@article {pmid42690834,
year = {2026},
author = {Lin, J and Vassilaki, M and St Sauver, J and Petersen, RC and Wi, CI and Juhn, YJ and Chen, J and Sham, Y and Sohn, S},
title = {Differential associations of individual- and neighborhood-level socioeconomic status with mortality in dementia: Findings from the Mayo Clinic Study of Aging.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261482043},
doi = {10.1177/13872877261482043},
pmid = {42690834},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) and related dementias are leading causes of death worldwide. While socioeconomic status (SES) is a critical determinant, its impact on mortality after diagnosis remains understudied.ObjectiveTo investigate the roles of neighborhood-level and individual-level SES in predicting mortality risk among older adults with incident dementia.MethodsWe analyzed data from 924 participants with incident dementia from the Mayo Clinic Study of Aging (N = 6909), a cohort with clinical follow-up visits every 15 months. We assessed mortality risk using Cox's time-varying survival regression, adjusting for time-fixed and time-varying covariates. Primary predictors were neighborhood-level SES (Area Deprivation Index [ADI]) and individual-level SES (housing-based SES index [HOUSES], education, and occupation). We also applied a random survival forest model to assess the predictive contribution of SES indicators and identify influential predictors.Results857 participants (92.7%) died, with a median time from dementia diagnosis to death of 29 months (IQR: 12-54). Lower SES measured by HOUSES was associated with increased mortality risk (HR 1.28, 95% CI 1.07-1.52). Conversely, ADI, education, and occupation were not associated with mortality. Male sex, older age, congestive heart failure and diabetes were associated with higher mortality risk. In predictive analysis, HOUSES ranked among the top 10 contributors to mortality risk.ConclusionsAmong older adults with dementia, lower HOUSES was associated with higher mortality risk beyond neighborhood-level deprivation, education, and occupation. Integrating this housing-based individual-level SES measure into dementia care planning may help identify patients with greater socioeconomic vulnerability and inform mortality risk stratification.},
}

@article {pmid42691074,
year = {2026},
author = {Fernandez, FX and Burke, SN and Nadel, L},
title = {Aging as a Continuation of Development: A Hypothesis and Framework.},
journal = {Perspectives on psychological science : a journal of the Association for Psychological Science},
volume = {},
number = {},
pages = {17456916261469175},
doi = {10.1177/17456916261469175},
pmid = {42691074},
issn = {1745-6924},
abstract = {Prevailing theories of cognitive aging depict late life as a period of compensatory decline-an effort to preserve performance despite progressive neural deterioration. We propose instead that aging represents a continuation of development: a genetically conserved, adaptive reorganization of memory systems that parallels the brain's earlier-life transitions. Drawing on convergent molecular, network, behavioral, and comparative evidence, we argue that the well-documented decline in episodic-memory precision reflects a deliberate recalibration of plasticity from hippocampal to cortical circuits, favoring semantic integration and schematic stability over rapid encoding of novel details. This shift, we suggest, is not a workaround for loss but an evolved optimization suited to the cognitive ecology of late life, when accumulated knowledge, social insight, and intergenerational teaching become primary adaptive functions. The resulting semantic mode of cognition supports narrative coherence, emotional regulation, and wisdom, distinguishing normal aging from pathological derailments such as Alzheimer's disease. We outline testable predictions across longitudinal, neuroimaging, and computational domains and reinterpret constructs like cognitive reserve as expressions of this developmental reallocation. By reframing aging as purposeful maturation rather than compensation, the adaptive-aging hypothesis positions late-life cognition as a distinct, evolutionarily honed phase of human development.},
}

@article {pmid42691219,
year = {2026},
author = {Iqbal, T and Tabassum, S and Imran, M and Tang, S and Xiao, P and Wei, T and Hailaiti, D and Fan, P and Lu, W and Li, H and Huang, J},
title = {The Glymphatic and Meningeal Lymphatic Systems: Gatekeepers of Brain Health in Aging and Neurodegeneration.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0009},
pmid = {42691219},
issn = {2152-5250},
abstract = {The discovery of the glymphatic system and of meningeal lymphatic vessels has substantially revised our understanding of how the central nervous system clears waste and maintains neuroimmune homeostasis. Acting in series, these two pathways remove interstitial solutes, metabolic by-products, and neurotoxic proteins such as tau and amyloid-β from the brain parenchyma and deliver them to the peripheral lymphatic system. Converging experimental and clinical evidence indicates that both pathways decline with age, and that impaired clearance contributes to the onset and progression of Alzheimer's disease, Parkinson's disease, and stroke, although the direction of causality in these associations is not yet fully resolved. In this review, we summarize current knowledge of the anatomy and physiology of the glymphatic and meningeal lymphatic systems; examine the molecular and cellular mechanisms by which their function deteriorates with age; appraise the imaging modalities and fluid biomarkers used to assess them; and evaluate the therapeutic strategies being developed to restore them. A clearer understanding of this clearance pathways may open new avenues for the treatment of age-related neurodegenerative disease.},
}

@article {pmid42691403,
year = {2026},
author = {Jain, M and Matysiak, S},
title = {Calcium Reshapes Aβ Aggregation at Anionic Lipid Membranes.},
journal = {The journal of physical chemistry. B},
volume = {130},
number = {35},
pages = {8770-8781},
doi = {10.1021/acs.jpcb.6c02606},
pmid = {42691403},
issn = {1520-5207},
support = {CHE-2202281//Division of Chemistry/ ; },
mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; *Calcium/chemistry/metabolism ; Molecular Dynamics Simulation ; *Lipid Bilayers/chemistry/metabolism ; Anions/chemistry ; Phosphatidylcholines/chemistry ; *Peptide Fragments/chemistry/metabolism ; Hydrophobic and Hydrophilic Interactions ; Protein Aggregates ; Phosphatidylserines/chemistry ; Static Electricity ; },
abstract = {Dysregulated calcium homeostasis is a hallmark of neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases. In Alzheimer's disease (AD), the aggregation of amyloid beta (Aβ) peptides at neuronal membranes is shown to be modulated by the presence of Ca2+ ions, yet the molecular mechanism by which Ca2+ reshapes Aβ aggregation at anionic membrane surfaces remains poorly understood. To address this knowledge gap, we employed coarse-grained molecular dynamics simulations to investigate the aggregation of the model amyloidogenic K16LVFFAE22 fragment of Aβ (Aβ16-22), on a mixed bilayer composed of 30% anionic phosphatidylserine (PS) and 70% zwitterionic phosphatidylcholine (PC) (30% POPS, 70% POPC) in the presence of Ca2+ ions. We find that Ca2+ ions screen the surface charge and reduce hydrophobic packing defects at the membrane surface. Since peptide binding is primarily driven by electrostatic interactions between positively charged residues and anionic lipids, followed by hydrophobic interactions, these Ca2+-induced changes delay peptide adsorption onto the bilayer, promoting the formation of larger aggregates in solution that subsequently adsorb as preformed aggregates. This is in contrast with the no-Ca2+ condition, where peptides bind earlier as small oligomers and aggregate on the bilayer. Following adsorption, PS-Ca2+-PS ionic bridges rapidly condense PS lipids around peptide aggregates and reduce their lateral mobility. This leads to larger, less ordered aggregates with shallower insertion and hydrophobic residues exposed to the solution, a structural feature associated with seeding-active aggregates. These findings align with Western blot analyses showing enhanced Aβ aggregation with Ca2+ ions and provide a molecular basis for the observed aggregation behavior. Together, our results provide mechanistic insight into how calcium alters the membrane-mediated aggregation pathway of amyloidogenic peptides, potentially informing therapeutic strategies against amyloid pathology.},
}

*Amyloid beta-Peptides/chemistry/metabolism
*Calcium/chemistry/metabolism
Molecular Dynamics Simulation
*Lipid Bilayers/chemistry/metabolism
Anions/chemistry
Phosphatidylcholines/chemistry
*Peptide Fragments/chemistry/metabolism
Hydrophobic and Hydrophilic Interactions
Protein Aggregates
Phosphatidylserines/chemistry
Static Electricity

@article {pmid42691413,
year = {2026},
author = {Mo, Y and Hou, Y and Su, R and Huang, Z and Tang, G and Du, L and Lu, Y},
title = {Conformational Features of Aβ25-35 and Its Mutants Suggest Toxic Structural Determinants: Insights from REST2 Simulations.},
journal = {The journal of physical chemistry. B},
volume = {130},
number = {35},
pages = {8855-8866},
doi = {10.1021/acs.jpcb.6c04178},
pmid = {42691413},
issn = {1520-5207},
support = {2018GXNSFBA050028//Natural Science Foundation of Guangxi Zhuang Autonomous Region/ ; 12464018//National Natural Science Foundation of China/ ; },
mesh = {*Amyloid beta-Peptides/chemistry/genetics/toxicity/metabolism ; *Peptide Fragments/chemistry/genetics/toxicity/metabolism ; *Molecular Dynamics Simulation ; Mutation ; Hydrophobic and Hydrophilic Interactions ; Hydrogen Bonding ; Protein Conformation ; Humans ; },
abstract = {The Aβ25-35 fragment is the shortest proteolytic fragment retaining the core neurotoxicity of full-length Alzheimer's amyloid-β (Aβ). To elucidate the structure-neurotoxicity relationships, we performed replica exchange with solute tempering 2 (REST2) simulations on wild-type (WT), N27A (less toxic), and M35A (more toxic) Aβ25-35 hexamers in explicit solvent. Our simulations show that N27A, WT, and M35A hexamers predominantly adopt 4-stranded, 6-stranded, and 5-stranded β-barrels, respectively, driven by hydrophobic interactions within residues I30-G33. Hydrogen bond counts and binding energies for adjacent peptide contacts and peptide-water interactions indicate that both β-barrel disassembly propensity and N-terminal hydration (residues G25-K28) correlate with the cytotoxicity trend (N27A < WT < M35A). Integrating our findings with established membrane damage mechanisms, we propose that (I) the disassembly propensity of dominant β-barrels governs their transition from off-pathway states to cytotoxic oligomers, and (II) N-terminal domain exposure (G25-K28) in on-pathway intermediates modulates peptide-membrane interactions. To reduce Aβ25-35 oligomeric toxicity, we recommend inhibiting hydrophobic core residues (A30-G33) to suppress aggregation and modulating N-terminal contacts to limit solvent exposure and membrane binding. Our simulations provide new insights into WT and mutant Aβ25-35 cytotoxicity and suggest therapeutic strategies for its attenuation.},
}

*Amyloid beta-Peptides/chemistry/genetics/toxicity/metabolism
*Peptide Fragments/chemistry/genetics/toxicity/metabolism
*Molecular Dynamics Simulation
Mutation
Hydrophobic and Hydrophilic Interactions
Hydrogen Bonding
Protein Conformation
Humans

@article {pmid42691466,
year = {2026},
author = {Beaufort, Q and Charbonnier, C and Ruellan, P and Ozkul-Wermester, O and Amar, V and Turpin, D and Quillard-Muraine, M and Gerardin, E and Dufour, D and Charidimou, A and Balageas, AC and Boulouis, G and Pasi, M and Wallon, D and Grangeon, L},
title = {Evaluation of Disease Severity Using CSF Biomarkers in Patients With Probable Cerebral Amyloid Angiopathy.},
journal = {Neurology},
volume = {107},
number = {6},
pages = {e218458},
doi = {10.1212/WNL.0000000000218458},
pmid = {42691466},
issn = {1526-632X},
mesh = {Humans ; *Cerebral Amyloid Angiopathy/cerebrospinal fluid/diagnostic imaging ; Female ; Male ; *Amyloid beta-Peptides/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; *tau Proteins/cerebrospinal fluid ; Retrospective Studies ; Aged ; *Severity of Illness Index ; *Peptide Fragments/cerebrospinal fluid ; Magnetic Resonance Imaging ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND AND OBJECTIVES: Cerebral amyloid angiopathy (CAA) is currently diagnosed using MRI-based Boston criteria. However, imaging markers represent downstream consequences of vascular injury and may not fully reflect disease severity. CSF biomarkers, particularly β-amyloid 1-42 (Aβ42) and β-amyloid 1-40 (Aβ40), may provide a more direct measure of vascular amyloid burden. We investigated the association between CSF biomarkers and hemorrhagic and nonhemorrhagic MRI markers of disease severity in probable CAA.

METHODS: We conducted a retrospective multicenter cohort study including consecutive patients diagnosed with probable CAA according to Boston criteria v2.0 at 2 tertiary centers (2014-2023) who underwent lumbar puncture (LP) as part of clinical evaluation. CSF Aβ42, Aβ40, total tau, and phosphorylated-tau 181 (p-tau181) were measured using standardized immunoassays. MRI markers included lobar cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), white matter hyperintensity burden, Fazekas score, and enlarged perivascular spaces in the centrum semiovale. Multivariable linear regression models were adjusted for age, sex, MRI sequence type, and delay between onset and LP. False discovery rate correction was applied for multiple testing. We also used principal component analysis to explore associations between MRI and CSF biomarkers.

RESULTS: A total of 102 patients were included (mean age at LP 72.0 ± 7.5 years; 65% male). Initial presentations were cognitive impairment in 53%, intracerebral hemorrhage in 34%, and transient focal neurologic episodes in 13%. Lower CSF Aβ40 and Aβ42 levels were significantly associated with greater cSS burden (standardized β -0.49 [95% CI -0.8 to -0.17], p = 0.002 and -0.42 [-0.73 to -0.11], p = 0.007, respectively) and higher Fazekas score (β -0.18 [-0.33 to -0.03], p = 0.02 and -0.23 [-0.38 to -0.08], p = 0.002) but not with CMB count. No significant association was found between tau species and MRI markers. Associations remained significant after stratification by CSF Aβ42/Aβ40-defined Alzheimer-like profile.

DISCUSSION: In probable CAA, lower CSF Aβ40 and Aβ42 levels are associated with established MRI markers of disease severity, independently of clinical presentation and concomitant Alzheimer-like profile. These findings suggest that CSF Aβ levels may reflect vascular amyloid burden rather than downstream neurodegeneration. Prospective longitudinal studies are needed to determine their prognostic value.},
}

Humans
*Cerebral Amyloid Angiopathy/cerebrospinal fluid/diagnostic imaging
Female
Male
*Amyloid beta-Peptides/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
*tau Proteins/cerebrospinal fluid
Retrospective Studies
Aged
*Severity of Illness Index
*Peptide Fragments/cerebrospinal fluid
Magnetic Resonance Imaging
Aged, 80 and over
Middle Aged

@article {pmid42691539,
year = {2026},
author = {Hsu, EC and Carder, P and Smith, L and Zhou, ZE and Yakusheva, O and Beeber, A and Jutkowitz, E and Thomas, KS},
title = {A Profile of Assisted Living Direct Care Workforce Training Requirements Across the United States.},
journal = {Journal of the American Medical Directors Association},
volume = {27},
number = {10},
pages = {106445},
doi = {10.1016/j.jamda.2026.106445},
pmid = {42691539},
issn = {1538-9375},
abstract = {OBJECTIVES: To characterize assisted living (AL) direct care worker (DCW) training requirements across the United States and how these regulations have changed over time. Specifically, we examine state-level profiles of training regulations, including duration, frequency, content, source of materials, evaluation, and changes in regulatory coverage.

