in amyloid- β clearance and release and neuroinflammation. Follow-up network analyses mechanistically implicated Regulator of G protein signaling 4 (RGS4) in the plausible therapeutic actions of arundine and TUDCA. A network pharmacology approach identified TUDCA and arundine as promising repurposing candidates in AD that rescue disease-relevant molecular phenotypes by acting on AD-associated genes through regulation of G protein signaling.},
}

@article {pmid41959306,
year = {2026},
author = {Wang, T and Shang, Y and McLean, JW and Yin, F and Brinton, RD},
title = {APOE4 Accelerates Menopause-Associated Brain Metabolic Shift and Disrupts Bioenergetic Adaptation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.11.710133},
pmid = {41959306},
issn = {2692-8205},
abstract = {INTRODUCTION: Disruption of brain glucose and lipid metabolism contributes to Alzheimer's disease (AD) and often emerges before clinical symptoms. Women are at elevated AD risk due to menopause-associated estrogen decline, which impairs mitochondrial function and glucose metabolism. Women's risk of AD is further elevated by the APOE4 allele, the strongest genetic risk factor for late-onset AD.

METHODS: To investigate the impact of APOE genotype on the menopausal metabolic transition, brain metabolomic and lipidomic profiling was conducted in humanized female APOE3/3, APOE3/4, and APOE4/4 mice across chronological and endocrinological stages of peri-to postmenopausal transition.

RESULTS: APOE3/3 mice exhibited dynamic regulation of brain metabolic systems that supported postmenopausal bioenergetic demand. In contrast, APOE3/4 and APOE4/4 mice displayed accelerated and altered metabolic shifts, resulting in postmenopausal amino acid depletion, reduced tricarboxylic acid (TCA) cycle intermediates, lipid accumulation, and alterations in brain lipid composition. A single APOE4 allele was sufficient to impair metabolic adaptation, while APOE4 homozygosity resulted in greater severity of deficits.

DISCUSSION: Outcomes of these analyses revealed that APOE4 accelerated menopause-related metabolic decline and compromised bioenergetic adaptation, providing a mechanistic basis for increased AD susceptibility and earlier onset in APOE4-positive women.},
}

@article {pmid41959309,
year = {2026},
author = {Komlo, R and Sengupta, K and Strus, E and Naidoo, N},
title = {Chronic short sleep in early life accelerates cognitive decline via disrupted proteostasis.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.26.714554},
pmid = {41959309},
issn = {2692-8205},
abstract = {Chronic short sleep (CSS) is an emerging public health issue that frequently begins in adolescence and is common among healthcare professionals and others engaged in shift work. Epidemiological studies associate CSS and sleep disruption with metabolic disorders, cardiovascular disease, cognitive decline, and heightened Alzheimer's disease risk. Building on our prior findings that sleep deprivation perturbs proteostasis and activates endoplasmic reticulum (ER) stress pathways, we investigated the long-term consequences of CSS in young adult wild-type mice over the course of one year. Mice exposed to CSS displayed impaired cognition in hippocampal dependent tasks by 28 weeks of age, indicating emerging memory deficits. At the molecular level, CSS disrupted hippocampal proteostasis-particularly protein folding processes-and triggered ER stress and activation of the unfolded protein response (UPR). Importantly, disrupted proteostasis preceded the behavioral decline, with diminution of the key chaperone and UPR regulator BiP occurring at 20-22 weeks of age. CSS also increased markers of cellular stress and neuroinflammation while reducing the expression of proteins associated with memory function. Age also seemed to be a cellular stressor, causing a longitudinal increase in UPR, ISR, and neuroinflammation markers. Together, these results indicate that both chronic short sleep and age compromise proteostasis and promote neuroinflammation, contributing to progressive cognitive dysfunction.},
}

@article {pmid41959421,
year = {2026},
author = {Zanderigo, E and Fatima, M and Becker, S and O'Neil, A},
title = {Alzheimer's Disease Brain Organoids as a Source of Disease-Relevant Amyloid-Beta Oligomers.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.09.710594},
pmid = {41959421},
issn = {2692-8205},
abstract = {Amyloid plaques are a hallmark of Alzheimer's disease (AD) progression; however, the early stages of plaque formation and the specific amyloid-beta (Aβ) species involved remain difficult to study. While post-mortem tissue provides insight into end-stage mature plaques, therapeutic development requires targeting the earliest Aβ oligomers to arrest plaque formation. Furthermore, inherently toxic soluble Aβ oligomers off-pathway from plaque formation are implicated as a driving force of AD pathology. It also remains unclear if the specific nature of key disease-relevant species can be accurately replicated in preparations of synthetic peptides.. To bridge this gap, we utilize brain organoids carrying AD mutations as a biologically authentic source for Aβ peptides and oligomers. We demonstrate that these mutations do not disrupt organoid development and that the resulting conditioned media contains Aβ oligomers with disease-relevant structures. Finally, we show that these oligomers can be concentrated and segregated via differential ultracentrifugation for further experimental applications.},
}

@article {pmid41959428,
year = {2026},
author = {Anderton, E and Burton, JB and King, CD and Foulger, AC and Bhaumik, D and Timonina, D and Mayeri, Z and Chamoli, M and Andersen, JK and Schilling, B and Lithgow, GJ},
title = {Shifts in protein aggregate stability define proteostasis decline in the aging human brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.27.714902},
pmid = {41959428},
issn = {2692-8205},
abstract = {Loss of proteostasis and the accumulation of insoluble protein aggregates are features of aging across model organisms and occur in all major age-related neurodegenerative diseases; yet how aggregation proceeds during normal human brain aging remains unknown. Here, using detergent-fractionation proteomics, we show that brain aging does not involve uniform aggregate accumulation; rather, the insoluble proteome undergoes asymmetric remodeling beginning in midlife, with maximum-stability aggregates declining sharply by old age and intermediate-stability aggregates accumulating progressively before accelerating after age 80. Intermediate-stability aggregates are prone to liquid-liquid phase separation and are enriched among Alzheimer's disease plaque and tangle constituents. Proteasome and cytosolic chaperone capacity predict individual differences in aggregate burden as strongly as chronological age, offering human-level evidence in support of therapies targeting these pathways. These findings establish aggregate remodeling as a feature of normal brain aging and position intermediate-stability aggregate accumulation as a molecular event on the path to neurodegenerative disease.},
}

@article {pmid41959502,
year = {2026},
author = {Hauser, RM and Limbo, HL and Brazell, JN and Moyers, BA and Lauzon, SN and Barinaga, EA and Johnston, SQ and Rogers, BB and Taylor, JW and Cochran, JN},
title = {Promoter mutagenesis and a massively parallel reporter screen of the MAPT locus identifies cis-regulatory elements and genetic variation effects.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.06.710116},
pmid = {41959502},
issn = {2692-8205},
abstract = {Tau neurofibrillary tangles are a hallmark of several neurodegenerative diseases called tauopathies, including frontotemporal dementia and Alzheimer's Disease. Ongoing clinical trials for tauopathies seek to reduce Tau in the brain through immunotherapy, antisense oligonucleotides, and siRNA. MAPT codes for Tau, therefore understanding how the MAPT gene is regulated and the effect of genetic variation at its regulatory elements is likely to have high relevance for tauopathies. We screened a ∼3 Mb region including the MAPT locus using 2 different massively parallel reporter assay (MPRA) strategies in KOLF2.1J h-NGN2 neurons and HEK293FT cells, identifying previously unannotated cis-regulatory elements (CREs). Using CRISPR interference (CRISPRi) in mixed neuron cultures, we identified a new CRE for MAPT , as well as 2 CREs for another nearby gene of interest, KANSL1 . Known genetic variation from the Alzheimer's Disease sequencing project was tested in a separate MPRA at the top CREs near the MAPT gene, identifying variants with altered regulatory effects including those at previously identified CREs for MAPT . Using a saturation mutagenesis screen of a 2,000 bp region encompassing the MAPT promoter, we assessed regulatory effects of each possible single nucleotide variant in this region. We identified several neuron-specific regulatory variant effects at this region, including a high confidence binding site for the transcription factors EGR2, ZBTB14, and TCLF5 at a region of high MPRA activity and genetic conservation.},
}

@article {pmid41959530,
year = {2026},
author = {Pandey, S and Talo, M and Siderovski, DP and Sumien, N and Bozdag, S},
title = {From General-Purpose to Disease-Specific Features: Aligning LLM Embeddings on a Disease-Specific Biomedical Knowledge Graph for Drug Repurposing.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.07.707871},
pmid = {41959530},
issn = {2692-8205},
abstract = {Identifying new therapeutic uses for existing drugs is a major challenge in biomedicine, especially for complex neurodegenerative conditions such as Alzheimer disease and related dementias (ADRD), where treatment options remain limited and relevant data are often sparse, heterogeneous, and difficult to integrate. Although general-purpose Large Language Model (LLM) embeddings encode rich semantic information, they often lack the task-specific biomedical context needed for inference tasks such as computational drug repurposing. We introduce Contextualizing LLM Embeddings via Attention-based gRaph learning (CLEAR), a multimodal representation-fusion framework that aligns LLM embeddings with the topological structure of a context-specific Knowledge Graph (KG). Across five benchmark datasets, CLEAR achieved state-of-the-art results, improving predictive performance (e.g., F1 score) by up to 30% over prior methods. We further applied CLEAR to identify FDA-approved drugs with potential for repurposing for ADRD, including Parkinson disease-related dementia and Lewy Body dementia. CLEAR learned a biologically coherent embedding space, prioritized leading ADRD drug candidates, and accurately summarized known therapeutic relationships for FDA-approved Alzheimer disease drugs. Overall, CLEAR shows that grounding biomedical LLM embeddings with context-specific KG signals can improve drug repurposing in data-sparse, real-world settings. GitHub: https://github.com/bozdaglab/CLEAR.},
}

@article {pmid41959564,
year = {2026},
author = {Simula, ER and Ercoli, T and Ruiu, E and Fais, M and Noli, M and Solla, P and Sechi, LA},
title = {Asparaginase-like protein 1 and human endogenous retroviruses link immune and gene dysregulation in dementia.},
journal = {Frontiers in cellular and infection microbiology},
volume = {16},
number = {},
pages = {1777560},
pmid = {41959564},
issn = {2235-2988},
mesh = {Humans ; *Endogenous Retroviruses/immunology ; *Dementia/immunology/virology/genetics ; Male ; Female ; Leukocytes, Mononuclear/immunology ; Aged ; Aged, 80 and over ; Middle Aged ; *Gene Expression Regulation ; Immunity, Humoral ; Enzyme-Linked Immunosorbent Assay ; Antibodies, Viral/blood ; },
abstract = {Dementia is increasingly recognized as a condition characterized not only by neurodegeneration but also by significant immune alterations, with potential consequences for both humoral immunity and peripheral gene regulation. However, the relationship between these processes when targeting neuronal and retroviral antigens remains poorly understood. This study investigated immune responses to asparaginase-like protein 1 and human endogenous retroviruses in different types of dementia. Plasma and peripheral blood mononuclear cells were collected from patients with dementia. Antibody reactivity against asparaginase-like protein 1 and human endogenous retroviruses was assayed by enzyme-linked immunosorbent assay, while peripheral gene expression was quantified by qPCR. Group comparisons and correlation analyses were performed. Patients exhibited increased antibody responses against asparaginase-like protein 1 and human endogenous retroviruses despite reduced peripheral expression of the corresponding genes. Within patients, antibodies against asparaginase-like protein 1 were inversely correlated with its transcript levels, whereas antibody responses to human endogenous retroviruses correlated positively with residual gene expression. Immune and transcriptional measures targeting these molecules were interrelated, indicating shared immune pathways. For the first time, this study identifies a coordinated relationship between humoral immune responses and peripheral gene expression in the dementia such as AD, MCI and mixed Dementia offering a novel context for interpreting immune dysregulation and suggesting potential immune-based biomarkers linked to neurodegenerative processes.},
}

Humans
*Endogenous Retroviruses/immunology
*Dementia/immunology/virology/genetics
Male
Female
Leukocytes, Mononuclear/immunology
Aged
Aged, 80 and over
Middle Aged
*Gene Expression Regulation
Immunity, Humoral
Enzyme-Linked Immunosorbent Assay
Antibodies, Viral/blood

@article {pmid41959610,
year = {2026},
author = {Pereira, LEC and Castro, FN and de Almondes, KM},
title = {The clock drawing test as a screening tool for detecting cognitive decline: an analysis in adults and elderly people from Natal (RN).},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1768390},
pmid = {41959610},
issn = {1662-5161},
abstract = {INTRODUCTION: The Clock Drawing Test (CDT) is widely used as a screening instrument for cognitive decline due to its simplicity and rapid administration. Despite its widespread clinical use, evidence regarding its diagnostic performance in the Brazilian Northeast region remains scarce.

METHODS: This study examined CDT performance in a clinical sample of 113 adults and older adults assessed at a neuropsychology service in Northeastern Brazil, focusing on CDT ability to identify cognitive decline and the effects of age, educational level, and clinical diagnoses. The study tested the following hypotheses: (1) there is a significant association between age and CDT scores; (2) there are significant differences in CDT scores across different educational levels; (3) there are significant differences in CDT scores across different clinical conditions, indicating potential for differential diagnosis; and (4) the test would demonstrate high sensitivity, specificity, and accuracy in the overall sample, as well as high sensitivity in detecting each diagnostic condition. Using Shulman's scoring method, descriptive analyses, Spearman's correlation, Kruskal-Wallis tests and metrics of sensitivity, specificity, and accuracy were conducted.

RESULTS: The sample had a mean age of 65.19 years and was predominantly characterized by low educational attainment. A negative, albeit weak, correlation was observed between age and CDT scores, as well as significant differences across educational levels. Diagnostic group comparisons also revealed significant differences, most notably between cognitively unimpaired individuals and patients diagnosed with Major Neurocognitive Disorder due to Alzheimer's disease. Although the CDT demonstrated adequate specificity, its overall sensitivity and accuracy were low. Sensitivity was high for Major Neurocognitive Disorder Due to Alzheimer's Disease, moderate for Major Neurocognitive Disorder due to Non-Alzheimer's Disease (Major Vascular Neurocognitive Disorder, Parkinson's Disease, Mixed Dementia, Wernicke-Korsakoff syndrome and Major Frontotemporal Neurocognitive Disorder) and low for Mild Neurocognitive Disorder.

DISCUSSION: These findings demonstrate that Shulman's method of CDT is not suitable for assessing cognitive decline in the illiterate and low-education population and raise important concerns regarding its standalone clinical utility, especially in specific neurological conditions. The present study underscores the need for future research employing alternative scoring methods and more representative samples to refine the applicability and diagnostic value of the CDT in clinical practice.},
}

@article {pmid41959735,
year = {2026},
author = {Zhang, X and Zhang, Z},
title = {Receptor-mediated endocytosis by Megalin: Exploring its role in ligand interaction and disease mechanisms.},
journal = {Genes & diseases},
volume = {13},
number = {4},
pages = {101891},
pmid = {41959735},
issn = {2352-3042},
abstract = {This review comprehensively summarizes the interaction mechanisms between Megalin and several key ligands, including calcium ions, gentamicin, ApoE, ANKRA2, FVIII, TTR, STC1, RAP, and MMP-9, focusing on the specific amino acid binding sites involved. The analysis highlights the structural basis of these interactions and their clinical relevance, particularly concerning diseases such as nephrotoxicity, Alzheimer's disease, metabolic disorders, and renal pathologies. This review comprehensively summarizes the specific binding sites of Megalin with its ligands and explores the mechanisms, including protein reabsorption, blood coagulation, and neuroprotection, by integrating the results of animal studies and human clinical studies. This review proposes a theoretical framework for designing therapeutic strategies that target the binding sites of Megalin with its ligands. Gene editing technology and monoclonal antibody therapy aim to regulate Megalin receptor-ligand interactions to achieve therapeutic effects on related diseases.},
}

@article {pmid41959743,
year = {2026},
author = {Guo, Y and Jiang, Q and Gu, Z and Cao, H and Zuo, C and Huang, Y and Song, Y and Chen, X and Wang, F},
title = {ACSL4 in Alzheimer's disease: Pathogenetic mechanisms and potential therapeutic targets.},
journal = {Genes & diseases},
volume = {13},
number = {4},
pages = {101858},
pmid = {41959743},
issn = {2352-3042},
abstract = {Iron metabolism plays a vital role in maintaining physiological homeostasis, and its dysregulation is implicated in a range of pathological consequences and illnesses, including Alzheimer's disease (AD). Prior studies have demonstrated that Tau protein and amyloid precursor protein are involved in iron homeostasis disorder. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a key contributor to AD pathogenesis and a promising therapeutic target. Acyl-CoA synthetase long-chain family 4 (ACSL4) is a lipid metabolizing enzyme that enhances ferroptosis sensitivity by promoting the incorporation of oxidizable polyunsaturated fatty acids into membrane phospholipids. Beyond ferroptosis, ACSL4 also plays crucial roles in neuroinflammation and oxidative stress, which are implicated in AD progression. Therefore, targeting ACSL4 is fantastic and has a lot of promise for treating AD. Nevertheless, the precise mechanisms through which ACSL4 contributes to AD pathology have yet to be fully elucidated. This review reveals a potentially vital role of ACSL4 in AD, focusing on its involvement in ferroptosis, oxidative stress, and neuroinflammation. Additionally, we describe some natural and synthetic compounds targeting ACSL4 with therapeutic potential in AD. Building on the theoretical findings of earlier studies about focused interventions of the ACSL4 path, our evaluation provided a broad basis for the clinical transformation in the treatment of AD strategies.},
}

@article {pmid41959752,
year = {2026},
author = {Earnest, TW and Yang, BY and Chowdhury, A and Ha, SM and Bani, A and Kim, SJ and Nazeri, A and Morris, JC and Benzinger, TLS and Gordon, BA and , and , and Sotiras, A},
title = {A unified model for staging amyloid and tau pathology in Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.30.26349752},
pmid = {41959752},
abstract = {UNLABELLED: Biological staging models are a key tool for assessing the severity of Alzheimer's disease (AD), supporting personalized medicine and playing a critical role in clinical trial design. Recently, researchers have leveraged positron emission tomography (PET) to inform data-driven staging models of brain pathology related to AD. However, most approaches have focused on staging either amyloid or tau progressions separately, while both pathologies constitute defining factors of AD. Here, we aimed to derive a data-driven staging model which encompasses the spatial spread of both amyloid and tau. We assembled a large sample (n=3,293) of individuals with both amyloid and tau PET imaging stemming from 8 neuroimaging studies of AD and aging. We applied unsupervised machine learning to estimate brain areas which showed coordinated pathological accumulation across our sample, and we used these regions to inform a data-driven model for staging amyloid and tau. The resulting six stage model showed two stages of amyloid progression followed by four stages of tau spread, which were associated with cross-sectional and longitudinal assessments of cognitive decline. Comparison of our biological staging model with clinical disease stages recommended by the Alzheimer's Association showed evidence of heterogenous symptom profiles. Replication of results in holdout data demonstrated the generalizability and prognostic value of our staging model. Together, these findings establish a comprehensive and rigorously validated biological staging model that jointly characterizes amyloid and tau progression, advances beyond global or anatomically predefined summaries, and provides a scalable framework for studying disease heterogeneity and progression in AD.

