@article {pmid42413380,
year = {2026},
author = {Sivalingam, AM},
title = {β-sitosterol and next-generation neuroprotection for multi-target strategies and the gut-brain axis in neurodegenerative diseases.},
journal = {The Journal of steroid biochemistry and molecular biology},
volume = {264},
number = {},
pages = {107080},
doi = {10.1016/j.jsbmb.2026.107080},
pmid = {42413380},
issn = {1879-1220},
abstract = {Neurodegenerative disorders such as Alzheimer's and Parkinson's diseases arise from complex interactions among oxidative stress, neuroinflammation, metabolic dysfunction, and dysregulated signaling networks. This review aim of the synthesize mechanistic evidence on β-sitosterol as a multi-target phytochemical and clarify how its actions connect to gut-brain axis modulation in neurodegeneration. The integrated mechanistic framework linking β-sitosterol's effects on cholesterol homeostasis, neuroinflammation, mitochondrial function, cholinergic signaling, and microbiota-barrier integrity to cognitive outcomes. Scope: preclinical and early translational evidence on β-sitosterol alone and with complementary phytochemicals, including nano-delivery strategies. Increasing evidence highlights phytochemicals as promising multi-target therapeutic agents capable of modulating these interconnected pathological processes. β-Sitosterol exhibits broad activity by regulating cholesterol metabolism, suppressing neuroinflammation, restoring redox balance, preserving mitochondrial function, and inhibiting important Alzheimer's diseases targets, including acetylcholinesterase and butyrylcholinesterase. The mechanisms action of β-sitosterol may (i) dampen microglial activation via TLR4/NF-κB signaling, (ii) activate Nrf2-dependent antioxidant responses (Nrf2/HO-1), (iii) support mitochondrial function and reduce ROS, (iv) stabilize membrane cholesterol and modulate amyloidogenic processing, and (v) inhibit acetylcholinesterase/butyrylcholinesterase to restore cholinergic tone. Complementary showing a neuroprotective effect actions of other phytochemicals such as curcumin, resveratrol, sulforaphane, and sinapic acid further enhance neuroprotection by modulating pathways like Nrf2/HO-1, TLR4/NF-κB, PI3K/Akt, and autophagy. Collectively, preclinical studies demonstrate that diverse botanical extracts significantly improve cognitive performance, reduce amyloid burden, restore cholinergic function, and attenuate neuroinflammation and oxidative damage. Emerging preclinical evidence suggests in rodent models of amyloid pathology, β-sitosterol (5-50 mg/kg) has been reported to improve memory in behavioral tests and reduce markers of neuroinflammation and oxidative stress; gut-brain effects include microbiota remodeling and enhanced barrier integrity, which correlate with reduced neuroimmune activation. Advances in nano-delivery systems and functional food formulations substantially improve phytochemical stability, bioavailability, and brain targeting. Available evidence is chiefly preclinical; clinical translation will require standardized dosing, pharmacokinetic and blood-brain barrier penetration studies, and randomized trials with microbiome and cognitive endpoints. Collectively, these findings position phytochemicals as promising candidates for multi-target disease modification and the development of next-generation neurotherapeutic strategies.},
}

@article {pmid42413499,
year = {2026},
author = {Vear, A and Olsen, SA and Lange, ECH and Müller, MA and Svendsen, C and Clemmensen, C},
title = {Preventative semaglutide and tirzepatide treatment does not alter disease progression in the 5xFAD mouse model of Alzheimer's disease.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {102906},
doi = {10.1016/j.xcrm.2026.102906},
pmid = {42413499},
issn = {2666-3791},
abstract = {There is growing evidence that long-acting mimetics of the gut-derived incretin hormones GLP-1 and GIP act as disease-modifying therapies for Alzheimer's disease (AD). Here, we temporally characterize the efficacy of the approved incretin receptor agonists semaglutide, a GLP-1R agonist, and tirzepatide, a GLP-1R/GIPR co-agonist, in preventing AD progression. In 5xFAD mice treated for 2 or 4 months, both incretin therapies lower body weight and improve glucose tolerance, yet neither compound produces measurable effects on memory or learning tasks, amyloid-β plaque deposition, or glial cell activation. In a non-amyloidogenic model, 3 days of incretin pre-treatment does not alter microglial activation or the expression of inflammatory markers following lipopolysaccharide (LPS) administration in mice. Our findings indicate that chronic semaglutide or tirzepatide treatment, even when initiated before overt pathology and delivered for a prolonged period, does not slow neuropathological progression in 5xFAD or LPS-treated mice.},
}

@article {pmid42413698,
year = {2026},
author = {Huynh, AL and Wrigley, S and Ward, D and Andrews, JS and Burrell, LM and Yates, PA},
title = {Assessing the relationships between frailty, sarcopenia and Alzheimer's disease biomarkers: a scoping review.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103246},
doi = {10.1016/j.arr.2026.103246},
pmid = {42413698},
issn = {1872-9649},
abstract = {INTRODUCTION: While both frailty and sarcopenia have been linked with the Alzheimer's disease (AD) clinical phenotype, their association with AD pathophysiology is unclear. This review aimed to identify current evidence of relationships between frailty, sarcopenia and AD biomarkers.

METHODS: Four databases (Ovid MEDLINE, Embase, PsycINFO, Web of Science) were searched for articles that explored relationships between frailty or sarcopenia and AD biomarkers. AD biomarkers (fluid, tissue, neuroimaging) were defined by the 2024 criteria for diagnosis and staging of AD: Alzheimer's Association Workgroup. Assessment of frailty and sarcopenia were by use of a method/tool defined by the authors of the study.

RESULTS: 8187 articles were screened, with 49 studies included (31 frailty, 22 sarcopenia, 4 both). For frailty, the main AD biomarkers evaluated were hippocampal volume (35%) and beta-amyloid [Aβ] positron electron tomography (PET) (29%). For sarcopenia, the most common AD biomarkers evaluated were hippocampal volume (36%) and Aβ PET (55%). The findings were limited by the heterogeneity of the available evidence, in particular, the variability in frailty/sarcopenia definitions, AD biomarker assessments and the predominance of cross-sectional studies. Potential associations were identified across some studies, but these associations were not consistent across all studies.

CONCLUSIONS: Conclusions are limited by substantial heterogeneity in the assessment of frailty, sarcopenia, AD biomarkers, and a lack of longitudinal data. Future studies are needed that include longitudinal analyses, consensus in AD biomarker, frailty and sarcopenia assessments, and incorporation of novel AD biomarkers, in particular tau and neuroinflammation, to help clarify these relationships.},
}

@article {pmid42413719,
year = {2026},
author = {Alameen, AAM and Al-Kuraishy, HM and Abdelaziz, AM and Al-Gareeb, AI and Albuhadily, AK and Batiha, GE},
title = {Targeting PARP1-dependent parthanatos in Alzheimer's disease: Mechanisms and therapeutic opportunities.},
journal = {Life sciences},
volume = {402},
number = {},
pages = {124578},
doi = {10.1016/j.lfs.2026.124578},
pmid = {42413719},
issn = {1879-0631},
abstract = {Alzheimer's disease (AD) is the predominant cause of dementia globally. This review clarifies the dual function of poly(ADP-ribose) polymerase 1 (PARP1) in AD pathogenesis, emphasizing its role in mediating parthanatos, a unique caspase-independent cell death mechanism. We analyze contemporary literature regarding PARP1 expression, parthanatos signaling, and pharmaceutical treatments in AD models. In addition, PARP1 exhibits context-dependent duality: its physiological nuclear expression in hippocampus neurons is essential for memory consolidation and decreases early in cognitive impairment, suggesting a correlative association with synaptic malfunction. In contrast, overactivity of PARP1 resulting from Aβ-induced oxidative stress and DNA damage induces neurodegeneration via multiple pathways, including NAD+/ATP exhaustion leading to metabolism collapse, creation of the AIF-MIF complex promoting parthanatos, NF-κB-induced neuroinflammation, dysregulation of mitophagy, and disruption of the neuroprotective SIRT1 signaling pathway. The overactivity contributes to a positive feedback loop, where PARP1 intensifies Aβ and tau protein accumulation while simultaneously disrupting the BBB. In preclinical models of AD, genetic knockout, pharmacologic agents such as PJ34 and MC2050, or precursors of NAD[+] such as nicotinamide and NMN attenuate Aβ deposition, normalize metabolism, and ameliorate cognitive decline. The PARP1/parthanatos pathway is at the center of the confluence of oxidative stress, DNA damage, metabolism disorder, and neuroinflammation in AD. Metformin and other PARP1 inhibitors offer intriguing treatment options. PARP1's cell-type- and intracellular location-dependent activity necessitates careful consideration of context, dose, and disease stage while developing therapies. The present understanding in this review could inform future research on PARP1 regulation in AD clinical practice.},
}

@article {pmid42413720,
year = {2026},
author = {Jiang, L and Zhang, Z and Luo, X and Wu, H and Huang, Z and Wu, W and Xu, S and Pan, J and Tan, Z},
title = {Steroidal alkaloid H89712 ameliorates neuroinflammation and memory deficits: Enhancing cerebral oxidative phosphorylation in APP/PS1 mice.},
journal = {Life sciences},
volume = {},
number = {},
pages = {124583},
doi = {10.1016/j.lfs.2026.124583},
pmid = {42413720},
issn = {1879-0631},
abstract = {AIMS: Alzheimer's disease (AD) poses a major health challenge with limited therapeutic options. This study aimed to investigate the anti-AD potential and underlying mechanism of a novel steroidal alkaloid, H89.

MATERIALS AND METHODS: In vitro, Aβ25-35-exposed HT-22 hippocampal neurons and LPS-stimulated BV2 microglia were used to assess H89 neuroprotection and anti-inflammatory activity. In vivo, 6-month-old APP/PS1 mice were orally administered H89 for 2 months. Spatial memory was assessed by Y-maze (YM) and Morris water maze (MWM). Hippocampal morphology, neuronal apoptosis (TUNEL/NeuN), Aβ deposition (IHC), microglial activation (IBA-1), inflammatory cytokines (ELISA), and oxidative phosphorylation (RNA-seq, qRT-PCR, Western blot) were examined. Brain malondialdehyde (MDA), ATP, and cellular ROS were quantified.

KEY FINDINGS: H89 (10 and 50 nM) significantly protected HT-22 cells against Aβ25-35-induced injury and attenuated LPS-induced TNF-α, IL-1β, and IL-6 secretion while elevating IL-10 in BV2 cells. In APP/PS1 mice, H89 increased novel arm exploration in the YM and target quadrant residence in the MWM, indicating improved spatial learning and memory. H89 ameliorated hippocampal neuronal morphology, reduced apoptosis, attenuated Aβ plaques and microglial activation (IBA-1), decreased TNF-α, IL-6 and MDA, and elevated IL-10 and cerebral ATP. Transcriptomic and molecular analyses confirmed that H89 upregulated oxidative phosphorylation-related genes and proteins (ATP5E, ATP5J2, NDUFA13, NDUFB3, COX7C, COX11). Cerebral ATP positively correlated with spatial memory but negatively correlated with neuroinflammation and oxidative stress.

SIGNIFICANCE: H89 exerts neuroprotective effects by enhancing mitochondrial oxidative phosphorylation and brain energy supply, concurrently suppressing neuroinflammation, oxidative stress, and neuronal apoptosis, suggesting its potential as a therapeutic candidate for AD.},
}

@article {pmid42413776,
year = {2026},
author = {Zafar, SA and Qin, W and Chengliang, L and Khan, AA and Faisal, MS},
title = {Thymus-derived myeloid programs track microglial tolerance states across human cohorts.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106221},
doi = {10.1016/j.neuint.2026.106221},
pmid = {42413776},
issn = {1872-9754},
abstract = {INTRODUCTION: Microglial functional positioning varies across individuals and disease contexts, yet conserved biological axes supporting reproducible cross-cohort inference remain poorly defined. Intrathymic T cell development offers a paradigm in which chemokines, extracellular matrix (ECM)/adhesion factors, and axon guidance cues jointly govern immune cell migration and selection. We asked whether thymus-derived transcriptional programs provide a transferable basis for quantifying microglial tolerance-like positioning across independent human cohorts.

METHODS: We applied consensus non-negative matrix factorization to Tabula Sapiens thymus single-cell transcriptomes to derive eight Myeloid Education Signatures (MES); under formal enrichment testing, two were significantly enriched for ECM/adhesion biology and the rest were treated as data-driven programs without a dominant axis. MES scores were projected into four independent microglia cohorts (SEA-AD, Olah, Tuddenham, multiple sclerosis; >100 donors) and related to a donor-level tolerance score (homeostatic minus activation gene-set activity). Glucocorticoid receptor (GR) activity, calibrated from an external perturbation dataset, was evaluated as a moderator. Cross-cohort synthesis used random-effects meta-analysis with sensitivity analyses and multiple testing control.

RESULTS: Seven of eight MES modules were inversely associated with tolerance positioning; the eighth (MES08, defined by CCL2/CXCL2 chemokine genes) showed the most heterogeneous coupling across cohorts. The association strengthened monotonically with microglial purity in three of four cohorts, was recapitulated in Visium spatial transcriptomics, and was robust to covariate adjustment, housekeeping-gene removal, and leave-one-dataset-out sensitivity. This coupling was preferential to thymus-derived modules: modules built identically from six other tissues (blood, spleen, liver, lung, bone marrow, lymph node) coupled 1.2 to 2.9 fold less strongly, across module-number and feature-selection choices. Under a formal per-module interaction model, GR activity did not moderate the association, a well-powered null reproduced with a canonical GR panel and an external cohort. Irisin pathway (five-gene FNDC5/PPARGC1A module) associations were modest and largely non-significant after correction.

CONCLUSIONS: Thymus-derived myeloid programs constitute a transferable, tissue-preferential axis inversely coupled to microglial tolerance-like positioning, without detectable glucocorticoid moderation.},
}

@article {pmid42413810,
year = {2026},
author = {Lv, Y and Jia, Y and Xu, B and Zhao, C and Fu, W and Zhang, Y and Li, B and Li, X},
title = {Atrazine induces Alzheimer's disease-like neurotoxicity by targeting SDHB and disrupting synaptic function: An integrated bioinformatic and in vivo study.},
journal = {Chemico-biological interactions},
volume = {437},
number = {},
pages = {112249},
doi = {10.1016/j.cbi.2026.112249},
pmid = {42413810},
issn = {1872-7786},
abstract = {Atrazine (ATR) is a globally prevalent herbicide linked to increased risks of cognitive impairment and neurodegeneration, but its molecular mechanism remains unclear. This study integrates bioinformatics, machine learning, and experimental validation to elucidate ATR induced Alzheimer's disease (AD)-like pathology. We combined predicted ATR targets with AD brain transcriptomics, identifying 32 shared genes enriched in neurodegeneration and synaptic signaling pathways. We constructed a diagnostic model using 14 machine learning algorithms; the ensemble model achieved an improved AUC of 0.891 in the training set, with external validation AUCs of 0.833, 0.869, and 0.900. SHAP interpretability analysis identified SDHB as the most important key risk factor. Molecular docking validated the stable binding between ATR and core target proteins, with binding energies ranging from -4.9 to -5.9 kcal/mol. Single-cell sequencing and in silico gene knockdown confirmed that SDHB deficiency primarily disrupts neuronal synaptic signaling pathways. In vivo experiments demonstrated that ATR exposure induces anxiety-like behavior and memory deficits, suppressed hippocampal SDHB, and elevated Aβ and p-tau levels. ATR also reduced synaptic markers PSD95 and SYP in a dose dependent manner, confirming SDHB suppression leads to synaptic damage. Based on these findings, we established the first standardized adverse outcome pathway (AOP) framework delineating the cascade of events from ATR-induced SDHB inhibition to cognitive impairment. This study demonstrates that ATR targets SDHB to induce synaptic dysfunction and AD-like neuropathology, offering a new mechanistic basis for environmental risk assessment.},
}

@article {pmid42413887,
year = {2026},
author = {Vallejo-Azar, MN and Freccero, P and Postillone, MB and Princich, JP and Solis, P and Medel, N and Lisso, J and Irureta, N and Morganti, S and Fernández, J and Collavini, S and Bendersky, M and Ramírez, A and Bernal, V and Kochen, S and Dalmasso, MC and Gonzalez, PN},
title = {GeNED.ar cohort: Neuroimaging Resource for Aging Studies in an Admixed Population from Argentina.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122117},
doi = {10.1016/j.neuroimage.2026.122117},
pmid = {42413887},
issn = {1095-9572},
abstract = {Well-characterized cohorts are essential for advancing neuroimaging biomarkers and refining models of brain aging and dementia across diverse populations. Despite growing neuroimaging research in Latin America, additional multimodal cohorts integrating imaging, genomic, and environmental data are needed to capture population diversity. We present GeNED.ar (Genetics and Neuroimaging of Aging and Dementia in Argentina), a multimodal cohort established in the Metropolitan Area of Buenos Aires to investigate brain aging in a population with genetic admixture and socioeconomic heterogeneity. The dataset combines two complementary recruitment strategies, community-based healthy participants and Memory Clinic attendees, including 3T MRI, genome-wide genotyping, and detailed sociodemographic data from 367 individuals aged 18-94 years. Participants comprise healthy individuals (n=235) and Memory Clinic attendees classified as cognitively unimpaired (n=65), mild cognitive impairment (n=37), Alzheimer's or mixed dementia (n=24), and vascular dementia (n=6). Genetic ancestry analysis (n=191) indicated a predominantly admixed population (65% European, 28.3% Native American) with significant differences across recruitment sources. Brain age gap (BAG), estimated from T1-weighted MRI, increased progressively along the clinical continuum, where people with dementia exhibited older-appearing brains relative to cognitively unimpaired participants, and intermediate values were observed in mild cognitive impairment. No independent associations were observed between BAG and individual genetic or environmental risk factors. By integrating multimodal MRI and genomic data across complementary recruitment settings, GeNED.ar provides a unique regional resource to evaluate neuroimaging biomarkers, facilitate cross-cohort validation, and strengthen the generalizability of aging and dementia models in genetically and socially diverse populations.},
}

@article {pmid42413935,
year = {2026},
author = {Lee, S and Kao, CY and Li, Z and Dan, T and Wu, G and Hao, W},
title = {Optimal control for anti-abeta treatment in Alzheimer's disease using a reaction-diffusion model.},
journal = {Journal of the Royal Society, Interface},
volume = {23},
number = {240},
pages = {},
doi = {10.1098/rsif.2025.1158},
pmid = {42413935},
issn = {1742-5662},
support = {1R35GM146894/GF/NIH HHS/United States ; DMS-2533995//NSF/ ; DMS 2208373//NSF/ ; DMS 2513176//NSF/ ; //Huck Chair in AI Mathematical Modeling from Penn State University's Huck Institutes of the Life Sciences/ ; },
mesh = {*Alzheimer Disease/diagnostic imaging/metabolism/drug therapy/therapy ; Humans ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Models, Biological ; Positron-Emission Tomography ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that severely impairs survival and quality of life. While anti-amyloid beta (Aβ) therapies can slow disease progression, their efficacy depends on personalized dosing that maximizes benefits and minimizes risks, such as amyloid-related imaging abnormalities (ARIA). Mathematical modelling offers a powerful tool for understanding AD dynamics and optimizing treatment, yet most models focus solely on temporal behaviour, overlooking spatial heterogeneity within the brain. In this study, we propose a spatially explicit reaction-diffusion model to describe Aβ plaque dynamics. We formulate an optimal control problem to minimize plaque concentration while balancing therapeutic efficacy and treatment risk. Under reasonable assumptions, we establish well-posedness and uniqueness of the optimal solution. A finite element method (FEM)-based numerical framework is developed to compute personalized treatment strategies. Our model is calibrated using longitudinal Aβ positron emission tomography (PET) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), enabling estimation of patient-specific parameters, such as growth rate and effective diffusivity. Results show that optimized treatment strategies consistently outperform constant dosing regimens across patient groups, achieving substantial reductions in cumulative amyloid burden while minimizing side effects. This integrated, data-driven framework advances personalized, spatially informed therapeutic optimization for AD.},
}

*Alzheimer Disease/diagnostic imaging/metabolism/drug therapy/therapy
Humans
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Models, Biological
Positron-Emission Tomography

@article {pmid42414168,
year = {2026},
author = {Lee, DR and Endo, AS and Kalbasi, TR and Turner, M and Jimenez, IA and Serrano, KS and Centeno, A and Reuben, DB},
title = {Psychiatric Hospitalization Precipitants and Outcomes in a Comprehensive Dementia Care Program.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.06.002},
pmid = {42414168},
issn = {1545-7214},
abstract = {OBJECTIVES: Characterize the precipitants and outcomes of psychiatric hospitalizations among patients enrolled in a comprehensive dementia care program and identify factors associated with discharge to higher-level residential setting.

DESIGN: Retrospective cohort study.

SETTING: UCLA Alzheimer's and Dementia Care Program.

PARTICIPANTS: Patients hospitalized at the UCLA Resnick Neuropsychiatric Hospital (NPH).

MEASUREMENTS: Precipitating reasons for hospitalization, patient demographic and clinical characteristics, hospitalization-level characteristics, and caregiver relationship. Discharge to higher-level residential settings (e.g., assisted living, nursing home). Change in scheduled Central Nervous System (CNS)-active medications (antipsychotics, antidepressants, and sedative/hypnotics).

RESULTS: There were 180 psychiatric hospitalizations among 150 patients, with a median age of 79 years (IQR, 73-85) at admission and MMSE score of 17 (IQR, 12-24) at first hospitalization. Agitation was the most common precipitating reason for hospitalization (n = 127, 71%). Median length of stay was 14 days (IQR, 9-26); 54 (30%) resulted in discharge to a higher-level residential setting. Agitation as the precipitant for hospitalization (aOR, 4.7; 95% CI, 1.7-12.9, p = 0.003) and male sex (aOR, 2.3; 95% CI, 1.0-5.5, p = 0.049) were associated with higher odds of discharge to a higher-level setting. Most hospitalizations resulted in no change in the number of scheduled CNS-active medications (e.g., 69% had no change in the number of scheduled antipsychotics), while escalation occurred in 19%-28%, depending on medication class.

CONCLUSION: Psychiatric hospitalization precipitated by agitation or involving male patients was often followed by transition to higher-level residential care. Future studies should evaluate whether earlier outpatient psychiatry involvement and proactive placement planning can reduce hospitalization and subsequent placement changes.},
}

@article {pmid42414260,
year = {2026},
author = {Sulatsky, MI and Stepanenko, OV and Kayda, AA and Stepanenko, OV and Mikhailova, EV and Sulatskaya, AI},
title = {Spontaneous aging of mature amyloids alters structural stability, cytotoxicity, and susceptibility to biological clearance.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-026-03245-1},
pmid = {42414260},
issn = {2058-7716},
support = {23-74-10092//Russian Science Foundation (RSF)/ ; },
abstract = {Accumulation of amyloid fibrils is a key factor in the pathogenesis of progressive diseases, including neurodegenerative disorders such as Alzheimer's and Parkinson's disease, as well as systemic amyloidosis. Although amyloid deposits are known to persist in vivo for years or even decades, it remains unclear how the structure and biological properties of mature fibrils evolve during prolonged post-assembly residence. Here, we addressed this question using a simplified cell-free aqueous model designed to isolate the intrinsic time-dependent behavior of mature amyloid aggregates from the complexity of the biological milieu. Specifically, we investigated the long-term evolution of two polymorphs of lysozyme amyloid fibrils as model systems with distinct clustering propensities that mimic the diversity of amyloid deposits. We challenge the assumption of amyloid stability by demonstrating their spontaneous degradation over 16 months at physiological temperature, a process we define as amyloid "aging". This process is characterized by aggregate declustering, fibril shortening, and progressive depolymerization into monomeric subunits, accompanied by a pronounced reduction in intrinsic toxicity across multiple human cell lines. Notably, "aged" fibrils were disassembled and degraded more efficiently than freshly prepared aggregates by the molecular chaperone α-B-crystallin and immune-associated proteases, including matrix metalloproteinase-9 and cathepsins B and D. However, this enhanced degradation revealed a paradox: accelerated processing of "aged" amyloids did not always reduce cytotoxicity and, in some cases, even exacerbated it, consistent with the generation of biologically active fibril-derived species rather than their complete conversion into non-toxic monomers. We provide the first systematic evidence that mature amyloids are dynamic structures undergoing spontaneous degradation that fundamentally alters their cytotoxicity and susceptibility to biological clearance. Our results introduce amyloid aging as a previously underappreciated dimension of amyloid biology and emphasize the need to account for fibril "age" when evaluating pathogenic potential and developing anti-amyloid therapeutic strategies.Spontaneous "aging" of amyloid fibrils leads to suprastructural remodeling: declustering, fibril shortening, and attenuated cytotoxicity. While "aged" aggregates are degraded more efficiently by immune-associated proteases and α-B-crystallin than "fresh" fibrils, this enhanced degradation does not reduce cytotoxicity and, in some cases, exacerbates it, highlighting the complex interplay between aggregate maturity and biological outcomes.},
}

@article {pmid42414290,
year = {2026},
author = {Li, H and Pan, W and Rajendran, S and Zang, C and Wang, F},
title = {Empowering clinical trial design with agentic intelligence and real-world data.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42414290},
issn = {2041-1723},
mesh = {Humans ; Electronic Health Records ; *Clinical Trials as Topic/methods ; *Research Design ; Machine Learning ; *Artificial Intelligence ; },
abstract = {Clinical trial design (CTD) is a time-consuming process that requires substantial domain expertise. Large-scale real-world data (RWD), such as electronic health records (EHR), encodes practice-based evidence that is of tremendous value to CTD. In recent years, many machine learning methods have been developed to extract such real-world evidence (RWE) from the RWD to inform CTD, but they still need to be communicated with the domain experts extensively in an iterative manner to be further refined and ultimately useful. In this paper, we introduce EmulatRx, an agentic framework that derives RWE for helping with CTD. Through the iterative conversation and analysis across agents with different roles, EmulatRx can autonomously refine trial protocols and finally generate a robust report containing insights that inform better CTD. We applied EmulatRx on the CTD process for both acute diseases (e.g., septic shock, acute heart failure, acute pulmonary edema, and acute kidney injury) using the MIMIC-IV data and chronic diseases (e.g., Alzheimer's disease and Parkinson's disease) using the INSIGHT Network across five New York City health systems. The results demonstrate EmulatRx's capabilities in facilitating and accelerating the CTD process.},
}

Humans
Electronic Health Records
*Clinical Trials as Topic/methods
*Research Design
Machine Learning
*Artificial Intelligence

@article {pmid42414687,
year = {2026},
author = {Pearson, H},
title = {How to avoid dementia - what the science really says.},
journal = {Nature},
volume = {655},
number = {8122},
pages = {294-297},
pmid = {42414687},
issn = {1476-4687},
}

@article {pmid42414714,
year = {2026},
author = {Álvarez-Rodríguez, L and Vázquez, C and Cordón, B and Garcia-Martin, E and de Moura, J and Novo, J and Ortega, M},
title = {3D OCT-Based Retinal Biomarker Analysis for Automatic Regional-Wise Characterization of Neurodegenerative Diseases.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10278-026-02098-5},
pmid = {42414714},
issn = {2948-2933},
support = {PI17/01726//Instituto de Salud Carlos III/ ; PI20/00437//Instituto de Salud Carlos III/ ; PI23/00935//Instituto de Salud Carlos III/ ; RD21/0007/0022//Instituto de Salud Carlos III/ ; FORT23/00010//Instituto de Salud Carlos III/ ; PID2023-148913OB-I00//Ministerio de Ciencia e Innovación/ ; ED431C 2024/33//Xunta de Galicia/ ; B23_23R//Gobierno de Aragón/ ; B50_24//Gobierno de Aragón/ ; },
abstract = {Neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), essential tremor (ET), multiple sclerosis (MS), and Parkinson's disease (PD) are complex disorders that often exhibit overlapping symptoms, leading to diagnostic challenges. Given the increasing interest in retinal imaging as a non-invasive biomarker for neurodegeneration, this study proposes a fully automated machine learning pipeline for disease characterization using optical coherence tomography (OCT). We analyze macular thickness patterns across three key and relevant retinal elements: retinal nerve fibre layer (RNFL), ganglion cell layer to Bruch's membrane (GCL-BM), and the total retina. These are processed by two complementary regional layouts: the standard ETDRS scheme and a custom 3 × 3 quadrant grid. These measurements are used to train multiple classifiers to distinguish between healthy controls and NDDs either collectively or individually. The proposed method processes 34,375 OCT B-scans from 353 subjects and highlights disease-specific thickness patterns with a pathological distinction score ranging up to 0.71 depending on the retinal region, disease, and classifier. Sector-based grids generally outperform quadrant-based ones, revealing highly localized pathological signatures. Our findings demonstrate that each disease manifests distinct retinal alterations, aligning with current clinical literature while offering novel insights for ET and PD. The study reinforces the potential of grid-based OCT analysis as a discriminative and fully automatic screening tool, paving the way for improved early diagnosis and differential analysis of NDDs through retinal biomarkers.},
}

@article {pmid42415081,
year = {2026},
author = {Perez-Toro, PA and Almizel, M and Nöth, E and Maier, A and Arias-Vergara, T},
title = {Generating Alzheimer's narratives using large language models.},
journal = {BMC medical informatics and decision making},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12911-026-03653-4},
pmid = {42415081},
issn = {1472-6947},
abstract = {BACKGROUND: Analyzing semi-spontaneous speech is a promising direction for supporting Alzheimer's disease (AD) assessment, yet progress is limited by the scarcity of annotated clinical data. Large Language Models (LLMs) offer new opportunities to generate synthetic narratives that may resemble speech patterns of both patients with AD and healthy controls during cognitive evaluation tasks such as the Cookie Theft Picture description.