DESIGN: Cross-sectional and longitudinal descriptive study using state policy data and AL directories from 2019, 2021, and 2023.

SETTING AND PARTICIPANTS: All US states' AL training-related regulations; all ALs and AL beds governed by those regulations.

METHODS: We used a mixed-methods approach with an explanatory sequential design (QUAN → qual), first conducting health services regulatory analysis followed by qualitative content analysis.

RESULTS: In 2023, 43 states (90% of ALs, nationally) required DCW training, 29 states required annual training frequency, 28 states specified training hours (median 10 hours), 28 required dementia-specific content, and 29 required training to cover at least 5 topics when onboarding. Common training topics included resident rights, emergency response, infection control, and personal care; dementia-specific training topics included Alzheimer's disease, behavior, communication, and dignity of residents, with only 2 states requiring training that addressed DCWs' well-being. Ten states mandated use of professionally designed courses, and 5 states required DCWs to complete an exam. From 2019 to 2023, 6 states made changes to the scope of dementia-specific training.

CONCLUSIONS AND IMPLICATIONS: While most states mandate DCW training and over half require annual frequency, duration, and cover 5 topic areas, few states specify sources of training materials or require competency checks. Lack of specificity in training requirements requires AL operators to determine what constitutes adequate training for DCWs to be successful. To better prepare the AL workforce for growing resident complexity, policymakers should consider promoting specific training requirements that ensure both onboarding and continuous education for DCWs, particularly around dementia care and workforce well-being.},
}

@article {pmid42691626,
year = {2026},
author = {Singh, R and Paliwal, T and Joshi, R and Paliwal, V and Dubey, P and Bhardwaj, S and Jain, S and Paliwal, S and Sharma, S},
title = {Targeting the protein tyrosine phosphatase 1B signaling axis in Alzheimer's disease: Emerging therapeutic potential of ivermectin.},
journal = {Biochemical and biophysical research communications},
volume = {835},
number = {},
pages = {154524},
doi = {10.1016/j.bbrc.2026.154524},
pmid = {42691626},
issn = {1090-2104},
abstract = {This study attempts to repurpose ivermectin (IVM) for AD by inhibiting the PTP1B enzyme. IVM is a widely known, commercially approved antiparasitic drug. The PTP1B enzyme dephosphorylates multiple kinase substrates and is responsible for metabolic regulation by the PI3K/AKT downstream signaling cascade. A similar signaling pathway is present in the brain. We assessed binding affinity in BIOVIA Discovery Studio Visualizer version 2021 and inhibitory activity using a commercially available ELISA kit. The streptozotocin (3 mg/kg, intracerebroventricularly)- induced AD mouse model was used to study the biological effects of IVM using NOR and Y-maze behavioral assays. Multiple disease physiologies, such as oxidative stress, mitochondrial complex (I-IV) dysfunction, brain insulin resistance, neuroinflammation, Aβ aggregation, apoptosis, and autophagy signaling cascade, were studied by assessing various biomarkers to generate a proof-of-concept. The docking study demonstrated potential interactions of IVM with the catalytic pocket of PTP1B enzyme, yielding a docking score of -8.0. To validate the docking protocol, the re-docked ligand was superimposed on the crystallographic ligand, resulting in an RMSD of 0.000 Å, therefore confirming the reliability of the computational approach. The calculated IC50 value of IVM by ELISA inhibitory assay was found 4.58 μM. The in vivo study of IVM (10 mg/kg) in the mouse model showed improvement in cognitive deficits on behavioral assays and was comparable to donepezil and DPM1001. The preliminary screening investigations through in vitro enzyme inhibition and molecular-level studies showed promising improvements in multiple physiological parameters that progressed to AD. The IHC showed a reduction in the Aβ plaque load and activated microglia cell count. These preliminary data demonstrate that IVM exhibits considerable PTP1B inhibitory potential and require further exploration in a robust, statistically powered preclinical study, followed by clinical trials, to repurpose it in AD and related conditions.},
}

@article {pmid42691699,
year = {2026},
author = {Reinhardt, AM and Theron, A and Tantoh, ALA and Malan, FP and Panayides, JL and Riley, DL},
title = {Integrated computational and automated flow synthesis platform for the rapid discovery of N-benzylpiperidine acetylcholinesterase inhibitors.},
journal = {European journal of medicinal chemistry},
volume = {319},
number = {},
pages = {119259},
doi = {10.1016/j.ejmech.2026.119259},
pmid = {42691699},
issn = {1768-3254},
abstract = {The principal constraint on early-stage medicinal chemistry in an academic setting is rarely the supply of chemical ideas, but the cycle time required to convert them into tested compounds. Here we benchmark an integrated platform that couples ensemble virtual screening, automated continuous-flow library synthesis with inline scavenging, and biological profiling. The platform was evaluated deliberately on a target-scaffold combination for which the pharmacology is already established: the N-benzylpiperidine carboxamide class, identified in our earlier virtual screening campaign against acetylcholinesterase (AChE)[1] and structurally anchored to the approved therapeutic donepezil (1). This choice makes platform performance, the measured variable. An 84-member virtual library was designed, triaged by ensemble docking, and synthesized on an automated flow platform; 54 members were isolated in ≥95% purity. Single-point screening at 5 μM identified ten compounds with ≥70% AChE inhibition, and dose-response determination against electric eel AChE (eeAChE) gave three sub-200 nM inhibitors: 69 (91 nM), 8 (93 nM) and 12 (117 nM), each exceeding galantamine (237 nM) and approaching donepezil (1, 42 nM) under identical assay conditions. Cytotoxicity against VERO cells was uniformly low (IC50 > 250 μM), giving selectivity indices above 2000. Molecular dynamics simulations and twelve single-crystal X-ray structures provide a structural basis for the observed structure-activity relationships, identifying a C-Br···O halogen bond to Asp72 as the origin of the ortho-bromo preference, and a binding-mode reversal that accounts for the loss of potency on benzylpiperazine extension. The complete cycle was executed in under three months by a three-person team. We report this as a measured platform capability rather than as accelerated drug discovery allowing the rapid generation of first-round leads.},
}

@article {pmid42691714,
year = {2026},
author = {Chen, J and Li, X and He, C and Yao, L and Han, T and Han, Q and Huang, J and Li, C and Song, X},
title = {Photoelectrochemical highly efficient detection of β-amyloid 1-42 based on in-situ grown donor-acceptor covalent organic frameworks combined with dual-aptamer sandwich amplification strategy.},
journal = {Talanta},
volume = {312},
number = {Pt C},
pages = {130537},
doi = {10.1016/j.talanta.2026.130537},
pmid = {42691714},
issn = {1873-3573},
abstract = {A highly sensitive dual-aptamer sandwich-type photoelectrochemical (PEC) sensor was developed for detecting β-amyloid 1-42 (Aβ42), whose abnormal accumulation in the brain has been considered as the molecular driver of Alzheimer's (AD) pathogenesis and progression. The sensor was constructed based on in-situ grown covalent organic frameworks (COFs) films. Using a simple room-temperature in-situ synthesis method, TAPB-TFPA COFs (TAPB: 1,3,5-tris(4-aminophenyl)benzene, TFPA: tris(4-formylphenyl)amine) films were successfully fabricated on indium tin oxide (ITO) electrodes. By exploiting the specific recognition between two aptamers and Aβ42, a sandwich complex was formed on the electrode surface. This architecture induces pronounced steric hindrance that impedes interfacial charge transfer, resulting in substantial attenuation of the photocurrent response and enabling highly specific detection of Aβ42. The PEC sensing platform exhibited a good linear response to Aβ42 in the concentration range of 1 pM to 1 μM, with a detection limit of 0.86 pM. Meanwhile, the sensor possessed excellent selectivity, reproducibility, and stability, and showed satisfactory detection accuracy in real human serum samples. This work provides a novel method for the detection of Aβ42 in the early diagnosis of AD, and also sheds light on the construction of high-performance PEC sensors and the application expansion of COF materials.},
}

@article {pmid42691753,
year = {2026},
author = {Ilaghi-Hoseini, S and Garkani-Nejad, Z},
title = {Comparative QSAR and Q-RASAR modeling of benzimidazole derivatives as dual AChE/BuChE inhibitors and design of novel anti- Alzheimer drug candidates supported by molecular docking, ADMET and molecular dynamic simulation.},
journal = {Journal of molecular graphics & modelling},
volume = {149},
number = {},
pages = {109550},
doi = {10.1016/j.jmgm.2026.109550},
pmid = {42691753},
issn = {1873-4243},
abstract = {Alzheimer's disease is a progressive neurological disorder characterized by memory loss, cognitive decline, and behavioral changes, and is one of the most important causes of dementia. Benzimidazole derivatives, as bioactive compounds, are promising candidates for the design of new anti-Alzheimer drugs due to their diverse biological activities. In this study, a dataset of 193 benzimidazole derivatives, whose IC50 values were experimentally measured and previously reported, was used to investigate anti-Alzheimer activity. All modeling and computational analyses were performed based on these experimental data. First, a comparative study between Quantitative Structure-Activity Relationship (QSAR) and Quantitative Read-Across Structure-Activity Relationship (Q-RASAR) methods was conducted using Multiple Linear Regression (MLR) and Support Vector Regression (SVR). Model performance was evaluated using statistical parameters such as Q[2], RMSE, and R, showing that Q-RASAR models had better predictive accuracy, stability, and interpretability. Molecular docking studies were then performed to investigate ligand-target interactions. Based on the results, a set of new compounds was designed and their biological activities were predicted using the developed models. Selected compounds were further validated through molecular docking and molecular dynamics simulations to assess complex stability. In addition, ADMET analyses were conducted to evaluate pharmacokinetic properties and toxicity. Among the designed compounds, compound 5 showed the best overall profile and was introduced as a lead candidate for further studies. This work provides valuable insights for the rational design of benzimidazole-based anti-Alzheimer agents and supports future research in this field.},
}

@article {pmid42691804,
year = {2026},
author = {Sato, S and Sasabuchi, Y and Yamana, H and Kohro, T and Yasunaga, H},
title = {Treatment Duration of Cholinesterase Inhibitor Formulations in Alzheimer's Disease.},
journal = {Journal of the American Medical Directors Association},
volume = {27},
number = {11},
pages = {106481},
doi = {10.1016/j.jamda.2026.106481},
pmid = {42691804},
issn = {1538-9375},
abstract = {OBJECTIVES: To examine treatment duration of oral and transdermal cholinesterase inhibitor formulations in older adults with severe Alzheimer's disease (AD) in routine clinical practice.

DESIGN: Retrospective population-based cohort study.

SETTING AND PARTICIPANTS: Linked medical and long-term care insurance claims databases from Tochigi Prefecture, Japan, between April 2019 and October 2023. We included patients aged ≥65 years with AD who were certified at care needs level 4 or 5 (indicating complete dependence in activities of daily living) or were institutionalized under the Japanese Long-Term Care Insurance system.

METHODS: Patients were classified according to the initial cholinesterase inhibitor formulation: oral formulations (donepezil or galantamine) or transdermal patches (rivastigmine or donepezil). The primary outcome was duration of treatment with the initial formulation. Continuous treatment was defined using a 30-day grace period. Kaplan-Meier analysis and Cox proportional hazards models were used to compare treatment discontinuation between groups. Hospitalization and mortality were evaluated as exploratory outcomes.

RESULTS: Among 8117 eligible patients, 6467 initiated oral formulations and 1650 initiated transdermal patches. Mean treatment duration was longer in the oral group than in the patch group (1.5 vs 0.6 years; log-rank P < .001). In adjusted Cox regression analysis, the patch group showed a higher risk of discontinuation than the oral group (hazard ratio, 11.3; 95% CI, 10.2-12.4). Hospitalization and mortality rates were lower in the oral group than in the patch group (236 vs 272 and 210 vs 272 per 1000 person-years, respectively).

CONCLUSIONS AND IMPLICATIONS: In older adults with severe AD, oral cholinesterase inhibitor formulations were continued substantially longer than transdermal patches. Given the limited evidence supporting prolonged cholinesterase inhibitor use in severe AD, these findings raise concerns regarding long-term prescribing practices in advanced dementia care.},
}

@article {pmid42692040,
year = {2026},
author = {Maure-Blesa, L and Carmona-Iragui, M and Barroeta, I and Arranz, J and Fernández, S and Rodríguez-Baz, Í and Benejam, B and Videla, L and Arriola-Infante, JE and Del Hoyo Soriano, L and Pertierra, L and Vaqué-Alcázar, L and Sanjuan, A and Bueno, A and Aranha, MR and Lorente, O and Morcillo-Nieto, AO and Ros-Castelló, V and Sierra-Marcos, A and Sánchez-Moreno, B and Lisgaras, CP and Blessing, E and Osorio, RS and Estanga, A and García-Sebastián, M and Ros, N and Stockbauer, AC and Nuebling, G and Remi, JM and McCarron, M and Lima, K and Dunne, P and Sirisi, S and Dols-Icardo, O and Belbin, O and Alcolea, D and Bejanin, A and Lleó, A and Giménez, S and Montes, N and de Asua, DR and McGlinchey, E and Levin, J and Rebillat, AS and Altuna, M and Fortea, J},
title = {Natural history and clinical impact of epilepsy in adults with Down syndrome: a multicentre clinical study.},
journal = {Lancet (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1016/S0140-6736(26)00980-3},
pmid = {42692040},
issn = {1474-547X},
abstract = {BACKGROUND: As individuals with Down syndrome age, they face high risks of Alzheimer's disease and epilepsy. With symptomatic Alzheimer's disease, late-onset myoclonic epilepsy in Down syndrome (LOMEDS) often emerges. We aimed to examine how epilepsy develops in Down syndrome, its timing relative to Alzheimer's disease symptom onset, and its effect on prognosis.

METHODS: We conducted a multicentre, observational, longitudinal study across seven international cohorts with an aggregate observation window from Oct 24, 2012, to July 28, 2025. We included adults with Down syndrome aged at least 18 years and with at least one longitudinal clinical assessment. Alzheimer's disease staging was done by clinical consensus. Active epilepsy required an epilepsy diagnosis plus ongoing antiseizure medication or at least one seizure within the past 5 years. We analysed active epilepsy prevalence, incidence and cumulative incidence, its timing with respect to symptomatic Alzheimer's disease, and its effect on survival and cognitive trajectories as well as electroencephalogram (EEG) abnormalities.