ONE SENTENCE SUMMARY: Using PET imaging from a large sample of individuals (n=3,293), we derive a data-driven model for staging amyloid and tau pathology.},
}

@article {pmid41959753,
year = {2026},
author = {Hanseeuw, BJ and Quenon, L and Bayart, JL and Boyer, E and Colmant, L and Salman, Y and Gérard, T and Huyghe, L and Malotaux, V and Kienlen-Campard, P and Pirson, FB and Lhommel, R and Dricot, L and Ivanoiu, A and Shamsundar, K and Pak, W and Soldo, J and Iqbal, K},
title = {Tau pathological activity in plasma before the onset of symptomatic Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.03.26350110},
pmid = {41959753},
abstract = {Alzheimer's disease (AD) and other tauopathies are characterized by the hyperphosphorylation of tau (pTau), leading to its aggregation in the brain, a process strongly predictive of neurodegeneration and future cognitive decline. Currently, tau positron emission tomography (PET) is the only validated method for detecting tau aggregates in vivo. However, its high cost, invasiveness, and limited accessibility restrict its use in clinical settings and preclude large-scale screening. Moreover, existing plasma biomarkers that quantify the level of pTau at specific sites (e.g., pTau217) have limited specificity for confirming AD-related tau aggregation, partly due to the heterogeneous and irregular phosphorylation patterns of pTau. Besides, the concentration of pTau is frequently elevated in the context of isolated amyloid-β pathology, which is less strongly associated with cognitive decline in the absence of aggregated tau. There is therefore an urgent need for a reliable and scalable blood-based biomarker of tau pathology. A key mechanism underlying AD tau pathology is the ability of pathologically active pTau (PA pTau) to bind to and seed normal tau, facilitating prion-like propagation of insoluble tau aggregates. Here, we assessed the diagnostic performance of the VeraBIND Tau assay, the first functional assay to detect PA pTau seeding activity in plasma. Seventy-nine cognitively unimpaired (CU) and 66 cognitively impaired older adults underwent blood sampling, cognitive assessment, amyloid-PET or cerebrospinal fluid (CSF) analysis, and [ [18] F]-MK6240 tau-PET imaging. Plasma pTau217 concentrations were quantified using the Lumipulse platform (Fujirebio). The VeraBIND Tau assay isolated PA pTau from plasma and evaluated its ability to bind recombinant normal tau using a tagged-tau chemiluminescent readout. VeraBIND Tau demonstrated 94.2% sensitivity and 96.1% specificity for predicting tau-PET positivity (AUC=0.97). It outperformed plasma pTau217 in CU individuals (PPV=85.9%), regardless of the pTau217 threshold used (maximal PPV of 57.5% using the 0.256pg/mL pTau217 threshold). This higher VeraBIND Tau diagnostic accuracy was driven by early tau-PET stages (Braak-like tau-PET stages 1-3; AUC=0.96 vs. 0.74 for pTau217, p=0.003). Moreover, both cross-sectional values and annual changes in VeraBIND Tau were significantly correlated with cognitive performance and entorhinal tau-PET signal (all absolute Spearman r≥0.23, p<0.05). These findings highlight the strong potential of VeraBIND Tau as a scalable and accurate screening tool to detect AD tau pathology in the general population. The assay may also help enrich clinical trials with tau-PET positive CU individuals, enhance clinical diagnostic workflows and support monitoring of tau-targeted therapies. Future work should evaluate its utility in optimizing triage and early-intervention strategies.},
}

@article {pmid41959759,
year = {2026},
author = {Mora Pinzon, M and Pasqualini, R and Navarro, V and Del Carmen Rosales, M and Franzese, O and Perales-Puchalt, J},
title = {When Care Depends on the Caregiver: Lived Experiences of Latino Families Navigating Dementia Care Pathways.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.29.26349413},
pmid = {41959759},
abstract = {INTRODUCTION: Latino families shoulder a disproportionate share of dementia care in the United States, yet encounter multilayered barriers that shape access, timeliness, and quality. This study explores the experiences of Latino care partners, focusing on how system-level, cultural, and linguistic factors shape dementia care.

METHODS: We conducted a qualitative study using semi-structured interviews with care partners of Latino individuals living with Alzheimer's disease and related dementias (ADRD). Interviews were conducted by phone or videoconference by a bilingual interviewer, and the interviews were recorded and transcribed verbatim. Data was analyzed using reflexive thematic analysis.

RESULTS: Twenty-three participants were recruited. Two meta-themes captured participants' experiences. (1) Mismatch Between the Healthcare System and the Lived Realities of Latino Families Affected by Dementia, which included three subthemes: a) Linguistic barriers that referred to the quality and dialect fit (over-literal jargon, unfamiliar regional vocabulary, poor adaptation to literacy); b) Cultural misfit, were dementia-care programs were not culturally or linguistically appropriate, or programs where cultural norms were disregarded; and c) Structural and systemic barriers, such as communication failures (e.g. voicemail loops, no responsiveness) and long waits/fragmented pathways that broke clinical momentum (e.g. months to a year for specialty appointment). The second theme was: The Central Role of the Latino Caregiver in Navigating Dementia Care, where, in the absence of pathway ownership, care partners served as navigators, interpreters, coordinators, and safety monitors, while also bearing the emotional and financial strain.

DISCUSSION: The narratives from care partners reveal specific mechanisms (e.g., caregiver hyper-advocacy and "maze-like" coordination failures) that, if addressed, can guide intervention design and policy aimed at redistributing coordination back to the system and improving outcomes for Latino families.},
}

@article {pmid41959760,
year = {2026},
author = {Belder, CRS and Heslegrave, AJ and Swann, O and Abel, E and Beament, M and Nasir, M and Rice, H and Weston, PSJ and Ryan, NS and Palmer, LJ and Brodtmann, A and Kleinig, T and Zetterberg, H and Fox, NC},
title = {Presymptomatic plasma biomarkers in autosomal dominant Alzheimer's disease: sequence and timing.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.30.26349682},
pmid = {41959760},
abstract = {BACKGROUND: Autosomal dominant Alzheimer's disease (ADAD) serves as a model for presymptomatic biomarker discovery. Characterising the temporal profile of plasma biomarker levels in presymptomatic individuals may enhance understanding of disease pathogenesis, inform future clinical trials, and guide clinical interpretation.

METHODS: We evaluated 124 proteins using a NUcleic acid-Linked Immuno-Sandwich Assay (NULISA) panel in 270 plasma samples from a longitudinal cohort study of ADAD, comprising 113 individuals (73 mutation carriers and 40 non-carriers). We determined the plasma proteomic changes that distinguished mutation carriers from non-carriers. We then used predicted age at symptom onset to determine the approximate timing of presymptomatic divergence in biomarker levels in carriers relative to non-carriers.

RESULTS: Nine proteins (Aβ42, BACE1, GFAP, pTau181, pTau231, pTau217, MAPT, NfL, and AChE) robustly differed between carriers and non-carriers, cross-sectionally. Longitudinal analyses showed Aβ42 levels were elevated in carriers at least 26 years before expected symptom onset. Carriers diverged from non-carriers in phosphorylated tau markers at 21-24 years before expected symptoms, total-tau at 19 years, GFAP and BACE1 at 14 years, and NfL at 6 years. Differences in AChE were seen in symptomatic individuals, likely reflecting cholinesterase inhibitor use.

CONCLUSION: Multiple plasma proteins are elevated in presymptomatic and symptomatic autosomal dominant AD mutation carriers relative to non-carriers. Changes in eight biomarkers occur sequentially from 26 to 6 years prior to symptom onset. Combining biomarkers may help in staging presymptomatic AD and optimise clinical trial inclusion. Further work is needed to assess how these findings generalise to non-monogenic AD.

The molecular pathology of Alzheimer's disease develops many years before the onset of symptoms, and multiple plasma biomarkers of Alzheimer's pathology have been identified. Understanding the timing of biomarker abnormality is important to guide trial design for the timing of interventions to prevent the onset of dementia.

WHAT THIS STUDY ADDS: Using an autosomal dominant Alzheimer's disease cohort, we identify multiple plasma biomarkers that distinguish mutation carriers from non-carrier familial controls and characterise the timing of these changes relative to symptom onset. We demonstrate that biomarkers show change many years before symptom onset: markers of abnormal tau phosphorylation more than 20 years prior, followed by markers of reactive astrocytosis and synaptic dysfunction approximately 15 years prior, and neurodegenerative markers within 10 years of symptoms.

Plasma biomarkers could be used in pre-clinical autosomal dominant Alzheimer's disease to chart disease trajectories and predict symptom onset, allowing targeted disease-modifying therapy implementation and optimised clinical trial design.},
}

@article {pmid41959766,
year = {2026},
author = {Betthauser, TJ and Teague, JP and Bruzzone, H and Heston, MB and Coath, W and Morse, JD and Ruiz de Chavez, EL and Carey, FJ and Navaratna, R and Cody, KA and Langhough, RE},
title = {Estimating tau onset age from tau PET imaging in two longitudinal cohorts using sampled iterative local approximation.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.01.26349872},
pmid = {41959766},
abstract = {UNLABELLED: Understanding the time course of Alzheimer's disease biomarkers of amyloid and tau pathology and their temporal relation to clinical symptoms is key to identifying optimal windows for disease intervention and planning future drug trials. The goal of this work was to determine the extent to which Sampled Iterative Local Approximation (SILA), an algorithm extensively validated for amyloid PET, is capable of modeling longitudinal tau (T) PET trajectories and estimating person-level tau positivity onset ages in two commonly analyzed brain regions and two tracers from two different cohorts.

METHODS: 385 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; mean (SD) age = 73.4 (7.3) years) with longitudinal flortaucipir tau PET and 288 participants from the Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center (collectively referred to as WISC; mean (SD) age = 67.4 (6.7) years) with longitudinal MK-6240 tau PET were included in the study. Standard uptake value ratios (SUVRs) in the entorhinal cortex and a meta-temporal ROI were modeled with SILA separately, for each cohort and region. Forward and backward SUVR and T+/- prediction were characterized with ten-fold cross-validation and in-sample validation techniques. Accuracy of estimated T+ onset ages (ETOA) was characterized in T- to T+ converters. Differences in ETOA were tested between APOE-e4 carriers and non-carriers, as well as differences in time T+ between levels of cognitive impairment.

RESULTS: SILA was able to accurately estimate retrospective change in tau SUVR in the meta-temporal region regardless of age, sex, APOE-e4 carriage, tau SUVR, and dementia (p >0.05) whereas dementia was associated with model residuals in entorhinal cortex (p ≤0.05; ADNI). In subsets of observed T- to T+ converters, the difference between "observed" and estimated meta-temporal T+ onset age [95% CI] was 0.12 [-0.27, 0.52] years for ADNI and -0.09 [0.93, 0.74] years for WISC. ETOA was significantly earlier, and odds of SILA-estimated T+ status were higher amongst APOE-e4 carriers (p <0.05) and those with dementia (p <0.05).

CONCLUSIONS: Our results suggest SILA can be used to accurately model longitudinal tau PET trajectories and retrospectively estimate individual T+ onset ages in the meta-temporal region. The accuracy of SILA time estimates in entorhinal cortex worsened amongst those with dementia in ADNI suggesting entorhinal cortex may only be suitable for studying the temporal progression of tau during the preclinical time frame.},
}

@article {pmid41959774,
year = {2026},
author = {Lin, W and Beric, A and Wisch, JK and Baker, B and Jerome, G and Minton, M and Preminger, S and Stauber, J and Schindler, SE and Dage, JL and Allegri, R and Aguillon, D and Benzinger, T and Chhatwal, J and Daniels, A and Day, GS and Devenney, E and Fox, NC and Goate, A and Gordon, BA and Barthélemy, NR and Hassenstab, J and Huey, E and Ikeuchi, T and Jayadev, S and Jucker, M and Ishiguro, T and Lee, JH and Levey, AI and Levin, J and Morris, JC and Perrin, RJ and Renton, A and Roh, JH and Xiong, C and Bateman, RJ and Ances, BM and Cruchaga, C and Karch, CM and Supnet-Bell, C and Llibre-Guerra, J and McDade, E and , and Ibanez, L},
title = {Abnormalities in core AD biomarkers precede inflammatory and glial markers in CSF in Autosomal Dominant Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.31.26349851},
pmid = {41959774},
abstract = {BACKGROUND: Increasing evidence suggests that accurate prediction of Alzheimer's disease (AD) symptom onset requires more than amyloid- and tau-centric biomarkers such as cerebrospinal fluid (CSF) Aβ42/40, total tau and p-tau181 and plasma p-tau217. Autosomal dominant AD (ADAD), caused by pathogenic PSEN1, PSEN2 and APP mutations with predictable age at symptom onset, presents a unique opportunity to characterize the chronological changes in proteins beyond amyloid and tau and clarify them as early biomarkers of disease onset or as biomarkers related to disease staging and progression monitoring.

METHODS: We measured 972 CSF samples corresponding to 484 participants of the Dominantly Inherited Alzheimer Disease Network (DIAN) using the NULISASeq 120 CNS Disease Panel. We first benchmarked the technology against gold-standard measurements followed by the identification of proteins that were differentially abundant in relation to mutation status and symptomatology. Next, we determined the chronological emergence of protein changes in relation to the estimated years to onset (EYO). Finally, we assessed whether specific protein measures improved the prediction of EYO in the ADAD.

FINDINGS: NULISA measurements were comparable to those previously published. We demonstrated that known early alterations in CSF amyloid and tau were followed by inflammatory and neurodegenerative responses suggesting that clinical manifestation of AD happens before the inflammatory processes is fully developed. Finally, we found a multi-protein composite approach for predicting EYO that outperformed single biomarker values.

INTERPRETATION: Our results suggest that the main CSF proteomic landscape changes in ADAD are due to the presence of a pathogenic mutation and occur prior to symptom onset. Improved performance of multi-protein composite to predict EYO compared to single biomarker values highlights the added value of multiplex proteomic signatures for biomarker panel development.

FUNDING: National Institute on Aging, Alzheimer's Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea, Spanish Institute of Health Carlos III.},
}

@article {pmid41959792,
year = {2026},
author = {Biondo, N and Suntay, JM and Sandhu, M and Estaban, JS and Pillai, J and Mandelli, ML and Mamuyac, E and Reyes, RJ and Guevarra, A and Henry, ML and Dronkers, NF and Gorno Tempini, ML and Grasso, SM and de Leon, J},
title = {Cognitive and brain reserve in bilingual speakers with clinical AD variants.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.27.26349575},
pmid = {41959792},
abstract = {INTRODUCTION: Bilingualism may confer resilience via enhanced neural integrity. However, evidence for bilingualism's neuroprotective effect is mixed, and studies across Alzheimer's disease (AD) variants are scarce. This study examined gray matter volume (GMV) differences between bilinguals and monolinguals with amnestic AD and logopenic variant primary progressive aphasia (lvPPA).

METHODS: In 136 amnestic AD and 88 lvPPA participants with neuropsychological assessments and structural MRI, we analyzed differences between monolinguals and bilinguals within each variant, controlling for demographic covariates.

RESULTS: Amnestic AD bilinguals exhibited less GMV in hippocampal, fusiform, and occipital regions compared to monolinguals. LvPPA bilinguals had less temporal and occipital volumes, but they had greater volumes in inferior parietal regions, which are considered a disease epicenter in lvPPA. Cognitive performance in monolinguals and bilinguals was comparable within variants.

DISCUSSION: Bilingualism may support cognitive reserve (preserved cognition despite reduced GMV) in both AD variants, with additional brain reserve in lvPPA.},
}

@article {pmid41959815,
year = {2026},
author = {Li, H and Yu, Y and Bhandarkar, A and Kumar, R and Clark, IH and Hu, Y and Cao, W and Zhao, N and Li, F and Tao, C},
title = {BSO-AD: An Ontology for Representing and Harmonizing Behavioral Social Knowledge in ADRD.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.30.26349756},
pmid = {41959815},
abstract = {OBJECTIVE: Behavioral and social factors (BSFs) substantially influence the risk, onset, and progression of Alzheimer's disease and related dementias (ADRD). A systematic representation of their interplay is essential for advancing prevention and targeted interventions. However, BSF-related knowledge is scattered across heterogeneous sources, limiting scalable evidence synthesis and computational analysis. To address this, we created a B ehavioral S ocial Data and Knowledge O ntology for AD RD (BSO-AD) to represent and integrate BSFs with respect to ADRD.