METHODS: This study evaluates whether models including GPT, T5/Flan-T5, LLaMA, Mistral, and Qwen can generate clinically plausible picture-description narratives under two configurations: Human-to-Bot, where an LLM responds directly to real interviewer prompts, and Bot-to-Bot, where two LLMs simulate both interviewer and participant roles. Models were fine-tuned on transcripts from the DementiaBank Pitt Corpus and assessed using lexical and semantic metrics, as well as human expert ratings. Generated narratives were further used to augment training data for an AD vs. healthy control classifier based on BERT embeddings and an MLP architecture.

RESULTS: LLMs differed substantially in their ability to reproduce clinically meaningful and semantically coherent narratives of patient-interviewer interactions. Mistral, LLaMA, and Qwen achieved the strongest automatic evaluation metrics, e.g., BERTScores above 0.90 in the Human-to-Bot condition-and produced narratives rated by human experts as fluent, plausible, and diagnostically informative. When combining real and synthetic narratives for classifier training, the highest F1-score reached 0.84, outperforming models trained on real data alone (F1 = 0.74). Synthetic data generated in Human-to-Bot settings contributed most to diagnostic improvements, whereas Bot-to-Bot interactions exhibited greater variability and reduced clinical realism.

CONCLUSION: LLMs can generate high-quality synthetic narratives that enhance downstream AD classification and show promising clinical plausibility in cognitive assessment contexts. Incorporating LLM-generated data provides a scalable strategy for mitigating data scarcity in dementia research. Future work should focus on improving fully synthetic dialogue quality, expanding multilingual capabilities, and refining evaluation frameworks to better capture clinically relevant linguistic features.},
}

@article {pmid42415114,
year = {2026},
author = {Strickland, MR and Holtzman, DM},
title = {ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer's disease and related disorders.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00970-0},
pmid = {42415114},
issn = {1750-1326},
support = {T32AG058518/NH/NIH HHS/United States ; RF1NS090934/NH/NIH HHS/United States ; },
abstract = {Apolipoprotein E (ApoE) is highly expressed in the central nervous system (CNS) where it plays a critical role in lipid homeostasis and in the etiology of Alzheimer's disease (AD) and related diseases. ApoE associates with lipids to form discoidal and spherical lipoproteins that carry lipid and protein cargo throughout the brain. In this review, we focus on the significance of ApoE as a lipoprotein and how this impacts the function of ApoE in homeostasis and disease. In the CNS, ApoE is primarily secreted by astrocytes, though other cells, including microglia, secrete ApoE under certain conditions. ApoE lipoproteins (LpE) secreted by different cell types carry unique lipids and proteins which alter its function. The lipidation state of ApoE alters its conformation and binding to different receptors and, consequently, its ultimate impact on AD pathology. Most dramatically, nonlipidated ApoE has minimal binding to the low density lipoprotein receptor (LDLR), while lipidation of ApoE restores high affinity binding to LDLR. Furthermore, the degree of ApoE lipidation also impacts ApoE receptor binding through changes in protein conformation and stoichiometry of ApoE molecules per lipoprotein. The lipidation state of ApoE also alters its interaction with amyloid-β and tau, the proteins involved in forming amyloid plaques and neurofibrillary tangles, the pathological hallmarks of AD. LpE also carry lipids and proteins that alter the function of ApoE. Understanding how the lipid and protein content of LpE interacts with the conformational changes that occur with lipidation and maturation are essential to mechanistically understanding the role of ApoE in homeostasis and disease pathogenesis. In this review, we highlight the current understanding of LpE biology in the CNS and delineate important areas of future research.},
}

@article {pmid42415176,
year = {2026},
author = {Eom, JW and Kim, KR and Kim, DH and Song, JG and Han, C and Kim, HW and Ha, S and Song, WJ and Kim, YH},
title = {Zinc-mediated lysosomal activation by 1H10 enhances autophagy and attenuates tau pathology in Alzheimer's disease models.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-026-01328-9},
pmid = {42415176},
issn = {1756-6606},
support = {NRF-2020R1I1A1A01061724//National Research Foundation of Korea/ ; RS-2023-NF001356//National Research Foundation of Korea/ ; 2025-RISE-01-019-04//The seoul RISE centor/ ; },
abstract = {Impaired autophagic flux and lysosomal dysfunction contribute critically to the accumulation of pathological protein aggregates in Alzheimer's disease (AD). Emerging evidence suggests that intracellular zinc dynamics regulate lysosomal function by modulating processes such as acidification and lysosomal biogenesis. We previously identified 1H10 as an AMP-activated protein kinase (AMPK) inhibitor and subsequently demonstrated its zinc-binding capacity and ability to regulate intracellular zinc homeostasis. Building on our prior findings that intra-lysosomal zinc promotes acidification and activates transcription factor EB (TFEB), we investigated whether 1H10 enhances lysosomal function through zinc mobilization in neurons, thereby improving autophagy and reducing pathological protein accumulation. In primary cortical neurons, 1H10 increased lysosomal abundance and enhanced lysosomal degradative capacity in a zinc-dependent manner, as demonstrated by increased cathepsin B activity and DQ-BSA degradation. It alleviated lysosomal dysfunction induced by v-ATPase inhibition and promoted autophagic flux, leading to reduced accumulation of amyloid-β (Aβ) and tau in neuronal models. In 5XFAD mice, 1H10 treatment showed trends toward improved spatial learning in the Morris water maze, reduced tau phosphorylation at Thr205 and Ser214, normalized LC3-II levels, and restored autophagic-lysosomal homeostasis, without significant changes in extracellular amyloid plaque burden. These findings indicate that zinc-mediated lysosomal activation by 1H10 enhances the autophagy-lysosomal pathway and attenuates tau pathology in AD models, suggesting that targeting lysosomal function may represent a potential therapeutic strategy for neurodegenerative disorders characterized by impaired proteostasis.},
}

@article {pmid42415281,
year = {2026},
author = {Aldana, BI and Freude, K},
title = {Chemokines in Alzheimer's Disease: Early Defence, Late Damage and the Impact of Sex and Infection.},
journal = {Basic & clinical pharmacology & toxicology},
volume = {139},
number = {2},
pages = {e70273},
doi = {10.1111/bcpt.70273},
pmid = {42415281},
issn = {1742-7843},
support = {R434-2023-242//Lundbeck Foundation/ ; N/A//Alzheimersfonden/ ; },
mesh = {Humans ; *Alzheimer Disease/immunology/metabolism ; *Chemokines/metabolism/immunology ; Animals ; Female ; Male ; Sex Factors ; Signal Transduction ; Virus Diseases/immunology ; Neuroinflammatory Diseases/immunology ; COVID-19/immunology ; Receptors, Chemokine/metabolism ; Brain/immunology/metabolism ; Sex Characteristics ; },
abstract = {Chemokines constitute a versatile signalling network maintaining homeostasis and glia-neuron communication in the healthy brain but become progressively dysregulated during aging and Alzheimer's disease (AD). This review examines how chemokine systems transition from tightly regulated homeostatic signals to drivers of chronic neuroinflammation in AD. We describe the major chemokine families (CC, CXC, CX3C) and their dominant central nervous system (CNS) receptors (CCR2, CXCR3, CX3CR1), which activate canonical inflammatory pathways including NF-κB, JAK/STAT and PI3K-AKT. In AD, chemokine dysregulation occurs in a coordinated manner across multiple functional modules, including recruitment-associated (CCL2, CXCL1), interferon-inducible (CXCL10), loss-of-restraint (CX3CL1) and vascular-associated chemokines. These alterations shift the network from regulated immune communication to self-sustaining inflammatory circuits perpetuating chronic neuroinflammation. These networks reprogram microglia and astrocytes into disease-associated phenotypes, amplify peripheral immune cell infiltration and destabilise synaptic function. Biological sex profoundly influences neuroinflammatory trajectories, with females exhibiting enhanced microglial senescence and interferon signalling, while males show accelerated complement activation. Viral pathogens, particularly neurotropic viruses (HSV-1, HHV-6, VZV) and SARS-CoV-2, actively reprogram chemokine networks, linking infection to amyloid-β accumulation, tau pathology and neurodegeneration. Therapeutically, chemokine axes represent precision targets requiring stage-matched, sex-stratified interventions rather than broad anti-inflammatory approaches. Understanding chemokine network dynamics offers mechanistic insights into AD pathogenesis and could provide pointers for therapeutic strategies.},
}

Humans
*Alzheimer Disease/immunology/metabolism
*Chemokines/metabolism/immunology
Animals
Female
Male
Sex Factors
Signal Transduction
Virus Diseases/immunology
Neuroinflammatory Diseases/immunology
COVID-19/immunology
Receptors, Chemokine/metabolism
Brain/immunology/metabolism
Sex Characteristics

@article {pmid42415306,
year = {2026},
author = {Gaetani, L and Nardi, G and Parnetti, L},
title = {Can the integration of blood-based biomarkers into Alzheimer's disease diagnosis revolutionize the field?.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/14737175.2026.2700246},
pmid = {42415306},
issn = {1744-8360},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a clinical-biological entity in which pathophysiological changes precede symptoms by years. Biomarkers are essential for early and accurate diagnosis, particularly in the era of disease-modifying therapies requiring biological confirmation. Cerebrospinal fluid (CSF) and amyloid positron emission tomography (amyloid-PET) are the reference standards, but increasing attention is devoted to blood-based biomarkers (BBMs) due to their scalability and cost-effectiveness.

AREAS COVERED: In this critical perspective, the authors critically appraise the current evidence supporting plasma phosphorylated tau at threonine 217 (p-tau217) as the leading BBM for AD. They also discuss its analytical performance, biological rationale, and diagnostic accuracy across the AD continuum, its relationship with established CSF, PET, and neuropathological biomarkers, its potential role in identifying patients eligible for disease-modifying therapies, and the main clinical and biological factors influencing its interpretation. Finally, they highlight current limitations, unresolved challenges, and give their future perspectives for the integration of plasma biomarkers into routine clinical practice.

EXPERT OPINION: BBMs are expected to reshape AD diagnostics. A stepwise approach, using plasma biomarkers as first-line tests followed by confirmatory CSF or PET, is currently the most feasible strategy. Ultimately, highly specific, brain-derived tau biomarkers may enable BBMs to replace CSF biomarkers.},
}

@article {pmid42415348,
year = {2026},
author = {Sohn, C and Pardo, S and Molleur, D and Paduri, SR and Lambert, M and Uttke, Z and Sohn, EJ and Thomas, MG and Weintraub, ST and Frost, B},
title = {Elevation of the mechanically-sensitive e protein emerin links nuclear mechanotransduction to tau-induced cytoskeletal remodeling in neurons.},
journal = {Nucleus (Austin, Tex.)},
volume = {17},
number = {1},
pages = {2697135},
doi = {10.1080/19491034.2026.2697135},
pmid = {42415348},
issn = {1949-1042},
mesh = {*Neurons/metabolism/pathology ; *Nuclear Proteins/metabolism/genetics ; Humans ; *Mechanotransduction, Cellular ; *tau Proteins/metabolism/genetics ; *Cytoskeleton/metabolism ; *Membrane Proteins/metabolism/genetics ; *Cell Nucleus/metabolism ; Animals ; Actins/metabolism ; },
abstract = {Neurodegenerative tauopathies, including Alzheimer's disease, are neuropathologically defined by pathological tau deposition. While tau drives neurotoxicity by disrupting cytoskeletal, nucleoskeletal, and genomic architecture, cellular mechanisms mediating tau-induced dysfunction of the cytoskeleton and nucleoskeleton are incompletely understood. Here, we identify proteins with differing abundance in a cellular tauopathy model, iTau. Building upon previous findings that pathogenic tau reduces nuclear tension, we find elevated levels of emerin, a central regulator of nuclear mechanotransduction, in iTau neurons and tau mutant iPSC-derived neurons. Neuronal emerin overexpression drives neurotoxicity, increases filamentous actin (F-actin), and induces nuclear invagination, mimicking cellular phenotypes of tauopathy. Alterations in emerin binding partners reflect its cytosolic relocalization in iTau neurons, suggesting that pathogenic tau may impact nuclear mechanotransduction by altering emerin levels and localization. Overall, we identify emerin as a potential mediator of cytoskeletal and nucleoskeletal remodeling in tauopathy and provide a foundation for future studies of emerin function in neurons.},
}

*Neurons/metabolism/pathology
*Nuclear Proteins/metabolism/genetics
Humans
*Mechanotransduction, Cellular
*tau Proteins/metabolism/genetics
*Cytoskeleton/metabolism
*Membrane Proteins/metabolism/genetics
*Cell Nucleus/metabolism
Animals
Actins/metabolism

@article {pmid42415414,
year = {2026},
author = {Nguyen, DD and Paine, M and Lee, S and Fazlollahi, A and Wang, BB and O'Sullivan, JD and Nestor, PJ},
title = {Global Rather Than Vertical-Selective Saccadic Abnormalities in Progressive Supranuclear Palsy.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70480},
pmid = {42415414},
issn = {2328-9503},
support = {//Mater Foundation/ ; 2023/GNT2030157//NHMRC Ideas/ ; },
abstract = {OBJECTIVE: To test whether vertical saccades are preferentially affected in Progressive Supranuclear Palsy (PSP).

METHODS: PSP patients (n = 24) were compared to age-matched controls (n = 94) and two degenerative groups (Alzheimer's disease, n = 20; Lewy body disease, n = 50). Video-oculography (sampling rate: 1000 Hz) was used to measure visually guided saccades (15.3° amplitude) in vertical and horizontal planes. Traditional corrected velocity alongside novel metrics of velocity interruption, vacillation, and directional instability were compared across diagnostic groups.

RESULTS: Vertical saccades were slower than horizontal in all groups including controls. Velocities were significantly slowed in PSP; however, the magnitude of slowing was comparable in vertical and horizontal directions. Similarly, vertical and horizontal velocities were strongly correlated in PSP (r = 0.77, p < 0.001), as they were in all other groups. Likewise, velocity interruption, vacillation, and directional instability were more disordered in the vertical compared to the horizontal axis in both controls and PSP (p < 0.05). Z-scores of all metrics in PSP were abnormal but with no predilection for vertical saccades. Vacillation was a predictor of saccade velocity.

INTERPRETATION: Contrary to conventional belief, vertical saccades were not selectively impaired in PSP. Instead, the findings indicated a more global disruption of the saccadic system. The clinical observation of impaired vertical saccades in PSP appears to be because vertical saccades are slower and more disordered than horizontal in the general population; thus, when abnormalities of saccades develop in all directions, it first reaches a threshold to be noticeable at the bedside in the vertical plane.},
}

@article {pmid42415688,
year = {2026},
author = {Hill, N and AlMuallim, HYO and Maddock, E and Hobbs, C and Clarke, E and Goncalves, MB and Corcoran, JPT},
title = {Treatment with KCL-286, a first-in-class retinoic acid receptor-β (RARβ) agonist, ameliorates neuronal DNA damage and inflammation in a mouse model of Alzheimer's disease.},
journal = {FEBS open bio},
volume = {},
number = {},
pages = {},
doi = {10.1002/2211-5463.70284},
pmid = {42415688},
issn = {2211-5463},
support = {110047/Z/15/Z/WT/WT_/Wellcome Trust/United Kingdom ; MR/R006466/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder for which effective disease-modifying therapies remain limited. Accumulation of neuronal DNA double-strand breaks (DSBs) is an early pathological event that contributes to genomic instability and neuronal vulnerability in AD. Therapeutic strategies that enhance DNA repair may therefore be of considerable interest. Here, using the Tg2576 mouse model of AD, we show that treatment with KCL-286, a selective retinoic acid receptor-β (RARβ) agonist, reduces neuronal DNA damage. KCL-286 enhances DSB repair in neurons, in part through upregulation of the DNA repair factor BRCA1, while also attenuating neuroinflammatory activation. In addition, KCL-286 normalises microglial and astrocytic morphology, consistent with reduced pathological glial activation. Together, these findings demonstrate that selective RARβ activation ameliorates neuronal DNA damage and neuroinflammation in a mouse model of AD, supporting further investigation as a potential disease-modifying therapeutic strategy.},
}

@article {pmid42415907,
year = {2026},
author = {Li, J and Chen, B and Jiang, J and Feng, Y and Zhang, R and Li, D and Wang, R and Long, Z and Ge, L and Guo, Y and Zhou, Z and Zou, W and Zhong, C and Liao, L},
title = {Efficacy of antioxidants as a therapy for Alzheimer's disease: a meta-analysis.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1878597},
pmid = {42415907},
issn = {2296-861X},
abstract = {BACKGROUND: Oxidative stress plays a central role in the pathogenesis of Alzheimer's disease (AD), contributing to neuronal damage, amyloid-beta aggregation, tau hyperphosphorylation, and neuroinflammation. Although antioxidants have been proposed as potential therapeutic agents, clinical trials have yielded inconsistent results.

OBJECTIVE: To systematically evaluate the efficacy of various antioxidants-including vitamins, polyphenols, and other antioxidant preparations-on cognitive function, oxidative stress biomarkers, neuropsychiatric symptoms, and disease progression in patients with AD.

METHODS: We conducted a systematic search of PubMed, Embase, and Web of Science from inception to October 2, 2025, for randomized controlled trials (RCTs) evaluating antioxidant interventions in AD patients. Study selection, data extraction, and quality assessment were performed independently by multiple reviewers. Meta-analyses were conducted using random-effects models where significant heterogeneity was present (I[2] > 50%). Outcomes included cognitive function scales (e.g., ADAS-Cog, MMSE), oxidative stress markers, neuropsychiatric symptoms, daily living abilities, neuroimaging measures, and fluid biomarkers.

RESULTS: A total of 23 RCTs comprising 10,537 participants were included. Antioxidants showed mixed effects across outcomes. While certain oxidative stress markers (urinary 8-iso-prostaglandin F2α: SMD 0.75, 95% CI 0.12-1.38) and neuropsychiatric symptoms (NPI: SMD -0.85, 95% CI -1.13 to -0.57) improved significantly, core cognitive endpoints such as ADAS-Cog (SMD 0.01, 95% CI -0.21 to 0.23) and MMSE (SMD 0.19, 95% CI -0.17 to 0.56) showed no significant benefit. Fluid biomarkers including Aβ42, p-tau, and t-tau remained unchanged. High heterogeneity was observed across multiple outcomes, reflecting variability in antioxidant types, dosages, and patient populations.

CONCLUSION: Antioxidants may improve certain oxidative stress markers and neuropsychiatric symptoms in AD patients but do not consistently enhance core cognitive function or alter AD-specific pathology. Current evidence does not support antioxidants as disease-modifying therapies, though they may serve as adjunctive interventions to improve quality of life and behavioral symptoms. Well-designed RCTs with longer follow-up and standardized protocols are warranted.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420261321660, identifier: CRD420261321660.},
}

@article {pmid42415930,
year = {2026},
author = {Wang, PJ and Yang, XY and Ji, L and Shi, JJ and Cai, XM and Sun, P and Liu, HX and Jiang, F and Yang, F},
title = {Peripheral metabolomic profiling reveals lipid and amino acid alterations associated with immuno-inflammatory responses in treatment-naïve late-onset Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1858299},
pmid = {42415930},
issn = {1663-4365},
abstract = {BACKGROUND: Immuno-metabolic dysregulation contributes to Alzheimer's disease (AD) pathogenesis, yet the peripheral metabolic landscape and its interplay with neuroinflammation remain poorly characterized in treatment-naïve, late-stage patients. This study aimed to delineate plasma metabolic alterations and immuno-metabolic interactions in Chinese first-time outpatients with late-onset AD (CFTO-LOAD).

METHODS: Untargeted metabolomics and ELISA were applied to plasma from 35 CFTO-LOAD patients and 35 sex-matched cognitively healthy controls (CHCs) to quantify metabolites, cytokines (TNF-α, IL-17, IL-9), and soluble Aβ/Tau markers.

RESULTS: A total of 875 differentially abundant metabolites (DAMs) were identified in CFTO-LOAD, comprising 227 upregulated and 648 downregulated species (P < 0.05), predominantly lipids, fatty acids (e.g., dodecanoic acid, arachidonic acid), and amino acids (e.g., L-arginine, L-leucine). KEGG analysis revealed enrichment in fatty acid and amino acid metabolism, GABAergic synapse, and intestinal immune network pathways. CFTO-LOAD patients exhibited elevated pro-inflammatory cytokines TNF-α and IL-17 (P adj < 0.05), reduced IL-9 (P adj < 0.001), increased soluble p-Tau, p-Tau181, and p-Tau217 (P adj < 0.01), and decreased Aβ42/Aβ40 ratio (P adj < 0.001). Linear regression identified significant correlations between differential metabolites and immune/pathological markers, including positive associations of dodecanoic acid with TNF-α (r = 0.34, P adj < 0.05) and arachidonic acid with Aβ42/Aβ40 ratio (r = 0.30, P adj < 0.05), and negative associations of arachidonic acid with p-Tau217 (r = -0.43, P adj < 0.01) and sphinganine 1-phosphate with TNF-α (r = -0.28, P adj < 0.05).

CONCLUSION: These findings characterize the peripheral immuno-metabolic landscape in treatment-naïve late-onset AD, identifying metabolic mediators that may mechanistically link neuroinflammation to Aβ and Tau pathology. This provides a foundation for biomarker development and therapeutic targeting in late-stage disease, pending independent validation.},
}

@article {pmid42415934,
year = {2026},
author = {Li, Q and Gu, M and Li, W},
title = {Exercise and neural circuit stability in early Alzheimer's disease: evidence across memory, executive, cholinergic, and circadian systems.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1863929},
pmid = {42415934},
issn = {1663-4365},
abstract = {Early Alzheimer's disease (AD) is increasingly understood as a phase in which neural circuit dysfunction emerges alongside molecular pathology and local neuronal injury. Although physical exercise has been linked to a deceleration in cognitive decline and beneficial cognitive and neural outcomes, most mechanistic explanations have predominantly focused on molecular or cellular pathways, with less emphasis on circuit-level interpretations. This narrative review integrates evidence from four neural systems that exhibit early vulnerability in AD and are pertinent to exercise-responsive cognitive or behavioral domains: the entorhinal cortex-dentate gyrus (EC-DG) circuit, the ventral hippocampus-medial prefrontal cortex (vHPC-mPFC) pathway, the medial septum/vertical diagonal band-hippocampal (MS/VDB-hippocampal) cholinergic circuit, and the suprachiasmatic nucleus-paraventricular nucleus (SCN-PVN) circadian axis. Across these systems, the evidence remains inconsistent. Direct circuit-level findings, including electrophysiological and functional-connectivity measurements, indicate circuit disruption in specific domains, whereas many exercise-related effects are inferred from molecular, structural, neurochemical, behavioral, or clinical-proxy outcomes. We therefore propose a multicircuit framework in which exercise may ameliorate AD-related cognitive and behavioral dysfunction through convergent but circuit-specific routes: EC-DG excitability and plasticity, vHPC-mPFC communication substrates, MS/VDB-hippocampal cholinergic modulation, and SCN-PVN circadian-neuroendocrine timing. This framework clarifies the evidence boundaries of exercise-related circuit modulation in early AD and identifies direct circuit-level measurements as a priority for future translational studies.},
}

@article {pmid42416049,
year = {2026},
author = {Yang, M and Liang, Z},
title = {GLP-1 receptor agonists in neurological diseases: mechanisms and therapeutic prospects from metabolism to neuroprotection.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1839620},
pmid = {42416049},
issn = {1664-3224},
mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy/metabolism ; Glucagon-Like Peptide-1 Receptor/metabolism ; *Neuroprotection/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used metabolic therapies for type 2 diabetes and obesity, with well-established cardiovascular benefits. Beyond glycemic control, accumulating experimental and clinical evidence suggests that GLP-1RAs exert pleiotropic actions relevant to neurological diseases. Metabolic dysfunction, chronic inflammation, oxidative stress, mitochondrial impairment, and neurovascular injury represent convergent mechanisms that contribute to neurodegeneration, cerebrovascular pathology, and metabolism-related brain disorders. Notably, these processes overlap with pathways modulated by GLP-1 signaling across systemic and central compartments. GLP-1 receptors are expressed in neurons, glial cells, and components of the neurovascular unit, providing a biological basis for possible neurological effects. Preclinical studies suggest that GLP-1RAs can reduce neuroinflammation and oxidative stress, support mitochondrial function, and help maintain blood-brain barrier integrity. Clinical findings, however, remain inconsistent. Studies in Parkinson's disease have reported encouraging signals, but biomarker evidence for disease modification is still limited. In Alzheimer's disease, clinical trials have produced mixed or negative results. These differences may reflect disease stage, patient selection, drug-specific pharmacology, central nervous system exposure, endpoint sensitivity, and treatment duration. Overall, GLP-1RAs may influence neurological disease through metabolic, inflammatory, and vascular pathways, but their clinical role remains unsettled. Future studies should use biomarker-informed designs, prespecified neurological endpoints, appropriate drug selection, and sufficiently long follow-up to determine which patients and disease stages are most likely to benefit.},
}

Humans
*Glucagon-Like Peptide-1 Receptor Agonists
Animals
*Neuroprotective Agents/therapeutic use/pharmacology
*Nervous System Diseases/drug therapy/metabolism
Glucagon-Like Peptide-1 Receptor/metabolism
*Neuroprotection/drug effects
Oxidative Stress/drug effects

@article {pmid42416144,
year = {2026},
author = {Huang, F and Guo, M and Yang, Y and Wang, Z},
title = {Aloe emodin attenuates Aβ1-42-Induced neurotoxicity in SH-SY5Y cells via downregulation of PPM1K.},
journal = {Open medicine (Warsaw, Poland)},
volume = {21},
number = {1},
pages = {20261473},
pmid = {42416144},
issn = {2391-5463},
abstract = {OBJECTIVES: To study the role and underlying mechanism of aloe emodin, a natural anthraquinone compound known for antioxidant, and anti-inflammatory activities, in Alzheimer's disease (AD).