FINDINGS: We included 4804 adults with Down syndrome (mean age 43 years [SD 13]): 3238 (67·4%) were cognitively stable, 267 (5·6%) had non-degenerative cognitive decline, 321 (6·7%) had prodromal Alzheimer's disease, and 978 (20·3%) had Alzheimer's disease dementia. Intellectual disability was mild in 1020 (24·6%) participants, moderate in 2352 (56·7%), and severe to profound in 779 (18·8%). Active epilepsy prevalence was 145·2 per adults with Down syndrome overall but significantly increased with age, particularly with symptomatic Alzheimer's disease, when epilepsy manifested mostly as myoclonic or tonic-clonic seizures. Cumulative incidence of epilepsy increased linearly after symptomatic Alzheimer's disease, from 9·5% (95% CI 7·8-11·3) at diagnosis to 56·9% (51·7-61·7) after 9 years. Risk of epilepsy increased with time since Alzheimer's disease diagnosis (adjusted odds ratio 1·33 per year [95% CI 1·22-1·45]; p<0·0001), severe-to-profound intellectual disability (2·14 per year [1·25-3·70]; p=0·0057), and APOE ε4 carriership (1·61 per year [1·04-2·49]; p=0·034), independent of age. LOMEDS was associated with increased mortality (hazard ratio 2·10 [95% CI 1·57-2·82]; p<0·0001), and faster cognitive decline. Interictal EEG abnormalities showed little diagnostic utility.

INTERPRETATION: Epilepsy increases sharply after symptomatic Alzheimer's disease onset in people with Down syndrome. The association of epilepsy with reduced survival and accelerated cognitive decline underscores the need for targeted preventive and therapeutic strategies against Alzheimer's disease-related epileptogenesis and hyperexcitability.

FUNDING: See Acknowledgments for funders.},
}

@article {pmid42692041,
year = {2026},
author = {Schlachetzki, Z and Rafii, MS},
title = {Late-onset seizures as a sentinel of Alzheimer's disease progression in Down syndrome.},
journal = {Lancet (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1016/S0140-6736(26)00959-1},
pmid = {42692041},
issn = {1474-547X},
}

@article {pmid42692204,
year = {2026},
author = {Camargo, LC and Jonas, A and Gering, I and Schemmert, S and Jacobs, D and Schäfer, M and Willbold, D and Willuweit, A and Kutzsche, J},
title = {Pharmacokinetic properties of the clinical drug candidate PRI-002 with regard to genotype, sex, age, dose-dependence and food effects in mice.},
journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences},
volume = {},
number = {},
pages = {107649},
doi = {10.1016/j.ejps.2026.107649},
pmid = {42692204},
issn = {1879-0720},
abstract = {The d-enantiomeric peptide RD2 (named Contraloid or PRI-002 in clinical trials) was developed for the direct disassembly of toxic amyloid-β (Aβ) oligomers, which are the most neurotoxic aggregate species and play a key role in the development and progression of Alzheimer´s disease (AD). PRI-002/RD2 already demonstrated its safety and tolerability in three phase I clinical trials in young healthy volunteers and patients with mild neurocognitive impairment (MCI) or mild dementia due to AD. Results from a phase II clinical trial with PRI-002/RD2 are expected this year, which was designed to demonstrate safety and efficacy of PRI-002/RD2 in patients at an early stage of AD. The objective of this study was to evaluate the effect of age, sex, genotype and food on the pharmacokinetics of intravenous or orally administered RD2 in male and female transgenic APPswe/PS1ΔE9 (APP PS1) (n=62) or wild type (wt) mice (n=169) under fed and fasted conditions. Age and concomitant food intake influenced the pharmacokinetics of RD2. Slightly higher plasma and brain levels were observed in young compared to old wt mice. However, the effect of food on plasma levels depended on the RD2 dose administered. While at lower doses (200 mg/kg) the effect was substantial, plasma levels were 15 times higher in fasted than in non-fasted animals, the effect was only minor at higher RD2 doses (600 mg/kg). The results of this study indicate the important influence of prior food intake on the bioavailability of the compound, which may also apply to patients and is therefore of interest in further clinical development.},
}

@article {pmid42692292,
year = {2026},
author = {Chen, H and Cui, XN and Deng, MY},
title = {Astrocyte Lipid Metabolism: From Physiological Homeostasis to Reactive Phenotype Plasticity in Neurodegeneration.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106255},
doi = {10.1016/j.neuint.2026.106255},
pmid = {42692292},
issn = {1872-9754},
abstract = {Astrocytes are one of the most abundant types of glial cells in the central nervous system (CNS) and play pivotal roles in metabolic support, synaptic regulation, and neurotransmitter homeostasis. Astrocytic dysfunction is closely associated with the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD), and lipid metabolism constitutes a central axis for maintaining astrocyte function and CNS homeostasis. Here, we provide a systematic review of recent advances in astrocyte lipid metabolism, summarizing the fundamental roles of astrocytes in the CNS and focusing on the biosynthesis, degradation, and trafficking mechanisms of fatty acids, cholesterol, and the tightly linked organelles known as lipid droplets. We further analyze the relationships and potential pathogenic mechanisms linking lipid metabolic disturbances, such as impaired fatty acid β-oxidation, cholesterol accumulation, and dysregulated lipid droplet dynamics, to neurodegeneration. The review also presents current frameworks for classifying reactive astrocytes, including the classical A1/A2 paradigm and more recently identified subtypes, and examines how lipid metabolic processes influence phenotype transitions. Finally, we propose a regulatory axis: lipid metabolism dysregulation leads to cellular phenotype conversion, which in turn drives disease progression, to emphasize the central role of lipid metabolism in astrocyte reactivity and neuropathology. This synthesis fills a gap in the literature at the interface of lipid metabolism and astrocyte functional regulation, and it offers a conceptual framework and candidate targets to guide future investigation into metabolic mechanisms of neurodegeneration and the development of precision therapeutic strategies.},
}

@article {pmid42692374,
year = {2026},
author = {Huang, X and Wang, J and Guo, W and Ye, W and Hu, X and Zhou, X and Xu, B and Cheng, A and Qian, PY},
title = {Spectinabilin mitigates Aβ-associated proteotoxic stress and preserves synaptic protein expression in cellular and Caenorhabditis elegans models.},
journal = {Pharmacological research},
volume = {232},
number = {},
pages = {108421},
doi = {10.1016/j.phrs.2026.108421},
pmid = {42692374},
issn = {1096-1186},
abstract = {Solubleamyloid-β(Aβ) assemblies, glutamate-associated injury, mitochondrial dysfunction, and synaptic failure are closely connected processes in Alzheimer's disease. Here, we investigated the neuroprotective activity of spectinabilin, a natural product isolated from the marine-derived bacterium Streptomyces spectabilis, using biochemical assays, neuronal cell models, and Caenorhabditis elegans (C. elegans) models of Aβ proteotoxicity. Spectinabilin directly associated with both monomeric and oligomer-enriched FITC-Aβ42 under microscale thermophoresis conditions, with apparent dissociation constants of 13.9 and 2.72 µM, respectively, and reduced the accumulation of ThT-positive β-sheet-rich assemblies and elongated fibrils in vitro. In differentiated HT22 cells and primary cortical neurons, spectinabilin attenuated glutamate- and oligomer-enriched Aβ42-associated reductions in cell viability and preserved mitochondrial membrane potential during Aβ42 exposure. In Aβ-expressing C. elegans, spectinabilin reduced ThS-reactive deposits and oxidative-stress-associated fluorescence, delayed paralysis, extended lifespan, and improved chemotaxis. Integrated transcriptomic analysis showed that spectinabilin partially opposed Aβ-model-associated alterations, particularly in synaptic signaling, G protein-coupled receptor-associated signaling, and membrane-potential-related pathways. Spectinabilin also increased synaptic and cAMP-related transcripts and restored Rab3A and VAMP2 expression while normalizing stress-associated CREB phosphorylation. H89 prevented the recovery of CREB regulation and presynaptic proteins, indicating a requirement for PKA-associated signaling. Together, these findings identify spectinabilin as a marine-derived small-molecule scaffold that modifies Aβ42 assembly and preserves mitochondrial and synaptic homeostasis across cellular and C. elegans models.},
}

@article {pmid42692748,
year = {2026},
author = {Hong, J and Silverman, DHS},
title = {FDG-PET in Cognitive Impairment and Dementia.},
journal = {PET clinics},
volume = {21},
number = {4},
pages = {483-497},
doi = {10.1016/j.cpet.2026.07.001},
pmid = {42692748},
issn = {1879-9809},
mesh = {Humans ; *Fluorodeoxyglucose F18 ; *Positron-Emission Tomography/methods ; *Dementia/diagnostic imaging ; *Radiopharmaceuticals ; *Cognitive Dysfunction/diagnostic imaging ; Brain/diagnostic imaging ; },
abstract = {Neuroimaging is crucial in early and accurate assessment of diagnosis, prognosis, and therapy optimization in patients with declining cognitive abilities. Imaging modalities now available for clinical indications related to neurodegenerative processes include Computed Tomography (CT), MR imaging, and PET imaging with 6 positron-emitting radiotracers approved at this time by the US Food and Drug Administration. The central focus of this article is the role of FDG-PET in clinical and research applications of patients with cognitive problems, and how the derived information may be effectively integrated with information acquired from other neuroimaging modalities.},
}

Humans
*Fluorodeoxyglucose F18
*Positron-Emission Tomography/methods
*Dementia/diagnostic imaging
*Radiopharmaceuticals
*Cognitive Dysfunction/diagnostic imaging
Brain/diagnostic imaging

@article {pmid42692750,
year = {2026},
author = {Sanchez, M and Kuret, J},
title = {Lysine methylation is an endogenous post-translational modifications of tau protein in human brain and a modulator of aggregation propensity.},
journal = {Methods in enzymology},
volume = {734},
number = {},
pages = {1-28},
doi = {10.1016/bs.mie.2026.05.044},
pmid = {42692750},
issn = {1557-7988},
mesh = {Humans ; *tau Proteins/metabolism/isolation & purification/chemistry/genetics ; *Protein Processing, Post-Translational ; Methylation ; *Brain/metabolism/pathology ; *Lysine/metabolism ; Protein Aggregates ; Alzheimer Disease/metabolism/pathology ; Protein Aggregation, Pathological/metabolism ; Tauopathies/metabolism/pathology ; Recombinant Proteins/metabolism/isolation & purification/chemistry/genetics ; Proteomics/methods ; Mass Spectrometry/methods ; },
abstract = {Tau protein undergoes a broad range of post-translational modifications in the brain, influencing its structure, solubility, and propensity to aggregate. This chapter presents an integrated methodological framework for characterizing tau methylation and evaluating its impact on tau biology. We describe procedures for isolating soluble and filamentous tau from post-mortem human brain tissue while preserving modifications for proteomic analysis. These approaches support precise mapping of methylation sites alongside other co-occurring modifications. To model methylation under controlled conditions, we outline protocols for recombinant tau expression, purification, and chemical reductive methylation, including radiolabeled assays for determining modification stoichiometry. We then detail biophysical assays used to assess how methylation alters tau conformation and aggregation propensity. This methodological framework supports experimentation seeking insight into mechanisms relevant to Alzheimer's disease and related tauopathies.},
}

Humans
*tau Proteins/metabolism/isolation & purification/chemistry/genetics
*Protein Processing, Post-Translational
Methylation
*Brain/metabolism/pathology
*Lysine/metabolism
Protein Aggregates
Alzheimer Disease/metabolism/pathology
Protein Aggregation, Pathological/metabolism
Tauopathies/metabolism/pathology
Recombinant Proteins/metabolism/isolation & purification/chemistry/genetics
Proteomics/methods
Mass Spectrometry/methods

@article {pmid42692760,
year = {2026},
author = {Qureshi, T and Balmik, AA and Chinnathambi, S},
title = {The extracellular Zinc-finger ubiquitin-binding domain of histone Deacetylase 6 enhances podosome formation in neuronal cells.},
journal = {Methods in enzymology},
volume = {734},
number = {},
pages = {301-326},
doi = {10.1016/bs.mie.2026.05.060},
pmid = {42692760},
issn = {1557-7988},
mesh = {*Histone Deacetylase 6/metabolism/chemistry/genetics ; Animals ; Humans ; *Neurons/metabolism/cytology ; *Podosomes/metabolism ; Zinc Fingers ; Protein Domains ; Ubiquitin/metabolism ; Histone Deacetylases/metabolism ; Protein Binding ; },
abstract = {Neurodegenerative disorders are characterized by progressive synaptic failure, neuronal loss, and the accumulation of pathological protein aggregates. A critical but often overlooked driver of this decline is cytoskeletal dysregulation, which compromises essential cellular functions ranging from intracellular transport to morphological stability. Histone Deacetylase 6 (HDAC6) is a central regulator of these dynamics, yet its role in neurodegeneration remains controversial: while its deacetylase activity is often linked to microtubule instability and toxicity, its ubiquitin-binding functions are essential for aggregate clearance. We have previously demonstrated that the ZnF-UBP domain acts as a direct modulator of cytoskeletal architecture, enhancing the formation of actin-rich migratory structures-such as podosomes and lamellipodia-and promoting neuritic outgrowth. It does this by inducing increased localization of actin remodelling proteins to the podosomes, ultimately conferring enhanced migration potential to cells. This chapter highlights the protocols essential for understanding the therapeutic potential of the HDAC6 Zinc Finger Ubiquitin-Binding Protein (ZnF-UBP) domain, in the context of actin remodelling through podosome structures.},
}

*Histone Deacetylase 6/metabolism/chemistry/genetics
Animals
Humans
*Neurons/metabolism/cytology
*Podosomes/metabolism
Zinc Fingers
Protein Domains
Ubiquitin/metabolism
Histone Deacetylases/metabolism
Protein Binding