MATERIAL AND METHODS: BSO-AD was developed following established ontology design principles, prioritizing reuse of existing ontology elements to ensure semantic interoperability. It was built upon the Social Determinants of Health Ontology (SDoHO) and the Drug-Repurposing Oriented Alzheimer's Disease Ontology (DROADO). BSF-related classes were enriched with ICD-10-CMZ55-Z65 codes and ADRD-related classes with AD-Onto. Relationships between BSFs and ADRD were derived through literature mining. Ontology quality was evaluated through Hootation-based expert review and an LLM-assisted framework assessing structural coverage and semantic coherence.

RESULTS: BSO-AD contains 2,275 classes, 153 object properties, and 49 data properties. Expert review demonstrated strong rational agreement (0.95), with disagreements resolved through discussion. LLM-based evaluation showed high category coverage rates (≥ 0.97) and robust semantic alignment with the relevant literature (average completeness = 0.79; conciseness = 0.94).

DISCUSSION AND CONCLUSION: BSO-AD is, to our knowledge, the first ontology to systematically represent BSFs and hierarchically model their interrelationships in ADRD. It establishes a semantic backbone for computational analysis and knowledge integration. The LLM-assisted evaluation framework demonstrates the feasibility of scalable, automated ontology assessment.},
}

@article {pmid41959833,
year = {2026},
author = {Grasso, SM and Bao, W and Marqués-Kiderle, SK and Casart Muñoz, N and Calabria, M and Sala, I and Sánchez-Saudinós, MB and Vera-Campuzano, E and Selma-González, J and Videla, L and Vaqué-Alcázar, L and Bejanin, A and García-Castro, J and Rodríguez-Baz, Í and Zhu, N and Arranz, J and Maure-Blesa, L and Rubio-Guerra, S and Barroeta, I and Illan-Gala, I and Carmona-Iragui, M and Belbin, O and Alcolea, D and Fortea, J and Lleó, A and Santos Santos, MÁ},
title = {Evidence for bilingualism as a cognitive reserve factor in biomarker-confirmed Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.31.26349879},
pmid = {41959833},
abstract = {INTRODUCTION: Bilingualism is a proposed cognitive reserve factor that delays symptom onset in Alzheimer's disease (AD), though current evidence lacks biomarker confirmation. This retrospective study examined bilingualism's association with symptom onset across AD clinical stages, including biomarker-confirmed cases.

METHODS: Participants from the Sant Pau Memory Unit spanning amnestic mild cognitive impairment (MCI), amnestic dementia, and biomarker-confirmed AD were analyzed, with balanced representation of active and passive Spanish-Catalan bilinguals. Linear regression models evaluated associations between bilingualism and reported age at symptom onset, controlling for education, sex, and disease severity.

RESULTS: Active bilingualism was associated with delayed symptom onset in amnestic MCI (2.21 years), amnestic dementia (1.42 years), and biomarker-confirmed AD (1.45 years; p s < .05). Higher education was associated with earlier onset, likely representing healthcare seeking behavior.

DISCUSSION: Bilingualism protects against earlier symptom manifestation in MCI and AD, supporting bilingualism as a contributor to cognitive reserve.},
}

@article {pmid41959929,
year = {2026},
author = {Wang, X and Yi, B},
title = {Molecular Mechanisms and Clinical Applications of Neural Regeneration Through Dental Pulp Stem Cells.},
journal = {Stem cells international},
volume = {2026},
number = {},
pages = {8069882},
pmid = {41959929},
issn = {1687-966X},
abstract = {Neural injuries affecting both the central nervous system (CNS) and peripheral nervous system (PNS) pose a great clinical challenge due to the neural tissue's limited self-regenerative capacity. Human dental pulp stem cells (hDPSCs), derived from the neural crest and easily obtained from extracted teeth, exhibit considerable potential for neural regeneration. This potential is attributed to their ability to directly differentiate into various neuronal cell types, paracrine effects, and interactions with biomaterial scaffolds. In this review, we reviewed the molecular mechanisms by which hDPSCs support neural repair, highlighting their direct neuronal differentiation function, neuroprotection function via paracrine signaling, and recent innovations in biomaterial scaffolds that enhance the viability of hDPSCs for neuroregenerative applications. Preclinical studies have shown promising therapeutic effects of hDPSCs in spinal cord injuries (SCI), strokes, Parkinson's disease (PD), Alzheimer's disease (AD), and peripheral nerve injuries. However, challenges remain, including optimizing neuronal differentiation specificity, ensuring immunological safety, and achieving scalable clinical applications. Future research should focus on standardizing manufacturing protocols, implementing strict quality control, and developing functional assays linked to neural recovery to maximize the potential of hDPSCs for nervous system regeneration.},
}

@article {pmid41960309,
year = {2026},
author = {Lee, WP and Wang, H and Leung, YY and Cheng, PL and Zheng, W and Valladares, O and Chung, WH and Kuzma, A and Naj, A and Vardarajan, B and Grsiwold, A and Haines, J and Wang, LS and Schellenberg, G},
title = {Rare coding variants from ADSP R5 whole-genome sequencing implicate novel genes in Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9013646/v1},
pmid = {41960309},
issn = {2693-5015},
abstract = {The Alzheimer's Disease Sequencing Project (ADSP) Release 5 provides whole-genome sequencing data from 58,507 individuals across diverse ancestries to discover rare coding variants and genes associated with Alzheimer's disease (AD) and AD-related traits. Gene-based aggregation tests identified 40 genes surpassing a Bonferroni-corrected gene-wide significance threshold, including established loci (TREM2, PSEN1) and putative novel candidates. In replication analyses, 21 genes showed nominal support in UK Biobank and Alzheimer's Disease Genetics Consortium (ADGC) cohorts, with eight genes (TREM2, ACADS, MFSD12, NUP210L, PIEZO2, PSEN1, SMURF2, AKAP13) supported under identical masks. Carrier-based analyses of AD-related traits linked rare variants to age at onset, neuropathology, cognition, and cerebrospinal fluid biomarkers (Aβ42, total tau, pTau181). Furthermore, we observed that AD-enriched variants were more likely to be ancestry-concentrated, and coalescent analyses indicated that AD risk alleles are younger than background variants. Together, these findings provide a multi-ancestry rare-variant resource for AD gene discovery.},
}

@article {pmid41960318,
year = {2026},
author = {Seijo, MA and Yohannes, PA and Rogers, AL and Gonzalez, JC and Banerjee, A and Kelley, H and Pierce, M and McQuail, JA and Hernandez, CM},
title = {Posttraumatic stress disorder is associated with Alzheimer's disease-relevant molecular remodeling in the amygdala of older Veterans.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9235023/v1},
pmid = {41960318},
issn = {2693-5015},
abstract = {Posttraumatic stress disorder (PTSD) has been associated with accelerated cognitive aging and increased risk for Alzheimer's disease (AD) and related dementias (ADRD), yet the neural substrates linking trauma-related psychiatric illness to late-life neurodegenerative vulnerability remain poorly defined. The amygdala plays a central role in threat processing and emotional memory and exhibits persistent hyperactivity in PTSD, but its molecular and pathological state in aging individuals with PTSD has not been systematically examined. Postmortem amygdala tissue from older adult donors (≥ 70 years) with lifetime PTSD (n = 5) and age-matched controls (n = 5) was obtained from the National PTSD Brain Bank. A multimodal analysis was performed integrating immunohistochemical quantification of β-amyloid and phosphorylated tau pathology, targeted transcriptional profiling of AD-related genes, gene network analysis, and protein quantification of pathological, inflammatory, and synaptic markers. PTSD cases showed enrichment of combined tau-amyloid pathology within the amygdala and significantly greater β-amyloid burden. Targeted transcriptomic profiling identified coordinated upregulation of AD-related genes involved in amyloid processing, lipid metabolism, proteostasis, and inflammatory signaling. Network analysis revealed an APP-centered molecular architecture with APOE, MAPT, and CLU functioning as highly connected secondary hubs. Protein analyses demonstrated increased amyloid-β and pTau231 abundance, selective markers of gliosis, and synaptic alterations characterized by elevated excitatory receptor expression and reduced inhibitory GABABR1a. Older adults with PTSD exhibit convergent evidence of AD-relevant molecular and pathological remodeling in the amygdala. These findings suggest that chronic trauma-related circuit dysregulation may intersect with aging-associated inflammatory and synaptic processes, creating a biological environment permissive for neurodegenerative vulnerability in emotionally salient brain circuits.},
}

@article {pmid41960330,
year = {2026},
author = {Gagliardi, G and Ciudad, JG and Micca, L and Kornum, BR and Gilat, M and Alfeo, AL and Cimino, MGCA and De Vos, M},
title = {Prototype-based sleep micro-structure learning for explainable and robust multimodal recognition of sleep-related conditions.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9169987/v1},
pmid = {41960330},
issn = {2693-5015},
abstract = {While sleep is fundamental to human health, sleep disturbances reduce quality of life and constitute risk factors for neurodegenerative diseases including Parkinson's and Alzheimer's. Automated sleep staging networks achieve human-level performance on multimodal physiological signals, but they operate as black boxes, limiting clinical trust and preventing the discovery and validation of sleep biomarkers linked to human health status.We propose ProtoSleepNet (PSN), the fist prototype-based sequence-to-sequence sleep staging architecture that achieves human-level sleep staging accuracy while providing interpretability through an intrinsic codebook of learned prototypes. Each prototype captures distinctive sleep microstructure patterns, visualized as physiologically meaningful features across EEG, EOG, and EMG channels. We validate PSN against state-of-the-art approaches on over 10,000 subject recordings across 10 benchmark datasets, demonstrating in-line or superior sleep staging performance, robustness to channel occlusion attacks, and interpretability through a novel explainability framework that translates abstract prototypes into clinically aligned natural-language matching rules.Finally, we show that prototype sequences (prototype-grams) from individual patients encode clinically relevant information: without any disease-specific training, prototype-grams effectively discriminate Parkinson's and Alzheimer's disease patients from healthy controls, revealing disease-specific sleep microstructure alterations aligned with known pathophysiology.},
}

@article {pmid41960333,
year = {2026},
author = {Murphy, EK and Hatch, K and Wise, SY and Fatanmi, O and Petrus, SA and Bhomia, M and Lecca, D and Knollmann-Ritschel, BEC and Perl, D and Singh, VK and Iacono, D},
title = {γ-Radiation Reduces phosphorylated-Tau in Rhesus Macaque Brains: Potential Implications for Alzheimer's Disease and other Tauopathies.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9077029/v1},
pmid = {41960333},
issn = {2693-5015},
abstract = {Background: Studies on the effects of γ-radiation on nonhuman primate (NHP) brains are limited, despite the critical need to understand the impact of radiation exposure on the brain from various sources like radiotherapy equipment, space travel, and potential nuclear events. Methods: We investigated molecular and neuropathological changes in rhesus macaque brains after a single 5.8 Gy total-body γ-radiation exposure. We analyzed samples dissected from frontal cortex (FCtx), hippocampus (Hippo), and cerebellum (CRB) of irradiated (RAD) vs. unirradiated/control (CTRL) animals. Western blotting and digital PCR (dPCR) analyses were used to measure different phosphorylated-Tau (pTau) forms and neurodegeneration markers (i.e., amyloid protein precursor [APP], neurofilament-light chain [NFL], glial fibrillary acidic protein [GFAP], ionized calcium-binding adapter molecule 1 [IBA1/AIF1], and myelin basic protein [MBP]). Results: We detected lower levels of different forms of soluble pTau species (pTau181, and pTau217, among others) in RAD vs. CTRL animals across all three examined brain regions. While APP and GFAP levels were unchanged in the FCtx, increased IBA1 and NFL levels were detected alongside decreased MBP levels. Moreover, dPCR data identified decreased expression of GFAP and MBP in the FCtx. Importantly, the molecular changes observed were not accompanied by overt signs of neurodegeneration or cellular abnormalities upon neuropathological assessment. Conclusions: These findings in irradiated NHPs' brains are novel and indicate that a single total-body γ-radiation exposure significantly alters soluble pTau levels after a few weeks from irradiation without causing obvious neurohistological damage. These results open intriguing new possibilities of exploring γ-radiation-based strategies to modulate the progression of tauopathies, including Alzheimer's disease.},
}

@article {pmid41960503,
year = {2026},
author = {Mondal, A and Gupta, S and Bhattacharjee, A and Podder, A and Jani, P},
title = {Exploring molecular pathways in Alzheimer's disease neurodegeneration using biomarkers.},
journal = {Bioinformation},
volume = {22},
number = {1},
pages = {47-50},
pmid = {41960503},
issn = {0973-2063},
abstract = {The need to better understand the role of tumor necrosis factor-alpha (TNF-α) in Alzheimer's disease (AD) and its relationship with brain atrophy and cognitive decline is highly relevant. Therefore, it is of interest to investigate the role of tumor necrosis factor-alpha (TNF-α) in Alzheimer's disease (AD) by analyzing its relationship with brain atrophy and cognitive decline in 80 AD patients. Our results show a significant correlation between increased CSF TNF-α levels and hippocampal atrophy. Additionally, TNF-α level were associated with other clinical variables, emphasizing its role in neuroinflammation. Thus, TNF-α as a potential biomarker for Alzheimer's disease progression. Further research is needed to assess its therapeutic potential. The advancement to knowledge in this study is the identification of a significant correlation between elevated TNF-α levels and hippocampal atrophy in Alzheimer's disease, supporting TNF-α as a potential biomarker for disease progression.},
}

@article {pmid41960571,
year = {2026},
author = {Li, X and Wu, Z and Yao, C and Zhang, P and Zhu, Q and Nan, S and Xiao, L and Qi, S},
title = {Porphyromonas gingivalis Promotes Neuroinflammation by Microglial Ferroptosis via NOX4/PPAR-α/PGC-1α Pathway.},
journal = {Research (Washington, D.C.)},
volume = {9},
number = {},
pages = {1163},
pmid = {41960571},
issn = {2639-5274},
abstract = {Background: Emerging evidence links Porphyromonas gingivalis (P.g), a keystone oral pathogen, neuroinflammation as a driver of Alzheimer's symptoms. This study aimed to investigate the molecular mechanism by which P.g triggers neuroinflammation and cognitive decline. Methods: Wild-type (WT) mice were orally gavaged with P.g for 8 weeks to evaluate cognitive function, neuronal integrity (p-Tau, hippocampal damage), and neuroinflammation. RNA sequencing analyzed brain transcriptomic, ferroptosis, and mitochondrial function after P.g induction was mainly analyzed. In vitro, the roles of NOX4/PPAR-α/PGC-1α pathway on ferroptosis, mitochondrial function, and inflammatory responses were evaluated after microglia were treated with P.g supernatant. Finally, NOX4-knockout mice were used to validate pathway specificity. Results: P.g administration in WT mice induced cognitive deficits, hippocampal neurodegeneration, p-Tau accumulation, and neuroinflammation, accompanied by dysregulated mitochondrial genes (NOX4, PPAR-α, and PGC-1α) and ferroptosis activation. P.g supernatant promoted microglial ferroptosis, mitochondrial dysfunction, and inflammatory cytokine release in vitro, which were reversed by NOX4 silencing. Mechanistically, NOX4 knockdown restored PPAR-α/PGC-1α signaling, suppressed ferroptosis, and mitigated inflammation in vitro. Critically, NOX4-knockout mice resisted P.g-induced cognitive impairment, neuronal loss, and neuroinflammatory responses in vivo. Conclusion: This study identified P.g-induced neuroinflammation and cognitive decline via microglial ferroptosis and mitochondrial dysfunction, which were regulated by the NOX4/PPAR-α/PGC-1α pathway. These findings highlight the link between oral health and brain pathology in Alzheimer's disease and propose NOX4 as a promising pharmacological target for cognitive preservation.},
}

@article {pmid41960639,
year = {2026},
author = {Alastalo, A and Haapea, M and Nordström, T and Tolppanen, AM and Miettunen, J and Nietola, M and Hartikainen, S and Jääskeläinen, E},
title = {Mortality of People With Alzheimer's Disease and Psychiatric Morbidity: A Nationwide Finnish Cohort Study.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {4},
pages = {e70210},
doi = {10.1002/gps.70210},
pmid = {41960639},
issn = {1099-1166},
support = {3165563//Academy of Finland/ ; //Suomen Lääketieteen Säätiö/ ; },
mesh = {Humans ; Finland/epidemiology ; Male ; *Alzheimer Disease/mortality/psychology ; Female ; Aged ; Aged, 80 and over ; *Mental Disorders/mortality/epidemiology ; Comorbidity ; Cohort Studies ; Cause of Death ; Registries ; Middle Aged ; },
abstract = {OBJECTIVES: Psychiatric comorbidities are common in Alzheimer's disease (AD), and they have a negative impact on quality of life, but their impact on mortality remains unclear. This study examined mortality among persons with AD and psychiatric morbidity compared to persons with AD without psychiatric morbidity. This is the first study to analyze Alzheimer's disease mortality based on the timing of earlier psychiatric morbidity.

METHODS: We utilized the nationwide register-based MEDALZ cohort, including 70,718 Finnish individuals diagnosed with AD between 2005 and 2011. Individuals were categorized into four groups based on the occurrence of their hospital-treated psychiatric diagnosis before the diagnosis of AD. Mortality was assessed over an 8-year follow-up. Chi-square test was used to compare the differences between the four groups in terms of causes of death and annual cumulative mortality. We determined cumulative mortality curves and hazard ratios, stratified by age, gender, cardiovascular disease, and the year of AD diagnosis.

RESULTS: During the 8-year follow-up, 70.4% of the AD cohort had died. Persons with earlier psychiatric morbidity had an AD diagnosis 1.4-4.3 years earlier and died 1.4-4.1 years younger. Mortality risk was slightly higher among those with psychiatric morbidity compared to those without (adjusted HRs 1.03-1.41), with the effect decreasing over the years of follow-up. Mortality risk was not affected by the timing of psychiatric morbidity.