METHODS: Aβ1-42-induced injury model was established using SH-SY5Y cells. A combination of CCK-8 assay, flow cytometry, ELISA, ROS fluorescence probe, RT-qPCR, and western blot assay was employed to systematically evaluate the effects of aloe emodin on cell viability, apoptosis, inflammation, and oxidative stress. Potential molecular targets were identified through bioinformatics analysis. The regulatory role of PPM1K in aloe emodin-mediated neuroprotection was further validated using PPM1K overexpression experiments.

RESULTS: Bioinformatics analysis revealed that PPM1K is significantly upregulated in AD and showed predicted in silico binding with aloe emodin. Aloe emodin markedly improved the viability of Aβ1-42-treated SH-SY5Y cells, suppressed apoptosis, reduced the release of pro-inflammatory cytokines, and attenuated ROS generation, accompanied by the downregulation of PPM1K expression. In contrast, overexpression of PPM1K significantly weakened the neuroprotective effects of aloe emodin, as evidenced by decreased cell viability and increased levels of apoptosis and oxidative stress.

CONCLUSIONS: Aloe emodin alleviates Aβ1-42-induced neuronal injury by targeting and downregulating PPM1K expression, suggesting that PPM1K is a critical mediator of the neuroprotective effects of aloe emodin.},
}

@article {pmid42416176,
year = {2026},
author = {Kim, DJ and Kim, YC and Jeong, BH},
title = {Association of SPHK1 polymorphisms with Alzheimer's disease susceptibility: Functional impact of the rs2247856 SNP on transcriptional efficiency.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70288},
pmid = {42416176},
issn = {2352-8737},
abstract = {INTRODUCTION: Sphingosine kinase 1 (SPHK1) has been implicated in the regulation of pro-resolving lipid mediators relevant to neuroinflammation in Alzheimer's disease (AD). However, no studies have evaluated the genetic association between SPHK1 polymorphisms and AD susceptibility.

METHODS: We analyzed genotype and allele frequencies of polymorphisms in the SPHK1 gene between patients with AD and healthy controls. In addition, transcription factor binding sites were evaluated. Furthermore, promoter activities associated with rs2247856 single nucleotide polymorphism (SNP) were assessed using a luciferase reporter assay.

RESULTS: Among the identified SNPs, the genotype distribution of rs2247856 showed a significant association with AD. Haplotype analysis revealed that haplotype 3 (CAGTACGG) was significantly more frequent in patients with AD than in controls. Profiler of Multi-Omics Data (PROMO) analysis suggested that the rs2247856 A allele disrupts the activating transcription factor 3 transcription factor binding site. Luciferase assays demonstrated significantly reduced promoter activity in constructs containing the A allele compared to the G allele (p < 0.001), indicating allele-specific regulation of SPHK1 transcription.

DISCUSSION: Our findings identify rs2247856 as a functional regulatory SNP in the SPHK1 gene associated with AD susceptibility. The reduced transcriptional activity of the A allele may impair SPHK1-mediated anti-inflammatory signaling, potentially contributing to AD pathogenesis.},
}

@article {pmid42416267,
year = {2026},
author = {de Leon, J and Allen, IE and Miller, Z and Dronkers, N and Henry, M and Gorno-Tempini, ML and Grasso, S},
title = {Reported symptoms and patterns of language impairment in bilingual speakers with primary progressive aphasia: a retrospective study.},
journal = {Aphasiology},
volume = {},
number = {},
pages = {},
pmid = {42416267},
issn = {0268-7038},
abstract = {BACKGROUND: The relative scarcity of studies of bilingual speakers with primary progressive aphasia (PPA) leads to knowledge gaps regarding their symptoms and patterns of language impairment. It is unknown if PPA symptoms in bilingual speakers differ from those of monolingual speakers. In addition, it remains unclear if one of a bilingual speaker's languages is more vulnerable to the onset of symptoms and/or is better preserved. Furthermore, bilingualism factors (e.g. order/age of language acquisition (L1/L2) and language dominance) may explain patterns of impairment both within and across the variants of PPA.

AIMS: To characterize the bilingualism factors, speech and language symptoms, and patterns of language impairment in a retrospective cohort of bilingual speakers with PPA.

METHODS: In a large cohort (N = 69) of bilingual speakers, we performed a chart review to extract information regarding self/caregiver-reported PPA symptoms, first language impacted by PPA at symptom onset, less preserved language at time of evaluation, and bilingual history factors (age/order of acquisition (L1/L2) and language dominance). We explored how emergence and presentation of symptoms associated with bilingualism factors.

RESULTS: The presenting symptoms were mostly consistent with current PPA diagnostic criteria, although symptoms unique to bilingual speakers were reported. The language reported to first be impacted by PPA, as well as the less preserved language at the time of evaluation, was generally reported to be the less dominant language, regardless of PPA variant. These measures did not associate as closely with age/order of acquisition (L1 versus L2).

CONCLUSION: Bilingual speakers with PPA may report additional symptoms that reflect their ability to speak more than one language. The less dominant language was most susceptible to the initial impact of PPA and also tended to the less preserved language at the time of evaluation. Future studies of bilingual speakers with neurodegenerative diseases should systematically consider bilingualism factors, which are likely to contribute to clinical presentation and disease progression.},
}

@article {pmid42416270,
year = {2026},
author = {Wang, A and Curel, T and Claeysen, S and Travers-Lesage, V and Cadot, M and Davis, A and Sopkova-de Oliveira Santos, J and Modeste, F and Brazzolotto, X and Nachon, F and Dallemagne, P and Since, M and Rochais, C},
title = {Combining β2-AR agonism with butyrylcholinesterase inhibition, a synergistic neuroprotective action against Alzheimer's disease.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {42416270},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder for which the current treatments remain largely symptomatic. Pleiotropic prodrug strategies offer a promising approach to address this complexity, combining complementary pharmacological mechanisms within a single molecular entity. In this study, we report the design, synthesis, and biological evaluation of novel carbamate-based pleiotropic prodrugs that combine butyrylcholinesterase (BuChE) inhibition and β2-adrenergic receptor (β2-AR) agonism. Seven salmeterol-derived carbamates were synthesized and evaluated for their cholinesterase inhibitory activity, β2-AR activity, and neuroprotective potential. Several derivatives exhibited potent and selective inhibition of human BuChE in the nanomolar range, revealing a clear structure-activity relationship driven by carbamate substitution and amine protection. Kinetics and LC-MS analyses demonstrated a pseudo-irreversible covalent inhibition mechanism associated with rapid enzyme reactivation, thereby enabling controlled salmeterol release. While carbamates behaved as inactive prodrugs at the β2-AR level, selected compounds displayed significant neuroprotective effects in a cellular model of amyloid-β-induced toxicity. Collectively, these findings validate salmeterol-derivated carbamates as innovative pleiotropic prodrugs and support the potential of combining BuChE inhibition and β2-AR agonism as a disease-modifying strategy for Alzheimer's disease.},
}

@article {pmid42416335,
year = {2026},
author = {Wang, XT and Wang, J and Zhao, XJ},
title = {Exercise training promotes neurogenesis in the adult hippocampus with a particular focus on cell cycle regulation.},
journal = {Frontiers in sports and active living},
volume = {8},
number = {},
pages = {1770350},
pmid = {42416335},
issn = {2624-9367},
abstract = {Adult neurogenesis is predominantly restricted to two neurogenic regions in the mammalian brain: the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus (DG) within the hippocampus. The hippocampus serves as a critical brain structure involved in learning and memory processes, and the continuous generation of new neurons contributes to enhanced synaptic plasticity. Accumulating evidence has demonstrated that impaired hippocampal neurogenesis is closely associated with various neuropsychiatric disorders, including Alzheimer's disease, epilepsy, and traumatic brain injury. Although the precise molecular and cellular mechanisms underlying adult neurogenesis remain incompletely elucidated, extensive research over the past several decades has identified numerous endogenous, exogenous, and environmental factors that modulate this process. Notably, exercise training, as a key exogenous stimulus, has been shown to promote adult hippocampal neurogenesis by influencing the neurochemical environment and functional integration of newly generated neurons. This review aims to summarize the relationship between cell cycle dynamics and adult hippocampal neurogenesis, with a particular emphasis on how physical exercise regulates the cell cycle to activate and promote the proliferation of neural stem cells (NSCs) in the DG, thereby facilitating the differentiation and lineage progression of neural progenitor cells. A deeper understanding of the regulatory mechanisms by which exercise enhances adult hippocampal neurogenesis may provide novel insights into the development of therapeutic strategies for neurological and psychiatric disorders.},
}

@article {pmid42416382,
year = {2026},
author = {Cabán, M and Abraído-Lanza, AF and Brown-Bradley, C and Meng, A and Tran, E and Lee, J and Wetmore, JB and Ottman, R and Siegel, K},
title = {The use of religion, prayer, and faith to cope with the receipt of Alzheimer's disease risk information in a research context: A qualitative study of Latinos in NYC.},
journal = {SSM. Qualitative research in health},
volume = {9},
number = {},
pages = {},
pmid = {42416382},
issn = {2667-3215},
abstract = {People commonly turn to religion when confronted with threatening events including illness. However, limited research has investigated the use of religious coping to manage distress associated with knowledge of one's risk for serious illnesses such as Alzheimer's disease (AD). To examine how they coped with receiving information about their risk for late-onset AD, semi-structured interviews were conducted with a sample of Latinos (ages 40-64) living in Northern Manhattan approximately 6 weeks, 9 and 15 months after receiving a numerical risk estimate (expressed as a percentage) of their chances of developing AD by age 85. Some also were told their APOE genotype, including whether it increased their susceptibility to late onset AD. Of 202 participants interviewed, 43 mentioned using religion to cope with the implications of receiving their AD risk information and the emotions it evoked and are the focus of this report. Five themes emerged from the data: 1) Praying to be protected from AD; 2) Praying to help manage emotions; 3) Giving control over to God; 4) Accepting AD as part of God's plan; and 5) Praying for the strength to accept one's fate and deal with whatever it brings. To our knowledge this is the first report describing how individuals use religion/spirituality to cope with the perceived implications of and the emotions elicited by receiving their AD risk information. This information can inform the development of culturally tailored support resources for those who choose to learn their risk status.},
}

@article {pmid42416856,
year = {2026},
author = {Ameenudeen, S and Srinivasan, H},
title = {Network pharmacology-based identification of hub genes targeted by ayurvedic formulation Triphala in controlling Alzheimer's disease by polypharmacological mechanisms.},
journal = {In silico pharmacology},
volume = {14},
number = {2},
pages = {186},
pmid = {42416856},
issn = {2193-9616},
abstract = {UNLABELLED: The multifactorial neurodegenerative disease known as Alzheimer's disease (AD) is typified by amyloid-β aggregation, tau hyperphosphorylation, neuroinflammation, and synaptic dysfunction, as well as progressive cognitive decline. Due to the limited effectiveness of conventional therapeutic approaches, multi-target agents must be investigated. A traditional Ayurvedic polyherbal formulation, Triphala contains a wide range of bioactive phytochemicals that have been shown to have neuroprotective effects. The molecular targets of Triphala phytocompounds related to AD pathology were clarified in the current study using a network pharmacology approach. BindingDB and SwissTargetPrediction were used to predict the putative protein targets of 18 phytocompounds, yielding 54 distinct targets. The STRING database was used to build a protein-protein interaction (PPI) network, which Cytoscape was then used to analyse. The following 7 important hub genes were identified using topological parameters (degree, betweenness, closeness centrality): BCL2, CASP3, MMP9, JUN, NFKB1, PTGS2, and ESR1. Potential mechanistic overlap was highlighted by the significant involvement of 20 genes in AD-related pathways and 30 genes in the lipid and atherosclerosis pathway, according to gene enrichment analysis using KEGG. Synaptic plasticity, oxidative stress response, neuroinflammatory signalling, and apoptosis regulation are the main functions of these genes. The integrative analysis highlights Triphala's polypharmacology mechanism and raises the possibility that it could be used as a multi-target therapeutic candidate for AD. This study offers a logical foundation for additional in vitro and in vivo validation of Triphala-derived neurotherapeutics as well as a systems-level framework for comprehending herb-compound-gene-disease interactions.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-026-00704-6.},
}

@article {pmid42416912,
year = {2026},
author = {Zou, Z and Liu, H and Lei, D and Jian, X and Li, X},
title = {Dynamic changes of gut microbiota during progression of three Alzheimer's disease mice models.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1849896},
pmid = {42416912},
issn = {1662-4548},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disorder characterized by cognitive impairment and irreversible neuronal degeneration, affecting approximately 55 million individuals worldwide. Despite extensive research efforts, the underlying pathogenic mechanisms of AD remain incompletely understood, and effective therapeutic strategies for preventing or delaying disease progression are still lacking. Increasing evidence suggests that the microbiota-gut-brain axis plays an important role in neurodegenerative diseases, including AD. However, the dynamic alterations of gut microbiota during AD progression across different transgenic mouse models remain poorly characterized.

METHODS: In the present study, we investigated age-dependent changes in gut microbiota composition in three commonly used AD mouse models, including APP/PS1, 3xTg, and 5xFAD mice, using 16S rRNA gene sequencing. Fecal samples were collected longitudinally at 2, 4, 6, and 8 months of age to evaluate microbial diversity, community structure, and differential bacterial taxa during aging and disease progression.

RESULTS: Our results demonstrated distinct and model-dependent alterations in gut microbiota composition across different stages of AD progression. Significant changes in microbial diversity and bacterial community structure were observed among the three AD mouse models and wild-type controls. In particular, dynamic alterations in Verrucomicrobiota, Proteobacteria, and Actinobacteriota were consistently identified during aging in AD mice. In addition, β-diversity, Linear discriminant analysis effect size (LEfSe), and correlation network analyses further revealed differential microbial signatures associated with different AD mouse models and age stages.

DISCUSSION: Overall, our findings provide additional evidence that gut microbiota composition undergoes dynamic alterations during aging in multiple AD mouse models and may be associated with AD-related progression. This study may contribute to a better understanding of microbiota-associated changes during AD development and provide a basis for future mechanistic studies targeting the microbiota-gutbrain axis in AD.},
}

@article {pmid42417039,
year = {2026},
author = {Feng, L and Jin, X and Li, X and Qu, T and Guo, H and Wang, Z and Quan, Y and Chen, L and Wang, L and Wang, Y},
title = {One-month early time-restricted eating enhances long-term memory by modulating brain fluid dynamics in males with metabolic syndrome: Evidence from perivascular diffusion and global blood-oxygen-level-dependent-cerebrospinal fluid coupling.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261465674},
doi = {10.1177/13872877261465674},
pmid = {42417039},
issn = {1875-8908},
abstract = {BackgroundMetabolic syndrome (MetS) serves as a precursor to Alzheimer's disease, a condition characterized by initial memory impairment and driven by dysregulated brain fluid dynamics. While time-restricted eating (TRE) improves memory in MetS, the mechanistic role of brain fluid dynamics in this process remains unclear.ObjectiveTo investigate whether a 1-month early TRE (eTRE) intervention enhances memory performance by improving brain fluid dynamics in individuals with MetS.MethodsTwenty-eight men with MetS and 30 matched healthy male controls underwent MRI scans. Brain fluid dynamics was assessed using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index and global blood-oxygen-level-dependent-cerebrospinal fluid (gBOLD-CSF) coupling. In the MetS group, metabolic risk factors, cognitive and psychological status, and memory performance were evaluated pre- and post-eTRE. Relationships between imaging indices and memory scores were examined by correlation analysis.ResultsAt baseline, men with MetS exhibited a lower DTI-ALPS index and higher gBOLD-CSF coupling than healthy controls (p < 0.05). After 1-month eTRE, the DTI-ALPS index increased (p < 0.001), while gBOLD-CSF coupling decreased (p = 0.027), approaching healthy control levels. Metabolic parameters and long-term memory performance also improved significantly (all p < 0.05). Changes in DTI-ALPS were positively correlated with delayed recall (r = 0.445, p < 0.05), whereas changes in gBOLD-CSF coupling were negatively correlated (r = -0.550, p < 0.05).ConclusionsA 1-month eTRE intervention improved long-term memory and brain fluid dynamics in males with MetS, providing a promising non-pharmacological strategy to counteract metabolic-driven neurodegenerative diseases.Trial registrationNational Medical Research Registration and Filing Information System (https://www.medicalresearch.org.cn/), MR-61-24-042065.},
}

@article {pmid42417046,
year = {2026},
author = {Weiss, JN and Eber, D and Cole, R},
title = {Dynamic light scattering spectroscopy and the Centiloid scale.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467030},
doi = {10.1177/13872877261467030},
pmid = {42417046},
issn = {1875-8908},
abstract = {Dynamic light scattering (DLS) spectroscopy measures the Brownian movement of particles. Fifteen patients underwent DLS measurement and positron emission tomography amyloid imaging. The DLS measurement is noninvasive, quantitative, and inexpensive, with immediate results. We report a significant correlation between DLS measurements and Centiloid values.},
}

@article {pmid42417051,
year = {2026},
author = {Agüero-Rabes, P and Roa-Escobar, J and Téllez, R and Mañanes, V and Gómez-Tortosa, E},
title = {Eligibility for lecanemab therapy in a biomarker defined memory clinic cohort: A five-year analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261466695},
doi = {10.1177/13872877261466695},
pmid = {42417051},
issn = {1875-8908},
abstract = {We assessed cross-sectional lecanemab eligibility (January 2026) in 479 patients with mild cognitive impairment or dementia who underwent Alzheimer's disease (AD) biomarker testing at a tertiary memory clinic (2021-2025). Overall eligibility was 16%, with exclusions due to negative biomarkers (41%), advanced disease stage (31%), APOE ε4/ε4 homozygosity (6%), and other safety reasons (6%). In the 2025 subgroup (n = 100), eligibility increased to 32%, reflecting fewer exclusions for disease progression and a targeted evaluation of patients likely to meet criteria. These findings highlight a narrow post-diagnosis therapeutic window and suggest an upper eligibility limit under the current appropriate use recommendations for anti-amyloid therapies.},
}

@article {pmid42417056,
year = {2026},
author = {Dimas-Harms, LJ and Moser, VA},
title = {The arsenic-Alzheimer's disease link: Emerging evidence and unanswered questions.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467042},
doi = {10.1177/13872877261467042},
pmid = {42417056},
issn = {1875-8908},
abstract = {Arsenic is a toxic heavy metal that reaches humans primarily through contaminated groundwater, presenting a persistent global public health concern. Chronic exposure, even at concentrations lower than current safety standards, disturbs brain development and function, raising concern that arsenic may contribute to Alzheimer's disease (AD). Wei et al. investigate early-life arsenic exposure and AD using Swedish national registries and geographic variation in groundwater arsenic. This work represents a critical step toward understanding whether historical environmental exposures in northern Europe have increased late-life neurodegenerative risk and underscores the importance of treating arsenic as a potentially modifiable environmental risk factor for AD.},
}

@article {pmid42417147,
year = {2026},
author = {Wang, Y and Nan, B and Gillen, DL and Corrada, MM},
title = {Statistical analysis of disease onset during lifespan with left truncation.},
journal = {Biometrics},
volume = {82},
number = {3},
pages = {},
doi = {10.1093/biomtc/ujag118},
pmid = {42417147},
issn = {1541-0420},
support = {R01 AG056764/NH/NIH HHS/United States ; RF1 AG075107/NH/NIH HHS/United States ; R01 AG021055/NH/NIH HHS/United States ; P30 AG066519/NH/NIH HHS/United States ; DMS 2412746//National Science Foundation/ ; },
mesh = {Computer Simulation ; Humans ; *Models, Statistical ; Data Interpretation, Statistical ; Dementia/mortality/epidemiology ; Alzheimer Disease/mortality ; *Age of Onset ; Statistics, Nonparametric ; },
abstract = {We consider a new nonparametric method for analyzing the onset of a chronic condition, e.g., dementia, when death occurs frequently in the study population. In contrast to the commonly used semi-competing risks or illness-death model, we study the distribution of the disease onset time conditional on the death time, which consists of two components that provide straightforward interpretations of the disease onset during the lifespan. Without imposing any model assumption, we propose a kernel-weighted product-limit estimator that properly handles the left-truncation, a common issue in aging studies. The estimator is asymptotically normal and its variance can be estimated by a Greenwood-type variance estimator. We use the integrated Brier score for the bandwidth selection and illustrate the proposed method with simulation studies, an analysis of The 90+ Study, and an analysis of the UC Health Data Warehouse.},
}

Computer Simulation
Humans
*Models, Statistical
Data Interpretation, Statistical
Dementia/mortality/epidemiology
Alzheimer Disease/mortality
*Age of Onset
Statistics, Nonparametric

@article {pmid42417152,
year = {2026},
author = {Ben-Hayun, R and Zifman, N and Hadad, R and Fogel, H and Levy-Lamdan, O and Verhovski, N and Yarovinsky, N and Ayoub-Agbaria, R and Tanne, D},
title = {Towards a neurophysiological diagnostic marker of Alzheimer's disease using transcranial magnetic stimulation combined with electroencephalography.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261463653},
doi = {10.1177/13872877261463653},
pmid = {42417152},
issn = {1875-8908},
abstract = {BackgroundA scalable, objective measure of cortical function that differentiates Alzheimer's disease (AD) from other causes of cognitive impairment is still lacking. Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) enables direct assessment of cortical reactivity.ObjectiveTo test whether left primary motor cortex (M1L) P30 amplitude captures AD-related excitability changes, distinguishes biomarker-confirmed AD patients from controls (CN) and from other non-AD causes of cognitive impairment.MethodsNinety participants underwent M1L TMS-EEG with Delphi-MD: biomarker-confirmed AD (n = 22), other cognitively impaired (n = 27: vascular/mixed n = 12; frontotemporal dementia n = 4; unknown etiology n = 11), and CN (n = 41).ResultsP30 differed across biomarker-confirmed AD, other cognitively impaired, and CN (Quade F(2,80) = 4.989, p = 0.009, ηp[2] = 0.11). Pairwise tests showed higher P30 in biomarker-confirmed AD versus other cognitively impaired (t = 2.117, p = 0.037, d = 0.61) and versus CN (t = 3.14, p = 0.002, d = 0.80). Among 27 clinically suspected AD tested for biomarkers, P30 was higher in biomarker + (22/27) versus biomarker- (5/27) (p = 0.035, d = 0.98), had good discriminatory performance for biomarker-confirmed AD (ROC = 0.853 [95% CIboot 0.627-1.000], p < 0.001), and was not associated with cerebrovascular changes (p = 0.455, d = 0.24).ConclusionsP30 amplitude is elevated in biomarker-confirmed AD relative to CN and other causes of cognitive impairment, aligning with amyloid-associated cortical hyperexcitability. These findings support P30 as a promising, non-invasive physiological biomarker to aid differential diagnosis and, potentially, disease monitoring in AD.Trial registry name and URL: https://clinicaltrial.health.gov.il/clinicaltrials/?MOHResearchId=MOH_2022-04-13_010726.},
}

@article {pmid42417271,
year = {2026},
author = {Anagnostakis, F and O'Toole, CK and Erus, G and Srinivasan, D and Cui, Y and Kokkorakis, M and Ma, X and Reitz, C and Brickman, AM and Kontos, D and Gupta, A and Payabvash, S and Konofagou, EE and McIlvain, G and Cheng, F and Baldwin, MR and Shou, H and Davatzikos, C and Resnick, S and Wen, J},
title = {Association of sleep duration with Alzheimer's disease and cognition.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71528},
doi = {10.1002/alz.71528},
pmid = {42417271},
issn = {1552-5279},
support = {RF1AG092412/GF/NIH HHS/United States ; RF1AG054409/GF/NIH HHS/United States ; U24NS130411/GF/NIH HHS/United States ; },
mesh = {Humans ; *Sleep Duration ; *Alzheimer Disease/diagnostic imaging/pathology ; Female ; Magnetic Resonance Imaging ; Male ; Atrophy/pathology ; *Cognition/physiology ; Brain/pathology/diagnostic imaging ; Aged ; Neuropsychological Tests/statistics & numerical data ; United Kingdom ; Sleep Initiation and Maintenance Disorders ; },
abstract = {INTRODUCTION: The association of sleep duration with Alzheimer's disease (AD) - related brain atrophy and cognition remains unclear.

METHODS: Among 38,816 participants in the UK Biobank, we examined the association between sleep duration and a validated machine-learning-derived magnetic resonance imaging (MRI) signature of AD-related atrophy (Spatial Pattern of Abnormality for Recognition of Early AD [SPARE-AD]) and three cognitive test scores using generalized additive models. Independently, electronic health records (EHR) from TriNetX were used to examine the 10-year AD risk associated with insomnia and hypersomnia.

RESULTS: Sleep duration exhibited a U-shaped association with SPARE-AD (p = 0.001), Trail Making Tests A and B, and the Digit Symbol Substitution Test (all p < 0.001). Short (5-6 hours) and long (9-10 hours) sleep duration were associated with poorer cognitive performance. Both insomnia and hypersomnia showed a high risk for Alzheimer's disease.

CONCLUSION: This study demonstrates a U-shaped association between sleep duration and AD-like atrophy and cognition.