@article {pmid42692766,
year = {2026},
author = {Balmik, AA and Sonawane, SK and Gorantla, NV and Chinnathambi, S},
title = {Mechanistic insights on HDAC6 ZnF UBP-Tau interaction through biophysical and computational approaches.},
journal = {Methods in enzymology},
volume = {734},
number = {},
pages = {79-103},
doi = {10.1016/bs.mie.2026.07.009},
pmid = {42692766},
issn = {1557-7988},
mesh = {*Histone Deacetylase 6/metabolism/chemistry ; *tau Proteins/metabolism/chemistry ; Humans ; Protein Binding ; Calorimetry/methods ; Protein Aggregates ; Magnetic Resonance Spectroscopy ; Nuclear Magnetic Resonance, Biomolecular ; },
abstract = {Histone deacetylase 6 is a unique cytoplasmic deacetylase implicated in cellular functions such as microtubule dynamics, protein quality control, ubiquitin-mediated degradation and neurodegenerative disorders. The ZnF UBP (zinc finger ubiquitin binding protein) domain of HDAC6 is known to be directly modulate several cellular processes linked to neurodegeneration such as sequestering polyubiquitinated aggregates and regulating protein aggregate clearance mechanisms in neurons. Microtubule associated protein Tau (MAP Tau) undergoes aggregation in neurodegenerative conditions like Alzheimer's disease (AD) and several other tauopathies. Tau is a natively disordered protein which is functionally regulated by wide array of post-translational modifications (PTMs) as well as by interacting with several proteins. This methodological study aims to understand the molecular interaction between HDAC6 ZnF UBP domain and Tau protein in order to elucidate the role of HDAC6 ZnF UBP domain in Tau aggregation and stability. We employed an integrated biochemical, biophysical and computational workflow to characterize the interaction between HDAC6 ZnF UBP and Tau. NMR spectroscopy, isothermal titration calorimetry and pull-down assay with purified HDAC6 ZnF UBP and Tau proteins demonstrated direct interaction between the two, with interaction associated structural perturbations and favourable binding kinetics as observed in NMR and ITC respectively. Computational analyses further suggest the formation of Tau-HDAC6 ZnF UBP complex and provided underlying molecular interactions involved in the binding of these two proteins. The findings in this study helps to advance the current understanding of regulatory role of HDAC6 specifically in Tau biology and further provides a useful framework for investigating the modulation of aggregation prone proteins via protein-protein interaction in neurodegenerative diseases.},
}

*Histone Deacetylase 6/metabolism/chemistry
*tau Proteins/metabolism/chemistry
Humans
Protein Binding
Calorimetry/methods
Protein Aggregates
Magnetic Resonance Spectroscopy
Nuclear Magnetic Resonance, Biomolecular

@article {pmid42693052,
year = {2026},
author = {Yu, YZ and Zhu, YH and Yang, XK and Wang, SS and Sun, JQ and Qiu, Y and Zhao, W and Yao, LM and Li, WR},
title = {[Danggui Shaoyao San promotes ketone body production and utilization to improve brain energy metabolism and prevent Alzheimer's disease].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {15},
pages = {4377-4386},
doi = {10.19540/j.cnki.cjcmm.20260505.801},
pmid = {42693052},
issn = {1001-5302},
mesh = {Animals ; Male ; *Ketone Bodies/metabolism/biosynthesis ; *Alzheimer Disease/metabolism/prevention & control/genetics/drug therapy ; *Drugs, Chinese Herbal/administration & dosage ; *Energy Metabolism/drug effects ; *Brain/metabolism/drug effects ; Mice ; Mice, Inbred C57BL ; Humans ; },
abstract = {This study focuses on the mechanism by which Danggui Shaoyao San(DSS) regulates hepatic fatty acid metabolism to promote ketone body production, transport, and utilization, thereby alleviating brain energy metabolism disorders in APP/PS1 mice and enhancing their cognitive abilities. Six SPF-grade 3-month-old male C57BL/6J mice served as the control group. Thirty 3-month-old male APP/PS1 mice were randomly allocated into a model group, a low-dose DSS(DSS-L, 3.2 g·kg~(-1)) group, a medium-dose DSS(DSS-M, 6.4 g·kg~(-1)) group, a high-dose DSS(DSS-H, 12.8 g·kg~(-1)) group, and a ketogenic diet(KD) group. The control and model groups received 8 weeks of normal saline gavage, while the DSS-L, DSS-M, and DSS-H groups received corresponding concentrations of DSS via gavage for 8 weeks. The KD group was fed the ketogenic diet for 8 weeks. After 8 weeks of treatment, the Morris water maze test, novel object recognition test, Y-maze test, and open field test were carried out to evaluate the cognitive function, memory processing, spatial memory, and spontaneous activity and exploratory behavior, respectively. A Roche meter was used to measure the fasting blood glucose level. The β-hydroxybutyrate(BHB) and lactate levels in the liver and brain tissue were quantified by the microplate assay. The adenosine triphosphate(ATP) and adenosine diphosphate(ADP) levels were detected by chemiluminescence. ELISA was employed to measure the serum level of insulin and brain tissue levels of mitochondrial complexes Ⅰ-Ⅳ, citrate synthase(CS), isocitrate dehydrogenase(ICD), and α-ketoglutarate dehydrogenase(α-KG). Immunofluorescence assay was employed to detect the expression of monocarboxylate transporter 2(MCT2) in the hippocampus. Western blot was used to determine the expression levels of 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2(HMGCS2) in the liver, as well as 3-oxoglutarate-CoA transferase(OXCT1) and 3-hydroxybutyrate dehydrogenase(BDH1) in the brain. The results showed that compared with the control group, the model group exhibited reduced time and distance in the target quadrant in the Morris water maze, weakened novel object recognition, decreased Y-maze alternation percentage, and reduced distance and average speed in the open field(P<0.01, P<0.001). Furthermore, the model group exhibited raised levels of fasting blood glucose, insulin in the serum, and lactic acid in the brain, declined level of BHB in the liver(P<0.05, P<0.01), reduced levels of mitochondrial respiratory chain complexes Ⅰ-Ⅳ, CS, ICD, α-KG, ADP and ATP in the brain tissue(P<0.01, P<0.001), down-regulated expression of HMGCS2 in the liver, OXCT1 in the cortex and hippocampus, and BDH1 in the hippocampus(P<0.05, P<0.01). Compared with the model group, the DSS groups and the KD group showed increases in time in the target quadrant, levels of BHB in the liver and brain, mitochondrial complexes Ⅰ and Ⅳ, CS, α-KG, and ATP, and expression of BDH1 in the hippocampus and OXCT1 in the cortex, and reduced levels of fasting blood glucose, insulin in the serum, and lactate in the brain(P<0.05, P<0.01). All the DSS groups exhibited increased average speed in the open field test(P<0.05, P<0.01). The distance in the target quadrant, levels of mitochondrial complexes Ⅱ and Ⅲ, ICD, and ADP, and expression of BDH1 in the cortex increased in the DSS-M, DSS-H, and KD groups(P<0.05, P<0.01). The novel object recognition index and HMGCS2 expression in the liver raised in the DSS-L, DSS-H, and KD groups(P<0.05, P<0.01). The total distance traveled in the open field test increased in the DSS-L, DSS-M, and KD groups(P<0.05, P<0.01). The percentage of alternation in the Y-maze test and MCT2 expression level in the DG region increased in the KD group(P<0.05). In addition, the OXCT1 expression level in the hippocampus was up-regulated in the DSS-H and KD groups(P<0.05, P<0.01). DSS can promote the generation of ketone bodies in the liver and the transport and utilization of ketone bodies in the brain tissue, thereby alleviating the brain energy crisis and cognitive impairment of APP/PS1 mice.},
}

Animals
Male
*Ketone Bodies/metabolism/biosynthesis
*Alzheimer Disease/metabolism/prevention & control/genetics/drug therapy
*Drugs, Chinese Herbal/administration & dosage
*Energy Metabolism/drug effects
*Brain/metabolism/drug effects
Mice
Mice, Inbred C57BL
Humans

@article {pmid42693124,
year = {2026},
author = {Martino-Adami, PV and Coutinho de Alvarenga, J and Freccero, P and Huber, H and Fernandez, J and Bolaños Burgos, IC and Postillone, MB and Tomé Oliveira Engelmann, G and Mintz, I and Romano Silva, MA and Medel, N and de Oliveira Hansen, E and Lisso, J and Dias Silva, N and Teixeira Carvalho, A and Irureta, N and de Miranda, DM and Vallejo-Azar, M and Cunha de Marco, LA and Heilmann-Heimbach, S and de Paula, JJ and Kochen, S and Teixeira de Ávila, R and Solis, P and Schneider, A and Gonzalez, P and de Mattos Viana, B and Dalmasso, MC and Camargos Bicalho, MA and Ramírez, A},
title = {Diagnostic performance of plasma pTau217 in genetically admixed South American populations.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42693124},
issn = {2041-1723},
mesh = {Humans ; Brazil ; Biomarkers/blood/cerebrospinal fluid ; *Amyloid beta-Peptides/blood/cerebrospinal fluid ; *Alzheimer Disease/blood/diagnosis/genetics ; Argentina ; Female ; *tau Proteins/blood/cerebrospinal fluid ; Male ; Aged ; *Peptide Fragments/blood/cerebrospinal fluid ; Apolipoprotein E4/genetics ; Aged, 80 and over ; },
abstract = {Plasma pTau217 is a leading biomarker for Alzheimer's disease, but evidence from genetically admixed populations in low- and middle-income countries remains limited. We evaluated the diagnostic performance of pTau217 and pTau217/Aβ42 measured using Simoa technology in memory-clinic cohorts from Brazil (Cog-Aging-Study, n = 353) and Argentina (GeNED.ar, n = 134). Here we show that both biomarkers accurately identified cerebrospinal fluid (CSF)-defined amyloid pathology in Cog-Aging-Study-Brazil and showed high concordance with clinical diagnosis across both cohorts. Classification performance was improved using two-cut-off approaches that account for diagnostic uncertainty. We further show that APOE-ε4, lower body mass index, and reduced kidney function were associated with higher pTau217 in Cog-Aging-Study-Brazil, whereas education also influenced biomarker levels in GeNED.ar-Argentina. African ancestry modified APOE-ε4 effect on CSF but not plasma biomarkers. These findings support the use of plasma pTau217-based biomarkers in genetically admixed South American populations and in settings with limited access to CSF testing and brain imaging.},
}

Humans
Brazil
Biomarkers/blood/cerebrospinal fluid
*Amyloid beta-Peptides/blood/cerebrospinal fluid
*Alzheimer Disease/blood/diagnosis/genetics
Argentina
Female
*tau Proteins/blood/cerebrospinal fluid
Male
Aged
*Peptide Fragments/blood/cerebrospinal fluid
Apolipoprotein E4/genetics
Aged, 80 and over

@article {pmid42693182,
year = {2026},
author = {Ghallab, DS and Okda, TM},
title = {Melatonin seed priming reconfigures the metabolomic profile and functional attributes of brown mustard (Brassica juncea L.) sprouts.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42693182},
issn = {2045-2322},
mesh = {*Mustard Plant/metabolism/drug effects/growth & development ; *Melatonin/pharmacology/metabolism ; *Seeds/metabolism/drug effects ; Metabolomics/methods ; *Metabolome/drug effects ; Glucosinolates/metabolism ; Seedlings/metabolism/drug effects ; Tandem Mass Spectrometry ; Germination/drug effects ; },
abstract = {While mustard seeds offer a prime store of biologically active compounds, there is insufficient data regarding the impact of melatonin (MT) priming on remodelling the chemical patterns, metabolic pathways, and biological attributes of mustard sprouts. Accordingly, the current work is directed to investigate the metabolic shifts in mustard sprouts post MT-priming treatments using UPLC-MS/MS and chemometric analyses. Given this, MT-primed sprouted samples witnessed a significant elevation of phenolic acids, specifically hydroxybenzoic, ferulic, syringic, and chlorogenic acids, with approximately 2.5- to 6-fold increments compared to unprimed controls. In MT-primed mustard sprouts, some aliphatic glucosinolates, such as gluconapin, glucotropaeolin, and sinigrin, revealed a notable elevation with fold increments of 3.5, 2.9, and 2.6, respectively, compared to unprimed counterparts. Further, some flavonoids and stilbenes, primarily isorhamnetin, syringetin-O-glucoside, quercetin, and isorhapontigenin, exhibited a notable enrichment pattern in primed mustard sprouts relative to the others. KEGG pathway analysis revealed phenylpropanoid biosynthesis, flavonoid biosynthesis, glucosinolate biosynthesis, and stilbenoid, diarylheptanoid and gingerol biosynthesis pathways as the key metabolic pathways primarily govern these metabolic fluctuations. Regarding AChE and MAO-B inhibitory screening, MT-primed sprouted samples recorded the most leading observations with IC50 = 7.667 ± 0.306 mg/dl and 45.389 ± 0.953 mg/dl, respectively. OPLS-driven correlation analysis pinpointed syringic, ellagic, and chlorogenic acid, along with quercetin, pterostilbene, sinigrin, gluconapin, and eicosapentaenoic acid, majorly detected in MT-primed samples, as biologically active compounds beyond their AChE and MAO-B inhibitory activities. These findings support melatonin priming as a sustainable, effective technique for creating high-quality, nutritious, and health-promoting agricultural products to rectify chronic diseases.},
}

*Mustard Plant/metabolism/drug effects/growth & development
*Melatonin/pharmacology/metabolism
*Seeds/metabolism/drug effects
Metabolomics/methods
*Metabolome/drug effects
Glucosinolates/metabolism
Seedlings/metabolism/drug effects
Tandem Mass Spectrometry
Germination/drug effects

@article {pmid42693185,
year = {2026},
author = {Dalakas, MC and Lünemann, JD},
title = {Role of complement and complement-targeted therapeutics in neurological diseases.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42693185},
issn = {1759-4766},
abstract = {Complement comprises a group of plasma and membrane proteins that provide an effective bridging function for innate and adaptive humoral immunity. Understanding complement pathophysiology is fundamental given that inappropriate complement function in host defence can lead to infectious diseases and inefficient disposal of altered, damaged or senescent cells can lead to or enhance autoimmune neurological processes. Although the rising number of approved drugs targeting complement pathways remains primarily focused on diseases with complement-fixing pathogenic antibodies (such as myasthenia gravis and neuromyelitis optica spectrum disorder), a robust pipeline of emerging treatments holds promise for expanding complement-targeted therapies to a broader spectrum of autoimmune neurological diseases, such as multiple sclerosis and even neurodegenerative diseases such as Alzheimer disease or amyotrophic lateral sclerosis. This Review presents insights into complement biology as it relates to the development or initiation of autoimmune and possibly degenerative diseases affecting the central and peripheral nervous systems or muscle. The effects, merits, risks and challenges of marketed drugs or biologic agents in ongoing phase I-III clinical trials engineered to inhibit proximal or distal components of the complement cascade are also discussed. Anti-complement therapeutics are destined to change the treatment of autoimmune neurologic conditions in which the therapeutic landscape is now becoming crowded with biologic agents targeting other key autoimmunity factors.},
}

@article {pmid42693199,
year = {2026},
author = {Hu, H and Lin, PB and Zeng, C and Li, Y and Bosch, ME and Emmerson, JT and Sharma, P and Ohara, RA and Dong, W and Wu, T and Du, S and Gao, W and Jiang, H and Yuan, L and Bao, X and Li, S and Vomund, AN and Erdmann-Gilmore, P and Gu, Y and Hu, M and Nulman, J and Miller, TM and Yokoyama, WM and Lichti, CF and Milbrandt, J and Perrin, RJ and Kipnis, J and Artyomov, MN and Murphy, KM and Ulrich, JD and Holtzman, DM},
title = {Priming of CD8[+] T cells by peripheral dendritic cells exacerbates tau-mediated neurodegeneration.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42693199},
issn = {1546-1726},
abstract = {Alzheimer's disease and primary tauopathies are marked by changes in adaptive immunity, with increased brain CD8[+] T cells correlating with tau pathology severity. However, how peripheral T cells get primed to enter the brain and contribute to tau-mediated neurodegeneration remains unclear. In different disease conditions, conventional type 1 dendritic cells (cDC1s) cross-present antigens to prime CD8[+] T cells into effector cells. We show that tauopathy mice lacking cDC1s or antigen cross-presentation are protected from neurodegeneration, with reduced brain CD8[+] T cell infiltration and glial activation. The remaining CD8[+] T cells exhibit limited clonal expansion, consistent with impaired priming. We further demonstrate that brain-derived antigens are presented in secondary lymphoid tissues, suggesting a site of T cell activation. Together, these findings establish cDC1-dependent peripheral priming as a key driver of CD8[+] T cell accumulation in the brain and tau-mediated neurodegeneration.},
}