CONCLUSION: Psychiatric comorbidity is associated with earlier AD onset and reduced lifespan; however, post-diagnosis survival appears to be largely determined by AD progression itself.},
}

Humans
Finland/epidemiology
Male
*Alzheimer Disease/mortality/psychology
Female
Aged
Aged, 80 and over
*Mental Disorders/mortality/epidemiology
Comorbidity
Cohort Studies
Cause of Death
Registries
Middle Aged

@article {pmid41960998,
year = {2026},
author = {Kjaergaard, D and Delgado-Álvarez, A and Waldemar, G and Beinhoff, U and Bekkhus-Wetterberg, P and Franzen, S and Illingworth, CH and Laks, J and Lozano-Ruiz, A and Lueschow, A and Matias-Guiu, JA and Pomati, S and Segers, K and Torkpoor, R and Wagle, J and Nielsen, TR},
title = {Diagnostic accuracy of the Multicultural Cognitive Examination (MCE) for detection of MCI and dementia in a diverse international cohort.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/13854046.2026.2652032},
pmid = {41960998},
issn = {1744-4144},
abstract = {OBJECTIVE: Accurate cognitive screening tests for culturally, linguistically, and educationally diverse populations remain scarce, contributing to diagnostic inequities. To address this, we examined the cross-cultural properties and diagnostic accuracy of the Multicultural Cognitive Examination (MCE) in classifying mild cognitive impairment (MCI), dementia, Alzheimer's disease (AD) dementia, and non-AD dementia in participants with diverse backgrounds.

METHOD: In this retrospective cross-sectional study, we aggregated data from 1,449 participants across 11 countries. Multiple linear regression models were used to determine the influence of demographic variables on MCE scores, which informed the creation of regression-based normative data. Diagnostic accuracies were examined using Receiver Operating Characteristics (ROC) curves.

RESULTS: The cohort consisted of 1001 cognitively intact participants, 140 patients with MCI, and 308 patients with dementia. 54.2% had immigrant backgrounds and originated from 63 different countries. MCE scores were significantly influenced by education and age, but not by sex or immigrant status. The MCE demonstrated high accuracy in differentiating cognitively intact participants from patients with dementia (AUC: .95) and MCI (AUC: .84). The MCE was both accurate for classifying AD dementia (AUC: .97) and non-AD dementia (AUC: .94).

CONCLUSIONS: This study supports the clinical utility of the MCE as a culturally robust and highly accurate cognitive screening test. Future studies should examine the ability of the MCE to monitor cognitive decline.},
}

@article {pmid41961243,
year = {2026},
author = {Porsteinsson, AP and Chumki, SR and Wang, D and Such, P and Palma, AM and Zhang, Z and Shah, A and Kalu, U and Montano, CB},
title = {Short-Term and Long-Term Safety Analyses of Brexpiprazole for Agitation Associated with Dementia due to Alzheimer's Disease: Timing and Duration of Adverse Events.},
journal = {Drug safety},
volume = {},
number = {},
pages = {},
pmid = {41961243},
issn = {1179-1942},
abstract = {INTRODUCTION: Agitation symptoms are a common and burdensome aspect of Alzheimer's dementia. Historically, agitation has been managed using off-label treatments such as atypical antipsychotics, but this approach is associated with safety concerns in older, more vulnerable patients. Brexpiprazole is an atypical antipsychotic that has been recently approved in several countries for the treatment of agitation associated with dementia due to Alzheimer's disease. Previous analyses show that brexpiprazole was efficacious and generally well tolerated for up to 24 weeks. Building upon previous work, this post hoc analysis aimed to evaluate the timing and duration of treatment-emergent adverse events (TEAEs) during brexpiprazole treatment.

METHODS: In a 12-week analysis, data were pooled from three phase 3, randomized, double-blind, placebo-controlled trials of brexpiprazole in participants with agitation associated with dementia due to Alzheimer's disease. In a separate 24-week analysis, brexpiprazole data were combined from a 12-week randomized trial and a 12-week active-treatment extension trial. The median time from starting treatment to first reporting a TEAE and the median duration of all TEAEs were determined.

RESULTS: A total of 1043 participants received at least one dose of trial medication. Over 12 weeks, brexpiprazole 2 or 3 mg/day (the approved therapeutic dosages in the United States, N = 366) compared to placebo (N = 388) had similar time to first TEAE (32 days and 28 days, respectively), similar duration of all TEAEs (6 days and 4 days), and longer time to discontinuation due to adverse events (47 days and 30 days). Over 24 weeks (N = 163), the time to first TEAE on brexpiprazole 2 or 3 mg/day was 52 days, and the duration of all TEAEs was 3 days. Among participants who did not report a TEAE in the 12-week parent trial, TEAEs were rare throughout the 12-week extension trial.

CONCLUSIONS: These exploratory analyses reinforce that brexpiprazole is generally well tolerated over 12 weeks, and also over 24 weeks among patients who tolerated the first 12 weeks of treatment. The results provide a practical clinical insight into the safety of brexpiprazole over time in patients with agitation associated with dementia due to Alzheimer's disease.

TRIAL REGISTRATION: Post hoc analysis of NCT01862640, NCT01922258, NCT03548584, NCT03594123 (ClinicalTrials.gov).},
}

@article {pmid41961577,
year = {2026},
author = {Dasgupta, M and Konar, A and Nagar, AK},
title = {Modeling Astrocyte-Driven Repair of Visuomotor Deficits in Alzheimer's Thalamic Circuitry.},
journal = {IEEE transactions on computational biology and bioinformatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TCBBIO.2026.3682803},
pmid = {41961577},
issn = {2998-4165},
abstract = {Alzheimer's Disease (AD) frequently manifests in visuomotor impairments, disrupting cholinergic signaling from the brainstem to the Thalamic Reticular Nucleus (TRN). The contribution of this work lies in the development of a biologically informed computational framework to model astrocyte mediated restoration of synaptic transmission, measured by a 'release probability (PR)' in TRN under cholinergic depletion. The model simulates three physiological states-healthy, damaged, and recovered by incorporating dual astrocytic mechanisms i.e., depolarization induced suppression excitation (DSE) and endocannabinoid mediated synaptic potentiation (e-SP). This is validated through in-vivo experiments conducted using functional near-infrared spectroscopy (fNIRS) in mice, performing visuomotor integration tasks. Both computational simulations and experimental measurements demonstrate that astrocytic feedback from functional thalamocortical relay cells (TCR) and interneurons (IN) can restore PR partially to approximately 70% of healthy levels despite complete ACh depletion. The bounded, asymmetric temporal dynamics, consistent with beta distribution characteristics reflect biologically realistic regulatory mechanisms maintaining synaptic homeostasis, exhibiting rapid initial potentiation followed by gradual decay. Sensitivity analyses reveal that when modulated with identical parameter values, excitatory TCR terminals produce greater PR with increasing astrocytic strengthening rate of indirect signaling, while inhibitory IN terminals dominate PR recovery under elevated astrocyte synapse coupling weights of indirect signaling. This highlights how excitatory and inhibitory astrocyte-targeted pathways work in tandem to shape recovery in a coordinated manner. The quantitative agreement between computational predictions and experimental measurements (within 2% error) provides evidence supporting astrocyte-based neuromodulation as a biologically grounded mechanism for restoring visuomotor function in AD.},
}

@article {pmid41961641,
year = {2026},
author = {Yang, L and Zhao, W and Zhao, J and Chen, S and Qin, X and Yang, Z and Kong, D and Zhang, W},
title = {Effects of ononin on cognitive and learning-memory functions in mild cognitive impairment.},
journal = {Neuroreport},
volume = {},
number = {},
pages = {},
doi = {10.1097/WNR.0000000000002264},
pmid = {41961641},
issn = {1473-558X},
abstract = {OBJECTIVE: This study aimed to investigate the potential of ononin in alleviating mild cognitive impairment (MCI) and to determine whether its effects depend on the functional recovery of neurons in the nucleus tractus solitarius (NTS).

METHODS: Four-month-old APP/PS1 mice were treated with 30-mg/kg ononin via oral gavage for 8 consecutive days. Cognitive behavior was assessed using the novel object recognition test, Y-maze test, and open field test. Cortical perfusion was measured by laser speckle contrast imaging. The activation of NTS neurons was detected using c-Fos immunofluorescence staining, while dendritic complexity and neuronal firing frequency were evaluated via Golgi staining and patch-clamp electrophysiology, respectively.

RESULTS: Ononin treatment significantly improved the novel object recognition index and spontaneous alternation rate in the Y-maze test in APP/PS1 mice. It also enhanced cerebral blood flow perfusion and increased the number of c-Fos-positive cells in the NTS, hippocampal CA1 region, and cortex. Furthermore, ononin increased dendritic intersections and restored dendritic spine density in NTS neurons to normal levels, along with significantly elevating their firing frequency.

CONCLUSION: Ononin may ameliorate MCI-like cognitive deficits in APP/PS1 mice by activating NTS neurons, restoring synaptic plasticity, and improving cerebral perfusion. These findings suggest that the NTS could serve as a potential target for early intervention in Alzheimer's disease.},
}

@article {pmid41961648,
year = {2026},
author = {Yu, Z and Hao, L and Zhang, H},
title = {Mendelian randomization study of genetic interactions between Alzheimer disease and celiac disease.},
journal = {Medicine},
volume = {105},
number = {15},
pages = {e48320},
doi = {10.1097/MD.0000000000048320},
pmid = {41961648},
issn = {1536-5964},
mesh = {Humans ; *Alzheimer Disease/genetics/epidemiology ; *Mendelian Randomization Analysis ; *Celiac Disease/genetics/epidemiology ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Prospective Studies ; Polymorphism, Single Nucleotide ; },
abstract = {Epidemiological evidence suggests an association between celiac disease (CeD) and Alzheimer disease (AD). However, the association between CeD and AD remains debated. Therefore, this study aims to explore the causal association between CeD and AD. This study utilized publicly available genome-wide association study datasets and performed bidirectional 2-sample Mendelian randomization analyses using methods such as inverse-variance weighting (IVW), weighted median, MR-Egger regression, simple mode, and weighted mode. In the prospective analysis, the results indicated that genetic susceptibility to CeD was associated with a decreased risk of AD (IVW OR = 0.97, 95% CI = 0.95-0.99, P = .03). However, no significant association was found between genetic susceptibility to AD and the risk of CeD (IVW OR = 1.11, 95% CI = 0.98-1.23, P = .11). The results of this bidirectional 2-sample Mendelian randomization analysis revealed a causal relationship between genetic susceptibility to CeD and a reduced risk of AD but failed to reveal a causal association between genetic susceptibility to AD and increased or decreased risk of CeD.},
}

Humans
*Alzheimer Disease/genetics/epidemiology
*Mendelian Randomization Analysis
*Celiac Disease/genetics/epidemiology
Genome-Wide Association Study
Genetic Predisposition to Disease
Prospective Studies
Polymorphism, Single Nucleotide

@article {pmid41961677,
year = {2026},
author = {Shen, Y and Zhou, J and Sun, B and Geng, L},
title = {Association of telomere length with cognitive function and dementia: A cross-sectional NHANES analysis and 2-sample Mendelian randomization study.},
journal = {Medicine},
volume = {105},
number = {15},
pages = {e48217},
doi = {10.1097/MD.0000000000048217},
pmid = {41961677},
issn = {1536-5964},
support = {20250601030RC//Jilin Provincial Department of Science and Technology/ ; },
mesh = {Humans ; Cross-Sectional Studies ; Mendelian Randomization Analysis ; Male ; Female ; *Dementia/genetics/epidemiology ; Aged ; *Cognition/physiology ; Nutrition Surveys ; Middle Aged ; Genome-Wide Association Study ; *Telomere/genetics ; },
abstract = {This study aimed to investigate the association between telomere length, cognitive function, and dementia, and to assess causality using Mendelian randomization (MR). This study included 1815 participants aged over 60 from the National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2002. Cognitive function was assessed using the digit symbol substitution test score, and telomere length was quantified as the mean leukocyte telomere length (telomere/single-copy gene) measured by quantitative polymerase chain reaction. Weighted multivariate linear regression was applied to examine the relationship between cognitive function and telomere length. Additionally, a 2-sample MR approach was employed to explore the genetic causal relationship between telomere length and dementia, and its subtypes, using summary-level genome-wide association studies data derived primarily from individuals of European ancestry. The primary analysis utilized inverse variance weighting, and a series of sensitivity analyses were conducted to ensure robustness of the results. In the cross-sectional observational analysis, longer telomere length was positively associated with higher digit symbol substitution test scores after full adjustment (T2 vs T1: β = 2.1, 95% confidence interval [CI]: 0.35-3.9, P = .022; T3 vs T1: β = 2.5, 95% CI: 0.69-4.3, P < .001). In the MR analysis, genetically predicted longer telomere length was causally associated with a reduced risk of all-cause dementia (odds ratio [OR] per 1-standard deviation increase: 0.90, 95% CI: 0.83-0.98, P = .017), Alzheimer's disease (OR: 0.87, 95% CI: 0.76-0.99, P = .036), and vascular dementia (OR: 0.80, 95% CI: 0.65-0.97, P = .026). However, no causal association was found with frontotemporal dementia or Parkinson's disease. Observational and genetic evidence jointly suggest that longer telomere length is associated with better cognitive function and may play a protective causal role against major forms of dementia.},
}

Humans
Cross-Sectional Studies
Mendelian Randomization Analysis
Male
Female
*Dementia/genetics/epidemiology
Aged
*Cognition/physiology
Nutrition Surveys
Middle Aged
Genome-Wide Association Study
*Telomere/genetics

@article {pmid41961681,
year = {2026},
author = {Wang, T and Zhu, W},
title = {Gender and racial differences in the relationship between mean arterial pressure, pulse pressure, and cognitive function in older adults: NHANES 2011 to 2014.},
journal = {Medicine},
volume = {105},
number = {15},
pages = {e48275},
doi = {10.1097/MD.0000000000048275},
pmid = {41961681},
issn = {1536-5964},
mesh = {Humans ; Male ; Female ; Aged ; Nutrition Surveys ; *Cognition/physiology ; Middle Aged ; Sex Factors ; *Arterial Pressure/physiology ; *Blood Pressure/physiology ; *Cognitive Dysfunction/ethnology/physiopathology ; United States/epidemiology ; Aged, 80 and over ; Cross-Sectional Studies ; White People/statistics & numerical data ; Neuropsychological Tests ; White ; },
abstract = {The impacts of mean arterial pressure (MAP) and pulse pressure (PP) on cognitive decline have not been fully characterized, and little is known about the gender and racial differences in this relationship. This study aimed to look into the above-mentioned relationship. Information was obtained from the National Health and Nutrition Examination Survey 2011 to 2014. The Consortium to Establish a Registry for Alzheimer's Disease Word Learning Test (CERAD W-L), the Animal Fluency Test, and the Digit Symbol Substitution Test (DSST) were used to assess cognitive functioning in participants aged 60 years and older. Weighted linear regression analyses were employed to detect the relationship between MAP, PP (continuous or quartiles), and 3 cognitive test scores. Additionally, forest maps and smooth curve fitting were utilized to demonstrate subgroup analyses stratified by gender and race. There were 2612 participants in this study. After fully adjusting for covariates, MAP was negatively correlated with cognitive functioning estimated by CERAD W-L (β: -0.026, 95% confidence interval [CI]: -0.045 to -0.008), and PP was negatively associated with cognitive test scores through DSST (β: -0.039, 95% CI: -0.065 to -0.013). This tendency remained statistically significant across different MAP quartile groups and PP quartile groups (P for trend < .01). In the CERAD W-L test, subgroup analyses stratified by race as well as sex revealed that the negative relationship between MAP, PP, and cognitive scores remained significant in females (MAP: β: -0.042, 95% CI: -0.066 to -0.017; PP: β: -0.018, 95% CI: -0.033 to -0.002) and non-Hispanic White (NHW; MAP: β: -0.031, 95% CI: -0.052 to -0.010; PP: β: -0.016, 95% CI: -0.029 to -0.002). Additionally, a negative relationship between PP and cognitive scores was also found in DSST in females (β: -0.044, 95% CI: -0.077 to -0.011) and NHW (β: -0.041, 95% CI: -0.070 to -0.012). Our study suggested that elevated levels of MAP and PP were negatively correlated with cognitive functioning, particularly in females and NHWs. Therefore, the management of MAP and PP might be helpful for the prevention of poor cognitive performance in the elders. However, the cross-sectional nature of this study limits causal inference.},
}

Humans
Male
Female
Aged
Nutrition Surveys
*Cognition/physiology
Middle Aged
Sex Factors
*Arterial Pressure/physiology
*Blood Pressure/physiology
*Cognitive Dysfunction/ethnology/physiopathology
United States/epidemiology
Aged, 80 and over
Cross-Sectional Studies
White People/statistics & numerical data
Neuropsychological Tests
White

@article {pmid41961749,
year = {2026},
author = {Liang, K and Guo, L and He, Y and Zhang, X},
title = {Multi-model analysis of the association between osteoporosis and cognition decline: from prospective cohorts.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-19},
doi = {10.1159/000551383},
pmid = {41961749},
issn = {1423-0208},
abstract = {BACKGROUND: Previous studies have suggested the possible association between osteoporosis and cognitive decline, but the participants number of studies is small and most of them have not been categorized in detail.

OBJECTIVES: This study examined the association between osteoporosis and the risk of cognitive impairment and Alzheimer's disease (AD), and explored which populations are most affected.

METHODS: We analyzed data from two prospective cohorts, the English Longitudinal Study of Ageing (ELSA) and the Health Retirement Study (HRS). We used multivariate regression, mixed-effects models, Cox models to assess the associations between osteoporosis and cognitive function at baseline, over time, and with AD risk. Subgroup analyses and sensitivity analyses were conducted.

RESULTS: A total of 28,919 participants were enrolled (57.11% females). At baseline, memory scores were significantly lower in the osteoporosis group [β=-0.37, 95% CI: -0.56, -0.18; p<0.001], particular in younger participants. Annually, memory scores also declined more rapidly in osteoporosis [β=-0.01,95% CI: -0.18, -0.02; p=0.018], especially in hypertension female. At baseline, osteoporosis was associated with a higher prevalence of Alzheimer's disease [OR=1.40, 95% CI 1.02-1.93; p=0.039], particularly among men. Over time, the cumulative effect of osteoporosis on AD increased steadily (Log-rank p<0.001). Younger males with osteoporosis showed high odds of developing AD.