DISCUSSION: These findings show that excessive or insufficient sleep is linked to worse brain health.},
}

Humans
*Sleep Duration
*Alzheimer Disease/diagnostic imaging/pathology
Female
Magnetic Resonance Imaging
Male
Atrophy/pathology
*Cognition/physiology
Brain/pathology/diagnostic imaging
Aged
Neuropsychological Tests/statistics & numerical data
United Kingdom
Sleep Initiation and Maintenance Disorders

@article {pmid42417429,
year = {2026},
author = {Pelkmans, W and Bikou, V and Salvadó, G},
title = {Timing the Alzheimer's disease pathological cascade.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag240},
pmid = {42417429},
issn = {1460-2156},
}

@article {pmid42417497,
year = {2026},
author = {Dubey, A and Chaurasia, A and Ansari, Z and Kushwaha, SK and Saraf, I and Kashaw, S and Swami, R and Kushwah, V},
title = {Targeting Autophagy in Alzheimer's Disease: Role of the AMPK/mTOR Pathway and Drug Repurposing.},
journal = {Drug development research},
volume = {87},
number = {5},
pages = {e70344},
doi = {10.1002/ddr.70344},
pmid = {42417497},
issn = {1098-2299},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Repositioning ; *Autophagy/drug effects ; *TOR Serine-Threonine Kinases/metabolism ; Signal Transduction/drug effects ; *AMP-Activated Protein Kinases/metabolism ; Animals ; Neuroprotective Agents/pharmacology/therapeutic use ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques and tau (τ) -related neurofibrillary tangles, often exacerbated by dysfunctional cellular clearance mechanisms. This manuscript explores the pivotal role of autophagy impairment in AD pathogenesis, with a specific focus on the AMPK/mTOR signaling axis as a primary regulatory pathway. Findings revealed that while mTOR overactivation suppresses autophagic flux and promotes the buildup of toxic protein aggregates, the activation of AMPK serves to restore homeostatic degradation processes. The review highlights that various pharmacological agent including rapamycin, metformin, trehalose, and curcumin, as well as repurposed drugs like lithium and statins can effectively enhance autophagy to ameliorate cognitive decline and neuroinflammation. Furthermore, herbal formulations such as Danggui Shaoyao San and phytoconstituents like Icariin demonstrate significant neuroprotective potential by modulating these same molecular pathways. Targeting autophagy represents a translationally viable approach for combating AD progression, with drug repurposing offering a time-efficient and cost-effective strategy. To advance these findings, future research should prioritize large-scale clinical trials to validate the efficacy of autophagy-inducing agents in human subjects. Additionally, investigating synergistic combinations of traditional bioactives with synthetic drugs and utilizing innovative delivery systems, such as intranasal nanotechnology-based platforms to bypass the blood-brain barrier, represents a promising frontier for developing effective, multi-targeted treatments against AD.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Drug Repositioning
*Autophagy/drug effects
*TOR Serine-Threonine Kinases/metabolism
Signal Transduction/drug effects
*AMP-Activated Protein Kinases/metabolism
Animals
Neuroprotective Agents/pharmacology/therapeutic use

@article {pmid42417611,
year = {2026},
author = {Heskett, MB and Vouzas, AE and Johnstone, B and Freese, KP and Yates, PA and Copenhaver, PF and Spellman, PT and Gilbert, DM and Thayer, MJ},
title = {Autosomal allelic inactivation at loci with variable replication timing and dosage sensitivity.},
journal = {eLife},
volume = {15},
number = {},
pages = {},
doi = {10.7554/eLife.109938},
pmid = {42417611},
issn = {2050-084X},
support = {R01GM130703/GM/NIGMS NIH HHS/United States ; RF1NS142814/NS/NINDS NIH HHS/United States ; R01GM083337/GM/NIGMS NIH HHS/United States ; 4K00CA245677-03/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; *Alleles ; Mice ; *DNA Replication Timing ; *Epigenesis, Genetic ; Humans ; *Gene Dosage ; *Genetic Loci ; *Gene Silencing ; },
abstract = {Autosomal monoallelic gene expression and asynchronous replication between alleles are established features of imprinted genes and genes regulated by allelic exclusion. Inactivation/Stability Centers (I/SCs) are recently described autosomal loci that exhibit epigenetic regulation of allelic expression and replication timing, with differences that can be comparable to those observed between the active and inactive X chromosomes . Here, we characterize >100 autosomal loci with allele-specific epigenetic regulation of replication timing and gene expression, defining them as I/SCs. I/SCs are approximately 1 Mbb in size and can contain both protein-coding and noncoding genes. In different single-cell derived clones, these genes may be expressed from a single allele, the opposite allele, both alleles, or not expressed at all. This stochastic, yet mitotically stable, pattern indicates that the choice of which allele is expressed is independent of parent of origin and independent of the expression status of the other allele. Similarly, alleles within I/SCs show varying replication timing, either earlier or later, that is also independent of the other allele. Additionally, we identify syntenic loci in the mouse genome that display epigenetic regulation of allelic replication timing, highlighting the genomic organization and conservation of I/SC-associated regulation between human and mouse genomes. The allele-restricted regulation described here creates extensive cellular mosaicism through a stable epigenetic mechanism. This mosaicism impacts numerous dosage-sensitive genes associated with human diseases such as Alzheimer, Parkinson, epilepsy, deafness, and impaired intellectual development.},
}

Animals
*Alleles
Mice
*DNA Replication Timing
*Epigenesis, Genetic
Humans
*Gene Dosage
*Genetic Loci
*Gene Silencing

@article {pmid42417835,
year = {2026},
author = {Singh, A and Singh, L and Dalal, D},
title = {Pharmacological mechanisms of fisetin in neurodegenerative disorders: regulation of neuroinflammatory, oxidative, and autophagic pathways.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42417835},
issn = {1432-1912},
abstract = {Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and related progressive neurological conditions, are characterized by irreversible neuronal loss, cognitive impairment, and motor dysfunction. Accumulating evidence identifies chronic neuroinflammation as a critical contributor to disease initiation and progression. In particular, activation of the TLR-4/NF-κB signaling cascade in glial cells promotes excessive production of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, together with induction of COX-2, iNOS, oxidative stress, and apoptosis, thereby exacerbating neuronal injury. Current pharmacotherapeutic strategies largely provide symptomatic benefit without effectively targeting the underlying pathogenic mechanisms. Fisetin, a naturally occurring flavonoid abundantly present in strawberries, apples, and persimmons, has recently attracted considerable attention owing to its pleiotropic neuroprotective properties. Experimental evidence indicates that fisetin suppresses TLR-4/NF-κB-mediated neuroinflammatory signaling, attenuates microglial activation, and enhances endogenous antioxidant defense through modulation of the Nrf2 pathway. Moreover, fisetin regulates apoptosis-associated mediators, thereby preserving neuronal integrity and survival. Notably, emerging studies demonstrate that fisetin-mediated inhibition of the TLR-4/Akt/mTOR signaling axis promotes autophagy-dependent α-syn clearance and neurogenesis, particularly in Parkinsonian models, highlighting its potential disease-modifying effects. These multifaceted pharmacological actions suggest that fisetin simultaneously targets interconnected inflammatory, oxidative, apoptotic, and proteostatic pathways implicated in neurodegeneration. Despite promising preclinical findings, additional investigations are required to elucidate its effects on inflammasome activation, glial cell crosstalk, pharmacokinetic behavior, and long-term clinical safety. Collectively, fisetin represents a promising multi-target therapeutic candidate for the management of inflammation-associated neurodegenerative disorders.},
}

@article {pmid42417851,
year = {2026},
author = {Talebnejad, MR and Zia, Z and Ostovan, VR and Nazarpour-Servak, M and Nowroozzadeh, MH},
title = {Retinal sublayer changes in cases with Alzheimer's disease and depression.},
journal = {Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie},
volume = {},
number = {},
pages = {},
pmid = {42417851},
issn = {1435-702X},
abstract = {PURPOSE: Alzheimer's disease (AD) and depression are two prevalent conditions in the elderly population, both of which may impact the structure or function of the visual pathway. This study simultaneously investigated the effects of AD and depression on optic nerve head and macular parameters using Optical Coherence Tomography (OCT) imaging.

METHODS: This cross-sectional study included two groups: 50 individuals with mild to moderate AD and 50 age-matched healthy controls (HCs). All participants underwent the Patient Health Questionnaire-9 (PHQ-9) and Mini-Mental State Examination (MMSE). Comprehensive ophthalmic examinations were performed, and individuals with significant refractive errors or ocular pathologies were excluded. Peripapillary RNFL (pRNFL) and macular layer imaging were conducted using Heidelberg OCT.

RESULTS: Compared to HCs, AD patients showed significant thinning of pRNFL in the supra temporal (HC: 136.38 ± 17.68 μm vs. AD: 127.45 ± 16.08 μm, P = 0.010) and infra temporal (HC: 139.46 ± 20.88 μm vs. AD: 127.99 ± 17.06 μm, P = 0.003) quadrants, while temporal and nasal sectors were not significantly different. Inner macular layers were also significantly reduced in the AD group: GCL volume (1.043 ± 0.073 vs. 0.981 ± 0.083 mm³, P < 0.001), IPL volume (0.872 ± 0.061 vs. 0.834 ± 0.048 mm³, P = 0.001), and GCC (2.832 ± 0.181 vs. 2.671 ± 0.192 mm³, P < 0.001). Depression severity correlated negatively with GCL volume (ρ = - 0.260, P = 0.009). In stepwise regression analysis, MMSE score was more strongly associated with GCL volume than depression status and entered the model as the main predictor (β = 0.489, P < 0.001). The MMSE × depression interaction term was also significant (β = -0.213, P = 0.020), indicating that depression modified the association between cognitive impairment and GCL thinning.

CONCLUSIONS: AD and depression in the elderly can influence the thickness of inner retinal layers, with dementia appearing to have a more pronounced effect than depression. These retinal changes may have important implications not only for the early diagnosis and monitoring of AD, but also for the accuracy of OCT-based detection of early glaucoma in patients with coexisting neuropsychiatric disorders-particularly in those with AD, where reliable visual field testing may also be challenging.},
}

@article {pmid42417853,
year = {2026},
author = {Zheng, H and Yang, H and Ma, H and Zhu, L and Liu, A and Hou, X and Yang, C and Ye, W},
title = {Dietary sialic acid intake and incident dementia: evidence from a large prospective cohort study.},
journal = {European journal of nutrition},
volume = {65},
number = {5},
pages = {},
pmid = {42417853},
issn = {1436-6215},
support = {82204023//National Natural Science Foundation of China/ ; 2022ZD0211600//National Major Science and Technology Projects of China/ ; XRCZX2020019//Research Start-up Fund of Fujian Medical University/ ; No.2023QH1065//Research Start-up Fund of Fujian Medical University/ ; },
mesh = {Humans ; Prospective Studies ; *N-Acetylneuraminic Acid/administration & dosage ; *Dementia/epidemiology/prevention & control ; Male ; Female ; *Diet/methods/statistics & numerical data ; Aged ; Middle Aged ; United Kingdom/epidemiology ; Risk Factors ; Incidence ; Proportional Hazards Models ; Alzheimer Disease/epidemiology ; Dementia, Vascular/epidemiology ; Follow-Up Studies ; },
abstract = {PURPOSE: Beneficial effects of sialic acid on cognition have been most often seen in cognitive development in infant models, whereas the relevant evidence from ageing population studies remains limited. We aimed to investigate the associations of dietary sialic acids and their subtypes (Neu5Ac and Neu5Gc) with the incident dementia in a large prospective study.

METHODS: A total of 210,796 middle-aged and older participants from UK Biobank were included in this study. Dietary sialic acids intake was estimated using repeated 24-h dietary recall questionnaires. Cox proportional hazards models were used to evaluate the association of sialic acid and its subtypes with dementia risk.

RESULTS: During a mean follow-up of 10.9 years, 2469 incident all-cause dementia were recorded, of which 1077 were Alzheimer's disease (AD), and 454 were vascular dementia (VaD). Compared with participants in the lowest quartile (median intake: 25.12 mg/d), participants in the third quartile of total sialic acids (median intake: 56.46 mg/d) were associated with a 18% lower risk of all-cause dementia (HR 0.82; 95% CI 0.73-0.92) and a 31% lower risk of VaD (HR 0.69; 95%CI 0.53-0.91), respectively. Similar associations were observed for Neu5Ac and Neu5Gc, respectively. After mutual adjustment, the association of Neu5Gc with all-cause dementia or VaD risk remained unchanged, whereas the association of Neu5Ac with dementia risk became non-significant after adjusting for Neu5Gc.

CONCLUSION: Our findings suggest a potential non-linear protective association between total sialic acid and risk of all-cause dementia and VaD.},
}

Humans
Prospective Studies
*N-Acetylneuraminic Acid/administration & dosage
*Dementia/epidemiology/prevention & control
Male
Female
*Diet/methods/statistics & numerical data
Aged
Middle Aged
United Kingdom/epidemiology
Risk Factors
Incidence
Proportional Hazards Models
Alzheimer Disease/epidemiology
Dementia, Vascular/epidemiology
Follow-Up Studies

@article {pmid42417935,
year = {2026},
author = {Gupta, A and Singh, S and Singh, TD},
title = {Regulation of NLRP3 inflammasome signaling in Alzheimer's disease: emerging neuroprotective role of phytochemicals.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42417935},
issn = {1568-5608},
abstract = {The Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that plays an important role in neuroinflammatory diseases, including Alzheimer's disease (AD). NLRP3 inflammasome activation involves upstream priming and activation signals, including amyloid-β aggregates, mitochondrial dysfunction, and oxidative stress, which promote inflammasome assembly and trigger downstream effector responses. This leads to caspase-1 activation and cleavage of GSDMD and the subsequent release of pro-inflammatory cytokines such as IL-1β and IL-18, thereby amplifying neuroinflammation and contributing to the neuronal damage characteristic of AD. Two known pathways of NLRP3 inflammasome activation are the canonical pathway, mediated by caspase-1, and the non-canonical pathway, mediated by caspase-11 (in mice) or caspase-4/5 (in humans). The use of phytochemicals to prevent NLRP3 inflammasome activation offers potential to reduce neuroinflammation and maintain neuronal integrity in AD. Phytochemicals such as resveratrol, ginkgolide B, and saffron, among others, have been shown to modulate the activity of the NLRP3 inflammasome through various mechanisms, including the inhibition of NLRP3 assembly, suppression of inflammasome priming signals, and regulation of downstream signaling pathways. Overall, phytochemicals that target NLRP3 inflammasome activation may offer potential benefits for AD management by attenuating neuroinflammation and protecting against neuronal damage.},
}

@article {pmid42418029,
year = {2026},
author = {Colitta, A and Mazzarone, T and Corsi, S and Petrozzi, L and Mengozzi, A and Del Chicca, M and Sessa, MR and Bacciardi, E and Virdis, A and Monzani, F and Baldacci, F and Turco, F and Siciliano, G},
title = {Plasma phosphorylated tau and cerebrovascular burden predict emergency department use in dependent older patients.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42418029},
issn = {1590-3478},
support = {I53C22000780001//European Union - Next Generation EU/ ; },
mesh = {Humans ; *tau Proteins/blood ; Female ; Male ; *Emergency Service, Hospital/statistics & numerical data ; Biomarkers/blood ; Aged ; Aged, 80 and over ; Prospective Studies ; *Cerebrovascular Disorders/blood ; *Cognitive Dysfunction/blood ; Phosphorylation ; *Frailty/blood ; Emergency Room Visits ; },
abstract = {BACKGROUND: Dependent older patients show high risk of adverse health outcomes when admitted to the emergency department (ED). The prompt identification of ED use risk factors in such population is hence needed. While frailty and cognitive impairment are a known clinical risk factors, biomarkers of most prevalent dementias have been scarcely investigated as possible ED use predictors. Within this framework, this prospective study explored whether plasma phospho-tau181 (ptau181) and cerebrovascular burden provide additional predictive value for 6-month ED use in elderly dependent patients, beyond frailty and age.

METHODS: We collected baseline clinical and laboratory data to validate a 32-item frailty index, while assessing cognitive impairment through the Mini-Mental State Examination. Biomarkers of cognitive impairment included plasma ptau181 and cerebrovascular burden, i.e., the Fazekas Scale. Binomial and Cox regression models tested the biomarkers of cognitive impairment as predictors of ED use, adjusting for frailty and age. The interaction between cognitive impairment biomarkers was explored.

RESULTS: Of the 102 recruited patients, 38 visited the ED. In the binomial models, the frailty index (OR = 1.69, p = 0.011) and the Fazekas Scale (OR = 3.57, p = 0.007) predicted ED use. At lower p-tau181 levels, ED admission risk increased only with higher cerebrovascular burden. Conversely, higher p-tau181 levels predicted ED use (OR = 4.90, p = 0.037) irrespective of cerebrovascular burden. No significant predictors of time to ED use emerged.

DISCUSSION: Beyond measures of clinical frailty, the routinary employment of cognitive impairment biomarkers may contribute identifying dependent older patients at short-term high risk of ED use, possibly reducing adverse health outcomes in such population.},
}

Humans
*tau Proteins/blood
Female
Male
*Emergency Service, Hospital/statistics & numerical data
Biomarkers/blood
Aged
Aged, 80 and over
Prospective Studies
*Cerebrovascular Disorders/blood
*Cognitive Dysfunction/blood
Phosphorylation
*Frailty/blood
Emergency Room Visits

@article {pmid42418159,
year = {2026},
author = {Panisello, L and Millet-Sigalat, M and Novau-Ferré, N and Mateu-Fabregat, J and Carrasco, M and Ettcheto, M and Félix-Soriano, E and Camins, A and Bulló, M},
title = {Nut consumption as a therapeutic strategy to preserve brain function, attenuate neuropathology, and modulate cross-tissue microRNAs in a mouse model of Alzheimer's disease.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6fo00445h},
pmid = {42418159},
issn = {2042-650X},
abstract = {Nutritional modulation of brain metabolism is emerging as a key strategy for preventing Alzheimer's Disease (AD), with potential to influence key pathologies such as amyloid beta/β (Aβ) accumulation, tau phosphorylation, and neuroinflammation. However, the biological mechanisms linking diet, metabolism, and AD remain poorly understood. The aim of this study is to investigate the neuroprotective effects of a nut-enriched diet (NED) on AD-like pathology using APPswe/PS1dE9 (APP) transgenic mice, focusing on cognition, neuroinflammation, Aβ burden, and the potential regulatory role of circulating and brain-tissue specific microRNA (miRNA). APP and wild-type (WT) male mice were fed either a control diet (CD) or NED providing 10% of total energy from mixed nuts. Behavioral performance, Aβ deposition, glial activation, and synaptic integrity were assessed, alongside miRNA profiling in serum, cortex, and hippocampus. In APP mice, NED enhanced hippocampal-dependent memory, reduced microglia and astrocyte reactivity, decreased cortical and hippocampal Aβ plaque burden, and preserved dendritic spine density. Multi-compartment miRNA analyses revealed that NED modulated several AD-relevant miRNAs involved in insulin signaling, neuroinflammation, and synaptic function. These miRNA alterations correlated with improved cognitive outcomes and attenuated neuropathology, suggesting coordinated metabolic and molecular reprogramming in response to dietary intervention. A nut-enriched diet exerted significant neuroprotective effects in an AD mouse model, potentially mediated through coordinated miRNA regulation and related metabolic pathways. These findings support nut consumption as a feasible nutrition-based strategy for AD prevention and identify candidate miRNAs that may serve as biomarkers or mechanistic mediators at the intersection of diet, metabolism, and neurodegeneration.},
}

@article {pmid42418262,
year = {2026},
author = {Hopkins, WD and Achorn, A and Mulholland, MM and Magden, E and Schapiro, SJ and Fults, CL and Mangin, JF and Meguerditchian, A},
title = {A Comparative Study of Aging and Cortical Folding in Chimpanzees and Olive Baboons.},
journal = {American journal of primatology},
volume = {88},
number = {7},
pages = {e70190},
doi = {10.1002/ajp.70190},
pmid = {42418262},
issn = {1098-2345},
support = {2021711//National Science Foundation/ ; AG-067419/NH/NIH HHS/United States ; },
mesh = {Animals ; *Pan troglodytes/physiology/anatomy & histology ; Female ; *Aging/physiology ; Male ; *Papio anubis/physiology/anatomy & histology ; *Cerebral Cortex/anatomy & histology/physiology ; Species Specificity ; Sex Factors ; Sex Characteristics ; Magnetic Resonance Imaging ; },
abstract = {In light of the evidence that nonhuman primates naturally develop Alzheimer's disease neuropathologies, there is a renewed interest in research on the comparative biology of aging, including neurological changes across the age groups in species with diverse lifespans. In this paper, we examined age-related differences in two measures of cortical folding, mean depth and fold opening, in a sample of chimpanzees (Pan troglodytes) and olive baboons (Papio anubis). We found significant species differences in the slope and pattern of age-related changes in cortical folding. As predicted, chimpanzees showed negative linear associations between age and mean depth and positive linear associations between age and fold opening, as we see in humans. However, contrary to our hypotheses, baboons showed positive quadratic associations between age and mean depth and negative quadratic associations between age and fold opening. Additionally, within the baboons but not the chimpanzees, significant sex differences were found in age-related differences in cortical folding. Here, male baboons showed significant linear associations between age, sulci depth, and fold opening, much like male and female chimpanzees. However, for female baboons, slopes of age-related differences in fold opening were flat or showed slight quadratic associations. It is possible that variation in primate social systems and/or reproductive aging may influence sex and species differences in brain aging. Longitudinal studies on primate brain aging, as well as comparative research with additional taxa, could shed light on the causes and implications of these differences.},
}

Animals
*Pan troglodytes/physiology/anatomy & histology
Female
*Aging/physiology
Male
*Papio anubis/physiology/anatomy & histology
*Cerebral Cortex/anatomy & histology/physiology
Species Specificity
Sex Factors
Sex Characteristics
Magnetic Resonance Imaging

@article {pmid42418270,
year = {2026},
author = {Caselli, RJ and Geldmacher, DS and Schilling, TB},
title = {A Narrative Review of Amyloid-β Monoclonal Antibodies for Alzheimer Disease: How Amyloid Species Engagement May Affect Clinical Outcomes.},
journal = {The neurologist},
volume = {31},
number = {4},
pages = {129-135},
doi = {10.1097/NRL.0000000000000679},
pmid = {42418270},
issn = {2331-2637},
support = {//Eli Lilly and Company, Indianapolis, IN/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/immunology/metabolism ; *Antibodies, Monoclonal/therapeutic use ; Plaque, Amyloid/drug therapy ; Animals ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a leading cause of death worldwide, with growing prevalence as life expectancy increases. An important neurological hallmark of AD is the deposition of extracellular neuritic amyloid-β (Aβ) plaques that can disrupt synaptic transmission and cause neuronal death. More recent studies suggest that targeting Aβ species can slow the progression of cognitive decline in AD.

REVIEW SUMMARY: This narrative review examines the efficacy of monoclonal antibodies targeting the amyloid-β (Aβ) protein in the treatment of AD. It discusses the mechanisms by which these antibodies aim to mitigate amyloid pathology and explores their clinical outcomes in various trials. The review highlights the importance of amyloid plaque reduction to less than 25 Centiloids observed through amyloid positron emission tomography (PET) scans as a predictor of slowing cognitive decline. The findings suggest that targeting insoluble amyloid plaques is crucial for achieving clinical benefits in AD treatment. This review also discusses the phenomenon of amyloid-related imaging abnormalities (ARIA) that may be associated with monoclonal antibody therapy.

CONCLUSION: Monoclonal antibodies that target Aβ monomers, soluble oligomers and protofibrils, and insoluble fibrils/plaques were developed, and not all have provided clinical benefit. Emerging evidence suggests that it is important to reduce amyloid plaque burden to less than 25 Centiloids, consistent with a visually negative amyloid PET scan, in order to slow cognitive decline in early symptomatic AD.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging/metabolism
*Amyloid beta-Peptides/immunology/metabolism
*Antibodies, Monoclonal/therapeutic use
Plaque, Amyloid/drug therapy
Animals

@article {pmid42418280,
year = {2026},
author = {Zhang, C and Chen, S and Zhao, H and Wang, Y and Zhou, L and Fan, H and Sun, Y},
title = {Phase Separation Drives Pathological Aggregation in Neurodegenerative Diseases: A 15-Year Bibliometric Landscape (2009-2024).},
journal = {Annals of the New York Academy of Sciences},
volume = {1561},
number = {1},
pages = {e70311},
doi = {10.1111/nyas.70311},
pmid = {42418280},
issn = {1749-6632},
support = {#82371153//National Natural Science Foundation of China/ ; #82571317//National Natural Science Foundation of China/ ; #ZR2022QH073//Natural Science Foundation of Shandong Province/ ; #ZR2025MS1188//Natural Science Foundation of Shandong Province/ ; #ZR2025LZ044//Natural Science Foundation of Yantai/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Phase Separation ; *Protein Aggregation, Pathological/metabolism/pathology ; *Bibliometrics ; Animals ; DNA-Binding Proteins/metabolism ; },
abstract = {Liquid-liquid phase separation (LLPS), a biophysical driver of membraneless organelle assembly, is central to pathological aggregation in neurodegenerative diseases. Initially linked to amyotrophic lateral sclerosis (ALS), LLPS dysregulation has now been implicated in Alzheimer's, Parkinson's, and frontotemporal dementia, where aberrant transitions convert dynamic condensates into insoluble fibrils. To systematically map this landscape, we employed CiteSpace-based bibliometrics to analyze 784 Web of Science articles from 2009 to 2024. Our analyses reveal dominant contributions from the United States, China, and Germany, with collaborative networks focusing on protein dynamics. Key hotspots include LLPS-driven aggregation of TARDBP (TDP-43), FUS, and α-synuclein, alongside stress granule dysfunction and nucleocytoplasmic transport defects. Emerging frontiers highlight therapeutic strategies targeting pathological condensates utilizing small-molecule chaperones and posttranslational modification modulators to restore cellular homeostasis. Our findings underscore LLPS as a critical axis bridging molecular pathology and translational innovation. The field is rapidly shifting from mechanistic exploration to therapeutic applications, emphasizing interventions to halt or reverse aggregation. By delineating global trends and changing priorities, our study highlights the transformative potential of phase-targeted interventions and provides a roadmap of groundbreaking interdisciplinary research into neurodegenerative disorders.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology
Phase Separation
*Protein Aggregation, Pathological/metabolism/pathology
*Bibliometrics
Animals
DNA-Binding Proteins/metabolism

@article {pmid42418295,
year = {2026},
author = {Gu, T and Guo, H and Guo, Z and Hua, S},
title = {Advances in the Core Role and Mechanisms of Mitochondrial Dysfunction in Alzheimer's Disease.},
journal = {Brain and behavior},
volume = {16},
number = {7},
pages = {e71418},
doi = {10.1002/brb3.71418},
pmid = {42418295},
issn = {2162-3279},
mesh = {*Alzheimer Disease/metabolism/pathology/physiopathology ; Humans ; *Mitochondria/metabolism/pathology ; Animals ; Mitophagy/physiology ; Oxidative Stress/physiology ; Mitochondrial Dynamics/physiology ; Energy Metabolism/physiology ; Mitochondria Associated Membranes ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Brain-Gut Axis/physiology ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a complex neurodegenerative disorder whose pathogenesis involves multi-level pathological alterations. This review aims to systematically elucidate the central role and multifaceted molecular mechanisms of mitochondrial dysfunction in the progression of AD.

METHODS: A comprehensive analysis of the existing literature was conducted, synthesizing findings from studies investigating mitochondrial involvement in AD pathology. The review focused on key mechanistic pathways, including energy metabolism deficits, oxidative stress, synaptic damage, mitochondrial dynamics, mitochondria-associated membranes (MAMs), mitophagy, and the gut-brain axis.