@article {pmid42693207,
year = {2026},
author = {Barnaghi, P and Fogel, A and Walsh, C and Nilforooshan, R and Ricotti, V and Voit, T},
title = {Applying a systemic approach that extends beyond the brain to Alzheimer's disease pathogenesis.},
journal = {Communications medicine},
volume = {6},
number = {1},
pages = {},
pmid = {42693207},
issn = {2730-664X},
support = {UK DRI-7002//RCUK | Medical Research Council (MRC)/ ; RCSRF2324-18-69//Great Ormond Street Hospital for Children (GOSH)/ ; RCSRF2324-18-69//Royal Academy of Engineering/ ; },
}

@article {pmid42693285,
year = {2026},
author = {Oberhauser, J and Ding, B and Reid, MM and Xie, WH and Yang, AC},
title = {VINE-seq and MultiVINE-seq for single-nucleus and multiome profiling of the brain vasculature.},
journal = {Nature protocols},
volume = {},
number = {},
pages = {},
pmid = {42693285},
issn = {1750-2799},
abstract = {The human cerebrovasculature is a critical yet historically understudied component of neurological health. Dysfunction of the diverse endothelial, mural, and perivascular cells that comprise cerebral vessels is central to diseases ranging from stroke to Alzheimer's disease. However, characterizing these cell populations at a molecular level has proven exceptionally challenging. Encased within a robust basement membrane, vascular cells resist standard dissociation methods, leading to their systematic depletion and underrepresentation in existing single-nucleus genomic atlases. This has created a major blind spot in neuroscience. To overcome this barrier, we developed vessel isolation and nucleus extraction for sequencing (VINE-seq) and its advanced iteration, MultiVINE-seq. The protocol provides a robust, reproducible workflow for the enrichment and high-resolution profiling of vascular, perivascular, and immune cells from fresh or frozen human and mouse brain tissue. First, intact vessels (predominantly capillaries and small arterioles/venules, 100 µm in diameter) are isolated from homogenized brain tissue via dextran-based density-gradient centrifugation, separating the vascular pellet from myelin and the parenchymal fraction. Second, the collected vessels are rigorously washed over a cell strainer to remove trapped contaminants. A critical innovation lies in the third stage: the optimized extraction of nuclei from purified vessels using enzymatic digestion. After extraction, the protocol uses fluorescence-activated cell sorting (FACS) to ensure collection of high-purity nuclei suitable for widely used droplet-based sequencing platforms (e.g., 10x Genomics single cell 3' or multiome). This protocol requires 4-5 h to complete and can be carried out by researchers with single-cell and flow cytometry training.},
}

@article {pmid42693315,
year = {2026},
author = {Tran, TH and Tran, TS and Tran, TD},
title = {Computational discovery and dynamic profiling of dual acetylcholinesterase and monoacylglycerol lipase inhibitors for Alzheimer's disease.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {42693315},
issn = {1573-501X},
abstract = {Alzheimer's disease is a multifactorial neurodegenerative disorder characterized by cholinergic dysfunction and neuroinflammation. Dual inhibition of acetylcholinesterase and monoacylglycerol lipase has emerged as a promising therapeutic approach. This study employed an integrative in silico workflow to identify potential dual acetylcholinesterase/monoacylglycerol lipase inhibitors from a molecular library derived from known inhibitors (rivastigmine, JZL-184, ABX-1431). A total of 365 compounds were screened via molecular docking, interaction-based filtering, ADME/toxicity prediction, and molecular dynamics simulations. Among them, compound H34 demonstrated a comparatively favorable overall computational profile, supported by MM/GBSA binding-energy estimates (ΔGbind = - 30.96 and - 37.34 kcal/mol) and comparatively favorable structural stability metrics (RMSD, RMSF, Rg, and SASA) in the MD simulations. Further ProLIF interaction mapping and free energy landscape analysis supported the persistent interaction profile and conformational behavior of the H34-protein complexes. Additionally, H34 displayed favorable pharmacokinetic properties and low predicted acute toxicity. These results highlight H34 as a promising dual-target candidate for Alzheimer's disease therapy and illustrate the effectiveness of integrated computational strategies in early-stage drug discovery.},
}

@article {pmid42693331,
year = {2026},
author = {Kamalov, F and Ibrahim, A},
title = {From Volumetrics to 3D Tensors: A Multi-Cohort Evaluation of Machine Learning and Deep Learning for Alzheimer's Classification.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10278-026-02240-3},
pmid = {42693331},
issn = {2948-2933},
support = {2024CANAD-KAM-060//Dubai Future Foundation/ ; },
abstract = {Automated Alzheimer's disease (AD) classification from structural MRI typically employs either feature-engineered machine learning (ML) or end-to-end 3D deep learning (DL). Addressing a lack of rigorous statistical comparison and multi-dataset validation in current literature, this study evaluates classical ML algorithms utilizing volumetric and voxel-based morphometry (VBM) features against 3D CNNs processing raw MRI tensors. Using the ADNI and OASIS datasets, models underwent internal 4-fold cross-validation and zero-shot cross-cohort testing to assess predictive performance, domain shift resilience, and clinical sensitivity. Welch's t-tests confirmed that 16 of 19 macro-regional brain aspects differed significantly between AD and cognitively normal subjects (p FDR < 0.05), led by the medial-temporal lobe. While DL architectures achieved marginal numerical superiority in peak accuracy on ADNI (DenseNet121: accuracy 0.92 ± 0.02 , F1 0.85 ± 0.04 , ROC-AUC 0.96 ± 0.02), they exhibited higher variance and lacked statistical significance compared to optimized ML baselines (XGBoost-VOL: F1 0.82 ± 0.03 ; p ≥ 0.28 for all 3D CNNs). On the highly imbalanced OASIS dataset, VBM-enhanced Logistic Regression matched top DL models in overall F1-score (0.68 ± 0.05) while delivering statistically superior AD recall (0.67 ± 0.04 ; p = 0.0026 versus baseline), exceeding every 3D CNN. Although both paradigms generalized robustly across cohorts (only a 2-4% zero-shot F1 reduction; ROC-AUC up to 0.9506), the findings highlight a crucial clinical trade-off: 3D CNNs autonomously extract complex spatial features, but simpler, interpretable ML models provide superior inferential stability and diagnostic sensitivity, making them highly viable for real-world deployment.},
}

@article {pmid42693456,
year = {2026},
author = {Tosi, G and Romano, D},
title = {Estimating and interpreting psychometric networks in neuropsychology: A tutorial with conceptual extensions.},
journal = {Journal of neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jnp.70076},
pmid = {42693456},
issn = {1748-6653},
abstract = {Network psychometrics has emerged as a promising framework for modelling the structure of neuropsychological data, offering a complementary perspective to traditional latent variable approaches or single test approaches. In neuropsychology, test performance is rarely interpreted in isolation, but rather as reflecting interacting cognitive processes. Network models provide a formal framework to represent these interdependencies by estimating conditional associations among observed variables. The present article provides a comprehensive tutorial on the estimation and interpretation of psychometric networks in neuropsychology. First, we offer a step-by-step guide to estimating a cross-sectional Gaussian Graphical Model (GGM), including data preparation, model selection, regularization, visualization and stability assessment, using a neuropsychological dataset from patients with Alzheimer's disease. Particular emphasis is placed on best practices for ensuring reproducibility and robustness, including the use of bootstrap procedures and reporting standards. Second, we outline key methodological extensions, including Exploratory Graph Analysis for dimensionality assessment, joint graphical models and Network Comparison Test for group comparisons, mixed graphical models for heterogeneous data and longitudinal network approaches. These methods are presented conceptually to illustrate how network analysis can be extended beyond basic cross-sectional applications. Finally, we discuss the strengths and limitations of network psychometrics in neuropsychology. We emphasize that network models represent statistical associations among observed test scores rather than direct representations of cognitive architecture and that their interpretation requires theoretical caution. When applied with methodological rigour and conceptual restraint, network analysis provides a flexible and integrative framework for investigating the structure of cognitive systems.},
}

@article {pmid42693483,
year = {2026},
author = {Hatterer, E and Broyer, L and Pecoraro, S and Cusin, F and Simsek, N and Breve, JJ and Clavel, M and Batenburg, KL and Klein, B and Zuidweg, T and Piché, K and Bourguignon, J and Bonnet-Gamard, M and Malinge, P and Gueneau, F and Moine, V and Anceriz, N and Masternak, K and Fischer, N and Gjølberg, TT and Telstad, JS and Calamera, G and Mester, S and Scheper, W and Van de Berg, WDJ and Courade, JP},
title = {A third-generation, high-affinity biparatopic anti-tau antibody inhibits intracellular tau aggregation seeded by Alzheimer's brain extracts.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42693483},
issn = {1758-9193},
support = {N/A//discoveric bio alpha ag/ ; },
mesh = {*tau Proteins/metabolism/immunology ; Humans ; *Alzheimer Disease/metabolism/pathology ; *Brain/metabolism/pathology/drug effects ; Animals ; *Protein Aggregation, Pathological ; },
abstract = {BACKGROUND: Tau immunotherapy has recently shown clinical promise but required high dosing. We developed NIDB-3101, a novel third-generation, high-affinity anti-tau biparatopic antibody designed for superior tau binding, aggregation inhibition, and extended half-life.

METHODS: NIDB-3101 binds tau's microtubule-binding region and C-terminal domains. Various binding and cellular functional assays using recombinants, but more importantly human AD extracts were used to assess NIDB-3101 benefits. Half-life mutations impact was assessed via FcRn binding and cellular assays recycling.

RESULTS: NIDB-3101 exhibited sub-nanomolar affinity, binding a broad spectrum of pathological tau species in AD homogenates, inhibited AD extracts-induced cellular effect compared to benchmark antibodies. Mutations enhanced hFcRn-mediated cellular recycling.

CONCLUSIONS: NIDB-3101 captures a broad spectrum of pathological tau species leading to strong cellular efficacy using human AD extracts, supporting further clinical development as a potential disease-modifying therapy for AD and related tauopathies.},
}

*tau Proteins/metabolism/immunology
Humans
*Alzheimer Disease/metabolism/pathology
*Brain/metabolism/pathology/drug effects
Animals
*Protein Aggregation, Pathological

@article {pmid42693677,
year = {2026},
author = {Qi, L and Wang, W and Abdullah, R and Zhao, Y and Wang, Z and Tang, Y and Luo, B and Peng, G},
title = {Neurobiological mechanisms of 40-Hz stimulation in Alzheimer's disease: evidence, heterogeneity, and constraints.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71806},
doi = {10.1002/alz.71806},
pmid = {42693677},
issn = {1552-5279},
support = {2025C01120//Key R&D Program of Zhejiang/ ; 2025C02104//"Leading Goose + X" Science and Technology Program of Zhejiang Province of China/ ; 2022YFC3602604//Ministry of Science and Technology of the People's Republic of China/ ; },
mesh = {*Alzheimer Disease/therapy/physiopathology ; Humans ; *Gamma Rhythm/physiology ; *Brain/physiopathology ; Animals ; *Deep Brain Stimulation/methods ; },
abstract = {Early disruption of gamma oscillations is increasingly recognized as a contributor to neurodegeneration and cognitive decline in Alzheimer's disease (AD), positioning 40-Hz stimulation as a promising neuromodulatory strategy. However, its neurophysiological and cognitive effects remain highly variable across studies, underscoring the need for a more integrated mechanistic framework. This review synthesizes current evidence on the neurobiological mechanisms engaged by 40-Hz stimulation in AD, including circuit-, cellular-, and system-level processes underlying network dynamics, glial responses, and multi-target biological effects. We further highlight the conceptual distinction between "physiological resonance" and "artificial superimposition" as a potential determinant of deep-brain engagement and therapeutic outcomes. By integrating both supportive and conflicting findings, we highlight disease stage, biological sex, and behavioral state as important contributors to the heterogeneity of 40-Hz stimulation outcomes. Building on these observations, we propose that future research should move toward mechanistic stratification and precision neuromodulation to facilitate clinical translation.},
}

*Alzheimer Disease/therapy/physiopathology
Humans
*Gamma Rhythm/physiology
*Brain/physiopathology
Animals
*Deep Brain Stimulation/methods

@article {pmid42693696,
year = {2026},
author = {Catakli, D and Ozen-Basoglu, O and Tuncgovde, EB and Ozsarlak-Sozer, G},
title = {The Crosstalk Between Diabetes and Alzheimer's Disease: A Molecular Perspective.},
journal = {Basic & clinical pharmacology & toxicology},
volume = {139},
number = {4},
pages = {e70294},
doi = {10.1111/bcpt.70294},
pmid = {42693696},
issn = {1742-7843},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/physiopathology/epidemiology ; *Diabetes Mellitus, Type 2/drug therapy/metabolism/epidemiology/physiopathology/complications ; Animals ; Insulin Resistance ; Signal Transduction/drug effects ; Brain/metabolism/drug effects ; Oxidative Stress ; Amyloid beta-Peptides/metabolism ; Hypoglycemic Agents/pharmacology/therapeutic use ; Insulin/metabolism ; },
abstract = {The global prevalence of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) is increasing significantly in an age-dependent manner. Growing evidence supports the conceptualization of AD as 'type 3 diabetes,' a term proposed to describe a metabolic disease primarily driven by impaired insulin signalling and insulin resistance within the brain. This review explores the shared molecular mechanisms underlying both T2DM and AD, including chronic neuroinflammation, oxidative stress, mitochondrial dysfunction and impaired glucose metabolism. Specifically, the crosstalk involves the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, where insulin resistance leads to increased glycogen synthase kinase 3β (GSK-3β) activity, promoting tau hyperphosphorylation and amyloid-β (Aβ) accumulation. Furthermore, the article examines the roles of the NOD-like receptor protein 3 (NLRP3) inflammasome, O-linked β-N-acetylglucosamine modification (O-GlcNAcylation), and the gut-brain axis as critical mediators linking metabolic dysfunction to neurodegeneration. Unlike previous reviews that predominantly address individual pathways in isolation, this review provides an integrated molecular framework that connects insulin resistance to neurodegeneration through converging signalling cascades and highlights emerging therapeutic targets including the NLRP3 inflammasome and O-GlcNAcylation as potential mechanistic bridges between T2DM and AD. Finally, the therapeutic potential of various antidiabetic agents such as glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and thiazolidinediones is discussed, as these drugs offer promising opportunities for the treatment and prevention of AD by targeting these common molecular pathways.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/physiopathology/epidemiology
*Diabetes Mellitus, Type 2/drug therapy/metabolism/epidemiology/physiopathology/complications
Animals
Insulin Resistance
Signal Transduction/drug effects
Brain/metabolism/drug effects
Oxidative Stress
Amyloid beta-Peptides/metabolism
Hypoglycemic Agents/pharmacology/therapeutic use
Insulin/metabolism

@article {pmid42693831,
year = {2026},
author = {Lin, LY and Wu, JS and Jeng, WJ and Tsai, CH and Liu, SY and Huang, TW and Yuliani, FS and Lin, SH},
title = {Dementia Risk After Glaucoma Surgery and Medical Therapy: A Multicentre Real-World Cohort Study.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {9},
pages = {e70252},
doi = {10.1002/gps.70252},
pmid = {42693831},
issn = {1099-1166},
mesh = {Humans ; Female ; Aged ; *Dementia/epidemiology/etiology ; *Glaucoma/surgery/drug therapy/therapy ; Male ; Middle Aged ; Risk Factors ; Aged, 80 and over ; Vision Disorders/epidemiology ; Alzheimer Disease/epidemiology ; Cohort Studies ; },
abstract = {BACKGROUND AND PURPOSE: Glaucoma, a neurodegenerative optic neuropathy and leading cause of irreversible vision loss, shares vascular and neurodegenerative mechanisms with dementia. The 2024 Lancet Commission newly identified visual impairment as a modifiable dementia risk factor. As glaucoma management ranges from long-term medical therapy to laser/surgical intervention, it remains uncertain whether treatment modality influences long-term systemic outcomes such as dementia. This study compares dementia risk in patients receiving glaucoma surgery versus medical therapy.