CONCLUSION: Osteoporosis was associated with a steeper decline in memory over follow-up, with evidence that this association was stronger among women with hypertension. Osteoporosis was also associated with a higher hazard of incident AD, and the association appeared stronger in men.},
}

@article {pmid41961910,
year = {2026},
author = {Asghar, S and Khan, MU and Jawaid, T and Rehman, R and Shafi, A and Alzahrani, AR and Rehman, ZU and Khan, A},
title = {Phytochemicals from Astragalus zederbaueri as Acetylcholinesterase Inhibitors for Alzheimer's Therapy.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0346177},
doi = {10.1371/journal.pone.0346177},
pmid = {41961910},
issn = {1932-6203},
mesh = {*Alzheimer Disease/drug therapy/enzymology ; *Cholinesterase Inhibitors/chemistry/therapeutic use/pharmacology ; *Astragalus Plant/chemistry ; Molecular Docking Simulation ; *Phytochemicals/chemistry/therapeutic use/pharmacology ; *Acetylcholinesterase/metabolism/chemistry ; Humans ; Molecular Dynamics Simulation ; },
abstract = {Alzheimer's Disease (AD), the dominant form of dementia that evolves with age, involves several mechanisms by which it progresses. The cholinergic hypothesis proposes that the activity of Acetylcholinesterase (AChE) causes the decline of cholinergic neurotransmission, which leads to Alzheimer's Disease. Considerable studies are being conducted to determine the best AChE inhibitor. This study evaluated 40 phytocompounds from the Astragalus zederbaueri plant as potential AChE inhibitors for Alzheimer's disease. The analysis of the phytochemicals was conducted using the control drug donepezil (co-crystallized ligand) through various computational tools and biological databases for docking, visualization, and simulation. The findings of our research showed that the key ligands according to the docking analysis were Rutin (AZ-29), Kaempferol-3-O-rutinoside (Nicotiflorin) (AZ-32), and Isoquercitrin (AZ-28); nevertheless, it was found that Rutin played the most effective role of an anti-AChE compound with an exceptional binding affinity of -15.043 kcal/mol. TRP341 and TYR286 were key amino acid residues in hydrogen bonds and π-π stacking interactions, respectively. The results of pharmacokinetic and toxicological analyses of these compounds were within the acceptable range. Moreover, the molecular dynamics simulation confirmed the stability of the complexes. Our findings suggest a novel phytochemicals from Astragalus zederbaueri for Alzheimer's disease, paving the way for further experimental validation and drug development.},
}

*Alzheimer Disease/drug therapy/enzymology
*Cholinesterase Inhibitors/chemistry/therapeutic use/pharmacology
*Astragalus Plant/chemistry
Molecular Docking Simulation
*Phytochemicals/chemistry/therapeutic use/pharmacology
*Acetylcholinesterase/metabolism/chemistry
Humans
Molecular Dynamics Simulation

@article {pmid41962111,
year = {2026},
author = {Sobiech, L and Wójcik, L and Jankowska, N and Turżańska, K},
title = {Periodontitis as a systemic inflammatory disorder - implications for cardiovascular and neurodegenerative diseases.},
journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)},
volume = {79},
number = {3},
pages = {646-650},
doi = {10.36740/WLek/218274},
pmid = {41962111},
issn = {0043-5147},
mesh = {Humans ; *Cardiovascular Diseases/etiology ; *Neurodegenerative Diseases/etiology ; *Periodontitis/complications/microbiology ; *Inflammation/complications ; },
abstract = {OBJECTIVE: Aim: Periodontitis is a chronic inflammatory condition associated with oral microbiome dysbiosis and the dominance of Gram-negative bacteria such as Porphyromonas gingivalis. It is characterized by progressive destruction of the supporting tissues of the tooth, leading to loss of connective tissue attachment, resorption of the alveolar bone, and, consequently to tooth loosening and loss. If left untreated, it leads to recurrent bacteremia and persistent systemic inflammation. The aim of this study is to discuss the mechanisms linking periodontitis to cardiovascular and neurodegenerative diseases.

PATIENTS AND METHODS: Materials and Methods: A comprehensive literature review was conducted examining clinical studies, systematic reviews, and meta-analyses assessing the impact of periodontal disease on the development of cardiovascular and neurodegenerative diseases.

CONCLUSION: Conclusions: Chronic activation of the immune response, oxidative stress, and lipid metabolism disorders promote endothelial dysfunction and the progression of atherosclerosis, increasing the risk of cardiovascular events. At the same time, systemic inflammation can affect the permeability of the blood-brain barrier and exacerbate neuroinflammatory processes, promoting β-amyloid accumulation and the progression of Alzheimer's disease. Analysis of the literature indicates the significant, albeit complex, nature of these relationships, emphasizing the importance of prevention and treatment of periodontal disease as part of comprehensive patient care. The key in the approach to periodontal patients is an interdisciplinary perspective, integrating dentistry, cardiology, neurology, and geriatrics.},
}

Humans
*Cardiovascular Diseases/etiology
*Neurodegenerative Diseases/etiology
*Periodontitis/complications/microbiology
*Inflammation/complications

@article {pmid41962139,
year = {2026},
author = {Mastrogiacomo, R and Miniero, DV and Rullo, M and Rizzi, F and Minervini, G and Panniello, A and Striccoli, M and Fanizza, E and Comparelli, R and Curri, ML and Catto, M and Liuzzi, GM and Pisani, L and Latronico, T and Depalo, N},
title = {Nanostructured Lipid Carriers Enhance Brain Delivery and Antioxidant Efficacy of a Small-Molecule MAO B Inhibitor for Neurodegenerative Disease Therapy.},
journal = {Molecular pharmaceutics},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.molpharmaceut.5c01754},
pmid = {41962139},
issn = {1543-8392},
abstract = {Neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, urgently require new therapeutic strategies. Monoamine oxidase B (MAO B), a mitochondrial enzyme involved in oxidative stress and neurotransmitter metabolism, has emerged as a promising target for neuroprotection. A 5-substituted-1H-indazole derivative (here referred to as compound 1) has been recently identified as a potent and safe MAO B inhibitor with antioxidant and neuroprotective properties. Unfortunately, compound 1 suffers from poor aqueous solubility and chemical stability under hydrolytic conditions, thereby limiting its therapeutic potential. To overcome these drawbacks, nanostructured lipid carriers (NLCs) were developed as delivery systems for compound 1. The coloading of luminescent carbon dots (CDs) together with compound 1 within NLCs further enabled investigation into NLCs' ability to permeate through the artificial blood-brain barrier (BBB) model, allowing a quantitative evaluation of crossing efficiency. Delivery via NLCs resulted in a markedly higher fraction of compound 1 crossing the BBB (∼26%) compared with the free molecule (∼2.6%). Encapsulation also retained antioxidant efficacy in SH-SY5Y cells, while the nanoformulations exhibited a good degree of cell tolerance, with viability remaining above 60% across the tested concentration range. These in vitro findings suggest that the proposed nanoformulation represents a promising strategy to enhance delivery of the investigated small molecule to the central nervous system (CNS), highlighting its potential application in neurodegenerative diseases (NDs).},
}

@article {pmid41962176,
year = {2026},
author = {Howell, GR and Territo, PR and Aylor, D and Goldstein, LE},
title = {Understanding the contribution of toxicant exposures to Alzheimer's disease and related dementias.},
journal = {Current opinion in neurobiology},
volume = {98},
number = {},
pages = {103192},
doi = {10.1016/j.conb.2026.103192},
pmid = {41962176},
issn = {1873-6882},
abstract = {Alzheimer's disease and related dementias (AD/ADRD) are modulated by gene-environment (GxE) interactions across the lifespan. Variants of specific genes increase AD risk and synergize with exposures to environmental toxicants ("exposome"), including neurotoxic metals and metalloids such as lead (Pb), cadmium (Cd), and arsenic (As). These neurotoxicants enter the body (via drinking water, contaminated food, and airborne particulates), transit in blood, cross the blood-brain barrier, and distribute in brain where the retained toxicant disrupts central nervous system development, structure, and function. Chronic exposure to these ubiquitous toxicants is common in disadvantaged communities, raising concerns about health risk disparities linked to geographic, socioeconomic, and racial demographics. While Pb, Cd, and As are established human neurotoxicants with suspected linkage to AD/ADRDs, the mechanisms underpinning AD/ADRD-related GxE interactions specific to metal-metalloid toxicant exposures are largely unknown and potentially modifiable. Preclinical models and resources are needed to facilitate research into the underlying mechanisms by which AD genetics and exposome affect brain health, aging, and AD/ADRD pathobiology.},
}

@article {pmid41962274,
year = {2026},
author = {Dong, Y and Wang, Y and Chen, K and Sun, G and Cao, X and Li, X and Lu, W and Dai, X and Huang, B and Chen, Y},
title = {Engineering versatile nanoplatforms for calcium homeostasis modulation and broad-spectrum disease therapies.},
journal = {Biomaterials},
volume = {333},
number = {},
pages = {124207},
doi = {10.1016/j.biomaterials.2026.124207},
pmid = {41962274},
issn = {1878-5905},
abstract = {Calcium ions (Ca[2+]) serve as a pivotal intracellular second messenger, participating in core physiological processes including cell proliferation, neurotransmission, and apoptosis. The maintenance of calcium homeostasis depends on the precise interplay of plasma membrane channels and intracellular organelle stores. Dysregulation of calcium signaling is implicated in the pathogenesis of multiple diseases, including Alzheimer's disease, cancer, and cardiovascular disorders. Conventional pharmacological interventions are limited by off-target effects, insufficient bioavailability, and a lack of temporal and spatial control. Ca[2+]-regulated nanoplatform achieves spatiotemporally controlled drug release and responsive calcium level modulation through advanced surface engineering and stimulus-responsive design, substantially improving therapeutic precision and efficacy. Furthermore, nanoprobes permit real-time monitoring of calcium dynamics with high sensitivity and resolution. This comprehensive review systematically summarizes and highlights significant advances in engineering versatile nanoplatforms for calcium homeostasis modulation, focusing on constructed nanocarriers for drug delivery, functional nano-regulators for calcium flux intervention, and sensitive nanoprobes for real-time calcium imaging and quantification. Current challenges and future directions are also discussed to inspire the development of next-generation nanotheranostic platforms for precise diagnosis and treatment of calcium homeostasis-related diseases.},
}

@article {pmid41962336,
year = {2026},
author = {Kumar, A and Khan, MN and Tiwari, AK and Islam, MM and Judder, MI},
title = {Targeting GPX4 in neurodegenerative disorder: Unlocking ferroptosis as a therapeutic frontier.},
journal = {Tissue & cell},
volume = {101},
number = {},
pages = {103523},
doi = {10.1016/j.tice.2026.103523},
pmid = {41962336},
issn = {1532-3072},
abstract = {Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation and disruption of cellular redox homeostasis. Among the key regulators of this process, glutathione peroxidase 4 (GPX4) plays a central role in maintaining membrane lipid integrity by reducing phospholipid hydroperoxides using glutathione as a cofactor. Impairment of GPX4 activity leads to the accumulation of toxic lipid peroxides, ultimately triggering ferroptotic cell death. Increasing evidence suggests that dysregulation of GPX4-mediated antioxidant defense contributes to the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions characterized by oxidative stress and iron imbalance. In recent years, targeting GPX4 and its associated metabolic pathways has emerged as a promising therapeutic strategy for modulating ferroptosis. This review summarizes the molecular mechanisms governing GPX4 regulation, including its interaction with glutathione metabolism, lipid peroxidation pathways, and iron homeostasis. Furthermore, we discuss emerging pharmacological modulators of GPX4 and ferroptosis, highlighting their potential applications in the treatment of neurological diseases. Understanding the regulatory network surrounding GPX4 may provide new insights into ferroptosis-based therapeutic interventions and facilitate the development of targeted strategies for the management of neurodegenerative disorders.},
}

@article {pmid41962350,
year = {2026},
author = {Mei, D and Su, H and Zhao, Y and Zhang, X and Jiang, C and Zhao, X},
title = {Immobilized enzyme reactor coupled with UHPLC-QTOF-MS for screening acetylcholinesterase inhibitory leads from Aconitum carmichaelii aerial parts.},
journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences},
volume = {1277},
number = {},
pages = {125058},
doi = {10.1016/j.jchromb.2026.125058},
pmid = {41962350},
issn = {1873-376X},
abstract = {The aerial parts of Aconitum carmichaelii Debx. (AAL), an abundant but discarded agricultural byproduct, represent an unexplored source of acetylcholinesterase (AChE) inhibitors. However, the direct screening of bioactive leads from such a complex matrix poses significant analytical challenges. Herein, we report an integrated platform coupling a magnetic immobilized enzyme reactor with ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) for effective screening of AChE inhibitory leads. The AChE was immobilized on magnetic chitosan microbeads (AChE@MCM) to create a reusable and stable bioreactor with an impressive 80.9% activity recovery and the ability to be reused over 8 times, along with enhanced pH stability. When applied to AAL extracts, this strategy efficiently fished out five potential AChE inhibitory leads with diverse structures, directly unveiling the untapped medicinal potential of this waste resource. Our work not only provides a sustainable approach to utilizing agricultural byproducts but also validates a powerful tool for rapid bioactivity-guided screening in complex natural products.},
}

@article {pmid41962454,
year = {2026},
author = {Fin, S and Moayedikia, A and Wiil, UK},
title = {Dual-model deep learning for Alzheimer's prognostication.},
journal = {Computers in biology and medicine},
volume = {208},
number = {},
pages = {111672},
doi = {10.1016/j.compbiomed.2026.111672},
pmid = {41962454},
issn = {1879-0534},
abstract = {Disease-modifying therapies for Alzheimer's disease demand precise timing decisions, yet current predictive models require longitudinal clinical observations and provide no uncertainty quantification-rendering them impractical at the critical first-visit encounter when treatment decisions must be made. We developed PROGRESS (PRognostic Generalization from REsting Static Signatures), a dual-model deep learning framework that transforms a single baseline cerebrospinal fluid (CSF) biomarker assessment into actionable prognostic estimates without requiring prior clinical history. The framework addresses two complementary clinical questions: a probabilistic trajectory network predicts individualized cognitive decline parameters with calibrated uncertainty bounds that achieve near-nominal coverage, enabling honest prognostic communication rather than false precision; and a deep survival model estimates time-to-conversion from mild cognitive impairment to dementia. Using data from over 3000 participants across 43 Alzheimer's Disease Research Centers in the National Alzheimer's Coordinating Center database, PROGRESS substantially outperforms existing approaches including Cox proportional hazards, Random Survival Forests, and gradient boosting methods for survival prediction. Risk stratification identifies patient groups with seven-fold differences in conversion rates, enabling clinically meaningful treatment prioritization. Leave-one-center-out validation demonstrates robust generalizability, with survival discrimination remaining strong across all held-out clinical sites despite heterogeneous measurement conditions spanning four decades of assay technologies. By combining superior survival prediction with trustworthy trajectory uncertainty quantification, PROGRESS bridges the gap between biomarker measurement and personalized clinical decision-making-providing the prognostic timeline that current staging approaches cannot offer.},
}

@article {pmid41962506,
year = {2026},
author = {Jiang, S},
title = {Restoring Theta-Gamma coupling in Alzheimer's disease: Toward network-based neuromodulation.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {3},
pages = {e00901},
doi = {10.1016/j.neurot.2026.e00901},
pmid = {41962506},
issn = {1878-7479},
}

@article {pmid41962542,
year = {2026},
author = {Zhang, J and Huang, Y and Chen, Y and Zhang, Y and Chen, J and Huang, Y and Zhong, H and He, H and Dai, X and Yan, X and Chen, W and Ye, Q and Chen, X and Zhang, J},
title = {Astrocytic calcium-dependent enzyme PAD2 governs microglia activity to exacerbate amyloid pathology via citrullinated vimentin.},
journal = {Immunity},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.immuni.2026.03.007},
pmid = {41962542},
issn = {1097-4180},
abstract = {Glial crosstalk surrounding amyloid-β (Aβ) plaques establishes a self-propagating inflammatory niche fueling Alzheimer's disease (AD), yet the molecular triggers remain incompletely defined. We found that the calcium-dependent enzyme peptidyl-arginine deiminase 2 (PAD2) was selectively upregulated in plaque-associated astrocytes in human AD cortex and multiple APP AD transgenic mouse models. Astrocyte-specific deletion of Padi2 in 5×FAD mice rescued learning and memory, lowered Aβ load, restrained pro-inflammatory microglial activation, and restored microglial phagocytosis. Multi-omics profiling tied these benefits to rewiring of the astrocytic proteome and the microglial transcriptome toward homeostasis. PAD2 converted astrocytic vimentin to citrullinated Cit-Vim175/184. The released Cit-vimentin drove a proinflammatory phenotype while dampening Aβ clearance in microglia-a process dependent on TLR4 signaling. Pharmacological PAD2 inhibition mimicked the genetic rescue, normalizing glial signatures and cognition. These findings identify PAD2-dependent vimentin citrullination as a key inter-glial signaling hub that worsens AD pathology and highlight PAD2 as a promising therapeutic target.},
}