RESULTS: The analysis revealed several critical mechanisms linking mitochondrial dysfunction to AD progression: (i) impaired mitochondrial energy metabolism, which establishes a causal relationship with oxidative stress and synaptic injury; (ii) dysregulation of mitochondrial fusion/fission dynamics, particularly the aberrant interactions of amyloid-beta (Aβ) and p-Tau with the fission protein Drp1 and the channel protein VDAC1; (iii) dysfunction of mitochondria-associated membranes (MAMs); (iv) defective mitophagy involving both the PINK1/Parkin pathway and receptor-mediated pathways; and (v) bidirectional crosstalk between mitochondria and the gut-brain axis. These interconnected pathways converge to amplify neuroinflammation and neuronal death.

CONCLUSION: Accumulated evidence positions mitochondrial dysfunction as a critical hub that integrates Aβ/Tau pathology, neuroinflammation, and neuronal loss, thereby perpetuating a self-sustaining vicious cycle in AD. Targeting mitochondrial bioenergetics, dynamics, quality control, and the mitochondria-inflammation axis offers substantial therapeutic promise. Emerging small molecules such as SS31 and DDQ have demonstrated protective effects in preclinical models. Future investigations should prioritize mechanistic dissection and translational research to facilitate the clinical development of mitochondria-targeted therapies for AD.},
}

*Alzheimer Disease/metabolism/pathology/physiopathology
Humans
*Mitochondria/metabolism/pathology
Animals
Mitophagy/physiology
Oxidative Stress/physiology
Mitochondrial Dynamics/physiology
Energy Metabolism/physiology
Mitochondria Associated Membranes
Amyloid beta-Peptides/metabolism
Brain/metabolism
Brain-Gut Axis/physiology

@article {pmid42418307,
year = {2026},
author = {Özbek, Y and Yener, GG},
title = {Neurophysiological Differentiation of Conversion to Alzheimer's Disease: Longitudinal Changes in P300 Amplitude as an Indicator of Mild Cognitive Impairment Progression.},
journal = {Brain and behavior},
volume = {16},
number = {7},
pages = {e71555},
doi = {10.1002/brb3.71555},
pmid = {42418307},
issn = {2162-3279},
mesh = {Humans ; *Cognitive Dysfunction/physiopathology/diagnosis ; *Alzheimer Disease/physiopathology/diagnosis ; *Event-Related Potentials, P300/physiology ; Disease Progression ; Female ; Longitudinal Studies ; Male ; Electroencephalography/methods ; Aged ; Neuropsychological Tests ; },
abstract = {PURPOSE: This longitudinal study investigated whether P300 event-related potential (ERP) amplitude demonstrates group-level and longitudinal differences between stable and progressive mild cognitive impairment (MCI), and whether these electrophysiological changes may serve as preliminary markers associated with Alzheimer's disease (AD) progression.

METHOD: Fifty-four participants, including 27 cognitively unimpaired (CU) individuals and 27 individuals with multi-domain amnestic MCI, underwent EEG recording during a visual oddball task at baseline and follow-up assessment. Within 1 year, 14 MCI participants progressed to AD (pMCI), while 13 remained stable (sMCI). P300 amplitudes were compared across groups and over time, and exploratory receiver operating characteristic (ROC) analyses were conducted to evaluate discriminative performance. Correlations between P300 amplitudes and cognitive measures were also examined.

FINDINGS: Baseline analyses demonstrated significantly reduced P300 amplitudes in both MCI groups compared to CU participants (p < 0.001), consistent with early cortical dysfunction. Longitudinally, CU and sMCI groups exhibited amplitude decline over time, whereas the pMCI group showed persistently stable but markedly low amplitudes. Exploratory ROC analyses suggested potential group-level discriminative utility for differentiating pMCI from both CU and sMCI participants. In addition, lower P300 amplitudes were significantly associated with poorer global cognitive performance and memory scores.

CONCLUSION: These findings suggest that reduced P300 amplitude, particularly at central electrode locations, may represent a preliminary electrophysiological marker associated with progression from MCI to AD. The results support the potential relevance of P300 measures in future prognostic and longitudinal biomarker research in Alzheimer's disease.},
}

Humans
*Cognitive Dysfunction/physiopathology/diagnosis
*Alzheimer Disease/physiopathology/diagnosis
*Event-Related Potentials, P300/physiology
Disease Progression
Female
Longitudinal Studies
Male
Electroencephalography/methods
Aged
Neuropsychological Tests

@article {pmid42418450,
year = {2026},
author = {Khandelwal, P and Duong, MT and Levorse, LM and Trotman, W and Bahena, A and Lim, SA and Denning, AE and Chung, E and Olm, CA and Radhakrishnan, H and Ittyerah, R and Prabhakaran, K and Mizsei, G and Schuck, T and Emrani, S and Vizcarra, JA and Robinson, J and Ohm, DT and Phillips, JS and Cohen, J and Wisse, LEM and Detre, JA and Nasrallah, IM and Brown, CA and Das, SR and Lee, EB and Tisdall, MD and Irwin, DJ and McMillan, CT and Wolk, DA and Yushkevich, PA},
title = {Postmortem brain MRI reveals differential associations of subcortical and limbic volumes with cortical thinning and neurodegenerative pathologies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71649},
doi = {10.1002/alz.71649},
pmid = {42418450},
issn = {1552-5279},
support = {P30 AG072979/NH/NIH HHS/United States ; RF1 AG056014/NH/NIH HHS/United States ; R01 AG069474/NH/NIH HHS/United States ; R01 AG054519/NH/NIH HHS/United States ; P01 AG017586/NH/NIH HHS/United States ; U19 AG062418/NH/NIH HHS/United States ; R01 NS109260/NH/NIH HHS/United States ; F30 AG074524/NH/NIH HHS/United States ; P01 AG084497/NH/NIH HHS/United States ; P01 AG066597/NH/NIH HHS/United States ; },
mesh = {Humans ; Female ; *Magnetic Resonance Imaging ; Male ; Aged ; *Lewy Body Disease/pathology/diagnostic imaging ; Atrophy/pathology ; *Brain/pathology/diagnostic imaging ; Aged, 80 and over ; tau Proteins/metabolism ; *Alzheimer Disease/pathology/diagnostic imaging ; DNA-Binding Proteins/metabolism ; *Frontotemporal Lobar Degeneration/pathology/diagnostic imaging ; alpha-Synuclein/metabolism ; *Cerebral Cortical Thinning/pathology/diagnostic imaging ; *Neurodegenerative Diseases/pathology/diagnostic imaging ; *Limbic System/pathology/diagnostic imaging ; Middle Aged ; },
abstract = {INTRODUCTION: The impact of different neuropathologies on deep brain structures remains to be understood. We examine subcortical and limbic volumetry in neurodegenerative diseases involving phosphorylated tau (p-tau), α-synuclein, and transactive response DNA binding protein 43 (TDP-43).

METHODS: We acquired neuropathological measures and brain segmentations from postmortem analysis of 132 donors with Alzheimer's disease (AD), Lewy body disease (LBD), frontotemporal lobar degeneration with TDP-43 (FTLD-TDP), and FTLD-tau.

RESULTS: LBD had the least subcortical, limbic, and cortical atrophy compared to AD, FTLD-TDP, and FTLD-tau. In donors with both AD and LBD pathologies, primary LBD was associated with less atrophy than primary AD. While AD had cortico-subcortical and cortico-limbic morphometric associations, LBD had more limited parieto-occipital cortico-limbic associations. FTLD-TDP had cortico-subcortical while FTLD-tau had cortico-subcortical and cortico-limbic associations. In AD and FTLD-tau, hippocampal volumes correlated with p-tau burden, neuron loss, and gliosis. In LBD, thalamic α-synuclein severity was associated with subcortical/limbic volumes.

DISCUSSION: Postmortem neuroimaging reveals disease- and region-specific structure-pathology relationships.},
}

Humans
Female
*Magnetic Resonance Imaging
Male
Aged
*Lewy Body Disease/pathology/diagnostic imaging
Atrophy/pathology
*Brain/pathology/diagnostic imaging
Aged, 80 and over
tau Proteins/metabolism
*Alzheimer Disease/pathology/diagnostic imaging
DNA-Binding Proteins/metabolism
*Frontotemporal Lobar Degeneration/pathology/diagnostic imaging
alpha-Synuclein/metabolism
*Cerebral Cortical Thinning/pathology/diagnostic imaging
*Neurodegenerative Diseases/pathology/diagnostic imaging
*Limbic System/pathology/diagnostic imaging
Middle Aged

@article {pmid42418454,
year = {2026},
author = {Bréchet, L and Toussas, K and Marie, D and Unschuld, PG},
title = {The Hippocampus Links Episodic Memory and Bodily Awareness.},
journal = {Brain and behavior},
volume = {16},
number = {7},
pages = {e71570},
doi = {10.1002/brb3.71570},
pmid = {42418454},
issn = {2162-3279},
support = {2024-CAD03//Dementia Research Switzerland- Synapsis Foundation/ ; PZ00P1_208686/SNSF_/Swiss National Science Foundation/Switzerland ; },
mesh = {Humans ; *Memory, Episodic ; *Hippocampus/pathology/diagnostic imaging/physiopathology ; *Awareness/physiology ; Female ; Male ; Aged ; Magnetic Resonance Imaging ; *Cognitive Dysfunction/pathology/physiopathology/diagnostic imaging/psychology ; Middle Aged ; Atrophy/pathology ; },
abstract = {PURPOSE: Episodic autobiographical memory does not occur in isolation from the body: every remembered event was once encoded from a first-person perspective. Yet whether the hippocampus, long recognized as the canonical substrate of memory, also underpins the embodied self has remained unknown.

METHOD: We combined structural T1-weighted MRI with behavioral assessments of episodic memory (Logical Memory delayed recall) and bodily awareness (ARSQ 2.0 Somatic Awareness subscale) in patients with mild cognitive impairment (MCI) and healthy comparison groups to test whether hippocampal volume predicts both outcomes.

FINDING: We show that hippocampal volume predicts not only episodic memory performance but also bodily awareness in patients with MCI. Hippocampal volume explained substantial variance in both domains, whereas a control region did not, underscoring regional specificity. This effect was paralleled by a reduction of hippocampal volume in MCI patients compared to older and younger adults. Notably, both high- and low-cognition older adults showed larger volumes than in MCI.

CONCLUSION: These findings provide the first structural evidence that hippocampal atrophy is associated with reductions in both remembering and embodiment, positioning the hippocampus as a key node linking memory and bodily selfhood. Beyond revealing a novel dimension of hippocampal vulnerability, this work suggests translational opportunities. These findings open the possibility that bodily awareness may prove useful as an early marker in future longitudinal studies of Alzheimer's disease.},
}

Humans
*Memory, Episodic
*Hippocampus/pathology/diagnostic imaging/physiopathology
*Awareness/physiology
Female
Male
Aged
Magnetic Resonance Imaging
*Cognitive Dysfunction/pathology/physiopathology/diagnostic imaging/psychology
Middle Aged
Atrophy/pathology

@article {pmid42418465,
year = {2026},
author = {Moghekar, AR and Rock, JA and Mohs, RC and Hansson, O and Stomrud, E and Palmqvist, S and Mattsson-Carlgren, N and Johnson, SC and Zetterberg, H and Radwan, RR and Junfola, J and Miller, MC and Buitrago, L and De Simone, FI and Martin, K and Dickson, D and Benina, N and Hawkins, DM},
title = {Multicenter validation of plasma p-tau217/ amyloid beta 1-42 ratio in symptomatic Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71644},
doi = {10.1002/alz.71644},
pmid = {42418465},
issn = {1552-5279},
support = {//National Institutes of Health (NIH)/ ; U19-AG033655/AG/NIA NIH HHS/United States ; P30-AG005146/AG/NIA NIH HHS/United States ; R01AG083740/AG/NIA NIH HHS/United States ; SG-23-1061717/ALZ/Alzheimer's Association/United States ; FO2024-0284//Swedish Brain Foundation/ ; 20243058//Kamprad Foundation/ ; FRS-0011//Family Rönström/ ; FRS-0004//Family Rönström/ ; AF-1011949//Swedish Alzheimer Foundation/ ; //Alzheimer's Drug Discovery Foundation (ADDF)/ ; AG027161//Wisconsin Registry for Alzheimer's Prevention (WRAP)/ ; AG021155//Wisconsin Registry for Alzheimer's Prevention (WRAP)/ ; //Wisconsin Alzheimer's Disease Research Center (WADRC)/ ; AG062715//Foundation for the National Institutes of Health/ ; //MultiPark at Lund University/ ; //Bundy Academy/ ; //Fujirebio US/ ; },
mesh = {Humans ; *Amyloid beta-Peptides/blood/cerebrospinal fluid ; *Alzheimer Disease/blood/diagnostic imaging/diagnosis/cerebrospinal fluid ; Female ; *tau Proteins/blood/cerebrospinal fluid ; *Peptide Fragments/blood/cerebrospinal fluid ; Male ; Positron-Emission Tomography ; Aged ; Biomarkers/blood/cerebrospinal fluid ; Middle Aged ; Sensitivity and Specificity ; Aged, 80 and over ; },
abstract = {INTRODUCTION: This study evaluated the diagnostic performance of the Lumipulse[®] G pTau 217/β-Amyloid 1-42 Plasma Ratio to detect amyloid positivity in patients with cognitive decline symptoms.

METHODS: The Lumipulse Plasma Ratio was evaluated using predetermined thresholds (≤0.00370 negative; ≥0.00738 positive) against cerebrospinal fluid (CSF) biomarker ratios or amyloid positron emission tomography (PET) imaging as references in 499 adults (≥50 years old) enrolled in prospective studies conducted across academic memory clinics and research centers.

RESULTS: Amyloid status was determined by CSF in 347 patients (189 positive [54.5%]) and by PET imaging in 152 patients (66 positive [43.4%]). The Lumipulse Plasma Ratio was positive in 219 patients (43.9%), negative in 182 (36.5%), and indeterminate in 98 (19.6%). Positive and negative predictive values were 91.8% and 97.3%, with a sensitivity and specificity of 97.6% and 90.8%, respectively.

DISCUSSION: The US Food and Drug Administration-cleared Lumipulse Plasma Ratio demonstrated high accuracy in identifying amyloid pathology and offers an alternative to CSF testing and amyloid PET imaging.},
}

Humans
*Amyloid beta-Peptides/blood/cerebrospinal fluid
*Alzheimer Disease/blood/diagnostic imaging/diagnosis/cerebrospinal fluid
Female
*tau Proteins/blood/cerebrospinal fluid
*Peptide Fragments/blood/cerebrospinal fluid
Male
Positron-Emission Tomography
Aged
Biomarkers/blood/cerebrospinal fluid
Middle Aged
Sensitivity and Specificity
Aged, 80 and over

@article {pmid42418471,
year = {2026},
author = {Hirsch, F and Frontzkowski, L and Steward, A and Roemer-Cassiano, SN and Biel, D and Zhu, Z and Palleis, C and Gnörich, J and Klonowski, M and Höglinger, G and Brendel, M and Franzmeier, N},
title = {Modular brain networks shape amyloid-driven tau spread and cognitive decline.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71617},
doi = {10.1002/alz.71617},
pmid = {42418471},
issn = {1552-5279},
support = {A2021026S//BrightFocus Foundation/ ; AARG-22-973496/ALZ/Alzheimer's Association/United States ; EXC21452SyNergy-ID390857198//Deutsche Forschungsgemeinschaft/ ; //Gerhard und Ilse Schick Stiftung/ ; },
mesh = {Humans ; *tau Proteins/metabolism ; Positron-Emission Tomography ; *Cognitive Dysfunction/metabolism/diagnostic imaging/pathology ; *Brain/metabolism/diagnostic imaging/pathology ; *Amyloid beta-Peptides/metabolism ; Female ; *Alzheimer Disease/metabolism/diagnostic imaging/pathology ; Male ; Aged ; Connectome ; *Nerve Net/diagnostic imaging/metabolism ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Alzheimer's disease involves trans-synaptic spread of tau pathology from temporal lobe epicenters, driven by amyloid beta (Aβ) deposition. How modular brain network architecture shapes this process and the ensuing cognitive decline remains incompletely understood. We tested whether the efficiency with which tau epicenters access cross-network communication pathways modulates Aβ-driven tau propagation.

METHODS: We combined baseline/longitudinal amyloid/tau positron emission tomography (PET) data across two independent AD cohorts (N = 490) with multimodal connectomics data. We quantified epicenter broadcast capacity (EBC), capturing whether tau epicenters preferentially access regions supporting cross-network communication or within-network communication.

RESULTS: Higher EBC was associated with faster Aβ-related global tau accumulation, greater spatial tau spread, and steeper cognitive decline. Effects were driven by stronger epicenter communication with cross-network connectors, whereas preferential within-network routing was associated with relative containment of tau spread.

DISCUSSION: We identify a mechanism through which epicenter connectivity biases Aβ-driven tau propagation toward brain-wide broadcast or regional containment, helping explain heterogeneity in disease progression.},
}

Humans
*tau Proteins/metabolism
Positron-Emission Tomography
*Cognitive Dysfunction/metabolism/diagnostic imaging/pathology
*Brain/metabolism/diagnostic imaging/pathology
*Amyloid beta-Peptides/metabolism
Female
*Alzheimer Disease/metabolism/diagnostic imaging/pathology
Male
Aged
Connectome
*Nerve Net/diagnostic imaging/metabolism
Aged, 80 and over

@article {pmid42418485,
year = {2026},
author = {Bahri, S and Palani, RS and Silvers, R and Michael, B and Lattanzi, V and André, I and Linse, S and Griffin, RG},
title = {High-resolution structure of monomorphic Aβ1-40 fibrils.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {28},
pages = {e2603575123},
doi = {10.1073/pnas.2603575123},
pmid = {42418485},
issn = {1091-6490},
support = {AG058504//HHS | NIH | National Institute on Aging (NIA)/ ; GM132997//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; VR2015-00143//Swedish Research Council/ ; },
mesh = {*Amyloid beta-Peptides/chemistry/ultrastructure/genetics ; *Peptide Fragments/chemistry/ultrastructure/genetics ; *Amyloid/chemistry/ultrastructure ; Humans ; Models, Molecular ; Alzheimer Disease/metabolism ; Magnetic Resonance Spectroscopy ; Protein Conformation ; Nuclear Magnetic Resonance, Biomolecular ; },
abstract = {Amyloid-β (Aβ) fibrils primarily composed of Aβ1-40 and Aβ1-42 form the core of senile plaques in Alzheimer's disease. Aβ1-40 fibrils may exhibit significant polymorphism influenced by sample preparation conditions, complicating atomic resolution structural characterization. To establish a reliable structural baseline, we developed a protocol for expressing and purifying recombinant Aβ1-40 that forms monomorphic fibrils under physiological conditions (pH 7.4). We present a high-resolution structure of these unseeded, monomorphic Aβ1-40 fibrils obtained using magic-angle spinning NMR spectroscopy (PDB ID 12GB). We obtained unambiguous chemical shift assignments for approximately 90% of the residues and measured over 500 distance and torsion angle restraints. The resolved structure, with a backbone RMSD of 0.63 ± 0.06 Å, shows two monomers per filament plane, with two distinct β-sheets (residues E11-E22 and K28-V39, respectively) running along the fibril axis with H-bonding between each plane, and the two strands linked by a flexible loop region. This structure reveals three continuous hydrophobic cores inside each filament which bury 24 hydrophobic side chains per filament plane: those of L17, F19, A21, V24, A30, I32, M35, V40 between the two β-strands within each monomer and I31, L34, V36, V39 between the two monomers. Small angle X-ray scattering reveals the size and geometry of the fibril cross-section, which is compatible with a two-filament arrangement with a total of 4 monomers per fibril plane.},
}

*Amyloid beta-Peptides/chemistry/ultrastructure/genetics
*Peptide Fragments/chemistry/ultrastructure/genetics
*Amyloid/chemistry/ultrastructure
Humans
Models, Molecular
Alzheimer Disease/metabolism
Magnetic Resonance Spectroscopy
Protein Conformation
Nuclear Magnetic Resonance, Biomolecular

@article {pmid42406869,
year = {2026},
author = {Miao, L and Hou, F and Li, G},
title = {Key targets and mechanisms by which gut microbiota-derived metabolites regulate Alzheimer's disease through the immune - inflammatory pathway: Based on network pharmacology and molecular docking.},
journal = {PloS one},
volume = {21},
number = {7},
pages = {e0352999},
doi = {10.1371/journal.pone.0352999},
pmid = {42406869},
issn = {1932-6203},
mesh = {*Alzheimer Disease/metabolism/immunology/microbiology ; *Molecular Docking Simulation ; Humans ; *Gastrointestinal Microbiome/immunology ; Signal Transduction ; *Network Pharmacology ; Inflammation/metabolism/immunology ; Protein Interaction Maps ; },
abstract = {This study integrated network pharmacology, bioinformatics, and molecular docking to explore potential immune-inflammatory pathways associated with the relationship between gut microbiota-derived metabolites and Alzheimer's disease (AD). A total of 260 gut microbiota - derived metabolites were initially retrieved, and 196 common targets were identified by intersecting predicted metabolite-associated targets with AD-related targets. Further screening identified 14 key overlapping targets, including IL6, NFKB1, IL1B, PTGS2, TLR4, and PPARG. Protein-protein interaction (PPI) network analysis identified IL6, NFKB1, IL1B, CXCL8, PPARG, FOS, and JUN as central hub genes. Functional enrichment analyses indicated that these targets were mainly involved in immune-inflammatory responses, response to lipopolysaccharide, oxidative stress-related processes, and regulation of apoptosis. KEGG pathway analysis further suggested that the overlapping targets were associated with several inflammation-related signaling pathways, including the NOD-like receptor, TNF, NF-κB, and MAPK signaling pathways. In silico pharmacokinetic and toxicity evaluation showed that several representative metabolites exhibited heterogeneous but informative drug-likeness and pharmacokinetic/toxicity-related profiles relevant to gut-brain-axis hypothesis generation. Molecular docking was performed as an exploratory structural assessment and suggested that selected metabolites, including Enterodiol, Coumarin, and 3,9-dihydroxy-6H-benzo[c]chromen-6-one, showed top-ranked predicted docking poses in computationally identified surface-accessible pockets of representative hub proteins such as IL6 and NFKB1, with docking scores ranging from - 6.8 to - 8.1 kcal/mol. These docking scores were interpreted only as qualitative descriptors of predicted structural compatibility and were not used to infer quantitative biological activity, target inhibition, or therapeutic efficacy. Overall, this study prioritizes a potential multi-target immune-inflammatory network centered on IL6, NFKB1, and IL1B, providing a hypothesis-generating framework for understanding the possible role of gut microbiota-derived metabolites in AD-related neuroimmune regulation. Further experimental studies are required to validate the predicted metabolite-target associations and clarify their biological relevance.},
}

*Alzheimer Disease/metabolism/immunology/microbiology
*Molecular Docking Simulation
Humans
*Gastrointestinal Microbiome/immunology
Signal Transduction
*Network Pharmacology
Inflammation/metabolism/immunology
Protein Interaction Maps

@article {pmid42407324,
year = {2026},
author = {Abdel-Rahman, SA and Gabr, MT},
title = {From DNA-encoded library (DEL) screening to in vivo validation: LILRB4 (ILT3)-targeted small molecules reprograms myeloid immune suppression.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {201},
number = {},
pages = {119740},
doi = {10.1016/j.biopha.2026.119740},
pmid = {42407324},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) remains a major unmet clinical challenge, with limited therapeutic strategies capable of effectively modulating neuroimmune dysfunction. Leukocyte immunoglobulin-like receptor B4 (LILRB4/ILT3) has recently emerged as an inhibitory microglial immune checkpoint implicated in ApoE-mediated suppression of amyloid-β (Aβ) clearance and inflammatory signaling, supporting its potential as a therapeutic target in AD. Here, we applied DNA-encoded library (DEL) screening of approximately 3.6 billion compounds to identify small molecule binders of LILRB4. Biophysical validation identified APX1 as a direct LILRB4 ligand with submicromolar affinity, which was further confirmed by cellular thermal shift assay (CETSA). Docking-guided mutagenesis studies defined a discrete ligand-binding interface involving key hotspot residues required for stable target engagement. Functionally, APX1 disrupted the LILRB4-ApoE interaction in orthogonal ELISA and biolayer interferometry assays. In human iPSC-derived microglia, APX1 suppressed SHP1/2 phosphorylation, attenuated NF-κB activation and IL-1β secretion, and restored Aβ42 uptake under ApoE-driven inflammatory conditions. APX1 further demonstrated favorable in vitro developability, metabolic stability, and CNS exposure properties. In the 5xFAD mouse model of AD, oral administration of APX1 improved cognitive performance, reduced cortical and hippocampal Aβ42 burden, suppressed neuroinflammatory cytokines, and decreased activated microglial populations. Collectively, these findings establish APX1 as a promising small molecule modulator of the LILRB4-ApoE signaling axis and support pharmacological targeting of neuroimmune checkpoints as a therapeutic strategy for AD.},
}

@article {pmid42407430,
year = {2026},
author = {Ghanbarian, E and Khorsand, B and Zheng, L and Woodworth, DC and Glover, CM and Corrada, MM and Sajjadi, SA and Grill, JD and Ezzati, A and , },
title = {Hippocampal asymmetry captures non-amyloid-related risk of memory decline and clinical progression.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100638},
doi = {10.1016/j.tjpad.2026.100638},
pmid = {42407430},
issn = {2426-0266},
abstract = {BACKGROUND: Hippocampal atrophy is a key marker of Alzheimer's disease (AD)- related neurodegeneration; however, hippocampal volume alone may not fully capture heterogeneity in cognitive decline. Left-right hippocampal asymmetry may provide complementary information, but its prognostic value for long-term cognitive decline, particularly in relation to AD pathology, remains unclear.

OBJECTIVES: To determine whether hippocampal total volume and left-right hippocampal asymmetry provide complementary and independent information in capturing cognitive decline and clinical progression, and to examine their relationship to AD pathology.

DESIGN: Analysis of baseline MRI and longitudinal cognitive data over 10 years in four domains of memory, language, executive, and visuospatial function, using harmonized cognitive data from the Alzheimer's Disease Sequencing Project - Phenotype Harmonization Consortium (ADSP-PHC).

SETTING: Participants from ADNI 1, ADNI GO, ADNI 2, and ADNI 3 PARTICIPANTS: A total of 1,142 dementia-free participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with available baseline structural MRI, cerebrospinal fluid (CSF) amyloid-β (Aβ42) and phosphorylated tau (p-tau-181), and longitudinal cognitive follow-up.

MEASUREMENTS: Total hippocampal volume (left + right) and hemispheric asymmetry (absolute left-right volumetric difference) were modeled simultaneously. Linear mixed-effects models examined associations with baseline performance and longitudinal change across four cognitive domains. Cox proportional hazards models assessed risk of clinical progression to clinical dementia over up to 10 years of follow-up (median follow-up 4 years; median 5 visits per participant). All analyses adjusted for age, sex, education, APOE ε4 status, and CSF biomarkers, with stratification by amyloid status.