METHODS: Glaucoma patients aged ≥ 40 years and diagnosed and managed before July 2021 were identified in the TriNetX database and followed from the first definitive treatment-surgery or initiation of medical therapy-until dementia diagnosis, death, or July 2026. The primary outcome was all-cause dementia; secondary outcomes included Alzheimer's disease, vascular dementia, and visual loss. Subgroup analyses examined surgical timing, modality, age, sex, and comorbidities.

RESULTS: After 1:1 propensity score matching, 51,923 patients were included in each cohort (mean age 64 years; 55.3% female). Glaucoma surgery was associated with reduced risks of all-cause dementia (HR 0.81) and vascular dementia (HR 0.53), a non-significant reduction in Alzheimer's disease (HR 0.87), and a higher risk of visual loss (HR 1.52), consistent with more advanced disease among surgical candidates. Associations were stronger with late surgery, traditional incisional procedures, younger age, and absence of comorbidities.

CONCLUSIONS: Patients who underwent glaucoma surgery were associated with a lower subsequent risk of all-cause dementia and vascular dementia, with a non-significant trend for Alzheimer's disease, compared with those receiving medical therapy. These findings suggest that surgical management is associated with more favourable long-term cognitive outcomes beyond ocular benefits, which may provide additional context for treatment-escalation decisions in suitable patients.},
}

Humans
Female
Aged
*Dementia/epidemiology/etiology
*Glaucoma/surgery/drug therapy/therapy
Male
Middle Aged
Risk Factors
Aged, 80 and over
Vision Disorders/epidemiology
Alzheimer Disease/epidemiology
Cohort Studies

@article {pmid42693839,
year = {2026},
author = {Aykora, D and Uzun, M},
title = {Plant-Derived Exosomes in Neurodegenerative Disorders and Age-Related Brain Dysfunction: From Isolation to Clinical Potential.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X456941260803062544},
pmid = {42693839},
issn = {1875-6190},
abstract = {INTRODUCTION: Plant-derived Exosome-like Nanovesicles (PELNs) have the potential to exhibit improved biological functions in multiple pathological disorders, particularly in neurodegenerative and age-related brain diseases. In this review, advanced isolation techniques, including Differential Ultracentrifugation (dUC), Size-Exclusion Chromatography (SEC), and Polyethylene Glycol (PEG) precipitation, were systematically evaluated to optimize the structural integrity, purity, and biological activity of PELNs.

METHODS: Novel studies on PELNs were the primary focus of this review. Evidence-based studies were compared and discussed in terms of chemical and functional characteristics, as well as optimized production strategies to enhance the therapeutic properties of PELNs.

RESULTS: According to the consensus of reviewed studies, PELNs demonstrate efficient cellular uptake due to their lipophilic chemical structures and modulate intracellular signaling pathways related to neurodegeneration. The main drawbacks of PELNs' utilization mostly depend on the extraction methods and limited delivery through the BBB. A combination of optimized methods, such as dUC and SEC, may exhibit maintained therapeutic strategies for neurological applications.

DISCUSSION: Due to the limited number of experimental studies in Parkinson's Disease (PD) and Alzheimer's Disease (AD), and brain aging, advances in PELNs extraction methods have been shown to enhance BBB delivery and therapeutic efficacy. Every study claims the superiority of its own method; however, none of these methods fully addresses the limitations inherent in producing optimal results.

CONCLUSION: PELNs represent a promising platform for neurological dysfunction and brain aging-related disorders. However, isolation and characterization methods must be carefully optimized and validated to ensure the production of therapeutically active PELNs suitable for BBB delivery.},
}

@article {pmid42693862,
year = {2026},
author = {Ardakani, RH and Dashtaki, M and Mohamadi-Zarch, SM and Bagheri, SM},
title = {Cortisol Dysregulation as a Major Factor in the Development of Neurodegenerative Diseases, Drug Targets and Therapeutic Prospects: A Comprehensive Review.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273466502260813092749},
pmid = {42693862},
issn = {1996-3181},
abstract = {Cortisol, regulated by the hypothalamic-pituitary-adrenal (HPA) axis, is critical for stress response, metabolism, and immune function. Its dysregulation is increasingly implicated in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). This review synthesizes evidence on cortisol's role in neurodegenerative disorders, exploring its mechanisms, clinical implications, and therapeutic potential. This study analyzed preclinical models, clinical studies, and biomarker data to elucidate cortisol's impact on neurodegeneration. Key mechanisms include glucocorticoid and mineralocorticoid receptor-mediated effects on synaptic plasticity, neuroinflammation, and oxidative stress. In AD, elevated cortisol accelerates cognitive decline, hippocampal atrophy, and amyloid-β accumulation. In PD, higher cortisol levels correlate with gait dysfunction and dopaminergic neuron loss. HD shows variable cortisol profiles, with early hypocortisolism shifting to hypercortisolism in later stages, linked to depression. In ALS, elevated cortisol hastens disease progression and neuroinflammation. In MS, HPA axis hyperactivity is associated with cognitive deficits and lesion activity, though it may support remyelination. Chronic stress exacerbates these effects across disorders, promoting neuronal vulnerability. Cortisol dysregulation is a significant contributor to neurodegenerative pathology, acting as both a biomarker and therapeutic target. Emerging interventions, including glucocorticoid receptor antagonists, cortisol synthesis inhibitors, and stress reduction strategies, show promise in mitigating neuronal damage. Personalized, stage-specific therapies and longitudinal studies are needed to optimize cortisol-targeted treatments for neurodegenerative diseases.},
}

@article {pmid42693863,
year = {2026},
author = {Chauhan, SB and Bhardwaj, A and Jain, C and Singh, I},
title = {Nano-Magnetism for Precision Neuroscience: Biohybrid Magnetoelectric Nanocarriers as Next-Generation Neural Drug Delivery Platforms.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273397455251030094458},
pmid = {42693863},
issn = {1996-3181},
abstract = {Neuroscience is making tremendous progress toward precision medicine, with nanotechnology playing a critical role in overcoming hurdles to successful brain medication delivery. Nano magnetism, namely biohybrid magnetoelectric nanocarriers (MENs), has emerged as a potential method for targeted and non-invasive medication delivery in neurological illnesses. These nanocarriers possess magnetoelectric properties, enabling stimulus-responsive drug release that is externally controlled. This allows for precise targeting across the blood-brain barrier (BBB), with exceptional spatial and temporal resolution. MENs can deliver neurotherapeutics deep into brain regions by combining magnetic guidance with electrical stimulation, thereby improving treatment outcomes for conditions such as Alzheimer's, Parkinson's, epilepsy, and glioblastoma. Furthermore, their biohybrid nature, which is accomplished by functionalizing nanocarriers with biocompatible coatings, peptides, or membranes produced from neural cells, increases biostability, decreases immune response, and improves neuron targeting. This review investigates the underlying concepts of magnetoelectric nanocarriers, production processes, and interactions with brain tissue. It dives deeper into recent advances in precision neural drug delivery, including the effect of external magnetic and electric fields on regulated drug release, neurostimulation, and neuromodulation. While MENs have tremendous promise, long-term biocompatibility, precise control systems, and regulatory restrictions continue to impede clinical translation. Future research should concentrate on enhancing nanocarrier design, increasing targeting efficiency, and undertaking large-scale preclinical and clinical trials. Magnetoelectric nanocarriers have the potential to transform non-invasive neurotherapeutics by bridging the gap between nano magnetism and neuroscience, resulting in safer and more successful treatment paradigms for complex brain illnesses.},
}

@article {pmid42693903,
year = {2026},
author = {Li, J and Liu, Q and Ma, Q and Shen, T and Xia, J and Yang, X and Liu, K and Li, N and Yan, B},
title = {Multilevel genomic, transcriptomic, and epidemiologic evidence linking diabetic retinopathy to Alzheimer disease.},
journal = {Journal of global health},
volume = {16},
number = {},
pages = {04311},
doi = {10.7189/jogh.16.04311},
pmid = {42693903},
issn = {2047-2986},
mesh = {Humans ; *Alzheimer Disease/epidemiology/genetics ; *Diabetic Retinopathy/genetics/epidemiology ; Mendelian Randomization Analysis ; Transcriptome ; Genetic Predisposition to Disease ; Genomics ; Multiomics ; Bayes Theorem ; },
abstract = {BACKGROUND: Diabetic retinopathy (DR) and Alzheimer disease (AD) share metabolic and vascular dysfunctions, but the extent to which they reflect overlapping genetic susceptibility and neurovascular-metabolic regulatory pathways remains unclear. We combined multi-omics analyses with population-based data to examine the genetic convergence, cellular pathways, and longitudinal association between DR and AD.

METHODS: We performed a two-sample Mendelian randomisation (MR) to estimate the association between genetically predicted DR liability and AD risk. We used Bayesian colocalisation analysis to identify shared genomic loci, and summary-data-based MR (SMR) to detect expression-mediated genes jointly associated with DR and AD. We analysed single-cell RNA sequencing data to characterise shared cellular features and related biological pathways. We also conducted an MR-based mediation analysis to explore whether lipid-related, metabolic, or inflammatory traits mediated the observed DR-AD association, and a longitudinal analysis of the UK Biobank cohort to assess the association between DR and incident AD.

RESULTS: With the MR analysis, we found that genetically predicted liability to DR was associated with a modest increase in AD risk. Colocalisation analysis supported a shared genetic signal. We identified three genes with shared expression-mediated associations across DR and AD through SMR. Functional enrichment analyses revealed partially overlapping neurovascular and metabolic pathways. Using MR-based mediation analysis, we found no significant intermediary traits linking DR and AD. Findings from the UK Biobank cohort were directionally consistent with the genetic analyses.

CONCLUSIONS: Genetic liability to DR is associated with an increased risk of AD and is accompanied by shared expression-mediated effects and convergent neurovascular-metabolic pathways. These findings support the possibility that DR may serve as a clinically accessible indicator of increased neurodegenerative vulnerability.},
}

Humans
*Alzheimer Disease/epidemiology/genetics
*Diabetic Retinopathy/genetics/epidemiology
Mendelian Randomization Analysis
Transcriptome
Genetic Predisposition to Disease
Genomics
Multiomics
Bayes Theorem

@article {pmid42694080,
year = {2026},
author = {Atri, TE and Denkinger, MN and Liu, J and Singh, A and Surdyn, M and Brown, VA and Martinez, G and Teran, M and Soza, V and Kuramoto, A and Marques, TM and Langbaum, JB and Atri, A and Ashton, NJ},
title = {Performance of upper-arm capillary blood collection for Alzheimer's disease and central nervous system biomarkers: comparison of Tasso+ and venous plasma.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.13.26360406},
pmid = {42694080},
abstract = {INTRODUCTION: Novel capillary-blood collection methods have not yet been evaluated for a wide range of central nervous system (CNS) and neurodegenerative disease-related proteins. Biomarkers of Alzheimer's disease (AD) and related disorders (ADRD) collected from devices like the Tasso+, a minimally invasive upper-arm capillary blood collection device, must be compared to traditional venipuncture to assess for validity.

METHODS: Participants underwent blood collection via traditional venipuncture and Tasso+ in a clinical research setting. The Nucleic Acid Linked Immuno-Sandwich Assay (NULISA) CNS panel was used for biomarker quantification in venous and Tasso-derived plasma.

RESULTS: Eighty-three participants (age mean±SD 76.8±8.2 years, 79.5% cognitively unimpaired) completed blood collection. Little to no correlation was found between venous and Tasso+ plasma for p-tau217, but the correlation was improved by using a brain-derived (BD)-p-tau217/BD-p-tau181 ratio. Extremely strong correlations were found for neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). Among the 131 biomarkers measured, 51 (38.9%) had a Pearson R ≥ 0.90; 27 (20.6%) had values between 0.70-0.90; 26 (19.9%) had values between 0.30-0.70; and 27 (20.6%) had values ≤0.30.