@article {pmid41962593,
year = {2026},
author = {Ran, X and Wang, M and Huang, J and Kuang, N and Tian, P and Wu, J and Feng, F and Luo, Y and Huang, N},
title = {Mechanistic Research and Therapeutic Prospects of Alternative Splicing in Neurodegenerative Diseases.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103133},
doi = {10.1016/j.arr.2026.103133},
pmid = {41962593},
issn = {1872-9649},
abstract = {One essential post-transcriptional regulatory mechanism that increases protein diversity in eukaryotes is alternative splicing. This process is crucial for maintaining nervous system function and is highly active in neurons. Dysregulation of alternative splicing is a common pathogenic factor in many neurodegenerative diseases. For example, splicing variants of tau protein and amyloid precursor protein are implicated in Alzheimer's disease; aberrant splicing of α-synuclein (SNCA) and upregulation of specific transcript variants of the Parkin (PARK2) gene occurs in Parkinson's disease; and aberrant splicing of Stathmin-2 (STMN2) pre-mRNA leads to the loss of axonal maintenance proteins in amyotrophic lateral sclerosis and frontotemporal dementia. This process is precisely regulated by trans-acting factors, a class of RBPs that specifically recognize and bind to cis-acting elements on precursor mRNA (pre-mRNA). These factors are primarily categorized into two major groups: serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs). Although hnRNPs and SR proteins have been shown to regulate neuronal alternative splicing, their complex regulatory networks and associated disease mechanisms remain incompletely understood, hindering the development of targeted therapies. This review summarizes the molecular mechanisms of alternative splicing and its regulatory features in neurodegenerative diseases. It also summarizes recent advances in splicing-based therapies and biomarkers, providing insights into disease mechanisms and therapeutic development.},
}

@article {pmid41962595,
year = {2026},
author = {Gong, X and Xu, C and Chen, X and Wang, K},
title = {A Multi-Omic Framework Reveals Cell-Type-Specific Mechanisms of Isofraxidin Action in Alzheimer Disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111862},
doi = {10.1016/j.brainresbull.2026.111862},
pmid = {41962595},
issn = {1873-2747},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by coordinated dysfunction across multiple brain cell types. Natural compounds with multi-target regulatory potential represent promising therapeutic candidates, yet their cell-type-specific mechanisms in the human AD brain remain incompletely understood. In this study, we integrated ligand-based target prediction with large-scale single-nucleus RNA sequencing (snRNA-seq) data from 201,074 nuclei obtained from AD and control human brain samples, together with subcluster-level functional profiling, cell-cell communication analysis, transcriptional regulatory network inference, and structure-based molecular docking and molecular dynamics simulations to systematically characterize the multicellular actions of isofraxidin. Our analyses identified 19 high-confidence isofraxidin targets exhibiting distinct enrichment patterns across AD-associated cell populations. Key targets-including ALOX5 in microglia, MAOB in astrocytes, HSPA1A in endothelial cells (EC), and CBR1 in oligodendrocytes (ODC)-were preferentially localized to disease-relevant cellular subclusters. snRNA-seq revealed marked remodeling of these cell types in AD, characterized by inflammatory microglia, reactive astrocytes, stress-impaired ECs and neurodegeneration-associated ODCs, which overlapped with the highest target enrichment. Functional and regulatory analyses indicated that these vulnerable states converge on oxidative stress, metabolic dysregulation, proteostasis impairment, and aberrant inflammatory signaling. Molecular docking and 100-ns molecular dynamics simulations further confirmed stable and energetically favorable binding of isofraxidin to its core targets. Collectively, this integrative single-cell framework delineates the cell-type-specific therapeutic landscape of isofraxidin in AD and highlights its potential to coordinately modulate key pathogenic pathways underlying neurodegeneration.},
}

@article {pmid41962633,
year = {2026},
author = {Delgado, N and Chaytor, NS and Beeri, MS and Hawks, ZW and Jung, L and Cleveland, M and Bulger, J and Grinspoon, E and Janess, K and Zuniga-Kennedy, M and Sliwinski, MJ and Chhatwal, JP and Kivisäkk, P and Kudva, YC and Rizvi, S and Rickels, MR and Pratley, R and Weinstock, RS and Germine, LT and Fonseca, LM},
title = {Plasma biomarkers of neurodegeneration and their associations with type 1 diabetes characteristics and glycemia.},
journal = {Diabetes research and clinical practice},
volume = {},
number = {},
pages = {113256},
doi = {10.1016/j.diabres.2026.113256},
pmid = {41962633},
issn = {1872-8227},
abstract = {AIMS: Type 1 diabetes (T1D) is associated with an increased risk of Alzheimer's disease and related dementias (AD/ADRD), although mechanisms remain unclear. This study examined the relationships between blood-based biomarkers of ADRD, diabetes-related factors, and glycemia in adults with T1D.

METHODS: This study analyzed 114 adults from the Glycemic Variability and Fluctuations in Cognitive Status in Adults with Type 1 Diabetes (GluCog) Study with available plasma samples. Regression models assessed relationships between biomarkers (Aβ42/Aβ40 ratio, GFAP, NfL, pTau181, pTau217), diabetes characteristics, and continuous glucose monitoring metrics (up to 20 days), adjusting for demographics and kidney disease. False discovery rate (FDR) correction was applied.

RESULTS: Lower Aβ42/Aβ40 ratios were associated with older age of T1D diagnosis and higher NfL concentrations with higher mean glucose, lower glucose time in range, more time spent with glucose above 180 and 250 mg/dL, higher HbA1c, neuropathy, and diabetic ketoacidosis. These remained significant after additional adjustment for kidney disease, although residual confounding by renal function cannot be excluded.

CONCLUSIONS: Higher NfL was linked with multiple measures of hyperglycemia and other diabetes-related complications, consistent with neuronal injury rather than suggesting an ADRD-specific process. Longitudinal studies are needed to clarify the mechanisms between NfL and glycemia in T1D.},
}

@article {pmid41962665,
year = {2026},
author = {Xie, X and Meng, J and Wang, Y},
title = {Frequency-Enhanced Fiber Orientation Distribution Super-Resolution Network with Application on Alzheimer's Disease.},
journal = {Journal of neuroscience methods},
volume = {},
number = {},
pages = {110769},
doi = {10.1016/j.jneumeth.2026.110769},
pmid = {41962665},
issn = {1872-678X},
abstract = {BACKGROUND: Diffusion MRI enables noninvasive assessment of white matter microstructure, but the accuracy of fiber orientation distribution (FOD) reconstruction remains limited by inter-voxel incoherence and insufficient modeling of high-order spherical harmonic dependencies. Existing FOD angular super-resolution approaches often lose orientation information in complex fiber configurations, and their applicability in disease-specific scenarios has been underexplored.

NEW METHOD: We introduce the Cross-Domain Attention FOD Network (CDAF-Net), which integrates a Frequency-enhanced Aggregated Spatial-Channel Attention module to jointly model frequency-domain, spatial, and channel features. The frequency branch captures long-range dependencies, while spatial and channel attentions highlight local critical structures, enabling efficient and accurate angular super-resolution. The apparent fiber density (AFD) derived from CDAF-Net was further evaluated using one-way ANOVA across Alzheimer's disease, mild cognitive impairment, and cognitively normal groups.

RESULTS: CDAF-Net yielded the most accurate reconstructions, achieving the closest alignment with reference FODs and showing clear advantages in regions with complex fiber crossings. Clinically, CDAF-Net-derived AFD exhibited bilateral fornix reductions consistent with disease progression and demonstrated significant group differences, with larger effect sizes and higher sensitivity than baseline approaches, while other white matter tracts did not reach significance.

Compared with state-of-the-art FOD angular super-resolution models, CDAF-Net produced lower orientation errors, better preserved directional information in multi-fiber regions, and provided more sensitive detection of microstructural alterations related to early Alzheimer's disease.

CONCLUSIONS: CDAF-Net improves FOD reconstruction fidelity and enhances sensitivity to early neurodegenerative changes, supporting its potential as a cost-effective alternative to multi-shell HARDI for early screening and clinical research applications.},
}

@article {pmid41962712,
year = {2026},
author = {Haseeb, M and Choi, H and Jeong, U and Kim, MS and Choi, S},
title = {NIM5 series brain-penetrant NLRP3 inflammasome inhibitors suppress neuroinflammation in EAE and Alzheimer's models.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {151905},
doi = {10.1016/j.ijbiomac.2026.151905},
pmid = {41962712},
issn = {1879-0003},
abstract = {Aberrant activation of the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome drives neuroinflammation in multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), and Alzheimer's disease (AD). No clinically approved CNS-active NLRP3 inhibitor exists, highlighting the need for brain-penetrant modulators. We report the discovery and characterization of a novel chemical scaffold of NLRP3 inhibitory modulators (NIM5 series) that selectively suppress inflammasome activation. Lead analogs potently inhibited interleukin-1β (IL-1β), caspase-1, and gasdermin D (GSDMD) activation in THP-1 cells (IC50 = 0.75 μM) without affecting NF-κB, NLRC4, or AIM2 signaling, as shown by immunoblotting and biophysical analyses. Mechanistic studies demonstrated direct NLRP3 binding, consistent with selective inhibition over NLRC4 and AIM2. Permeability assays demonstrated robust blood-brain barrier penetration and CNS availability in vitro. In vivo, systemic administration attenuated neuronal injury, improved behavioral outcomes, and reduced neuroinflammatory markers in both EAE and Aβ-induced mouse models. These findings establish a brain-penetrant NLRP3 inhibitor chemotype for CNS-targeted therapeutic development.},
}

@article {pmid41962757,
year = {2026},
author = {Zhang, M and Lin, C and Zhang, W and Wang, X},
title = {Cognition-enhancing drugs: current landscape, mechanisms, and future prospects.},
journal = {Drug discovery today},
volume = {},
number = {},
pages = {104665},
doi = {10.1016/j.drudis.2026.104665},
pmid = {41962757},
issn = {1878-5832},
abstract = {Cognition-enhancing drugs (CEDs) are pharmacological agents aimed at improving memory, attention, and executive function. This review explores both established and emerging CEDs that target neurotransmitter systems, neuroinflammation, and neuroplasticity. It discusses innovative design strategies, such as multi-target agents and prodrugs, and examines clinical challenges in Alzheimer's disease and other conditions. We address ethical, societal, and regulatory concerns, especially those relating to non-medical use, highlighting the importance of responsible development and precision-based approaches in cognitive therapeutics.},
}

@article {pmid41962917,
year = {2026},
author = {Lynch, DH and Lynch, ME and Wessell, KL and Lin, FC and Toles, M and Mitchell, SL and Hanson, LC},
title = {Stage of Disease Among Hospitalized Persons Living With Dementia: A Multisite Study.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {106183},
doi = {10.1016/j.jamda.2026.106183},
pmid = {41962917},
issn = {1538-9375},
abstract = {OBJECTIVES: To examine dementia stage and factors associated with stage among hospitalized older adults with Alzheimer's disease and related dementias (ADRD).

DESIGN: Secondary analysis of baseline data from the multisite ADRD-Palliative Care (ADRD-PC) clinical trial screening cohort.

SETTING AND PARTICIPANTS: Five US medical centers; hospitalized adults aged ≥55 years with ADRD identified at admission. Dementia stage was classified using the Global Deterioration Scale (GDS) as mild (GDS 3-4), moderate (GDS 5-6), or severe (GDS 7).

METHODS: Multinomial logistic regression identified demographic and clinical characteristics independently associated with dementia stage. Independent variables included age, race, admitting service (general medicine, subspecialty/surgery, intensive care unit), and dementia diagnosis; models were clustered by site.

RESULTS: Among 6303 hospitalized patients with ADRD, 39.3% had mild dementia, 57.8% moderate, and 2.9% severe. Compared with those with mild dementia, individuals with moderate dementia had higher odds of being older (75-84 years: adjusted odds ratio [aOR], 1.34; 95% CI, 1.17-1.53; ≥85 years: aOR, 2.02; 95% CI, 1.76-2.33), Black (aOR, 1.45; 95% CI, 1.27-1.66), less often admitted to subspecialty/surgical services (aOR, 0.65; 95% CI, 0.58-0.73), and more often diagnosed with Alzheimer's disease (aOR, 1.85; 95% CI, 1.62-2.12). Individuals with severe dementia had higher odds of being Black (aOR, 2.43; 95% CI 1.72-3.43) or Asian (aOR, 2.95; 95% CI, 1.57-5.54), less often admitted to subspecialty/surgical services (aOR, 0.39; 95% CI, 0.26-0.58), and more often diagnosed with Alzheimer's disease (aOR, 2.67; 95% CI, 1.9-3.77).

CONCLUSIONS AND IMPLICATIONS: Moderate-stage dementia was the most common stage among hospitalized patients with ADRD. Patients with moderate or severe dementia were more likely to be older, identify as Black, be admitted to general medical services, and have Alzheimer's disease. Staging and related characteristics may guide hospital-based interventions to improve care for people with ADRD.},
}

@article {pmid41963258,
year = {2026},
author = {Bayram, S and Gültekin, YS and Gültekin, P},
title = {Rural-Urban Disparities in Alzheimer's Disease Risk Among Older Adults in Türkiye: A Comparative Study.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {3},
pages = {e70167},
doi = {10.1111/psyg.70167},
pmid = {41963258},
issn = {1479-8301},
mesh = {Humans ; *Alzheimer Disease/epidemiology/diagnosis ; Male ; Female ; Aged ; *Rural Population/statistics & numerical data ; Cross-Sectional Studies ; *Urban Population/statistics & numerical data ; Risk Factors ; Aged, 80 and over ; Turkey/epidemiology ; *Health Status Disparities ; Prevalence ; Socioeconomic Factors ; },
abstract = {AIM: As Türkiye's population ages, the prevalence of Alzheimer's Disease (AD) and its associated risk factors is a growing public health concern. Previous research suggests that rural populations may face disproportionately higher rates of chronic diseases, limited healthcare access, and lower socioeconomic status, which could contribute to elevated AD risk. This study aimed to investigate and compare AD risk levels among older adults residing in rural versus urban areas of a province in Türkiye.

METHODS: This cross-sectional comparative study was conducted in Düzce province, located in the Western Black Sea region of Türkiye, encompassing both urban (Düzce city center and its districts) and rural (forest villages) settlements. A total of 759 older adults (365 rural, 394 urban) were recruited using a multi-stage sampling method. Participants completed the Turkish Australian National University Alzheimer's Disease Risk Index Short Form (TR-ANU-ADRI-SF) to determine AD risk factors and the Dementia Screening Form (AD8) to determine self-reported cognitive status. Data were analysed using descriptive statistics, Independent Samples t-tests, Chi-square tests, and Multivariate Linear Regression Analysis.

RESULTS: Significant differences were observed between rural and urban older adults across several socio-demographic and health characteristics. Rural older adults had a significantly higher mean TR-ANU-ADRI-SF score (9.03 ± 9.89 for rural vs. 1.12 ± 7.49 for urban, p < 0.001). Based on AD8 scores, the rate of self-reported cognitive concerns (SCC) was also significantly higher in rural older adults (35.6%) (p < 0.01). However, after adjusting for age, gender, and years of education, residence status was no longer found to be independently associated with TR-ANU-ADRI-SF scores (B = -0.134; p > 0.05).

CONCLUSION: In conclusion, the higher risk of AD observed in older adults living in rural areas appears to stem primarily from differences in age and education level, rather than from residential status. These findings highlight the importance of addressing educational inequalities and promoting lifelong cognitive engagement as key strategies to reduce the risk of AD, particularly in rural populations.},
}

Humans
*Alzheimer Disease/epidemiology/diagnosis
Male
Female
Aged
*Rural Population/statistics & numerical data
Cross-Sectional Studies
*Urban Population/statistics & numerical data
Risk Factors
Aged, 80 and over
Turkey/epidemiology
*Health Status Disparities
Prevalence
Socioeconomic Factors

@article {pmid41963316,
year = {2026},
author = {Smith, AM and Lorkiewicz, SA and Arslan, B and Montoliu-Gaya, L and Ashton, NJ and Wilson, EN and Alcolea, D and Rodríguez-Baz, Í and Fortea, J and Young, CB and Winer, JR and Shahid-Besanti, M and Vossler, H and Plastini, MJ and Pan, T and Vera-Campuzano, E and Sala, I and Mendiola, JH and Ramirez, V and Kerchner, GA and Andreasson, KI and Henderson, VW and Montine, TJ and Tian, L and Mormino, EC and Zetterberg, H and Poston, KL and Abdelnour, C},
title = {Plasma phosphorylated tau 217 detects amyloid-β in neuronal synuclein disease.},
journal = {NPJ Parkinson's disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41531-026-01341-8},
pmid = {41963316},
issn = {2373-8057},
support = {PI18/00435, PI22/00611, INT19/00016, INT23/00048//Instituto de Salud Carlos III/ ; P50 AG047366/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; R21AG058859/NH/NIH HHS/United States ; K23 NS075097, R01NS115114/NH/NIH HHS/United States ; #2023-00356, #2022-01018, #2019-02397//Swedish Research Council/ ; No 101053962//HORIZON EUROPE European Research Council/ ; No 101081334//HORIZON EUROPE European Research Council/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; #201809-2016862//Alzheimer's Drug Discovery Foundation/ ; #ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C//AD Strategic Fund and the Alzheimer's Association/ ; #22HLT07//European Partnership on Metrology/ ; #FO2022-0270//Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden/ ; No 860197//Horizon 2020 Framework Programme/ ; JPND2021-00694//European Union Joint Programme - Neurodegenerative Disease Research/ ; UKDRI-1003//National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; },
abstract = {Multiple proteinopathies commonly coexist in neurodegenerative diseases, making it essential to evaluate plasma biomarker performance in these complex diseases. While plasma biomarkers accurately detect amyloid-β pathology in Alzheimer's disease (AD), their performance is unknown in neuronal synuclein disease (NSD). We aimed to determine the accuracy of plasma pTau217, pTau181, Aβ42/40, GFAP, and NfL to detect amyloid-β in NSD, then establish and validate cut points for the most promising marker. We included 253 participants (180 discovery; 73 validation). In the discovery cohort, NSD status was defined by CSF α-synuclein seed amplification assay and amyloid-β status by CSF Aβ42/40. Participants included individuals with clinical Lewy body disease (LBD), AD, and cognitively unimpaired. Validation cohorts consisted of clinically diagnosed LBD participants. In the discovery cohort, plasma pTau217, pTau181, Aβ42/40, and GFAP significantly differed by amyloid-β status regardless of NSD status, while NfL was highest in NSD+/Aβ+ participants. Among all biomarkers, plasma pTau217 showed the best diagnostic performance (AUC = 0.92, 95% CI = 0.81-0.98). Applying plasma pTau217 cut points to pre-screen clinically diagnosed LBD participants reduced the need for confirmatory amyloid-β PET or CSF in 41-56%. These findings support plasma pTau217 as a minimally-invasive tool for identifying pathological amyloid-β in neuronal synucleinopathies with mixed Alzheimer's disease pathology.},
}

@article {pmid41963454,
year = {2026},
author = {Malakar, V and Roy, D and Dugar, N and Mali, PC and Malakar, CC and Gautam, M and Poddar, NK},
title = {Computational investigation of biochanin a targeting DEPTOR in Alzheimer's disease with in vitro cellular validation of neuroprotective activity.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-47343-7},
pmid = {41963454},
issn = {2045-2322},
}

@article {pmid41963691,
year = {2026},
author = {Fyfe, I},
title = {Targeting gut pathology is effective in an Alzheimer disease model.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {41963691},
issn = {1759-4766},
}

@article {pmid41772480,
year = {2026},
author = {Lv, H and Cai, Y and Mo, D and Gao, X and Wei, M and Xu, J and Jing, F and Zhang, Y and Fang, X and Wu, W and Xiang, Y and Ma, X},
title = {The relationship between low birth weight and neurological disorders: a prospective cohort study in the UK Biobank.},
journal = {BMC neurology},
volume = {26},
number = {1},
pages = {},
pmid = {41772480},
issn = {1471-2377},
support = {cstc2021ycjh-bgzxm0008//Chongqing Talents: Exceptional Young Talent Project/ ; },
abstract = {BACKGROUND: Birth weight as a marker of fetal growth has been linked to later health outcomes, but its relationship with adult neurological disorders is less well characterised, and few large studies have evaluated multiple neurological disorders within a unified analytical framework.