RESULTS: The study cohort included 546 women (47.8%), with a mean age of 72.54 ± 6.98 years. Smaller total hippocampal volume was consistently associated with worse baseline performance and faster decline across all four cognitive domains, even after adjustment for amyloid and tau. In contrast, greater left-right hippocampal asymmetry was selectively associated with worse performance and faster decline in memory, independent of total hippocampal volume. In amyloid-stratified analyses, total hippocampal volume showed broad associations with cognitive performance across multiple domains in both amyloid-positive and amyloid-negative participants, whereas hippocampal left-right asymmetry demonstrated selective associations with memory performance, which were observed only among amyloid-negative individuals. With respect to clinical progression to dementia, smaller total hippocampal volume was associated with a higher risk of progression in the overall cohort and within both amyloid groups. In contrast, hippocampal asymmetry was associated with progression risk only among amyloid-negative individuals (hazard ratio per SD increase = 1.31, 95% CI: 1.03-1.65).

CONCLUSIONS: Hippocampal total volume and asymmetry capture distinct aspects of neurodegeneration, with asymmetry providing additional prognostic information for memory decline and clinical progression in the absence of detectable amyloid pathology.},
}

@article {pmid42409055,
year = {2026},
author = {Sigvard, CS and Franco-Valiente, JM and Mato, G},
title = {Adversarial attacks on a multimodal Alzheimer's disease detection system reveal complex interdependences between heterogeneous modalities.},
journal = {Biomedical physics & engineering express},
volume = {},
number = {},
pages = {},
doi = {10.1088/2057-1976/ae866f},
pmid = {42409055},
issn = {2057-1976},
abstract = {Multi-modal models that fuse neuroimaging with clinical assessment data represent the current state of the art for automated Alzheimer's disease detection, yet their adversarial robustness remains poorly understood. We systematically investigated adversarial vulnerability in CogniNetMM, a model that fuses 3D structural MRI volumes with neuropsychological clinical variables, using the Fast Gradient Sign Method and DeepFool in three modality configurations: MRI only, clinical variables only, and both jointly. We further introduced a mean attack framework, in which the average perturbation vector across samples serves as a fixed-direction probe of the decision boundary, decoupling the contribution of attack direction from that of sample position.During training, we identified modality collapse, a training instability in which the fusion layer progressively suppresses the MRI pathway. Collapse probability decreased with larger batch sizes and was further reduced by stratified sampling on class-imbalanced data. Across all clinical variable configurations and both attack methods, the joint multi-modal attack achieved higher success than the average of the two unimodal attacks. For DeepFool, the advantage was strong enough that the joint attack outperformed each unimodal attack individually near the decision boundary. The mean attack replicated this result under a fixed perturbation direction, confirming that the advantage is a structural property of the fused decision boundary rather than an artifact of per-sample gradient alignment. These findings are consistent with a concave original-class region in the joint input space: non-linear modality coupling creates adversarially reachable regions that neither modality perturbation can access independently. Together, these results show that heterogeneous data fusion introduces emergent adversarial vulnerabilities beyond what unimodal analysis predicts, and that standard training practices on imbalanced medical datasets carry a risk of silent modality suppression.},
}

@article {pmid42409153,
year = {2026},
author = {Emam, M and Alatawi, FS and Alzamil, Y and Haj, N and Mahbub, AA and Ahmed, AM and Albadri, S and Alazzam, MB and , },
title = {Chemometric profiling reveals selective circulating bile acid remodeling in Alzheimer's disease.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {},
number = {},
pages = {121218},
doi = {10.1016/j.cca.2026.121218},
pmid = {42409153},
issn = {1873-3492},
abstract = {Bile acids, cholesterol-derived metabolites, have been implicated in Alzheimer's disease (AD), but it remains unclear whether these changes reflect broad concentration differences or selective chemical remodeling of the circulating bile acid pool. This study examined whether circulating bile acid chemistry differs across cognitively normal (CN; n = 243), mild cognitive impairment (MCI; n = 325), and AD (n = 136) participants, with emphasis on conjugation status, primary-secondary transformation, hydrophobicity/polarity balance, sulfation-related chemistry, and chemometric profiles. Analyses were corrected for multiple comparisons using the FDR method. The results demonstrated that AD participants exhibited selective alterations in circulating bile acid chemistry. Specifically, the conjugated bile acids glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid (GDCA), and taurodeoxycholic acid (TDCA) were significantly elevated in AD, whereas unconjugated bile acids, glycoursodeoxycholic acid (GUDCA), and glycolithocholic acid sulfate (GLCAS) did not differ significantly after FDR correction. Chemistry-derived indices further indicated higher total conjugated bile acids, glycine- and taurine-conjugated bile acid indices, secondary-derived bile acid burden, conjugated/unconjugated ratio, secondary/primary ratio, and hydrophobic/hydrophilic ratio in AD. In contrast, the sulfated/hydrophobic ratio was lower, suggesting a relatively reduced contribution of sulfated bile acids compared with the hydrophobic component. Compositional log-ratio analyses supported a shift toward conjugated, secondary-derived, and hydrophobic bile acid chemistry, while chemical-chemical correlation analyses revealed stronger coupling among conjugation, secondary transformation, hydrophobicity, and sulfation-related indices in AD. Overall, AD was associated with structured bile acid remodeling, mainly involving conjugated, secondary-derived, and hydrophobic domains. Future mechanistic studies are needed to clarify the biological basis of these bile acid alterations.},
}

@article {pmid42409186,
year = {2026},
author = {Yang, X and Chen, S and Zhang, M and Fan, X and Wang, M and Fan, H},
title = {Global Research Trends and Mechanistic Insights of Sirtuins in Alzheimer's Disease: A Bibliometric and Translational Review.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112029},
doi = {10.1016/j.brainresbull.2026.112029},
pmid = {42409186},
issn = {1873-2747},
abstract = {BACKGROUND: The sirtuin (SIRT) family of NAD[+]-dependent deacetylases has emerged as a central regulator in Alzheimer's disease (AD)-related pathophysiological pathways. However, the global publication landscape, research hotspots, and translational implications of SIRT-related AD research remain insufficiently integrated.

METHODS: Publications on sirtuins in AD was conducted in the Web of Science Core Collection database. Bibliometric analysis was performed using CiteSpace (version 6.4.1), VOSviewer (version 1.6.20), bibliometrix R package (https://www.bibliometrix.org), and Scimago Graphica (Version 1.0.46.0) to analyze trends, co-authorship, citation patterns, and research topics.

RESULTS: A total of 1,141 publications from 62 countries were identified, with 71% being original research articles. The field showed sustained growth with notable acceleration after 2015. China led in publication output (357 articles, 31.3%), while the United States ranked first in total citations (22,190). The University of Barcelona and the University of California System were the most productive institutions. Co-authorship analysis identified 6,019 authors with an average of 6.47 co-authors per document. Co-citation analysis emphasizes the central role of high-impact journals like Nature and PNAS. The thematic evolution in keyword analysis shows a shift from descriptive neurodegeneration studies toward mechanistic research, identifying oxidative stress, SIRT1/SIRT3 signaling, epigenetic regulation, amyloid-β, the mTOR pathway, autophagy, and neurogenesis as major hotspots. Biological interpretation of these hotspots suggests that SIRTs may contribute to AD pathophysiology through oxidative stress regulation, autophagy, epigenetic modulation, neurogenesis, and amyloid-β-related pathways, supporting their potential relevance to molecularly targeted strategies based on preclinical evidence. Citation burst analysis indicated emerging post-2015 interest in NAD⁺ metabolism and multi-target therapeutics, while persistent gaps remain in isoform-specific investigations, integrated multi-molecular studies, and robust clinical validation.

CONCLUSIONS: This study provides a comprehensive bibliometric and translational framework for SIRT-related AD research. Future research should prioritize mechanistic validation, address translational barriers including isoform selectivity and blood-brain barrier permeability, and expand investigation of under-studied SIRT isoforms.},
}

@article {pmid42409396,
year = {2026},
author = {Park, SM and Ko, AJ and Lim, JH and Park, EC},
title = {Income level and the risk of incident dementia among adults aged ≥50 with newly diagnosed type 2 diabetes: a population-based cohort study using the NHIS-Senior database in South Korea.},
journal = {BMJ open},
volume = {16},
number = {7},
pages = {e112641},
doi = {10.1136/bmjopen-2025-112641},
pmid = {42409396},
issn = {2044-6055},
mesh = {Humans ; *Diabetes Mellitus, Type 2/epidemiology/complications ; Republic of Korea/epidemiology ; Female ; Male ; Middle Aged ; *Dementia/epidemiology/etiology ; Aged ; *Income/statistics & numerical data ; Retrospective Studies ; Risk Factors ; Incidence ; Databases, Factual ; Low Socioeconomic Status ; Socioeconomic Disparities in Health ; Sex Factors ; },
abstract = {INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a well-established independent risk factor for dementia and is associated with dementia pathophysiology; however, the role of income level remains uninvestigated in this patient population. The aim of this study was to examine the association between income level and incident dementia risk among adults aged ≥50 years with newly diagnosed T2DM.

RESEARCH DESIGN AND METHODS: We conducted a retrospective population-based assessment of Korean National Health Insurance Service-Senior Cohort (2002-2019) data. Individuals aged ≥50 years with a new primary or secondary diagnosis of T2DM from 2004 onward were included. Sex and income level were assessed. Subgroup analyses were performed to examine differences in dementia risk across income levels and assess whether associations between income levels and dementia risk varied by dementia subtype.

RESULTS: Among women with newly diagnosed type 2 diabetes, those in the low-income group showed a significantly higher risk of incident dementia compared with the high-income group (deciles 9-10) (HR=1.19, 95% CI 1.11 to 1.28). In men with newly diagnosed type 2 diabetes, a significant increase in dementia risk was observed only among Medical Aid recipients relative to the high-income group (HR=1.44, 95% CI 1.18 to 1.77). Similarly, women within this patient population showed significantly elevated risks among Medical Aid recipients (HR=1.33, 95% CI 1.11 to 1.61) and those in the first income decile. Subtype analyses further revealed that being a Medical Aid recipient was associated with an increased risk of vascular dementia in men, while lower income levels (including Medical Aid recipients and deciles 1 and 3) were associated with a higher risk of Alzheimer's disease in women all in comparison to their high-income counterparts.

CONCLUSIONS: Among middle-aged and older adults with newly diagnosed T2DM, having a lower income was significantly associated with elevated dementia risks, with the greatest risk observed among low-income women. The association between income level and dementia risk differed by dementia subtype, with vascular dementia and Alzheimer's disease being more prevalent among low-income men and low-income women, respectively. These findings highlight the need for sex-specific and income-specific dementia prevention strategies.},
}

Humans
*Diabetes Mellitus, Type 2/epidemiology/complications
Republic of Korea/epidemiology
Female
Male
Middle Aged
*Dementia/epidemiology/etiology
Aged
*Income/statistics & numerical data
Retrospective Studies
Risk Factors
Incidence
Databases, Factual
Low Socioeconomic Status
Socioeconomic Disparities in Health
Sex Factors

@article {pmid42409639,
year = {2026},
author = {Zhang, X and Grigoryan, KA and Scherf, N and Wu, Q and Villringer, A and Schroeter, ML and Mueller, K},
title = {Mapping the Heart-Brain Continuum beyond Heart Failure: Why Neurology Matters.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.2274-25.2026},
pmid = {42409639},
issn = {1529-2401},
abstract = {To investigate whether cardiac dysfunction predicts further gray matter microstructural integrity and whether this integrity mediates the association with cognitive performance, we conducted a prospective observational cohort study of 73 patients (20 females and 53 males; mean age 54.8 years) from the Leipzig Heart Study. We performed baseline cardiac assessments followed by diffusion-weighted magnetic resonance imaging and cognitive testing after a follow-up of 3.5 years. Participants included patients with established heart failure and matched patients without heart failure presenting with suspected coronary artery disease. We assessed baseline cardiac biomarkers including left ventricular ejection fraction and N-terminal pro-B-type natriuretic peptide. The main outcomes were gray matter microstructural integrity (mean diffusivity) and cognitive performance. Mediation analysis evaluated whether regional mean diffusivity mediated the association between cardiac function and cognition. Across all 73 participants, a lower baseline ejection fraction predicted greater future gray matter mean diffusivity even in patients without clinical heart failure, acting as an early-stage indicator. Conversely, higher natriuretic peptide levels predicted extensive microstructural damage exclusively in the established heart failure group. Notably, increased mean diffusivity in Alzheimer's disease-vulnerable regions (specifically the cingulate and lingual gyri) significantly mediated the association between cardiac health and subsequent memory performance. In conclusion, cardiac dysfunction is associated with a predictable continuum of brain microstructural damage where conventional imaging previously failed. Crucially, this microstructural degradation mediates the link to memory decline, identifying brain microstructural integrity as a high-priority targets for upstream intervention aimed at preserving cognitive health.Significance Statement This study establishes a specific link between cardiac dysfunction and cognitive decline based on microstructural brain alterations. We identify a "heart-brain continuum" where routine cardiac biomarkers predict future brain microstructural damage. Crucially, this microstructural degradation targets Alzheimer's disease-vulnerable regions and acts as the mediator driving memory loss. By validating gray matter mean diffusivity as a sensitive tracker of this progression, our findings underscore that preserving brain microstructural integrity is a critical target in patients with cardiac dysfunction, offering a vital opportunity to intervene upstream before the onset of dementia.},
}

@article {pmid42409643,
year = {2026},
author = {Costa, RKM and Souza, FR and Silva, RDS and Rey, NA and Pimentel, AS},
title = {The Effect of Cu[2+] and Zn[2+] Ions' Nonbonded Interactions on the Aggregation of β-Amyloid 1-16 and 25-35 Fragments─A Molecular Dynamics Simulation Study.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00057},
pmid = {42409643},
issn = {1948-7193},
abstract = {Alzheimer's disease is linked to the formation and accumulation of extracellular β-amyloid aggregates, with toxicity primarily attributed to soluble oligomeric species, as proposed by the oligomeric hypothesis. Concurrently, the metal ion hypothesis suggests that transition metal ions, such as Cu[2+] and Zn[2+], directly modulate the aggregation process and the structural stability of β-amyloid (Aβ) fragments. In this study, molecular dynamics simulations were employed to produce collective variables to investigate the effects of these ions and their concentrations on the aggregation of the β-amyloid 1-16 and 25-35 fragments in aqueous solution for the first time. The free energy profile of aggregation indicates that the presence of Cu[2+] ions slightly decreases the energy associated with the aggregation of the β-amyloid 1-16 fragment, suggesting it acts as a modulator that partially stabilizes the oligomers. In contrast, we report for the first time that Zn[2+] ions do not reduce the energy barrier for the aggregation of the β-amyloid 1-16 fragment in aqueous solution. Zn[2+] displays a higher affinity for the acidic residues of Aβ1-16, establishing more frequent, yet less selective, contacts compared to those observed for Cu[2+] ions. The main finding is that Cu[2+] and Zn[2+] ions modulate the early aggregation pathway of β-amyloid. In particular, at high concentrations, Cu[2+] favors the formation of small, structurally ordered proto-oligomers enriched in antiparallel β-sheets, rather than simply increasing aggregate size, whereas Zn[2+] does not exhibit an analogous effect under the conditions studied. This metal-induced stabilization of β-sheet-rich low-order oligomers, particularly pronounced for Cu[2+], identifies early secondary structure transitions as the primary determinant of amyloid toxicity and a critical molecular event in Alzheimer's disease. The evidence presented in this study enhances our understanding of the oligomeric and metal ion hypotheses of Alzheimer's disease.},
}

@article {pmid42410071,
year = {2026},
author = {Suo, X and Wan, P and Yu, J and Zhu, X and Tian, C and Li, S and Sun, G and Liu, H and Liu, S and Geng, M and Tian, J and Yang, W and Zhang, Y},
title = {The Protective Effects of Small-Molecule Compound 0242 Against LPS-Induced Neuroinflammation and in P301S Tau Transgenic Mice.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42410071},
issn = {1573-6903},
support = {2024CXPT029, 2025CXPT011//Key R&D Program of Shandong Province, China/ ; SYS202205//Shandong Laboratory Program/ ; ZR2024QH615//Shandong Provincial Natural Science Foundation/ ; },
mesh = {Animals ; Lipopolysaccharides/toxicity ; Mice, Transgenic ; *tau Proteins/genetics/metabolism ; Female ; *Neuroinflammatory Diseases/chemically induced/metabolism/drug therapy/prevention & control ; Mice ; Microglia/drug effects/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; Alzheimer Disease/drug therapy/metabolism ; Hippocampus/drug effects/metabolism ; Mice, Inbred C57BL ; },
abstract = {Neuroinflammation and tau pathology are central drivers of Alzheimer's disease (AD) progression, necessitating multi-target therapeutic strategies. Here, we evaluated the efficacy and mechanisms of 0242, a novel small-molecule derivative optimized from the berberine scaffold. In lipopolysaccharide (LPS)-stimulated BV-2 microglia, 0242 treatment significantly inhibited cell activation and nitric oxide release without cytotoxicity, while downregulating the mRNA levels of pro-inflammatory cytokines IL-1β and TNF-α. Transcriptomic profiling revealed that 0242 modulated LPS-induced inflammatory gene signatures by enriched core signaling cascades, including NF-κB, TLR, and JAK-STAT and upregulating cytoprotective genes such as ceruloplasmin (Cp) and Bcl2a1b. In vivo, oral administration of 0242 attenuated hippocampal astrocyte and microglial activation in an LPS-induced acute neuroinflammatory mouse model. Furthermore, in female P301S tau transgenic mice, 0242 treatment significantly improved spontaneous locomotor activity and recognition memory. Histological and biochemical analyses confirmed that 0242 suppressed hippocampal glial activation and reduced total tau protein levels in the prefrontal cortex. Collectively, these findings suggest that 0242 may exert potent anti-neuroinflammatory effects by modulating multiple immune signaling cascades and uniquely alleviates tau pathology in AD.},
}

Animals
Lipopolysaccharides/toxicity
Mice, Transgenic
*tau Proteins/genetics/metabolism
Female
*Neuroinflammatory Diseases/chemically induced/metabolism/drug therapy/prevention & control
Mice
Microglia/drug effects/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology
Alzheimer Disease/drug therapy/metabolism
Hippocampus/drug effects/metabolism
Mice, Inbred C57BL

@article {pmid42410083,
year = {2026},
author = {Costello, H and Reeves, S and Glue, P and Young, AH and Howard, R},
title = {Depression in neurodegenerative disease: neurobiological mechanisms and emerging treatments.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42410083},
issn = {1476-5578},
abstract = {Depression is one of the most common and disabling neuropsychiatric complications of neurodegenerative diseases. In Alzheimer's disease (AD) and Parkinson's disease (PD), depressive syndromes affect more than one-third of patients and are associated with accelerated cognitive decline, reduced quality of life, and increased healthcare utilisation. Despite this burden, current antidepressant treatments show little or no efficacy in these populations, suggesting that depression arising in the context of neurodegeneration may reflect distinct underlying neurobiological mechanisms. Emerging evidence from molecular imaging, neuropathology, and cognitive neuroscience indicates disease-specific disruption of monoaminergic, glutamatergic, inflammatory, and reward-related circuits in AD and PD. These alterations may undermine the mechanisms of action of standard antidepressants and contribute to treatment resistance. Yet patients with cognitive impairment are routinely excluded from antidepressant trials, and few high-quality studies have evaluated novel therapies in neurodegenerative disease. In this narrative review, we synthesise current evidence on the neurobiological mechanisms underpinning depression in AD and PD and critically evaluate emerging pharmacological and neuromodulatory therapies targeting glutamatergic, serotonergic, dopaminergic, immune, and circuit-level dysfunction. Here, we highlight that depression in neurodegenerative disease offers a unique and underutilised model for mechanistically guided antidepressant development. We identify how interventions including glutamate modulators, dopaminergic agents, kappa opioid antagonists, immune-modulating therapies, and next-generation brain stimulation approaches may offer therapeutic promise. By aligning treatment development with disease-specific circuit and molecular pathology, this framework may improve outcomes for this neglected population while advancing precision psychiatry more broadly.},
}

@article {pmid42410123,
year = {2026},
author = {Wiseman, S},
title = {Glycosylation in Alzheimer's disease.},
journal = {Nature neuroscience},
volume = {29},
number = {7},
pages = {1528},
doi = {10.1038/s41593-026-02373-2},
pmid = {42410123},
issn = {1546-1726},
}

@article {pmid42410180,
year = {2026},
author = {Rudroff, T},
title = {The dual diversity crisis in alzheimer's disease research: why neuroimaging biomarkers and clinical trials keep failing.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42410180},
issn = {2509-2723},
abstract = {Alzheimer's disease clinical trials have failed at a rate exceeding 99% over two decades, and neuroimaging biomarkers developed in discovery cohorts have repeatedly disappointed in validation and clinical application. Standard explanations address symptoms rather than structural causes. I argue that Alzheimer's disease research is caught in a Dual Diversity Crisis: the simultaneous neglect of population diversity and individual neurobiological heterogeneity as compounding validity threats. The first dimension concerns the systematic over-reliance on Western, young, healthy, and university-affiliated (WYHU) research samples, from which biomarker normative standards are derived and then applied universally to a demographically distinct clinical population. The second concerns the erasure, through group-level analysis, of the substantial neurobiological heterogeneity that exists within any sample regardless of its demographic composition. The critical structural insight is that these two problems do not add; they multiply. A WYHU-derived group average is doubly unrepresentative: it misrepresents the target population demographically and conceals the individual variance that exists even within that already-unrepresentative sample. FDG-PET evidence demonstrates that biological sex accounts for approximately 30 times more metabolic variance than diagnostic category in patients with equivalent symptom profiles, directly challenging the construct validity of threshold-based trial inclusion. Correcting the Dual Diversity Crisis requires treating demographic diversity and individual neurobiological characterization as primary design parameters, not post-hoc corrections. Until this reconceptualization occurs, translational failure in Alzheimer's disease research remains the structurally expected outcome.},
}

@article {pmid42410183,
year = {2026},
author = {de Oliveira Portugal Couto, C and Hass das Eiras, ML and Juliao de Morais, JL and Leal Cordeiro Júnior, CW and Forlenza, OV and de Jesus Rodrigues de Paula, V},
title = {Chronic Lithium Exposure Reshapes PI3K-mTOR-linked Proteostatic Networks in the Hippocampus of an Alzheimer's Disease Mouse Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42410183},
issn = {1559-1182},
mesh = {Animals ; *Hippocampus/metabolism/drug effects/pathology ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Phosphatidylinositol 3-Kinases/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *TOR Serine-Threonine Kinases/metabolism ; *Lithium/pharmacology/administration & dosage/therapeutic use ; Signal Transduction/drug effects ; Protein Interaction Maps/drug effects ; Proteomics ; Mice ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β deposition, tau pathology, and alterations in signaling pathways involved in neuronal survival and protein homeostasis. Lithium has been suggested as a potential neuroprotective treatment, but the molecular mechanisms associated with its long-term effects are still not fully understood. In this study, we investigated the effects of chronic lithium treatment on hippocampal proteins associated with PI3K-related signaling in triple-transgenic Alzheimer's disease (3xTg-AD) mice. Wild-type and transgenic animals received either a lower or higher lithium dose for eight months. Hippocampal samples were analyzed by LC-MS/MS proteomics followed by protein interaction and functional enrichment analyses. From a total of 7768 identified proteins, bioinformatic analyses identified 157 proteins shared between APP-, MAPT-, and PI3K-associated datasets. Further network analyses identified 18 proteins related to PI3K signaling, including seven proteins shared among all three datasets: FKBP1A, HSPA1B, HSPA8, RAS-related proteins, RPL13, RPL19, and RPL24. These proteins are associated with protein folding, translation regulation, cellular stress responses, and signaling pathways. Chronic lithium treatment was associated with changes in the expression of these proteins in both wild-type and transgenic animals. The observed effects differed between the two lithium concentrations tested and did not follow a simple linear pattern. Our findings suggest that long-term lithium exposure is associated with changes in molecular networks related to proteostasis and translational regulation in the hippocampus. Although additional studies are needed to better understand the mechanisms involved, these results provide a proteomic framework for investigating lithium-sensitive pathways that may be relevant to Alzheimer's disease.},
}

Animals
*Hippocampus/metabolism/drug effects/pathology
*Alzheimer Disease/metabolism/drug therapy/pathology
*Phosphatidylinositol 3-Kinases/metabolism
Mice, Transgenic
Disease Models, Animal
*TOR Serine-Threonine Kinases/metabolism
*Lithium/pharmacology/administration & dosage/therapeutic use
Signal Transduction/drug effects
Protein Interaction Maps/drug effects
Proteomics
Mice

@article {pmid42410250,
year = {2026},
author = {Rana, JK and Pinarbasi, ES and Fernandez, MG and Navratna, V and Conway, KS and Lieberman, AP and Barmada, SJ and Mosalaganti, S},
title = {CTE-type tau filaments in Alzheimer's disease with co-morbid LATE-NC.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42410250},
issn = {1432-0533},
support = {R01NS097542/NH/NIH HHS/United States ; 1DP2GM150019/NH/NIH HHS/United States ; },
}

@article {pmid42410282,
year = {2026},
author = {Festa, N and Alexovitz, K and Sifnugel, N and Cohen, I and Faustino, IV and Khasnavis, S and Young, J and Iscoe, M and Mecca, AP and Han, L and Hwang, U},
title = {Assigning Probable Dementia Status Using Routinely Collected Electronic Health Record Data.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70562},
pmid = {42410282},
issn = {1532-5415},
support = {KL2TR001862/NH/NIH HHS/United States ; P30AG021342/AG/NIA NIH HHS/United States ; P30AG073104/AG/NIA NIH HHS/United States ; R03AG088893/AG/NIA NIH HHS/United States ; R33AG069822/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: More than half of older adults with Alzheimer's Disease and Related Dementias (ADRD) are undiagnosed, limiting timely access to person-centered care. Therefore, clinicians, researchers, and population health managers need scalable, reproducible approaches to monitor both prevalence and diagnostic gaps. We evaluated whether a decision-analytic modeling framework can translate a limited number of clinician-adjudicated cases of ADRD into a probabilistic computational phenotype for accurate, population-level assignments of probable ADRD in the emergency department (ED) setting using routinely collected electronic health record (EHR) data.

METHODS: Retrospective cohort study of 5000 adults aged ≥ 65 years from nine EDs within a large integrated health system (2014-2022). We randomly selected 500 individuals for clinician adjudication of dementia status (reference cohort), reserving the remaining 4500 as a phenotyping cohort. We developed the phenotype as a logistic regression model trained on adjudicated cases, embedding pattern-mixture multiple imputation to address information bias. We applied decision-curve analysis to evaluate clinical utility across probabilistic thresholds. We applied the phenotype to assign dementia status to 4500 unadjudicated patients and compared clinical characteristics to adjudicated cases.

RESULTS: The mean (SD) age was 77.4 (9.0) years; 55.4% were women; 102 individuals (20.4%) had clinician-adjudicated ADRD. The model demonstrated good discrimination (AUROC 0.87; 95% CI 0.82-0.91). Decision-curve analysis revealed net clinical benefit across examined thresholds (predicted probabilities 12%-32%), identifying an additional 16-18 probable ADRD cases per 100 older adults. Among those without ADRD-related diagnosis codes, net benefit ranged from 8 to 13 additional correct identifications per 100. Phenotype-assigned cases closely resembled clinician-adjudicated cases (standardized mean differences ≤ 0.20).