DISCUSSION: The Tasso+ accurately measures NfL and GFAP, but caution is warranted when measuring other AD/ADRD biomarkers, as agreement with venous plasma appears to be protein or ratio dependent. These results highlight that important biomarker-specific differences must be considered when translating capillary blood collection approaches. They also further support foundations for development of these methods, highlighting both the opportunities and remaining challenges for translating the promise of blood-based biomarkers beyond AD/ADRD specialty clinics and research settings.},
}

@article {pmid42694129,
year = {2026},
author = {Wear, D and Hussaini, SA and Yu, WH},
title = {Sleep and stress as modifiable drivers of Alzheimer's disease.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {84},
pmid = {42694129},
issn = {3005-1940},
abstract = {Proper sleep and stress maintenance are essential for health and may contribute to disease progression when dysregulated. This review highlights the intricate links between sleep, stress, and Alzheimer's disease, including underlying neural circuitry and mechanisms that contribute to disease. Sleep is essential for protein clearance pathways including autophagy and the glymphatic system, which are impaired in neurodegenerative diseases. Similarly, chronic stress incites neuroinflammatory responses known to be elevated in brains of patients with neurodegeneration. As a result, it is perhaps unsurprising that tau pathology and neurodegeneration affect sleep and stress circuitry in the brain, including the Locus Coeruleus and Lateral Hypothalamus, beginning in prodromal phases of Alzheimer's disease. Though the precise mechanisms underscoring these vulnerabilities are incompletely understood, this provides a unique therapeutic opportunity for targeting these pathways in early Alzheimer's disease patients with concomitant sleep impairments and/or chronic stress. In this review, we offer insights into these relationships including specific brain region involvements, the contribution of molecular mechanisms of disease, and these translational opportunities which may arise.},
}

@article {pmid42694243,
year = {2026},
author = {Akinyemi, T and Pola, I and Tan, K and Olalusi, O and Yaria, J and Ogunde, G and Traichel, W and Rahmouni, N and Oguntiloye, O and Fagbemi, A and Cadmus, E and Popoola, F and Therriault, J and Ogunronbi, M and Olujobi, D and Famuyiwa, O and Akinyemi, J and Pascoal, T and Owolabi, M and Rosa-Neto, P and Udeh-Momoh, CT and Ladokun, O and Romero-Ortuno, R and Ogunniyi, A and Lawlor, B and Kalaria, R and Zetterberg, H and Benedet, AL and Akinyemi, R},
title = {Blood-based biomarkers of Alzheimer's disease and neurodegeneration in an indigenous African cohort using both Simoa and NULISA platforms.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {80},
pmid = {42694243},
issn = {3005-1940},
abstract = {In low- and middle-income countries, Alzheimer's disease (AD) constitutes a growing public health burden. However, AD biomarkers research remains underrepresented in African populations. This study assesses core biomarkers of AD and their relevance in the African context as potential aid in clinical diagnosis. Nigerian older adults from VALIANT cohort (n = 967) underwent biomarker quantification in plasma (p-tau217, GFAP, NfL, Aβ42 and Aβ40) employing both the Single Molecule Assay (Simoa, Quanterix) and Nucleic acid-Linked Immuno-Sandwich Assay (NULISA, Alamar). Biomarkers were associated with disease severity in clinical-diagnostic and clinical-biological groups, with stepwise increases of p-tau217, NfL and GFAP from cognitively unimpaired to dementia (p < 0.05). Results were consistent across platforms. Comparison between sexes showed higher biomarker levels in male participants across diagnostic groups. A significant effect of apoE-E4 proteotype on p-tau217 levels, after adjusting for age and sex was identified. These findings support the application of plasma AD biomarkers in the African context and the relevance of further AD biomarker research in diverse populations.},
}

@article {pmid42694256,
year = {2026},
author = {Shukla, S and Kolmetzky, D and Goyani, S and Samantaray, K and Sinha, A and Kramer, PA and Tomar, D and Jadiya, P},
title = {Matrix and intermembrane space-specific mitochondrial stress response in Alzheimer's disease.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {83},
pmid = {42694256},
issn = {3005-1940},
abstract = {Alzheimer's disease (AD) lacks effective therapies, partly due to an incomplete understanding of mitochondrial dysfunction, a key driver of neurodegeneration. Mitochondria activate the unfolded protein response (UPR[mt]) to maintain proteostasis, but the roles of matrix- and intermembrane space (IMS)-associated stress responses in AD remain unclear. Here, we used human microglial-like cells expressing mutant amyloid precursor protein together with compartment-targeted mitochondrial proteotoxic stressors to investigate matrix (UPR[mt-MM]) and IMS (UPR[mt-IMS]) stress responses. RNA-seq revealed activation of mitochondrial stress pathways and suppression of synaptic and lipid signaling in AD-like cells. UPR[mt-MM] promoted robust immune activation, severe oxidative phosphorylation defects, increased mitochondrial reactive oxygen species, and cell death. In contrast, UPR[mt-IMS] preferentially induced interferon signaling and suppressed antioxidant pathways. Notably, suppression of ATF5-dependent UPR[mt] signaling rescued mitochondrial dysfunction and reduced Aβ release. Together, these findings demonstrate that matrix- and IMS-targeted mitochondrial stress elicit distinct microglial responses and identify mitochondrial proteostasis as a potential therapeutic target in AD.},
}

@article {pmid42694370,
year = {2026},
author = {Song, J and Yuan, Y and Wang, M and Li, J and Ding, R and Jia, Y and Wang, Z and Xie, Z and Li, Z and Zhang, Z},
title = {Liuwei Dihuang pills attenuates cognitive dysfunction in APP/PS1 mice through restoring mitochondrial homeostasis and activating the IRS/AKT/GSK3β insulin signaling pathway.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1873606},
pmid = {42694370},
issn = {1663-9812},
abstract = {INTRODUCTION: Alzheimer's disease (AD) features progressive cognitive decline, Aβ aggregation, neurofibrillary tangles, mitochondrial dysfunction and central insulin resistance, lacking effective disease-modifying treatments. Liuwei Dihuang Pills (LWDHP) exert neuroprotective effects, while its dual regulatory mechanisms targeting mitochondrial homeostasis and cerebral IRS/AKT/GSK3β insulin signaling remain unclear.

METHODS: APP/PS1 transgenic mice were used as AD models. Morris water maze assessed spatial cognition; immunofluorescence detected Aβ and MAP2; transmission electron microscopy observed neuronal/synaptic ultrastructure; western blot quantified synaptic proteins and insulin signaling cascade molecules.

RESULTS: LWDHP significantly rescued spatial learning and memory deficits, reduced cerebral Aβ plaques and tau hyperphosphorylation. LWDHP balanced mitochondrial fusion-fission via upregulating PGC-1α/MFN2 and downregulating FIS1, elevated synaptic structural proteins (MAP2, PSD-95, SYN), restored cerebral insulin sensitivity by elevating InsR, normalizing IRS-1/AKT/GSK3β phosphorylation, and suppressing tau hyperphosphorylation.

DISCUSSION: LWDHP alleviates AD cognitive impairment through dual regulation of mitochondrial homeostasis and IRS/AKT/GSK3β insulin signaling, providing solid preclinical evidence for its anti-AD application.},
}

@article {pmid42694457,
year = {2026},
author = {Ake, C and Cervantes, E and Garcia, C and Hammons, H and Obawole, L and Morton, I and Pham, L and Salas, B and Stacks, S and Villarreal, L and York, F and Biglari, S and Yeragi, E and Lillvis, E and Moulton, M and Keene, A},
title = {The effects of obesogenic diet on a Drosophila model of frontotemporal dementia.},
journal = {microPublication biology},
volume = {2026},
number = {},
pages = {},
pmid = {42694457},
issn = {2578-9430},
abstract = {Tau aggregation is a hallmark of neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia. Here, we tested how an obesogenic diet affects a Drosophila tauopathy model across multiple behavioral assays. In group-housed flies, mutant tau shortened lifespan, and this effect was worsened by a high-sugar diet. We also examined sleep, motor behavior, and sensory responsiveness. Tau-expressing flies differed from controls in all assays, but these deficits were not further exacerbated by diet. These findings reveal assay-specific diet effects and highlight the value of using multiple behavioral measures to characterize tau mutant phenotypes.},
}

@article {pmid42694464,
year = {2026},
author = {Xu, L and Zhang, Y and Jiang, L and Xing, JF and Hu, J and Lan, T and Ta, G},
title = {Microglia-mediated neuroinflammation in Alzheimer's disease: mechanisms and emerging therapeutic targets.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1902577},
pmid = {42694464},
issn = {1662-5102},
abstract = {Alzheimer's disease is a complex neurodegenerative disorder characterized pathologically by amyloid-β deposition and pathological tau aggregation. Amyloid-β deposition typically occurs during the preclinical stage; however, amyloid burden does not exhibit a simple linear relationship with neurodegeneration or cognitive decline. In contrast, the spatial distribution of tau pathology is more closely associated with clinical progression. As the resident innate immune cells of the central nervous system, microglia participate in the recognition, uptake, and containment of amyloid-β and tau. Nevertheless, persistent exposure to damage-associated signals can lead to lysosomal dysfunction, dysregulated lipid metabolism, and mitochondrial impairment in microglia, thereby amplifying neuroinflammation, aberrant synaptic elimination, and neuronal injury. The traditional binary M1/M2 classification is inadequate to capture the continuous, overlapping, and context-dependent functional states of microglia, which vary across brain regions, genetic backgrounds, and disease stages. This review integrates recent evidence from genetic, single-cell/single-nucleus, and spatial transcriptomic studies and proposes a "cellular state-pathological network-therapeutic window" framework. We systematically discuss the roles of microglia in amyloid-β plaque seeding and compaction, NLRP3 inflammasome activation, mitochondrial DNA-cGAS-STING signaling, complement-mediated synaptic engulfment, and bidirectional microglia-tau feedback. On this basis, we critically evaluate the mechanistic rationale, stage dependence, and translational limitations of therapeutic axes involving TREM2/CD33, P2X7-NLRP3 and cGAS-STING, CSF1R/complement, and TNF-TNFR1-RIPK1. Current evidence suggests that the key to microglia-targeted therapy is not the broad activation or suppression of immune responses, but rather the biomarker-guided and disease-stage-specific modulation of pathogenic signaling while preserving homeostatic functions such as plaque containment, debris clearance, synaptic maintenance, and tissue repair.},
}

@article {pmid42694478,
year = {2026},
author = {Cui, Q and Zheng, K and Liu, Q and Wang, L and Liu, Y and Bai, R and Zhang, W and Guo, J and Chang, X and Wang, J},
title = {From metabolism to neurodegeneration: how microglial functional reprogramming drives neurodegenerative diseases.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1921079},
pmid = {42694478},
issn = {1662-5099},
abstract = {Microglia are brain-resident myeloid cells that maintain central nervous system homeostasis and respond dynamically to neuronal injury, protein aggregation, and alterations in the local metabolic environment. Single-cell and single-nucleus studies demonstrate that microglial responses in neurodegenerative diseases are highly heterogeneous and cannot be adequately explained by the classical M1/M2 polarization model. Increasing evidence further indicates that metabolic remodeling is not merely a consequence of activation but a determinant of microglial migration, phagocytosis, inflammatory signaling, redox balance, organelle function, and interactions with surrounding neural cells. In this review, we propose a microglial immunometabolic trajectory framework in which metabolic states are viewed as branching and potentially reversible determinants of cellular function rather than fixed stages of a universal disease pathway. We summarize how glucose metabolism, mitochondrial function, lipid metabolism, amino acid metabolism, lysosomal activity, and redox regulation shape microglial plasticity. We further examine relationships among transcriptionally defined states, including disease-associated microglia, microglia associated with neurodegeneration, lipid-droplet-accumulating microglia, and other disease-enriched populations, while emphasizing that transcriptional similarity does not necessarily imply metabolic function or lineage progression. Comparative evidence from Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis indicates that common metabolic regulators, including HIF-1α, mTOR, PKM2, TREM2, APOE, and NLRP3, exert disease-specific effects with unequal mechanistic support. We further distinguish associative metabolic signatures from intervention-based causal evidence and discuss limitations of animal models, immortalized cell lines, postmortem tissue, and induced pluripotent stem cell-derived microglia. Finally, we highlight the need for cell-specific, state-resolved, and temporally precise metabolic interventions that restore defined microglial functions without compromising physiological immune surveillance.},
}

@article {pmid42694488,
year = {2026},
author = {Wang, M and Qian, Y and Huang, E and Chu, C and Gao, T and Chen, S and Zhao, N and Luo, C and Liu, Y and Zheng, X and Hu, H and Han, B and Chen, M and Mao, W and Li, W},
title = {Identification of interleukin-11 as a comorbid risk factor for prostate cancer and Alzheimer's disease using integrated bioinformatics and machine learning.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1911726},
pmid = {42694488},
issn = {1664-3224},
mesh = {Male ; *Interleukin-11/genetics/metabolism ; Humans ; *Alzheimer Disease/epidemiology/genetics/immunology/metabolism ; *Prostatic Neoplasms/epidemiology/genetics/metabolism/immunology ; *Machine Learning ; Animals ; Mice ; Risk Factors ; Computational Biology/methods ; Comorbidity ; Gene Expression Profiling ; Cell Line, Tumor ; Transcriptome ; Gene Expression Regulation, Neoplastic ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Prostate cancer (PCa) and Alzheimer's disease (AD) are age-related disorders with a complex epidemiological association and limited therapeutic options. Identifying shared molecular drivers may reveal new treatment targets.

OBJECTIVE: To identify common transcriptomic signatures between PCa and AD and validate the role of interleukin-11 (IL11) as a functional comorbidity factor.

METHODS: Multi-cohort transcriptomic datasets (GSE48350, GSE5281 and GSE28146 for AD; TCGA-PRAD, DKFZ2018 and MSKCC for PCa) were analyzed. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed, followed by a two-tier machine learning pipeline (Random Forest and LASSO Cox regression) to screen overlapping genes. Immune infiltration was evaluated by CIBERSORT and single-cell transcriptomics for PCa. The functional role of IL11 was assessed in RM-1 murine and DU145 human PCa cells using colony formation, wound healing, Transwell assays, and immunocompetent C57BL/6 orthotopic and subcutaneous xenograft models. The cognitive effects of IL11 were evaluated using Morris water maze (MWM) tests, and the neuropathological changes were assessed by detecting hippocampal amyloid-β (Aβ) deposition. Additionally, a cross-sectional analysis was performed in a population cohort (n=215) to investigate the associations between IL11 levels and AD pathological biomarkers.

RESULTS: A total of 455 shared candidate genes were identified, and a 10-gene signature (NDRG4, ISG15, IL11, ENO2, DYNC1I1, DNASE1, ATP6V1G2, ATCAY, ANLN, AGAP9) was established. The risk score effectively stratified PCa patients with poor progression-free interval (log-rank P < 0.001; AUC for 1-,3-,5-year = 0.78,0.73,0.70), validated in two external cohorts (DKFZ2018, MSKCC). IL11 was the top candidate and was significantly upregulated in both diseases. High IL11 expression correlated with an immunosuppressive microenvironment, characterized by increased M2 macrophages and regulatory T cells, and with higher tumor mutation burden. Single-cell analysis localized IL11 to a subset of cancer-associated fibroblasts. In vitro, IL11 treatment enhanced PCa cell proliferation, migration, and invasion. In vivo, intraperitoneal IL11 accelerated PCa tumor growth in mice. In the MWM test, IL11-treated mice exhibited significantly longer escape latencies and fewer platform crossings, which were accompanied by increased hippocampal Aβ deposition, suggesting that IL11 induced cognitive dysfunction. Cross-sectional cohort analyses further linked higher serum IL11 to reduced CSF Aβ42 and elevated p-tau181.