METHODS: We analyzed 279,842 UK Biobank participants with self-reported birth weight. Birth weight was modeled continuously (per 1-kg increment) and categorically (low < 2.5 kg, reference 2.5–4.0 kg, high ≥ 4.0 kg). Incident multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD), epilepsy, migraine and cerebrovascular disease (CVD) were ascertained from hospital and registry records (ICD-10). Logistic regression estimated OR and 95% CI, adjusting for age, sex, education, race, and socioeconomic status, with stratification by sex and age.

RESULTS: Low birth weight was associated with higher risk of AD (OR = 1.31, 95% CI 1.14–1.51), epilepsy (OR = 1.37, 95% CI 1.24–1.51), and CVD (OR = 1.32, 95% CI 1.25–1.40). AD showed a U-shaped pattern, with high birth weight increasing risk (OR = 1.19, 95% CI 1.04–1.36). Each 1-kg increase in birth weight corresponded to 12% lower odds of epilepsy (OR = 0.88, 95% CI 0.84–0.93) and 11% lower odds of CVD (OR = 0.89, 95% CI 0.85–0.94). Findings were consistent across sex and age strata, and no associations were observed for MS, PD, or migraine after full adjustment.

CONCLUSIONS: Low birth weight was independently associated with increased risk of AD, epilepsy, and CVD in adulthood, but not with MS, PD, or migraine, after adjustment for measured confounders. These observational findings, which remain susceptible to residual confounding and measurement error, support the Developmental Origins of Health and Disease framework and underscore the enduring influence of early-life growth on neurological health. Future research should incorporate objective birth records, encompass more diverse populations, and explore how birth weight can be integrated into life-course risk prediction models and prenatal preventive strategies.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12883-026-04761-4.},
}

@article {pmid41776475,
year = {2026},
author = {Mekonen, EW and Endalew, SA and Ferede, YA and Birhan, GW},
title = {Antibacterial and antioxidant activities of Inula confertiflora extracts.},
journal = {BMC complementary medicine and therapies},
volume = {26},
number = {1},
pages = {},
pmid = {41776475},
issn = {2662-7671},
abstract = {BACKGROUND: Antimicrobial-resistant pathogenic microorganisms are disease causing microbes that cause several diseases in humans, animals, and plants. Currently, these microorganisms cause more than a quarter of the reported diseases worldwide. The other current global health risk is the imbalance generation of free radicals in human physiology, which exposes several millions to oxidative stress diseases like Alzheimer, Cancer, and Diabetes.

OBJECTIVE: The objective of this study was to evaluate the antibacterial and antioxidant activities of Inula confertiflora roots, stems, and leaves extracts.

METHOD: The methanolic, ethyl acetate, and petroleum ether extracts of the roots, stems, and leaves of this plant were separately evaluated against the Gram-positive bacteria strains Enterococcus faecalis, Staphylococcus aureus, and Gram-negative bacteria Klebsiella pneumonia using the agar well diffusion method. Each crude extract was also evaluated by an invitro antioxidant activity test against DPPH free radical reagent.

RESULT: The crude extrats showed moderate to high activities against two Gram-positive bacterial strains, S. aureus and E. faecalis. The petroleum ether extract of the leaves showed the highest activity (39.97 ± 0.12 mm inhibition diameter) against S. aureus. All crude extracts also showed strong free radical scavenging activity, with a maximum percentage scavenging value. The root petroleum ether extracts showed 99.18 ± 0.06% scavenging activity at 1000 (µg/ml) concentration.

CONCLUSION: Extracts from this plant are potentially effective against S. aureus and E. faecalis; they also have strong free radical scavenging activities.},
}

@article {pmid41776637,
year = {2026},
author = {Wang, L and Wang, F and Wang, X and Chen, X and Li, C and Shan, K and Zhou, H and Wu, G and Xu, Z and Kong, X and Wei, P},
title = {The lung-brain axis: elucidating the mechanisms of pulmonary-driven neurological disorders.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41776637},
issn = {1742-2094},
support = {22201164//National Natural Science Foundation of China/ ; 82571352//National Natural Science Foundation of China/ ; QDZDZK-2025064//the Qingdao Key Health Discipline Development Fund/ ; ZR2024QH041//the Natural Science Foundation of Shandong Province/ ; QDKY2023ZD02//the Scientific Research Foundation of Qilu Hospital of Shandong University/ ; 2024M761822//China Postdoctoral Science Foundation/ ; },
abstract = {The brain and lungs represent two of the most vital organs in the human body. The conceptualization of the lung-brain axis has advanced our understanding of the bidirectional communication between the respiratory and central nervous systems. Accumulating evidence indicates that pulmonary diseases, including chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome and infections such as bacterial pneumonia, influenza and Coronavirus Disease 2019, along with airborne environmental exposures, constitute significant risk factors for various neurological disorders. The lung-brain axis is primarily mediated by microbial, immune, neural, metabolic and hormonal pathways. These mechanisms contribute to the disruption of blood-brain barrier integrity, the activation of neuroglial cells and the dysfunction of the cerebrovascular system, ultimately causing neuronal injury and diverse neurological conditions. Environmental factors, notably airborne particulate matter and chemical pollutants, further amplify the crosstalk among these mechanisms, extending the neurological risk. Here, we summarize the current knowledge regarding the association between pulmonary dysfunction and the development and progression of neurodegenerative diseases (such as Alzheimer’s disease and Parkinson’s disease), stroke, anxiety/depression, epilepsy, and migraine. Additionally, potential therapeutic strategies targeting the lung–brain axis are discussed to foster further research in this emerging field. Elucidating the complex interactions within the lung–brain axis will not only deepen our understanding of the shared pathophysiological mechanisms but also open novel avenues for the early diagnosis, prevention, and treatment of related neurological diseases.},
}

@article {pmid41862973,
year = {2026},
author = {Marei, HE},
title = {Enhancer-based gene therapy: a new path for precision medicine.},
journal = {Hereditas},
volume = {163},
number = {},
pages = {},
pmid = {41862973},
issn = {1601-5223},
abstract = {Enhancers are critical cis-regulatory elements that regulate gene expression in a context-dependent manner by integrating transcription factor binding, chromatin state, and the three-dimensional organization of the genome. Recent advances in functional genomics and synthetic biology have increased interest in harnessing enhancer activity to regulate the expression of therapeutic genes. Unlike traditional approaches that rely on promoter-driven gene regulation, enhancer-based approaches can bias transgene expression toward specific cellular states or disease contexts; however, this control remains probabilistic and highly dependent on the chromatin environment. This review summarizes current knowledge of enhancer biology, discusses new strategies for utilizing enhancer function directly, and examines the potential benefits and drawbacks of using enhancer-based strategies for gene therapy applications. Often delivered using adeno-associated virus (AAV) vectors with tailored capsids, enhancers in gene therapy can be included into expression cassettes. Astrocyte- or microglia-specific enhancers in the brain enable enriched or preferential distribution of neuroprotective or immunomodulatory genes, hence lowering unintentional expression in non-target cell types. It is important to control gene expression for specific cell types for the treatment of neurodegenerative conditions such as Alzheimer’s or Parkinson’s disease, were unintentional gene expression results in negative consequences. However, the uses of enhancer-guided gene therapy go beyond the central nervous system. In cancer, therapeutic constructs are designed to inhibit oncogenic expression or induce tumor suppression pathways, using enhancers in either malignant or immune cells as a target. Similarly, through the use of tissue-specific enhancers in cardiovascular and regenerative medicine, lineage-enriched genes can be used to promote repair of damaged tissues and enhance functional recovery. Enhancer-based systems that modulate the levels of gene expression (enhancer systems that adjust gene expression to levels that are physiologically appropriate for a given cell type) may also be useful in diseases caused by imbalances of gene dosage (e.g., haploinsufficiency and copy number variations). However, despite the potential promise of enhancer-driven gene therapy, many technical and translational hurdles remain. Mapping and validating the function of cell-type-specific enhancers is hampered by the dynamic, context-dependent regulation of chromatin. The identification of enhancers across a variety of developmental stages and clinical states is being accelerated through the combination of recent advances in single-cell epigenomic techniques (e.g., ATAC-seq, ChIP-seq, and multi-omic integration). Recent advances in non-viral delivery methods and AAV capsid engineering are improving the safety, efficacy, and scalability of enhancer-driven gene therapies. However, there must be careful regulatory oversight to avoid unintentional activation of enhancers and ensure continuing efficacy of enhancer-guided therapies. This paper provides an overview of the conceptual basis of enhancer-driven gene therapies, the currently available applications, and barriers to their clinical application. We show how the combination of delivery technology, synthetic biology, and genomics is enabling new possibilities for tailored gene therapy particular to cell- and disease-specific. Enhancer-driven gene therapy could become an important component of next-generation precision medicine by addressing current challenges and using creative technology.},
}

@article {pmid41951582,
year = {2026},
author = {Kimura, T and Yamakawa, A and Mitsumori, R and Niida, S and Ozaki, K and Shigemizu, D},
title = {Whole-genome sequencing reveals an East Asian-specific rare variant of INPP5J associated with Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04027-0},
pmid = {41951582},
issn = {2158-3188},
abstract = {Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly, yet no curative treatments are available. Although genome-wide association studies (GWASs) have identified numerous genetic risk factors, these factors often differ among ethnic groups, and the mechanisms driving LOAD onset remain poorly understood. Most GWASs of LOAD have been conducted in European populations; the expansion of future studies to non-European populations should uncover novel genetic factors underlying LOAD pathogenesis. To identify novel LOAD-susceptible genes, we conducted whole-genome sequencing data analysis on 1928 Japanese individuals including 325 patients with LOAD and 1603 cognitively normal elderly controls. A GWAS for common variants identified a statistically significant association signal in rs429358, within the apolipoprotein E gene (APOE), which defines the APOEε4 haplotype. This association was successfully replicated in an independent Japanese replication cohort of 4768 samples, genotyped using the Asian Screening Array. For rare variants, a gene-based association study identified two rare variants, rs769490815 and rs1921732305, in Inositol polyphosphate 5-phosphatase (INPP5J) as potential candidates for LOAD association. Due to their extremely low allele frequencies, these variants were not included on the genotyping array and could not be evaluated in the replication cohort. However in vitro functional analyses revealed that the ethnicity-specific p.K687T mutation (rs1921732305) significantly reduced the phosphatase activity of INPP5J, suggesting a potential pathogenic role in LOAD.},
}

@article {pmid41951598,
year = {2026},
author = {Zhao, S and Ye, R and Tang, QY and Attaallah, B and Toniolo, S and Saleh, Y and Rouse, MA and Garrard, P and Broulidakis, MJ and Thompson, S and Manohar, SG and Irani, SR and Ang, YS and Lockwood, P and Apps, MAJ and Hu, P and Wang, K and Rowe, JB and Le Heron, C and Husain, M},
title = {The social dimension of apathy: evidence for a distinct domain from 11,243 individuals across health and neurocognitive disorders.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04023-4},
pmid = {41951598},
issn = {2158-3188},
support = {226645/Z/22/Z//Wellcome Trust (Wellcome)/ ; 226645/Z/22/Z//Wellcome Trust (Wellcome)/ ; 226645/Z/22/Z//Wellcome Trust (Wellcome)/ ; 220258/WT_/Wellcome Trust/United Kingdom ; 226645/Z/22/Z//Wellcome Trust (Wellcome)/ ; 82171917//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82471271//National Natural Science Foundation of China (National Science Foundation of China)/ ; MR/V007173/1//RCUK | Medical Research Council (MRC)/ ; MC_UU_00030/14//RCUK | Medical Research Council (MRC)/ ; SUAG/092 G116768//RCUK | Medical Research Council (MRC)/ ; 02/2019//Canterbury Medical Research Foundation (CMRF)/ ; },
abstract = {Apathy is a highly prevalent and disabling neuropsychiatric syndrome, but its multi-dimensional structure is a challenge for progress towards better identification and treatment. A crucial unresolved question is whether social disengagement reflects a distinct deficit in social motivation or a by-product of diminished initiative or emotional blunting. Previous studies have been constrained by modest sample sizes and limited use of apathy-specific instruments or phenotypically narrow cohorts. Here, we analysed item-level data from 11,243 individuals recruited across multiple centres, including 1154 neurological patients with Alzheimer's disease, Parkinson's disease, frontotemporal dementia, autoimmune encephalitis and small vessel disease, alongside people with depression and healthy adults. Across exploratory and confirmatory factor analyses, symptom-level network modelling, and lifespan analyses, social apathy consistently emerged as a coherent and separable dimension. This pattern was preserved across health, psychiatric, and neurocognitive cohorts, from adolescence through late life. Recognising social apathy as an independent domain reframes a central aspect of mental health-the motivation to connect, care, and act for others-and provides a foundation for more precise assessment and for interventions targeting both social and neurobiological mechanisms.},
}

@article {pmid41951832,
year = {2026},
author = {Islam, N and Akçesme, B},
title = {Single nucleotide polymorphisms affecting galantamine binding to acetylcholinesterase in Alzheimer's disease: a structural bioinformatics study.},
journal = {Journal of computer-aided molecular design},
volume = {40},
number = {1},
pages = {},
pmid = {41951832},
issn = {1573-4951},
mesh = {*Galantamine/chemistry/metabolism ; Humans ; *Alzheimer Disease/drug therapy/genetics/enzymology ; *Acetylcholinesterase/chemistry/genetics/metabolism ; *Cholinesterase Inhibitors/chemistry/metabolism/pharmacology ; Molecular Dynamics Simulation ; *Polymorphism, Single Nucleotide ; Molecular Docking Simulation ; Protein Binding ; Computational Biology ; Binding Sites ; Ligands ; Catalytic Domain ; Thermodynamics ; },
abstract = {Galantamine, an acetylcholinesterase (AChE) inhibitor used for symptomatic treatment of Alzheimer's disease (AD), shows substantial inter-individual variability in clinical response. Missense single nucleotide polymorphisms (SNPs) within the AChE active-site gorge may modulate inhibitor recognition. In this computational study, binding residues were defined from human AChE inhibitor co-crystal structures and cross-referenced with dbSNP missense variation, followed by in-silico predictions of variant impact, evolutionary conservation and folding stability, and assessment of ligand engagement by docking and molecular dynamics (MD) with MM/GBSA binding-energy estimation. Using complexes containing galantamine (GNT) and a donepezil-like ligand (E20), 11 of 807 AChE missense variants overlapped binding-site residues, highlighting Phe294 (UniProt Phe326) and His447 (UniProt His479). ConSurf classified His447 as highly conserved, and MUpro predicted decreased folding stability for His447 substitutions. SwissDock docking indicated that His447Gln retains a plausible GNT binding pose and yielded the least favourable docking score among the tested variants, consistent with a potential reduction in binding strength. MD simulations (200 ns) of wild-type and His447Gln AChE-GNT complexes supported preserved global structural integrity of the complex over the simulated timescale, while indicating local remodelling of the GNT binding microenvironment. MM/GBSA estimates from terminal snapshots suggested a modestly less favourable theoretical binding free energy for His447Gln relative to wild-type (approximately 2.0 kcal mol[-1]). Given that His447 is the catalytic triad histidine, such substitutions may have consequences for catalysis in addition to inhibitor binding; these in-silico findings require experimental validation using site-directed mutagenesis with kinetic and binding assays.},
}

*Galantamine/chemistry/metabolism
Humans
*Alzheimer Disease/drug therapy/genetics/enzymology
*Acetylcholinesterase/chemistry/genetics/metabolism
*Cholinesterase Inhibitors/chemistry/metabolism/pharmacology
Molecular Dynamics Simulation
*Polymorphism, Single Nucleotide
Molecular Docking Simulation
Protein Binding
Computational Biology
Binding Sites
Ligands
Catalytic Domain
Thermodynamics