CONCLUSIONS: A probabilistic computational phenotype derived from routinely collected EHR data accurately reproduced clinician-adjudicated ADRD status and demonstrated net clinical benefit, including among ED patients whose ADRD was not captured by diagnosis codes. Adoption of this replicable framework may enable healthcare organizations to strengthen ADRD surveillance and reduce underdiagnosis.},
}

@article {pmid42410293,
year = {2026},
author = {Kumar, RR and Kamaljeet, and Kosey, S},
title = {Neuroinflammation in neurodegenerative diseases: pathogenic pathways and emerging pharmacotherapeutic targets in Alzheimer's and Parkinson's disease.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42410293},
issn = {1568-5608},
abstract = {Neuroinflammation is now widely recognized as a key contributor to the initiation and progression of neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). Chronic activation of brain-resident immune cells, including microglia and astrocytes, in response to misfolded protein aggregates such as amyloid-β and tau in AD and α-synuclein in PD, promotes maladaptive immune signaling, sustained cytokine release, and disruption of the blood-brain barrier (BBB). This chronic brain inflammation leads to synaptic dysfunction, neuronal loss and ultimately clinical deterioration. These processes are accompanied by disease-specific factors, such as inflammation of the gut-brain axis in PD and genetic modulators including APOE4, TREM2, and LRRK2. Furthermore, the development of fluid biomarkers together with neuroimaging techniques has improved early detection and monitoring of neuroinflammation leading to personalized therapeutic approaches. Clinical trials targeting microglial phenotypes, cytokine signaling, inflammasome activity, and genetic risk factors are emerging therapeutic strategies. Model limitations and heterogeneity of patients present challenges, but insights into neuroimmune interactions could provide a path forward for disease-modifying strategies. The present review aims to summarize new knowledge about the protective and detrimental aspects of neuroinflammation in AD and PD, providing an analysis on these developing prospects for targeted interventions toward slowing or stopping neurodegeneration.},
}

@article {pmid42410536,
year = {2026},
author = {Lim, CY and Sim, Y and Lee, YG and Ye, BS and Sohn, B},
title = {Comparative evaluation of automated MRI-based brain volumetry software for estimating cognitive domains in early Alzheimer's disease.},
journal = {BMC medical imaging},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12880-026-02535-5},
pmid = {42410536},
issn = {1471-2342},
support = {SMO124041//Samsung Medical Center/ ; RS-2023-00237618//National Research Foundation of Korea/ ; IIS-KR-0045//Bracco Imaging Korea/ ; },
abstract = {BACKGROUND: Brain volumetry software is widely accepted for assessment in Alzheimer's disease. However, direct comparisons for software-specific prediction capabilities across cognitive domains have not been reported. This study evaluates the performance of four brain volumetry software programs in predicting domain-specific cognitive scores in patients with early Alzheimer's disease (AD) using a consistent deep learning model.

METHODS: A total of 255 patients with amyloid PET-confirmed AD were retrospectively enrolled. Brain volumetric features were extracted from 3D T1-weighted MRI using four software programs (AQUA, DeepBrain, A-finder, and FreeSurfer). A multi-layer perceptron model incorporating seven clinical variables and software-specific volumetric features was trained to predict six cognitive outcomes: the Mini-Mental State Examination (MMSE) score and five Seoul Neuropsychological Screening Battery (SNSB) domain scores. Model performance was evaluated using mean squared error and Pearson's correlation coefficient (r).

RESULTS: The FreeSurfer-based model showed the numerically highest correlation for MMSE (r = 0.56), language (r = 0.38), visuospatial (r = 0.21), and frontal/executive functions (r = 0.32). The AQUA-based model showed the numerically highest correlation for attention (r = 0.40), and DeepBrain for memory (r = 0.38). MMSE scores were generally better predicted than domain-specific scores across all models.

CONCLUSION: Brain volumetry software showed modest, domain-dependent associations with cognitive scores in early AD, with the strongest signal for MMSE and no statistically significant prediction for visuospatial function. These findings support the potential of brain volumetry software to partially estimate domain-level cognitive profiles, while differences across software should be interpreted with caution rather than as evidence of intrinsic software superiority.},
}

@article {pmid42410640,
year = {2026},
author = {Gambacorta, N and Trisciuzzi, D and Mastrolorito, F and Leonetti, F and Altomare, CD and de Candia, M and Catto, M and Amoroso, N and Ciriaco, F and Nicolotti, O},
title = {MINERVA: a public XAI-powered platform advancing multi-target discovery in Alzheimer's disease.},
journal = {Journal of cheminformatics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13321-026-01253-y},
pmid = {42410640},
issn = {1758-2946},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder involving a complex interplay of interconnected pharmacological targets, a feature that limits the success of traditional single-target medicinal chemistry approaches. Here, we present MINERVA (Multi-target Interactive Network for Explainable Research and Visualization in Alzheimer's disease), a public web-based platform designed to support multi-target drug discovery assisted by eXplainable Artificial Intelligence (XAI) strategies. MINERVA integrates large-scale disease-focused high-quality data comprising as many as 70,960 small molecules annotated across 33 AD relevant targets, taken from ChEMBL and CADRO databases. To capture different levels of pharmacological relevance, four distinct pharmacological thresholds (i.e., 10 μM, 1 μM, 100 nM, and 10 nM) were set to enable the parallel exploration of weak to high-affinity ligand spaces. Independent Balanced Random Forest (BRF) classifiers were trained for each AD target threshold combination using an extended core-substituent fingerprint, which ensures robustness against class imbalance and chemical heterogeneity. MINERVA incorporates a probability binning based domain of applicability (DoA) to quantify prediction reliability and a SHAP-based explainability framework to fairly map fragment-level contributions directly onto chemical structures. MINERVA is freely accessible at https://prometheus.farmacia.uniba.it/minerva/.Scientific contributionHerein we introduce MINERVA, the first freely accessible platform that combines large-scale AD-related data curation, multi-target prediction, and multi-threshold bioactivity modeling within a fully explainable and user-friendly environment. By enabling transparent, ligand-based exploration of chemical space across multiple AD pathways, MINERVA provides a unique and practical resource for accelerating multi-target drug discovery in the neurodegenerative research area.},
}

@article {pmid42410680,
year = {2026},
author = {Stocks, J and Barbieri, E and Los, MA and Thompson, CK and Gefen, T and Geula, C and Mesulam, MM and Weintraub, S},
title = {Neuropathology-specific language features in primary progressive aphasia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71633},
doi = {10.1002/alz.71633},
pmid = {42410680},
issn = {1552-5279},
support = {5R01AG077444/NH/NIH HHS/United States ; P30AG072977/NH/NIH HHS/United States ; P30AG013854/NH/NIH HHS/United States ; R01AG062566/NH/NIH HHS/United States ; //the Florane and Jerome Rosenstone Fellowship/ ; //the Karen Toffler Charitable Trust/ ; },
mesh = {Humans ; *Aphasia, Primary Progressive/pathology ; Male ; Aged ; Female ; Alzheimer Disease/pathology ; Aged, 80 and over ; Neuropsychological Tests ; Pick Disease of the Brain/pathology ; Supranuclear Palsy, Progressive/pathology ; Middle Aged ; Corticobasal Degeneration/pathology ; Tauopathies/pathology ; *Language ; Brain/pathology ; },
abstract = {INTRODUCTION: Primary Progressive Aphasia (PPA) clinical syndromes do not align consistently with underlying pathology. This study aimed to identify language markers for specific neuropathologies using both standard clinical tests and narrative speech analysis.

METHODS: We analyzed data from 82 autopsy-confirmed PPA cases, including Alzheimer's disease (AD), transactive DNA-binding protein 43 (TDP-43) type C (TDP-C), Pick's disease, and 4R-tauopathies (progressive supranuclear palsy/ cortico-basal degeneration (PSP/CBD). Linear mixed-effects regression was used to analyze performance on standardized aphasia tests and narrative speech variables.

RESULTS: TDP-C showed severe semantic deficits but high fluency, while AD was distinguished by impaired repetition. Narrative analysis differentiated 4R-Tauopathies: CBD patients demonstrated significantly poorer syntax and irregular verb inflection than PSP or Pick's, whereas PSP showed the lowest fluency.

DISCUSSION: While standard tests effectively capture lexical-semantic features in AD and TDP-C, narrative measures reveal subtle grammatical and fluency differences critical for distinguishing specific tauopathies. This study outlines a more robust approach for predicting underlying pathology in PPA.},
}

Humans
*Aphasia, Primary Progressive/pathology
Male
Aged
Female
Alzheimer Disease/pathology
Aged, 80 and over
Neuropsychological Tests
Pick Disease of the Brain/pathology
Supranuclear Palsy, Progressive/pathology
Middle Aged
Corticobasal Degeneration/pathology
Tauopathies/pathology
*Language
Brain/pathology

@article {pmid42410707,
year = {2026},
author = {Bindra, S and Pandian, R and Mathew, B and Anal, JMH},
title = {Quinoxaline-Based Monoamine Oxidase Inhibitors: Design Strategies, Synthesis, Structure-Activity Relationships, and Therapeutic Potential in Neurological Disorders: A Review From 1996 to 2026.},
journal = {ChemMedChem},
volume = {21},
number = {13},
pages = {e70330},
doi = {10.1002/cmdc.70330},
pmid = {42410707},
issn = {1860-7187},
mesh = {*Monoamine Oxidase Inhibitors/chemistry/chemical synthesis/pharmacology/therapeutic use ; *Quinoxalines/chemistry/pharmacology/chemical synthesis/therapeutic use ; Structure-Activity Relationship ; Humans ; *Monoamine Oxidase/metabolism ; *Drug Design ; *Nervous System Diseases/drug therapy/metabolism ; Molecular Structure ; Animals ; },
abstract = {Monoamine oxidases (MAOs) are key enzymes involved in the metabolism of neurotransmitters and play a significant role in the pathophysiology of neurological disorders such as depression, Parkinson's disease, and Alzheimer's disease. Inhibition of MAOs, particularly MAO-A and MAO-B, has emerged as a promising therapeutic strategy. Quinoxaline is an emerging scaffold with promising biological activities against various molecular targets, owing to its rich repertoire of bioactive molecules. Due to their favorable pharmacological profiles and structural versatility, quinoxaline derivatives have gained considerable attention among the various scaffolds explored. This review highlights rational design strategies for developing quinoxaline-based MAO inhibitors, focusing on structure-activity relationships (SARs) that govern their potency and selectivity. Modifications at specific positions of the quinoxaline ring system and the nature of substituents have demonstrated significant impacts on MAO-A versus MAO-B selectivity, metabolic stability, and blood-brain barrier permeability. This review primarily focuses on elucidating recent advancements in quinoxaline scaffolds targeting MAO inhibitors, including structural developments, structural-activity relationships (SAR), and potential therapeutic applications in neurological disorders, to help researchers develop a new generation of MAO inhibitors.},
}

*Monoamine Oxidase Inhibitors/chemistry/chemical synthesis/pharmacology/therapeutic use
*Quinoxalines/chemistry/pharmacology/chemical synthesis/therapeutic use
Structure-Activity Relationship
Humans
*Monoamine Oxidase/metabolism
*Drug Design
*Nervous System Diseases/drug therapy/metabolism
Molecular Structure
Animals

@article {pmid42410730,
year = {2026},
author = {Lorenz, AS and Sathe, A and Yang, Y and Durant, A and Wu, Y and Kim, ME and Gao, C and Newlin, NR and Ramadass, K and Kanakaraj, P and Khairi, NM and Li, Z and Yao, T and Huo, Y and Dumitrescu, L and Shashikumar, N and Pechman, KR and Risacher, SL and Beason-Held, LL and An, Y and Arfanakis, K and Erus, G and Davatzikos, C and Habes, M and Wang, D and Tosun, D and Toga, AW and Thompson, PM and Mormino, EC and Zhang, P and Schilling, K and Albert, M and Kukull, W and Biber, SA and Landman, BA and Johnson, SC and Bendlin, B and Schneider, J and Bennett, DA and Jefferson, AL and Resnick, SM and Saykin, AJ and Below, JE and Hohman, TJ and Archer, DB and , and , and , },
title = {Genetic architecture of the limbic white matter microstructure in aging and Alzheimer's Disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71630},
doi = {10.1002/alz.71630},
pmid = {42410730},
issn = {1552-5279},
support = {K01-EB03289/NH/NIH HHS/United States ; R01-EB017230/NH/NIH HHS/United States ; R01-AG074339/NH/NIH HHS/United States ; P30-AG066515/NH/NIH HHS/United States ; K01-AG073584/NH/NIH HHS/United States ; U24-AG074855/NH/NIH HHS/United States ; 75N95D22P00141/NH/NIH HHS/United States ; R01-AG059716/NH/NIH HHS/United States ; UL1-TR000445/NH/NIH HHS/United States ; UL1-TR002243/NH/NIH HHS/United States ; R01-AG034962/NH/NIH HHS/United States ; R01-AG056534/NH/NIH HHS/United States ; U19-AG03655/NH/NIH HHS/United States ; NIAAG021155/NH/NIH HHS/United States ; NIAAG027161/NH/NIH HHS/United States ; NIAAG037639/NH/NIH HHS/United States ; NIAAG054047/NH/NIH HHS/United States ; U01AG024904/NH/NIH HHS/United States ; 26PRE1558066//American Heart Association/ ; IIRG-08-88733/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/diagnostic imaging ; *Aging/genetics/pathology ; *White Matter/pathology/diagnostic imaging ; Genome-Wide Association Study ; Female ; Male ; Aged ; *Limbic System/pathology/diagnostic imaging ; Polymorphism, Single Nucleotide ; Aged, 80 and over ; Diffusion Magnetic Resonance Imaging ; },
abstract = {INTRODUCTION: Limbic white matter (WM) abnormalities are prevalent in aging and Alzheimer's disease (AD), but genetic drivers are unclear.

METHODS: In 2614 older adults (mean age ± SD: 73.7 ± 9.8 years; 26% cognitively impaired) from seven harmonized cohorts enriched for cognitive impairment, we quantified free-water-corrected diffusion MRI (dMRI) metrics in seven limbic tracts. We estimated single nucleotide polymorphism (SNP) heritability, performed cohort genome-wide association studies (GWASs) with meta-analysis, evaluated shared genetic architecture and enriched pathways, and assessed AD relevance using brain RNA-seq data.

RESULTS: Limbic WM is heritable (h[2] = 0.26-0.60; pFDR < 0.05). Meta-GWAS identified six loci (p < 5 × 10[-] [8]), including a signal implicating CDH19, an oligodendrocyte-enriched cell-adhesion gene. Additional loci were near the KC6, SENP5, RORA, FAM107B, and MIR548A1 genes. In brain tissue, RORA, FAM107B, and KC6 expression was associated with cognition and AD neuropathology. Results converged on insulin and immune biology and shared genetic architecture with lipid and cardiovascular traits.

DISCUSSION: Limbic WM microstructure is genetically influenced and links oligodendrocyte and vascular-inflammatory biology to AD-relevant outcomes.},
}

Humans
*Alzheimer Disease/genetics/pathology/diagnostic imaging
*Aging/genetics/pathology
*White Matter/pathology/diagnostic imaging
Genome-Wide Association Study
Female
Male
Aged
*Limbic System/pathology/diagnostic imaging
Polymorphism, Single Nucleotide
Aged, 80 and over
Diffusion Magnetic Resonance Imaging

@article {pmid42411051,
year = {2026},
author = {Chen, HJ and Guo, Y and Huang, W and Hu, A and Liu, T and Chen, F},
title = {Glymphatic dysfunction associates with regional white matter hyperintensities and plasma amyloid-β burden across the Alzheimer's disease continuum.},
journal = {Psychological medicine},
volume = {56},
number = {},
pages = {e220},
doi = {10.1017/S0033291726105005},
pmid = {42411051},
issn = {1469-8978},
mesh = {Humans ; *Alzheimer Disease/blood/physiopathology/diagnostic imaging/pathology ; *Amyloid beta-Peptides/blood ; Female ; Male ; *White Matter/diagnostic imaging/pathology ; *Glymphatic System/physiopathology/diagnostic imaging ; Aged ; *Cognitive Dysfunction/blood/physiopathology/diagnostic imaging/pathology ; Diffusion Tensor Imaging ; *Cerebral Small Vessel Diseases/diagnostic imaging/physiopathology ; Biomarkers/blood ; Magnetic Resonance Imaging ; Prospective Studies ; Middle Aged ; },
abstract = {BACKGROUND: Glymphatic system dysfunction has been increasingly implicated in Alzheimer's disease (AD), yet its relationships with cerebral small vessel disease (CSVD), plasma biomarkers, and cognitive impairment across the AD remain incompletely understood.

METHODS: We prospectively recruited 216 participants from Hainan General Hospital, including healthy controls (HC), individuals with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD dementia. All participants underwent brain magnetic resonance imaging, plasma biomarker testing, and neuropsychological assessments. White matter hyperintensity (WMH) volume from T2-weighted fluid-attenuated inversion recovery images served as a marker of CSVD. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) index assessed glymphatic function. Plasma amyloid β-protein (Aβ) concentrations measured peripheral Aβ levels as a surrogate indicator of amyloid pathology.

RESULTS: The ALPS index was significantly lower in AD patients compared with HC, SCD, and MCI groups (all P < 0.01) and tended to be lower in the MCI group relative to SCD. After controlling for demographics and APOE4 status, ALPS positively correlated with the plasma Aβ42/Aβ40 ratio (r = 0.16, P = 0.038). ALPS index showed significant negative correlations with log-transformed juxtaventricular and juxtacortical WMH volumes (r = -0.32, P < 0.001; r = -0.19, P = 0.010), with marginal correlation for periventricular WMH (r = -0.13, P = 0.052).

CONCLUSION: Plasma Aβ levels and regional WMH burden are associated with glymphatic dysfunction as indicated by reduced ALPS. Impaired glymphatic clearance also correlates with cognitive impairment, providing theoretical support for novel pathophysiological hypotheses and potential therapeutic targets in AD pathogenesis.},
}

Humans
*Alzheimer Disease/blood/physiopathology/diagnostic imaging/pathology
*Amyloid beta-Peptides/blood
Female
Male
*White Matter/diagnostic imaging/pathology
*Glymphatic System/physiopathology/diagnostic imaging
Aged
*Cognitive Dysfunction/blood/physiopathology/diagnostic imaging/pathology
Diffusion Tensor Imaging
*Cerebral Small Vessel Diseases/diagnostic imaging/physiopathology
Biomarkers/blood
Magnetic Resonance Imaging
Prospective Studies
Middle Aged

@article {pmid42411077,
year = {2026},
author = {Singh, P and Bhardwaj, S and Nagarajan, K},
title = {A Review on the Mechanisms of Neurodegeneration and the Potential of Plant Bioactives in Managing Neurological Conditions.},
journal = {Current aging science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118746098388719251206111338},
pmid = {42411077},
issn = {1874-6128},
abstract = {Neurodegenerative disorders encompass a wide range of debilitating neurological conditions characterized by the progressive loss of specific neuronal populations in the central and/or peripheral nervous systems. This disease often leads to a gradual decline in cognitive, motor, and sensory abilities. This review explores the role of various lifestyle factors, such as age, sex, poor diet, depression, etc., which contribute to the onset and progression of NDDs. Various diseases are included in the neurodegenerative disorder, like Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and Lewy body disease, which are chronic conditions that significantly impact cognitive and motor functions. A literature search was conducted in the scientific database using the keywords "neurodegenerative disorders, phytoconstituents, and herbals". This review includes a collection of reports from ScienceDirect, Scholar Google, and PubMed, all searched up to 2024. The results were assessed, gathered, and reported in this paper. A total of 241 articles were included, with exponential growth in publication numbers from 1985 to 2024. Effective management and control of NDDs require addressing these risk factors, alongside exploring therapeutic interventions. Some plants and herbs used to treat neurodegenerative diseases, such as curcumin, ashwagandha, ginkgo biloba, epigallocatechin-3-gallate, quercetin, ginseng, and resveratrol, have shown potential to improve neuronal health and mitigate disease progression. This review highlights the dual role of natural compounds in promoting improvements and upregulating brain function while potentially reducing degradation. The phytopharmaceuticals show the potential for treating neurological conditions with better efficacy and safer profiles. The review suggested that future research should focus on integrating lifestyle modifications and natural therapies to enhance the quality of life for individuals at risk or suffering from neurodegenerative diseases.},
}

@article {pmid42411090,
year = {2026},
author = {Cabrera, J and Fuentealba, D and Montecinos, D and Caballero, J and Areche, C and Caballero, L and Melo, F and Cornejo, A},
title = {Barbatolic Acid Prevents Tau and Amylin Interaction and Stimulates the Growth of Acetylated Microtubules in Cell Culture.},
journal = {Current drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113894501474373260623073848},
pmid = {42411090},
issn = {1873-5592},
abstract = {INTRODUCTION: Neurodegenerative disorders, including Alzheimer's disease and related tauopathies, involve tau aggregates that correlate closely with cognitive decline. Clinical evidence indicates that patients with type 2 diabetes-characterized by amylin accumulation-experience exacerbated neurodegenerative symptoms, suggesting a cooperative pathologic effect between both proteins.

METHODS: Using isothermal titration calorimetry, fluorimetry, intrinsic fluorescence, molecular docking, cell culture, and confocal microscopy, we characterized the hydrophobic interactions driving the tau-amylin relationship and evaluated the efficacy of small molecules to inhibit these interactions and protect microtubule stability.

RESULTS: Tau and amylin co-assemble into morphologically distinct amyloid structures driven by hydrophobic interactions. Notably, barbatolic acid and divaricatic acid effectively disrupt this interprotein interaction. In Neuro2a (N2a) cell cultures, barbatolic acid promoted neuronal differentiation more effectively than retinoic acid. Furthermore, N2a cells exposed to tau aggregates pre-treated with barbatolic acid maintained intact acetylated microtubule networks, indicating a protective role in preserving cytoskeletal stability.

DISCUSSION: The tau-amylin interaction can be disrupted by barbatolic and divaricatic acid via interference with key lysine residues, offering a plausible therapeutic strategy to mitigate aggregate toxicity. Additionally, the unique ability of barbatolic acid to preserve and promote stable microtubule formation reveals a novel dual mechanism of action.

CONCLUSION: Because current treatments for neurodegenerative diseases remain palliative, developing multi-target compounds with these dual characteristics offers a promising path forward in pharmacophore design.},
}

@article {pmid42411093,
year = {2026},
author = {Afolabi, BL and Ajibola, AA and Adeyanju, AA and Akanji, MA and Adeyemi, OS},
title = {Revisiting Alzheimer's Disease Mechanisms: Amyloid Dynamics, and Emerging Insights.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050395410251029173713},
pmid = {42411093},
issn = {1875-5828},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by synaptic dysfunction, glial cell activation, and deterioration of neurons. Multiple pathways contribute to its pathophysiology, including β-amyloid (Aβ) plaque formation, intracellular neurofibrillary tangles, oxidative neuronal damage, and inflammatory responses. While Aβ deposition is considered an early trigger in the disease cascade, clinical symptom progression correlates more strongly with tau pathology and inflammatory responses. Recent concerns over data integrity in several high-profile AD studies have prompted critical re-evaluations of widely accepted hypotheses, emphasizing the urgent need for scientific transparency, reproducibility, and independent validation. In compiling this review, we prioritized findings supported by converging evidence from multiple experimental approaches and replication across independent cohorts. The hypothesis that an imbalance between Aβ42 synthesis and clearance is a central factor in AD has gained support from recent evidence, despite ongoing debate over the amyloid β-protein hypothesis. Dominant mutations associated with early-onset AD are primarily found in the amyloid precursor protein, which serves as the substrate for Aβ production, or in presenilin, the protease responsible for Aβ formation. The identification of presenilin as the catalytic site for β-secretase has provided crucial insights into AD pathogenesis. This review synthesizes current understanding of AD mechanisms, highlights emerging insights from multi-omics and spatial transcriptomic technologies, and discusses the evolving therapeutic landscape. Despite setbacks, the field continues to advance through methodological innovation and a revived interest in AD research integrity, offering hope for early diagnosis, more targeted treatments, and ultimately, disease-modifying therapies.},
}

@article {pmid42411214,
year = {2026},
author = {Ibrahim, MA and Baiomy, AAA and Khalil, HA and Anwar, MM and Mohamed, AS},
title = {Neuroprotective Role of Echinochrome in Aluminium Chloride-induced Alzheimer's Disease in Rats.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026474798260627120211},
pmid = {42411214},
issn = {1875-5739},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is the foremost neurodegenerative disorder and a variant of dementia observed in clinical environments. Echinochrome is a potent antioxidant and a natural bioproduct derived from sea urchins. The current study investigates the neuroprotective efficacy of echinochrome against aluminium chloride-induced AD in rats.

METHODS: AD was induced using AlCl3 at a dosage of 200 mg/kg over a duration of four weeks, and the experimental design had four groups. The control group, AD group, and echinochrome were administered at 0.1 mg/kg and 1 mg/kg via intraperitoneal injection for 4 weeks.

RESULTS: The administration of echinochrome led to a decrease in escape latency time in the Morris maze, as well as reductions in malondialdehyde, nitric oxide, amyloid beta, tau protein, and acetylcholinesterase activity, while increasing levels of dopamine, serotonin, epinephrine, norepinephrine, glutathione, catalase, glutathione-S-transferase, and hippocampal histology. Moreover, echinochrome reinstates normal hippocampal histology, augmenting the number of pyramidal cells in the Cornuammonis area, as well as granular cells in the dentate gyrus region.

DISCUSSION: The administration of echinochrome to AD rats resulted in a reduction of escape latency time of the Morris maze, oxidative stress, amyloid beta, and Tau, while also restoring normal neurotransmitter levels and hippocampal histology.

CONCLUSION: Echinochrome exhibits neuroprotective properties against aluminium chloride-induced AD. The neuroprotective mechanisms of echinochrome include reducing oxidative stress, preventing the accumulation of amyloid beta and tau proteins, and suppressing acetylcholinesterase activity.},
}

@article {pmid42411221,
year = {2026},
author = {Sharma, A and Kaur, A and Khan, J and Pandey, H},
title = {Phyto-Nanotherapeutics for Alzheimer's Disease: Current Progress and Future Perspectives.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249455878260609100548},
pmid = {42411221},
issn = {1875-6166},
abstract = {Alzheimer's Disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive and behavioral impairment and represents a major cause of dementia worldwide. It primarily affects the elderly population. The disease is marked by progressive neuronal damage, leading to impairments in cognition, behavior, emotions, and communication. Although currently available therapies provide symptomatic relief, they fail to alter disease progression, necessitating the development of more effective therapeutic strategies. Phytoconstituents have gained considerable attention due to their neuroprotective properties and multitargeted mechanisms of action against pathways implicated in AD. However, their clinical application is limited by poor Blood-Brain Barrier (BBB) permeability, low bioavailability, and inadequate solubility. Nanotechnology offers a promising approach for brain-targeted drug delivery by enhancing the therapeutic efficacy of phytoconstituents through advanced nanocarrier systems. This review explores the synergistic potential of phytoconstituents and nanocarriers for the management of AD, aiming to improve therapeutic outcomes and overcome existing limitations. It further highlights the integration of medicinal plant-based compounds with nanotechnology as a novel strategy for AD treatment. The combination of nanocarriers and phytoconstituents may facilitate enhanced BBB penetration and improved neuroprotection. Notably, nanomedicine- based approaches, including phytoconstituent-loaded nanoparticles and liposomes, demonstrate significant potential to overcome delivery barriers and enable efficient drug transport to the brain.},
}

@article {pmid42411229,
year = {2026},
author = {Hu, Z and Su, Y and Xi, J and Li, J},
title = {Diagnostic Accuracy of Plasma p-tau181 Measured Using Automated Chemiluminescent Immunoassays for Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050477953260623073513},
pmid = {42411229},
issn = {1875-5828},
abstract = {INTRODUCTION: To evaluate the diagnostic accuracy of plasma p-tau181 measured on fully automated immunoassay platforms for detecting Alzheimer's Disease (AD), and to determine how performance varies according to the reference standard used to define AD pathology.