@article {pmid41951843,
year = {2026},
author = {Komy, MHE and Aldosari, BN and Zaki, RM and Bafail, R and Yusif, RM and Abdelgawad, MA and Elmowafy, M and Abuhelwa, AY and Eid, HM},
title = {Intranasal co-delivery of riluzole and berberine via chitosan-coated PLGA nanoparticles for synergistic neuroprotection in Alzheimer's disease: formulation, characterization, and pharmacokinetics analysis.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41951843},
issn = {1432-1912},
support = {DGSSR-2024-01-02058//Al Jouf University/ ; },
abstract = {This study presents an intranasal chitosan-coated PLGA nanoparticle system co-loaded with riluzole (RLZ) and berberine (BER) to achieve synergistic neuroprotection and enhanced brain targeting for Alzheimer's disease therapy. Chitosan-coated PLGA nanoparticles containing riluzole and berberine (RLZ-BER-CTS-PLGA) were prepared via a modified single emulsion-solvent evaporation method using 0.9% PLGA and 1% PVA, and 0.99% chitosan. The optimized formulation exhibited a size of 203.5 nm, zeta potential of + 34.7 mV, and high entrapment efficiencies of 73.9% (RLZ) and 71.4% (BER). In vitro release showed sustained delivery, with only 36.3% BER and 28.4% RLZ released after 2 h compared to 82.6% and 57.3% from suspensions. Ex vivo nasal permeation demonstrated 2.8-fold (BER) and 2.1-fold (RLZ) increases in permeability coefficients relative to drug suspensions. Pharmacokinetic evaluation confirmed superior brain delivery, with intranasal RLZ-BER-CTS-PLGA achieving Cmax levels of 596 ng/mL for BER and 1345 ng/mL for RLZ, versus only 213 ng/mL and 385 ng/mL from intranasal suspensions. Direct transport percentage (DTP) reached 81.4% for BER and 56.4% for RLZ, with corresponding drug targeting efficiencies (DTE) of 536.6% and 229.3%. Histopathology confirmed nasal safety with no mucosal irritation. These results establish chitosan-functionalized PLGA nanocarriers as a promising noninvasive co-delivery platform for multifunctional Alzheimer's therapeutics.},
}

@article {pmid41952326,
year = {2026},
author = {Youssef, H and Gatto, RG and Ghayal, NB and Estades Ayuso, V and Jansen-West, KR and Dunmore, JA and Song, Y and Yue, M and Cook, CN and DeTure, M and Rawlinson, BD and Castanedes-Casey, M and Jack, CR and Petersen, RC and Dickson, DW and Petrucelli, L and Whitwell, JL and Prudencio, M and Josephs, KA},
title = {Biochemical and Immunohistochemical Associations of TDP-43 and Cryptic RNA With Hippocampal and Amygdala Volumetrics in Alzheimer's Disease.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78223},
pmid = {41952326},
issn = {1531-8249},
abstract = {OBJECTIVE: Immunohistochemically (IHC) measured transactive response DNA-binding protein 43 (TDP-43) inclusions are observed in Alzheimer's disease (AD) and are associated with medial temporal lobe atrophy. Accumulation of cryptic exons occurs in AD in response to TDP-43 pathology. We aimed to assess relationships between IHC and biochemically measured insoluble TDP-43 and cryptic exons and assess associations with hippocampal and amygdala volume loss and atrophy rates on magnetic resonance imaging (MRI).

METHODS: Eighty-one neuropathologically diagnosed AD cases were analyzed. For biochemistry, insoluble TDP-43 was quantified using a Meso-scale discovery (MSD) immunoassay. IHC-TDP burden was quantified with digital histopathology. Cryptic RNAs were assessed via quantitative real-time polymerase chain reaction (qRT-PCR). Thirty-eight cases had serial brain MRI. Hippocampal and amygdala volumes were calculated using FreeSurfer. Regression models were used to investigate associations among IHC-TDP-43 status/burden, MSD-TDP status/levels, cryptic RNAs, and hippocampal and amygdala volumes and atrophy rates.

RESULTS: IHC-TDP(+) cases exhibited elevated levels of MSD-TDP and cryptic RNAs (KCNQ2, STMN2, and UNC13A) and increased MSD-TDP levels were associated with increased cryptic RNA levels, in the hippocampus and amygdala. IHC-TDP(+) cases had smaller hippocampal and amygdala volumes compared to IHC-TDP(-) cases. MSD-TDP(+) cases had smaller hippocampal volumes and faster amygdala rates of atrophy compared with MSD-TDP(-) cases. Higher KCNQ2 and UNC13A levels were associated with smaller amygdala volumes.

INTERPRETATION: MSD-TDP level is a reliable surrogate for IHC-based TDP-43 status. Both TDP-43 and cryptic RNA levels are associated with reduced medial temporal volumes, suggesting cryptic exons may be playing a role in brain volume loss in AD. ANN NEUROL 2026.},
}

@article {pmid41952419,
year = {2026},
author = {Jiang, X and Toomey, CE and Lashley, T and Gatt, A},
title = {Widespread hnRNP K Mislocalisation Suggests Differential Neuronal Vulnerability in the Neurodegenerative and Ageing Human Brain.},
journal = {Neuropathology and applied neurobiology},
volume = {52},
number = {2},
pages = {e70072},
doi = {10.1111/nan.70072},
pmid = {41952419},
issn = {1365-2990},
support = {579/ALZS_/Alzheimer's Society/United Kingdom ; //Alzheimer's Research UK/ ; //Association of Frontotemporal Dementia/ ; //BRAIN non-clinical post-doctoral fellowship/ ; //My Name'5 Doddie Foundation/ ; },
mesh = {Humans ; *Brain/pathology/metabolism ; Male ; Aged ; Female ; *Aging/pathology/metabolism ; *Neurons/metabolism/pathology ; *Heterogeneous-Nuclear Ribonucleoprotein K/metabolism ; Aged, 80 and over ; Middle Aged ; *Neurodegenerative Diseases/pathology/metabolism ; Alzheimer Disease/pathology/metabolism ; Frontotemporal Lobar Degeneration/pathology/metabolism ; },
abstract = {Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a widely distributed RNA-binding protein in the human brain, playing a crucial role in post-transcriptional regulation, including mRNA metabolism and neuroplasticity. We have previously identified an increase in neuronal hnRNP K mislocalisation in cases of frontotemporal lobar degeneration (FTLD) compared to controls, where loss of nuclear hnRNP K was linked to alternative splicing events. However, the broader distribution of hnRNP K mislocalisation across different brain regions, other diseases and its pathological significance remains unclear. This study systematically examined hnRNP K mislocalisation across 13 brain regions from 19 cases, including different pathological subtypes of FTLD, Parkinson's disease (PD), Alzheimer's disease (AD) and age-matched neurologically normal controls, using immunohistochemistry and quantitative image analysis. The results of the study show that hnRNP K mislocalisation is observed throughout the brain, characterised by nuclear depletion and cytoplasmic aggregation. In the cerebral cortex, mislocalisation was most pronounced in the frontal lobe and least in the occipital lobe, with significant predominance in the depth of sulci compared to gyri. Notably, the basal ganglia, thalamus, medulla and cerebellum exhibited particular vulnerability to hnRNP K pathology. In contrast, Purkinje cells within the cerebellum and CA1-CA2 pyramidal neurons within the hippocampus showed lower levels of mislocalisation. Furthermore, levels of hnRNP K mislocalisation within the putamen correlated significantly with motor symptoms, suggesting a potential link between hnRNP K pathology and motor dysfunction. These findings highlight the propensity of hnRNP K mislocalisation in neurodegenerative diseases and the aged brain and underscore the need for further investigation into its functional consequences.},
}

Humans
*Brain/pathology/metabolism
Male
Aged
Female
*Aging/pathology/metabolism
*Neurons/metabolism/pathology
*Heterogeneous-Nuclear Ribonucleoprotein K/metabolism
Aged, 80 and over
Middle Aged
*Neurodegenerative Diseases/pathology/metabolism
Alzheimer Disease/pathology/metabolism
Frontotemporal Lobar Degeneration/pathology/metabolism

@article {pmid41952807,
year = {2026},
author = {Burns, B and Xue, Y and Scharre, DW and Ning, X},
title = {Flexible Multimodal Neuroimaging Fusion for Alzheimer's Disease Progression Prediction.},
journal = {Applications of medical artificial intelligence. AMAI (Workshop) (4th : 2024 : Taejon-si, Korea)},
volume = {16206},
number = {},
pages = {235-245},
pmid = {41952807},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease with high inter-patient variance in rate of cognitive decline. AD progression prediction aims to forecast patient cognitive decline and benefits from incorporating multiple neuroimaging modalities. However, existing multimodal models fail to make accurate predictions when many modalities are missing during inference, as is often the case in clinical settings. To increase multimodal model flexibility under high modality missingness, we introduce PerM-MoE, a novel sparse mixture-of-experts method that uses independent routers for each modality in place of the conventional, single router. Using T1-weighted MRI, FLAIR, amyloid beta PET, and tau PET neuroimaging data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we evaluate PerM-MoE, state-of-the-art Flex-MoE, and unimodal neuroimaging models on predicting two-year change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores under varying levels of modality missingness. PerM-MoE outperforms the state of the art in most variations of modality missingness and demonstrates more effective utility of experts than Flex-MoE.},
}

@article {pmid41952858,
year = {2026},
author = {Calderón-Garcidueñas, L and Hernández-Luna, J and Galaz-Montoya, CI and Clouston, SAP and Aiello-Mora, MV and Amaro de Gante, J and Stommel, EW and Torres-Jardón, R and Nalbantoglu, OU},
title = {Cortical, subcortical, and cerebellar atrophy and cognition deficits in Metropolitan Mexico City teens and young adults exposed to fine particulate matter (PM2.5) - neurodegeneration is in progress.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1772916},
pmid = {41952858},
issn = {1664-2295},
abstract = {Exposure to environmental fine particulate matter (PM2.5), ultrafine PM (UFPM) and nanoparticles (NPs) are associated with accumulation of amyloid-β1-42 peptides, phosphorylated-Tau, alpha-synuclein and transactive response DNA binding-protein-43 misfolded aberrant proteins, consistent with the biological definitions of overlapping Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS) in 99% of ≤40-year-old Metropolitan Mexico City (MMC) forensic autopsies. Structural and volumetric brain responses in vivo are critical in young MMC residents. We performed volumetric and whole-brain correlation analyses in 75 healthy volunteers: 45 MMC 31.2 ± 14.7 y old and 30 low-pollution 31.8 ± 4.8 y old controls, matched by ethnicity, socioeconomic status, nutrition, and BMI. MMC residents exhibited fronto-parietal and temporal lobes, precentral gyrus, hippocampi, basal ganglia, thalamus, amygdala and cerebellar atrophy. The most common atrophy pattern was cortical first parietal and fronto-parietal lobes, combined with gray matter (GM) atrophy in cerebellar lobules IV and V left and right III, IV and V and VI.MMC participants had mild cognitive impairment (Montreal Cognitive Assessment Score 22.8 ± 3.2). GM atrophy involving right globus pallidus and pulvinar and cerebellar white matter (WM) bilaterally were associated with lower cognitive performance and high BMI to subiculum, posterior orbital gyrus and insula, inferior temporal gyrus, supplementary motor cortex, and cuneus WM atrophy. PM2.5 exposure and BMI appear to play key roles in early neurodegenerative disease biology and may contribute to adverse effects on academic and occupational performance, neuropsychiatric disorders, behavioral regulation, risk of substance use initiation, and psychopathy. Neuroradiologists across the world need to know cortical and subcortical, including extensive hippocampal, stratium and cerebellar atrophy identifies overlapping patterns of regional atrophy associated with MCI, AD, bvFTD, PD and ALS, in young urbanites. There is an urgent need for early pediatric neuroprevention interventions, non-invasive AD, PD and TDP-43 biomarkers, in-depth characterization of emission pollutants exposures and their effective control. Denial is no longer an option.},
}

@article {pmid41952870,
year = {2026},
author = {Liu, W and Bai, Y and Qu, W and Zhang, X and Zhou, S and Luo, H and Zhu, M and Li, D and Fang, X},
title = {Intervention of ginseng-derived macromolecular drugs in Alzheimer's disease: exploring mechanisms and assessing potential.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1752446},
pmid = {41952870},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder for which effective treatments remain elusive. This review aims to explore the roles, mechanisms, and therapeutic potential of three principal ginseng components, including ginseng polysaccharides (GPS), ginseng proteins (GP), and ginseng glycoproteins (GGP), in the prevention and management of AD. We systematically reviewed recent literature related to these components in AD research. By analyzing evidence from cellular experiments, animal models, and preliminary clinical studies, we evaluated their effects on core pathological processes. These ginseng-derived compounds exert neuroprotective effects via multiple pathways. Specifically, they inhibit the aggregation of amyloid-β (Aβ) and reduce the hyperphosphorylation of tau protein. Furthermore, they demonstrate significant anti-neuroinflammatory and antioxidant activities, which protect neurons from damage and enhance cognitive functions, including memory and learning. The efficacy of these components has been consistently demonstrated across various AD experimental models. In conclusion, GPS, GP, and GGP exhibit promise as multitarget therapeutic agents against AD, underscoring a potential pathway for developing novel natural product-based treatments. Although current preclinical results are promising, further rigorous clinical trials are necessary to validate their efficacy and safety in humans. Therapeutic strategies targeting these components may therefore offer new hope for AD patients.},
}

@article {pmid41952872,
year = {2026},
author = {Burgio, F and Pezzetta, R and Gooijers, J and Nordio, S and Mantini, D},
title = {Neural and motor mechanisms of handwriting: from healthy aging to neurodegenerative disorders.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1758541},
pmid = {41952872},
issn = {1663-4365},
abstract = {Handwriting is a complex cognitive and motor skill supported by a distributed brain network involving cortical, subcortical, and cerebellar regions responsible for planning, execution, and sensorimotor integration. Beyond its communicative role, handwriting provides biologically meaningful information about brain function and motor control, serving as a sensitive marker of both normal and pathological changes. Age-related alterations, such as reduced fine motor precision, impaired sensory feedback, and cognitive slowing, contribute to the progressive decline in handwriting fluency and legibility. Importantly, distinctive handwriting patterns may be associated with early signs of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and Multiple Sclerosis, reflecting disease-specific alterations in motor and cognitive circuits. Advances in digital technology now enable high-resolution, quantitative analysis of handwriting kinematics, offering promising and scalable tools for diagnosis, longitudinal monitoring, and personalized rehabilitation. Furthermore, interventions incorporating fine motor and visuomotor coordination exercises, adaptive writing, and cognitive training may help preserve handwriting abilities and promote adaptive neural changes. In this review, we synthesize current evidence on the neural, behavioral, and technological mechanisms underlying handwriting across aging and neurodegenerative conditions. We provide an integrated overview of neural substrates, age- and disease-related alterations, and emerging digital approaches for assessment and intervention, highlighting their relevance for research and clinical practice. Overall, handwriting has the potential to offer a powerful, non-invasive window into brain health, bridging neuroscience, aging research, and digital medicine.},
}

@article {pmid41952873,
year = {2026},
author = {Misrani, A and Ngwa, C and Liu, F},
title = {Mitochondrial dysfunction in Alzheimer's disease and related sex differences.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1761702},
pmid = {41952873},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD), the most common form of dementia, accounts for 70% of cases and remains a major healthcare challenge due to its rising prevalence and lack of disease-modifying treatments. Clinically, AD is a sexually dimorphic disease. Women exhibit more rapid cognitive decline and accelerated brain atrophy during mild cognitive impairment and early dementia, whereas men more frequently present cardiovascular comorbidities, earlier mitochondrial dysfunction, and greater neuropsychiatric symptoms. AD is marked by amyloid-β (Aβ) plaques, neurofibrillary tangles, neuroinflammation, and neuronal loss, with mitochondrial dysfunction emerging as a key early contributor that exhibits sex specific phenotypes. Mitochondria are vital for neuronal function by generating ATP, maintaining calcium homeostasis, and regulating oxidative stress. However, mitochondria in AD exhibit impaired ATP synthesis, excessive reactive oxygen species (ROS) production, calcium dysregulation, and disrupted fission-fusion dynamics. AD mitochondrial dysfunction can be measured by molecular markers, such as increased expression of fission-related protein Drp1, decreased biogenesis regulator PGC-1α, and elevated oxidative stress markers like malonaldehyde, nitotyrosine and protein carbonyls. Accumulating data suggest that sex differences in mitochondrial dysfunction are attributed to either sex hormonal or sex chromosomal effects, which eventually contribute to sex dichotomic phenotypes of AD. This review collected data regarding mitochondrial dysfunction in AD, with an emphasis on sex differences in oxidative stress, energy metabolism, and regulatory pathways.},
}

@article {pmid41953002,
year = {2026},
author = {Chen, C and He, Y and Ni, Y and Song, D and Chu, M and Zhang, W},
title = {Machine learning and free energy clustering reveal PAH protein binding linked to AD risk.},
journal = {iScience},
volume = {29},
number = {4},
pages = {115311},
pmid = {41953002},
issn = {2589-0042},
abstract = {This study develops a computational framework integrating bioinformatics, machine learning, and ΔG clustering to prioritize polycyclic aromatic hydrocarbons (PAHs) for Alzheimer's disease (AD)-associated neurotoxicity. PAH targets were predicted from ChEMBL/STITCH databases; AD-related differentially expressed genes (DEGs) were identified via WGCNA and differential expression analysis of GEO datasets. Protein-protein interaction (PPI) networks, GO/KEGG enrichment, and XGBoost feature selection identified PARP1, PTPN1, and ITGA4 as candidate core PAH targets enriched in neuroinflammation, microglial activation, lipid metabolism, and atherosclerosis pathways. Molecular docking produced ΔG heatmaps for clustering 16 PAHs into eight toxicity-similarity categories. Category-average ΔG values correlated linearly with literature LD50/BMDL data (ρ = 1, p = 0.0417), yielding an empirical relationship BMDL = 1.723 × ΔG + 22.602. Zebrafish motility assays provided preliminary support (Spearman ρ = -1.0, p = 0.167; n = 3). This pipeline provides initial insights into PAH mechanisms and potential therapeutic targets, pending experimental validation.},
}