MATERIALS AND METHODS: A systematic search was conducted across major databases for studies reporting the diagnostic accuracy of plasma p-tau181. Eligible studies enrolled adults across the Alzheimer's disease continuum and applied either CSF Aβ42/40, combined CSF Aβ42/40 and ptau181, or clinical diagnostic criteria as the reference standard. Data were synthesized using random- effects models. HSROC modeling was applied to estimate pooled sensitivity, specificity, and AUC.

RESULTS: A total of 19 studies involving 4266 participants were included. Most studies (18/19) used the Lumipulse platform, whereas only 1 study used Elecsys. Therefore, the pooled estimates mainly reflect Lumipulse-based evidence. Pooled sensitivity and specificity were 0.81 and 0.77 (AUC 0.84) when CSF Aβ42/40 defined amyloid pathology. When combined, CSF amyloid and tau positivity was required; sensitivity and specificity were 0.83 and 0.78 (AUC 0.86). Using clinical diagnostic criteria, pooled sensitivity reached 0.92, with a specificity of 0.78 (AUC 0.84). However, these subgroup estimates should be interpreted cautiously because substantial between-study heterogeneity remained, and some subgroups contained only a small number of datasets.

DISCUSSION: P-tau181 measured by automated chemiluminescent immunoassays showed promising diagnostic performance across reference standards, but the summary estimates are influenced by substantial heterogeneity and should not be interpreted as universally transferable measures of performance.

CONCLUSION: The results support plasma p-tau181 as a promising scalable biomarker for AD. However, because the available evidence is predominantly derived from Lumipulse-based studies, it remains insufficient to determine whether comparable performance extends to other automated CLIA platforms.},
}

@article {pmid42411439,
year = {2026},
author = {Zhu, J and Xie, H and Ouyang, Y and Zhu, T and Liu, Q and Liu, W and Xiong, S and Liu, M},
title = {Exploring the Microbiome-Kynurenine Axis in Mild Cognitive Impairment: From Gut to Brain.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {6},
pages = {48660},
doi = {10.31083/JIN48660},
pmid = {42411439},
issn = {0219-6352},
support = {2024JK2132//Projects of the science and technology innovation Program of Hunan Province/ ; 2024RC1061//Projects of the science and technology innovation Program of Hunan Province/ ; 20257637//Scientific Research Project of Hunan Provincial Health Commission/ ; [2022] 256//State Administration of Traditional Chinese Medicine 2022 Youth Qihuang Scholars Training Program (National Letter of Traditional Chinese Medicine Education)/ ; [2022] 357//Hunan Provincial Graduate Joint Cultivation Base for Acupuncture-Moxibustion and Tuina of Hunan University of Chinese Medicine (Hunan Provincial Department of Education Notice)/ ; [2021] 356//Acupuncture Bioinformation and Smart Wellness Innovation and Entrepreneurship Education Center of Hunan University of Chinese Medicine (Hunan Provincial Department of Education Notice)/ ; [2020] 19//Innovative Graduate Cultivation Base for Chinese Medicine Sub-health of Hunan University of Chinese Medicine (University Administrative Research Document)/ ; },
mesh = {Humans ; *Kynurenine/metabolism ; *Gastrointestinal Microbiome/physiology ; *Cognitive Dysfunction/metabolism/microbiology/immunology ; Animals ; *Brain/metabolism ; *Dysbiosis/metabolism/immunology ; },
abstract = {Mild cognitive impairment (MCI) represents a critical prodromal stage of Alzheimer's disease. This review synthesizes current evidence to present a coherent pathological cascade driving MCI progression: gut microbiota dysbiosis (e.g., enrichment of Prevotella and depletion of Akkermansia) triggers a butyrate deficit and compromise of intestinal integrity, leading to systemic inflammation. This inflammatory milieu upregulates indoleamine 2,3-dioxygenase 1 (IDO1), shifting tryptophan metabolism toward the kynurenine pathway and resulting in the dominance of neurotoxic branches (3-hydroxykynurenine [3-HK], quinolinic acid [QUIN]) over neuroprotective kynurenic acid (KYNA). This metabolic imbalance promotes N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity, oxidative stress, and neuroinflammation, which collectively precipitate synaptic dysfunction and cognitive decline. We explicitly highlight this "gut-immune-metabolic" vicious cycle as the core framework of MCI pathology. Targeting this cycle through a dual strategy-restoring microbial diversity and pharmacologically inhibiting the IDO1/kynurenine 3-monooxygenase (KMO) enzymes-represents a promising therapeutic approach to delay the transition from MCI to dementia.},
}

Humans
*Kynurenine/metabolism
*Gastrointestinal Microbiome/physiology
*Cognitive Dysfunction/metabolism/microbiology/immunology
Animals
*Brain/metabolism
*Dysbiosis/metabolism/immunology

@article {pmid42411440,
year = {2026},
author = {Ye, T and Shuai, Y and Liu, Y and Liu, S and Tang, X and Tian, W and Zhang, Y and Kong, Y},
title = {Efficacy and Safety of Transcranial Direct Current Stimulation on Multiple Health Outcomes in Neurological Disorders: An Umbrella Review of Meta-Analyses of Randomized Controlled Trials.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {6},
pages = {47145},
doi = {10.31083/JIN47145},
pmid = {42411440},
issn = {0219-6352},
mesh = {*Transcranial Direct Current Stimulation ; Humans ; *Nervous System Diseases/therapy ; *Randomized Controlled Trials as Topic ; Meta-Analysis as Topic ; Systematic Reviews as Topic ; *Outcome Assessment, Health Care/statistics & numerical data ; },
abstract = {BACKGROUND: Neurological disorders are a leading cause of disability worldwide. Transcranial direct current stimulation (tDCS) is a promising therapeutic tool for neurological disorders. However, a consensus on clinical recommendations for using tDCS in patients with neurological disorders is lacking. In this umbrella review, we aimed to establish evidence-based guidance for using tDCS to treat neurological disorders.

METHODS: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 2020. PubMed/MEDLINE, Embase, the Cochrane Library, the Web of Science, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) were systematically searched to identify and evaluate existing systematic reviews and meta-analyses on the use of tDCS for neurological disorders. Quality was assessed using the Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) and the Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) tool. The Hartung-Knapp-Sidik-Jonkman random effects model was employed for reanalysis.

RESULTS: A total of 17 systematic reviews and meta-analyses encompassing 358 randomized controlled trials and 7160 participants were analyzed. tDCS demonstrated efficacy across seven distinct health conditions, including stroke, Parkinson's disease, Alzheimer's disease, cerebellar ataxia, fibromyalgia, disorders of consciousness, and migraine. Adverse effects were rarely reported, with the exception of mood changes associated with fibromyalgia. Our results indicated that tDCS significantly improved 34 distinct health outcomes related to these conditions.

CONCLUSIONS: We found that tDCS may be a promising treatment for neurological disorders, with mild and infrequent adverse effects. Further studies are warranted to validate the therapeutic potential of tDCS in the reported neurological conditions, investigate additional neurological health outcomes, and explore the underlying mechanisms of tDCS effects. The PROSPERO Registration: CRD42024589432, https://www.crd.york.ac.uk/PROSPERO/view/CRD42024589432.},
}

*Transcranial Direct Current Stimulation
Humans
*Nervous System Diseases/therapy
*Randomized Controlled Trials as Topic
Meta-Analysis as Topic
Systematic Reviews as Topic
*Outcome Assessment, Health Care/statistics & numerical data

@article {pmid42411493,
year = {2026},
author = {Stefano, GB},
title = {Beyond Amyloid: Evolutionary and Immune-Metabolic Perspectives on Alzheimer's Disease.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {31},
number = {6},
pages = {53859},
doi = {10.31083/FBL53859},
pmid = {42411493},
issn = {2768-6698},
mesh = {Humans ; *Alzheimer Disease/metabolism/immunology/pathology ; Animals ; *Amyloid beta-Peptides/metabolism/immunology ; Immunity, Innate ; Brain/metabolism/immunology/pathology ; Mitochondria/metabolism ; Biological Evolution ; Gastrointestinal Microbiome ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a multifactorial and systems-level disorder that extends beyond the classical amyloid cascade hypothesis. Rather than dismissing established concepts such as tau pathology, synaptic dysfunction, vascular compromise, mitochondrial abnormalities, and impaired proteostasis, emerging evidence suggests that these processes may interact dynamically with chronic immune activation, microbial signaling, and systemic metabolic stress. Recent studies examining the microbiome-gut-brain axis, chronic infection, innate immunity, and systemic immune-metabolic dysfunction have broadened the conceptual framework of AD pathogenesis. Importantly, amyloid-β (Aβ) is now understood to possess evolutionarily conserved antimicrobial and immunomodulatory properties, suggesting that amyloid deposition may initially represent a protective host-defense response rather than solely a toxic pathological event. This perspective does not overturn the amyloid cascade model but instead reframes amyloid biology within a broader adaptive evolutionary context in which chronic or dysregulated activation becomes maladaptive during aging. The present opinion article integrates these converging concepts into a unified framework in which AD emerges from the prolonged interaction among immune responses, microbial exposures, metabolic disturbances, mitochondrial dysfunction, vascular injury, and age-associated failures in proteostatic resilience. This integrative interpretation seeks to humanize the disease process by viewing neurodegeneration not simply as isolated protein accumulation, but as the gradual exhaustion of ancient host-defense and energy-regulatory systems that were originally evolutionarily advantageous for survival.},
}

Humans
*Alzheimer Disease/metabolism/immunology/pathology
Animals
*Amyloid beta-Peptides/metabolism/immunology
Immunity, Innate
Brain/metabolism/immunology/pathology
Mitochondria/metabolism
Biological Evolution
Gastrointestinal Microbiome

@article {pmid42411865,
year = {2026},
author = {Wang, MT and Zhao, RC and Huang, M and Chen, J and Li, XP and Liu, YH and Wang, YJ},
title = {Plasma profiling of B lymphocyte-associated cytokines in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261464184},
doi = {10.1177/13872877261464184},
pmid = {42411865},
issn = {1875-8908},
abstract = {BackgroundImmunological dysregulation is a hallmark of Alzheimer's disease (AD), a neurodegenerative disorder characterized by amyloid-β (Aβ) plaque accumulation and hyperphosphorylated Tau protein pathology. AD is associated with altered humoral immunity, which may play a role in its pathogenesis.ObjectiveThis study aimed to investigate alterations in plasma levels of B lymphocyte-associated cytokines and their clinical relevance in AD.MethodsWe performed quantitative detections of 13 cytokines associated with B lymphocytes (TNF-β, IL-13, IFN-γ, TNF-α, IL-2, BAFF, IL-6, CD40L, IL-10, IL-12p70, IL-4, IL-17A, and IL-7) in plasma and analyzed their associations with cognitive functions and biomarkers of AD.ResultsWe found that plasma levels of CD40L, BAFF, TNF-β, IL-6 and IL-17A were increased in AD patients. However, the plasma IL-10 concentrations were decreased in Aβ-PET[+] subjects. Plasma levels of CD40L, BAFF, TNF-β, IL-6, IL-17A were negatively associated with the plasma Aβ42/40 ratio. Plasma levels of IL-10 were negatively associated with pTau181. Plasma levels of BAFF were negatively associated with MMSE scores.ConclusionsThese findings demonstrate an altered B lymphocyte-associated cytokine secretion profile in AD patients, which correlates with the clinical severity and biomarkers of the disease.},
}

@article {pmid42411930,
year = {2026},
author = {Verma, S and Ambatwar, R and Datusalia, AK and Khatik, GL},
title = {Kynurenic Acid, a Key Endogenous Neuroprotective Agent: Role of Its Derivatives in Therapeutics.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00081},
pmid = {42411930},
issn = {1948-7193},
abstract = {Kynurenic acid (KYNA) is an endogenous molecule that acts as a nonselective antagonist of ionotropic glutamate receptors and has been shown to have neuroprotective properties. Although KYNA has shown considerable therapeutic potential in neurodegenerative disorders, its limited permeability across the blood-brain barrier restricts its direct clinical application. To overcome this limitation, various ester and amide derivatives have been developed as prodrugs to enhance brain delivery and subsequently release KYNA within the central nervous system. Beyond serving as prodrugs, KYNA derivatives have attracted substantial interest in medicinal chemistry due to their ability to interact with multiple molecular targets. Additionally, these compounds exhibit a wide range of biological activities, including potential treatments for Alzheimer's disease, Parkinson's disease, Huntington's disease, and psychiatric disorders. Therefore, kynurenic acid-based scaffolds have prompted further research into their derivatives, leading to a range of structurally distinct products. Here, we discuss the neuroprotective role of KYNA and its derivatives, which exhibit diverse bioactivities.},
}

@article {pmid42411943,
year = {2026},
author = {McKay, TB and Kelly Graves, O and Mitchell, M and Mueller, A and Simon, C and Patel, P and Turco, I and Bertsch, J and Albanese, ML and Gleeson, E and Wint, A and Novak, A and Baker, S and Qu, JZ and Akeju, O},
title = {Intraoperative Lipoproteins Associated with Postoperative Delirium in a Prospective Observational Study of Older Adults Undergoing Cardiac Surgery.},
journal = {Journal of cardiothoracic and vascular anesthesia},
volume = {40},
number = {2},
pages = {571-582},
doi = {10.1053/j.jvca.2025.09.235},
pmid = {42411943},
issn = {1532-8422},
mesh = {Humans ; Prospective Studies ; Female ; Male ; *Cardiac Surgical Procedures/adverse effects/trends ; Aged ; Middle Aged ; *Delirium/blood/diagnosis/etiology ; Biomarkers/blood ; *Lipoproteins/blood ; *Postoperative Complications/blood/diagnosis ; Cohort Studies ; Cardiopulmonary Bypass/adverse effects ; },
abstract = {OBJECTIVE: To evaluate serum lipoproteins and other metabolites and their potential associations with the development of postoperative delirium.

DESIGN: Prospective observational cohort study.

SETTING: Single-site academic medical hospital.

PARTICIPANTS: Patients age 60 years and older scheduled for major cardiac surgery with cardiopulmonary bypass (CPB).

INTERVENTIONS: Delirium assessments were performed at baseline and twice daily up to postoperative day 3. The primary outcome evaluated serum collected before surgery, at the start and end of CPB, and on postoperative day 1.

MEASUREMENTS AND MAIN RESULTS: Sixty-five patients were recruited, with 18% of subjects developing postoperative delirium within 3 days of surgery (10 of 57 subjects with complete cognitive assessments). Metabolomic analysis of serum revealed an association between the abundance of cholesterol in large high-density lipoprotein (L-HDL-C%) at the start of CPB and the development of postoperative delirium (odds ratio per standard deviation increment in biomarker concentration, 0.23; 95% confidence interval [CI], 0.08-0.66). Serum neurofilament light chain was inversely correlated with L-HDL-C% levels at the same time point (Spearman ρ, -0.39; 95% CI, -0.59 to -0.15) and was significantly higher at the end of CPB in subjects who developed delirium compared to subjects who did not develop delirium (median, 20.4 [interquartile range (IQR),16.1-25.4] pg/mL vs 11.9 [IQR, 7.9-16.9] pg/mL).

CONCLUSION: Circulating blood biomarkers during surgery may provide insight into postoperative cognitive outcomes and should be evaluated in larger cohorts.},
}

Humans
Prospective Studies
Female
Male
*Cardiac Surgical Procedures/adverse effects/trends
Aged
Middle Aged
*Delirium/blood/diagnosis/etiology
Biomarkers/blood
*Lipoproteins/blood
*Postoperative Complications/blood/diagnosis
Cohort Studies
Cardiopulmonary Bypass/adverse effects

@article {pmid42411944,
year = {2026},
author = {Zhang, T and Ma, G and Wang, W and Huang, Q and Sun, S and Yang, H and Hong, X},
title = {Mortality trends and projections for type 2 diabetes with concomitant Parkinson's versus Alzheimer's disease among older United States adults, 1999-2023: A retrospective cohort study.},
journal = {Medicine},
volume = {105},
number = {27},
pages = {e49321},
pmid = {42411944},
issn = {1536-5964},
support = {ZKX18049//the Nanjing Municipal Medical Science and Technique Development Foundation, the Nanjing Key Medical Department (of Chronic NonCommunicable Disease Prevention and Control/ ; },
mesh = {Humans ; *Diabetes Mellitus, Type 2/mortality/epidemiology/complications ; United States/epidemiology ; *Alzheimer Disease/mortality/epidemiology/complications ; Retrospective Studies ; *Parkinson Disease/mortality/epidemiology/complications ; Aged ; Female ; Male ; Aged, 80 and over ; Comorbidity ; Mortality/trends ; },
abstract = {Although type 2 diabetes mellitus (T2DM) frequently co-occurs with Parkinson's disease (PD) and Alzheimer's disease (AD), a systematic comparison of their combined mortality burdens remains lacking. This study aimed to compare long-term mortality trends and project future burdens among older US adults with T2DM comorbid with either PD or AD. A retrospective cohort study was conducted using national mortality data (1999-2023) from the CDC WONDER database. Decedents were identified using ICD-10 codes for T2DM with PD (E11 + G20) or AD (E11 + G30). Temporal trends were analyzed to estimate annual percentage change (APC) and average annual percentage change (AAPC), and future age-adjusted mortality rates were projected through 2030. Both conditions exhibited sustained upward mortality trends from 1999 to 2023, with T2DM with PD showing higher relative growth (AAPCs) but lower absolute burden than T2DM with AD. The steepest increases in death counts occurred among Hispanic/Latino individuals and in the Western United States, while the highest AAPCs in age-adjusted mortality were seen among Hispanic/Latino adults with T2DM and AD and in the Western United States for both conditions. Males had higher age-adjusted mortality for T2DM with PD, whereas females had higher absolute death counts for T2DM with AD. Mortality for T2DM with PD peaked at ages 75 to 84, while for T2DM with AD it rose continuously with age. A marked shift from institutional to home-based deaths was observed. Projections indicate age-adjusted mortality will exceed 2023 levels by over 20% by 2030, reaching 6.66 (T2DM with PD) and 15.99 (T2DM with AD) per 1,00,000. Mortality associated with T2DM comorbid with PD or AD is escalating, characterized by distinct demographic and geographic disparities. These findings underscore the urgent need for integrated clinical screening, stratified prevention strategies, and strengthened community-based care to mitigate the growing burden of these complex multimorbidities.},
}

Humans
*Diabetes Mellitus, Type 2/mortality/epidemiology/complications
United States/epidemiology
*Alzheimer Disease/mortality/epidemiology/complications
Retrospective Studies
*Parkinson Disease/mortality/epidemiology/complications
Aged
Female
Male
Aged, 80 and over
Comorbidity
Mortality/trends

@article {pmid42411945,
year = {2026},
author = {Nakamura, Y and Tsushio, T and Tanahashi, M and Suganami, H and Omori, T and Nishiyama, K and Aoki, H and Nagakura, N},
title = {Post Hoc Subgroup Analysis by Disease Severity in a Non-Inferiority Trial of Donepezil 27.5 mg Transdermal Formulation in Japanese Patients With Mild-to-Moderate Alzheimer Disease.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000738},
pmid = {42411945},
issn = {1546-4156},
support = {//Teikoku Seiyaku/ ; },
abstract = {BACKGROUND: The efficacy of cholinesterase inhibitors varies depending on the severity of Alzheimer disease. We examined the effects of the disease severity on the efficacy of donepezil 27.5 mg patches in Japanese patients with Alzheimer disease.

METHODS: A post hoc analysis of covariance using per-protocol set in a noninferiority study of donepezil 27.5 mg patches with donepezil hydrochloride 5 mg tablets (JapicCTI-194582) was conducted after imputation of missing data using multiple imputations.

RESULTS: No apparent imbalances in the extracted confounding factors were observed between the 2 treatment groups. The baseline value of the Alzheimer Disease Assessment Scale (Japanese version) cognitive subscale was adjusted using analysis of covariance. Least-squares mean of changes from baseline in the Alzheimer Disease Assessment Scale (Japanese version) cognitive subscale at week 24 for each group were -1.661 (-2.681 to -0.640) (donepezil patch) and 0.065 (-0.987 to 1.117) (donepezil hydrochloride tablet). The difference in the least-squares mean (95% CI) between 2 groups was -1.726 (-3.1913 to -0.2602, P=0.021).

CONCLUSIONS: A post hoc analysis of covariance using the per-protocol set suggested that donepezil patches may be more effective than donepezil tablets in slowing cognitive decline in patients with mild Alzheimer disease.},
}

@article {pmid42411987,
year = {2026},
author = {Ghaedrahmat, Z and Almasi, F and Shamsi Goushki, J and Moghiseh, Z},
title = {The role of organochlorine pesticides as environmental factors in Alzheimer's disease in human studies: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261465828},
doi = {10.1177/13872877261465828},
pmid = {42411987},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a prevalent neurodegenerative disorder among the elderly, influenced by both genetic and environmental factors. Organochlorine pesticides (OCPs) have recently been identified as potential environmental risk factors due to their bioaccumulation in adipose tissue and neurotoxic properties.ObjectiveThis systematic review aimed to examine the human evidence regarding exposure to OCPs and the risk of AD. The results of the meta-analysis showed that exposure to pesticides is significantly associated with an increased risk of AD.MethodsA comprehensive search was performed across major scientific databases, including PubMed/MEDLINE, Scopus, Web of Science, the Cochrane Library, and Embase.ResultsPooled estimates (random effects meta-analysis) of the four eligible studies showed a significant positive association between exposure to OCPs and the risk of AD (OR = 2.19; 95% CI: 1.40-3.42). These findings indicate that exposure to OCPs may significantly increase the risk of AD. The substantial heterogeneity among studies (I[2] = 84.58%) may partly reflect differences in exposure assessment approaches, such as biomonitoring-based measurements compared with occupational or geographically inferred exposure assessments.ConclusionsThese findings highlight the importance of controlling occupational and environmental exposures to pesticides in preventing neurodegenerative outcomes. The findings suggest that chronic exposure to lipophilic pesticides, particularly persistent chlorinated compounds, may contribute to neurodegenerative processes implicated in the pathophysiology of AD. Therefore, more studies with similar designs and more precise exposure measurements are needed to confirm the results and reduce the heterogeneity.},
}

@article {pmid42412004,
year = {2026},
author = {Zhang, J and Wang, Y and Lu, Z and Yang, Y and Wang, J and Zhao, L and Li, F and Miao, M and Chen, WM and Wu, SY and Sun, M},
title = {HbA1c trajectories after SGLT2 inhibitor initiation and the risk of dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261462927},
doi = {10.1177/13872877261462927},
pmid = {42412004},
issn = {1875-8908},
abstract = {BackgroundType 2 diabetes mellitus (T2DM) is a major risk factor for dementia, yet the prognostic value of early dynamic glycemic changes following glucose-lowering therapy remains underinvestigated.ObjectiveTo determine whether early glycated hemoglobin (HbA1c) trajectories after initiating sodium-glucose cotransporter 2 inhibitors (SGLT2i) predict long-term dementia and mortality risks.MethodsThis retrospective new-user cohort study utilized electronic health records from the TriNetX Global Network. Adults with T2DM initiating their first SGLT2i were included. To mitigate immortal-time bias, a 1-year landmark design was applied. Patients were stratified by baseline HbA1c and classified into improved, stable, or worsened trajectories based on values 91-455 days post-initiation. Propensity-score matching was performed within strata. The primary outcome was all-cause dementia.ResultsAmong 172,050 matched patients, modest HbA1c worsening in those with Good baseline control (<7.0%) did not increase dementia risk (HR 0.93; 95% CI, 0.75-1.15). However, in patients with Fair baseline control (7.0-8.9%), worsening to Poor control significantly increased dementia (HR 1.39; 95% CI, 1.11-1.74) and mortality risks. Conversely, among those with Poor baseline control (≥9.0%), trajectory improvement conferred substantial neuroprotection, reducing the risk of dementia (HR 0.64; 95% CI, 0.51-0.79) and mortality (HR 0.71; 95% CI, 0.60-0.84). These findings provide clinically actionable evidence linking glycemic dynamics to neurodegenerative risk, particularly Alzheimer's disease and related dementias.ConclusionsDynamic HbA1c trajectories following SGLT2i initiation independently predict dementia risk. Integrating trajectory-based assessments into routine care provides an actionable, scalable biomarker to guide timely treatment intensification and mitigate diabetes-related neurocognitive decline.},
}

@article {pmid42412039,
year = {2026},
author = {Shi, Y and Ci, R and Geng, C and Zhang, X and Zheng, N and Qin, Y},
title = {Disruptions of the diffusion tensor image analysis along the perivascular space index and dynamic functional connectivity across the Alzheimer's disease spectrum: Implications for cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261465700},
doi = {10.1177/13872877261465700},
pmid = {42412039},
issn = {1875-8908},
abstract = {BackgroundAcross the Alzheimer's disease spectrum (ADS), spanning subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia, the interplay between alterations in diffusion tensor imaging (DTI) analysis along the perivascular space (ALPS), brain functional connectivity, and cognitive impairment (CI) remains poorly understood.ObjectiveTo evaluate DTI-ALPS index and brain network across clinical stages of ADS and assess whether brain network disruptions mediates the association between DTI-ALPS index and CI.MethodsA total of 188 ADS patients and 77 healthy controls (HC) were recruited. The DTI-ALPS index, dynamic functional connectivity (dFC) and network topology were estimated from MRI. Group differences were assessed using analysis of covariance. Mediation analyses examined whether disruptions in dFC or topology mediated the association between the DTI-ALPS index and CI.ResultsCompared with HC, SCD patients showed significantly reduced ALPS index in the left hemisphere, whereas MCI and AD patients showed significantly reduced ALPS index in both hemispheres. While topology showed no significant differences across ADS, dFC analysis revealed stage-specific alterations, with abnormalities in higher-order cognitive systems in the early stage and in primary processing systems in later stages. Mediation analysis indicated that dFC disruption, but not topology abnormalities, mediated the association between reduced DTI-ALPS index and CI in ADS patients.ConclusionsDecreased DTI-ALPS index and abnormalities in higher-order cognitive systems emerged as early as the SCD stage and exhibited stage-dependent differences across disease severity. Importantly, dFC disruption mediated the association between reduced DTI-ALPS index and CI, suggesting a potential underlying pathological mechanism.},
}