CONCLUSION: IL11 acts as a shared risk factor related to PCa progression and cognitive decline in AD, representing a convergent molecular pathway and a potential therapeutic target for both age-related diseases.},
}

Male
*Interleukin-11/genetics/metabolism
Humans
*Alzheimer Disease/epidemiology/genetics/immunology/metabolism
*Prostatic Neoplasms/epidemiology/genetics/metabolism/immunology
*Machine Learning
Animals
Mice
Risk Factors
Computational Biology/methods
Comorbidity
Gene Expression Profiling
Cell Line, Tumor
Transcriptome
Gene Expression Regulation, Neoplastic
Mice, Inbred C57BL

@article {pmid42694538,
year = {2026},
author = {Gavilan, J and Panes-Fernández, J and Araya, A and Pérez-Manríquez, C and Becerra, J and Varas, P and Moraga-Cid, G and Yévenes, GE and Fuentealba, J},
title = {Correction: Unraveling the neuroprotective mechanisms of elephant black garlic extract against beta amyloid peptide-induced neurotoxicity.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1960775},
doi = {10.3389/fnut.2026.1960775},
pmid = {42694538},
issn = {2296-861X},
abstract = {[This corrects the article DOI: 10.3389/fnut.2025.1725284.].},
}

@article {pmid42694561,
year = {2026},
author = {Shi, L and Zhou, C and Han, H and Lu, M and Li, M and Miao, J and Feng, S and Zhou, X and Chen, H and Ren, L},
title = {The APOE4-estrogen-microglia axis in perimenopausal cognitive changes: mechanisms and therapeutic implications.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1925850},
pmid = {42694561},
issn = {1664-3224},
mesh = {Humans ; *Microglia/metabolism/immunology ; *Estrogens/metabolism/deficiency ; Animals ; *Apolipoprotein E4/metabolism/genetics ; Female ; *Perimenopause/metabolism ; Alzheimer Disease/metabolism ; *Cognition ; },
abstract = {Alzheimer's disease (AD) exhibits marked sex differences, with women bearing a disproportionate burden of disease, particularly after midlife. Among the major factors contributing to this vulnerability, the apolipoprotein E ϵ4 allele (APOE4) and the abrupt endocrine transition of perimenopause have emerged as two critical and potentially synergistic drivers of neurodegeneration. Microglia, the resident immune cells of the central nervous system, lie at the center of this interaction because they integrate genetic, hormonal, metabolic, and inflammatory signals that shape amyloid clearance, synaptic remodeling, and neuroimmune homeostasis. Accumulating evidence indicates that APOE4 impairs microglial phagocytosis, disrupts lipid handling and lysosomal function, promotes pro-inflammatory activation, and compromises neurovascular integrity. In parallel, estrogen normally restrains microglial inflammatory signaling and supports phagocytic, metabolic, and reparative functions through estrogen receptor-dependent pathways. During perimenopause, fluctuating estrogen deficiency removes these protective constraints, thereby increasing the susceptibility of microglia to APOE4-driven dysfunction. This review synthesizes current evidence supporting an integrated pathogenic framework centered on the "APOE4-estrogen deficiency-microglia axis." We discuss how this axis promotes chronic neuroinflammation, synaptotoxicity, amyloid and tau pathology, mitochondrial dysfunction, blood-brain barrier disruption, and large-scale network disconnection, ultimately accelerating cognitive decline in women. We also summarize relevant experimental models, including APOE-targeted murine paradigms, ovariectomy and accelerated ovarian failure models, human induced pluripotent stem cell-derived microglia, and emerging single-cell and spatial omics approaches. Finally, we highlight translational opportunities, including precision hormone-based interventions, selective estrogen receptor modulation, TREM2-centered microglial therapies, APOE4-directed molecular and genetic strategies, and biomarker-guided multi-target interventions during the perimenopausal "window of opportunity." By integrating molecular mechanisms with translational perspectives, this review proposes a precision medicine framework for preventing or delaying neurodegenerative progression in high-risk perimenopausal women.},
}

Humans
*Microglia/metabolism/immunology
*Estrogens/metabolism/deficiency
Animals
*Apolipoprotein E4/metabolism/genetics
Female
*Perimenopause/metabolism
Alzheimer Disease/metabolism
*Cognition

@article {pmid42694564,
year = {2026},
author = {Lu, P and Liu, M and Zhang, L and Fan, JJ and Sun, Y},
title = {Synergistic Regulation of Alzheimer's Disease and Intestinal Microbiota Metabolism Mediated by the Gut-Brain Axis: A Comprehensive Analysis from a Multidisciplinary Perspective.},
journal = {International journal of medical sciences},
volume = {23},
number = {9},
pages = {2939-2962},
pmid = {42694564},
issn = {1449-1907},
mesh = {Humans ; *Alzheimer Disease/microbiology/metabolism/immunology/therapy ; *Gastrointestinal Microbiome/immunology/physiology ; *Brain/metabolism/immunology ; Animals ; Multiomics ; *Brain-Gut Axis/immunology/physiology ; *Dysbiosis/microbiology/immunology ; },
abstract = {Alzheimer's disease (AD), as a neurodegenerative disease with the interaction of multiple factors, has a close association between its pathological process and the metabolic imbalance of the gut microbiota mediated by the gut-brain axis. This review systematically summarizes the molecular mechanisms by which the gut microbiota regulates the functions of the central nervous system bidirectionally through molecular pathways such as metabolites (e.g., short-chain fatty acids, tryptophan-kynurenine metabolites), immunomodulatory mediators (e.g., cytokines, chemokines), and bioactive substances (e.g., γ-aminobutyric acid, 5-hydroxytryptophan) via the gut-brain axis. It synthesizes current evidence suggesting the imbalance of microbiota homeostasis may be closely associated with the core pathologies of AD (including β-amyloid deposition and tau protein hyperphosphorylation) through mechanisms such as the activation of the C/EBPβ-AEP signaling pathway, induction of chronic neuroinflammation, oxidative stress cascade reactions, and metabolic network remodeling. These findings, primarily derived from preclinical models and correlational human studies, indicate potential mechanisms but require further causal validation and rigorous clinical translation, including the downregulation of butyrate synthesis pathways and their associated epigenetic and immunomodulatory consequences (as mechanistically dissected in Section 5.2). Multi-omics integration (metagenomics, metabolomics, spatial transcriptomics) has delineated characteristic microbial and metabolic alterations in AD, while computational approaches are beginning to elucidate the complex networks underlying these associations (see Sections 6 and 7 for details).Intervention strategies based on microbiota regulation (such as microbiota-targeted dietary interventions and postbiotics) are emerging as promising approaches, although their clinical applications remain in early stages. Preliminary evidence suggests that fecal microbiota transplantation may improve cognitive outcomes in AD patients with comorbid conditions; however, rigorous randomized controlled trials are essential to validate its efficacy and safety. Critically, translating these mechanistic insights into clinical practice requires overcoming three translational bottlenecks: inferring causality from correlational multi-omics data, resolving species/strain-level functional heterogeneity masked by genus-level taxonomy, and establishing standardized safety protocols for live biotherapeutic products. Addressing these challenges defines the near-term roadmap for precision medicine in AD. However, current research still faces challenges such as the heterogeneity of cross-omics data, the lack of technical standardization, and insufficient interdisciplinary cooperation mechanisms. In the future, it is necessary to promote the early molecular diagnosis and personalized targeted treatment of AD through longitudinal multi-omics dynamic monitoring, modeling of the microbiota-host interaction network, and optimization of the ethical-translational medicine framework.},
}

Humans
*Alzheimer Disease/microbiology/metabolism/immunology/therapy
*Gastrointestinal Microbiome/immunology/physiology
*Brain/metabolism/immunology
Animals
Multiomics
*Brain-Gut Axis/immunology/physiology
*Dysbiosis/microbiology/immunology

@article {pmid42694579,
year = {2026},
author = {Morgans, W and Sharrocks, AD and Iqbal, M},
title = {Scalable joint non-negative matrix factorization for paired single cell gene expression and chromatin accessibility data.},
journal = {NAR genomics and bioinformatics},
volume = {8},
number = {3},
pages = {lqag104},
pmid = {42694579},
issn = {2631-9268},
mesh = {*Chromatin/metabolism/genetics ; Single-Cell Gene Expression Analysis ; Humans ; Algorithms ; *Single-Cell Analysis/methods ; *Computational Biology/methods ; Software ; Animals ; Gene Expression Profiling/methods ; },
abstract = {Single-cell multi-modal technologies provide powerful means to simultaneously profile cellular states. These are now being employed to study gene regulatory mechanisms in a variety of biological systems. Tailored computational methods for integration and analysis of these data are much needed, with desirable properties in terms of efficiency-to cope with high dimensionality of the data, interpretability-for downstream biological discovery and hypothesis generation, and flexibility-to easily incorporate future modalities. Existing methods cover some but not all of the desirable properties for effective integration and analysis of these data. Here, we present a highly efficient method, q-intNMF, for representation and integration of single-cell multi-modal data using joint non-negative matrix factorization, which can facilitate discovery of linked regulatory topics in each modality. We provide thorough benchmarking using large publicly available datasets against five popular existing methods. q-intNMF performs comparably against the current state-of-the-art methods across a range of metrics. Additionally, q-intNMF provides advantages in terms of computational efficiency and interpretability of discovered regulatory topics in the original feature space. We illustrate this enhanced interpretability in providing insights into cell state changes associated with Alzheimer's disease. q-intNMF is available as a Python package with extensive documentation and use cases at https://github.com/wmorgans/quick_intNMF.},
}

*Chromatin/metabolism/genetics
Single-Cell Gene Expression Analysis
Humans
Algorithms
*Single-Cell Analysis/methods
*Computational Biology/methods
Software
Animals
Gene Expression Profiling/methods

@article {pmid42694581,
year = {2026},
author = {Peng, Y and Jin, C and Sun, Y and Mu, W and Zheng, X},
title = {Roles of IL-34 in neurological diseases: neuroprotection, inflammatory regulation, and myeloid plasticity.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1898176},
pmid = {42694581},
issn = {1664-3224},
mesh = {Humans ; Animals ; *Interleukins/metabolism/immunology ; *Neuroprotection ; *Nervous System Diseases/metabolism/immunology ; *Myeloid Cells/immunology/metabolism ; Inflammation/metabolism ; Cell Plasticity ; },
abstract = {Interleukin-34 (IL-34) is a brain-enriched cytokine and a tissue-restricted ligand of colony-stimulating factor-1 receptor (CSF-1R) that plays an important role in microglial development, survival, and functional specialization. A growing body of evidence indicates that IL-34 is dysregulated in both central and peripheral nervous system diseases and exerts pleiotropic effects not only through CSF-1R but also through non-canonical receptors, including TREM2, syndecan-1, and PTP-ζ. Under physiological conditions, IL-34 is constitutively produced predominantly by neurons across both the central and peripheral nervous systems. However, in pathological settings, its cellular sources expand dynamically: in CNS diseases, IL-34 is primarily derived from stressed neurons and reactive astrocytes, whereas in PNS disorders, it is robustly upregulated by injured sensory neurons, satellite glial cells, and reactive Schwann cells. IL-34 contributes to the regulation of resident glia in the CNS, while evidence from peripheral immune disorders suggests that it may also influence infiltrating myeloid-cell adaptation under pathological conditions. In this review, we highlight the multiple effects of IL-34 and its receptor network on CNS-resident, peripheral glial, and peripheral immune cells, with particular attention to the available data supporting its dual role in neuroprotection and inflammatory amplification. We synthesize recent findings regarding IL-34's role in myeloid reprogramming, particularly in orchestrating transcriptional and functional phenotypic shifts. While current literature provides evidence linking IL-34 to these transcriptional changes, its contribution to metabolic and epigenetic remodeling remains an emerging field. Furthermore, our findings summarized in this manuscript may help evaluate whether targeting IL-34-related pathways can be exploited for therapeutic intervention in neurodevelopmental, neurodegenerative, cerebrovascular, and peripheral nerve pathologies.},
}

Humans
Animals
*Interleukins/metabolism/immunology
*Neuroprotection
*Nervous System Diseases/metabolism/immunology
*Myeloid Cells/immunology/metabolism
Inflammation/metabolism
Cell Plasticity

@article {pmid42694654,
year = {2026},
author = {Wu, Y and Duan, L and Zhang, L and Wang, S and Yan, H and He, M and Wang, T and Li, L and Gao, Y},
title = {TREM2 as a central hub of neuroimmune-metabolic crosstalk in central nervous system disorders: from microglial biology to therapeutic targeting.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1912989},
pmid = {42694654},
issn = {1664-3224},
mesh = {Humans ; *Microglia/metabolism/immunology ; *Receptors, Immunologic/metabolism/genetics/immunology ; *Membrane Glycoproteins/metabolism/genetics/immunology ; Animals ; *Central Nervous System Diseases/metabolism/immunology/therapy ; Signal Transduction ; *Neuroimmunomodulation ; },
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-enriched immunoreceptor that functions as a central regulator of microglial adaptation by integrating immune surveillance, lipid sensing, metabolic reprogramming, and phagocytic responses in the central nervous system (CNS). Through association with the adaptor protein DAP12, TREM2 activates interconnected signaling networks involving the SYK pathway, PLCγ2-mediated Ca[2+] signaling, PI3K-AKT-mTOR signaling, NF-κB activation and inflammatory regulatory pathways, thereby shaping microglial survival, migration, clearance capacity, and interactions with surrounding neural and immune cells. Increasing evidence from genetic studies, single-cell transcriptomics, spatial analyses, and human-derived microglial models indicates that TREM2 dysfunction contributes to diverse CNS disorders; however, its biological consequences are highly dependent on disease stage, pathological substrate, cellular context, and microenvironmental cues. In Alzheimer's disease, TREM2 regulates amyloid-β-associated microglial responses, lipid metabolism, and synaptic remodeling, while its effects on tau-driven neurodegeneration remain controversial. In Parkinson's disease, stroke, epilepsy, and amyotrophic lateral sclerosis, TREM2 influences α-Syn clearance, inflammatory resolution, tissue repair, and microglial state transitions, but may exert beneficial or maladaptive effects depending on temporal dynamics and disease-specific stressors. Emerging clinical evidence, including TREM2 variants, soluble TREM2 (sTREM2) biomarkers, and human multi-omics studies, highlights both the translational potential and complexity of targeting this pathway. Herein, this review summarizes the molecular mechanisms, physiological functions, and disease-specific roles of TREM2 in CNS disorders, critically discusses unresolved controversies and species-specific challenges, and evaluates emerging therapeutic strategies toward biomarker-guided and stage-specific modulation of TREM2 signaling. Understanding how to restore appropriate microglial adaptability rather than simply enhance or suppress TREM2 activity may provide a foundation for precision therapies in CNS disorders.},
}

Humans
*Microglia/metabolism/immunology
*Receptors, Immunologic/metabolism/genetics/immunology
*Membrane Glycoproteins/metabolism/genetics/immunology
Animals
*Central Nervous System Diseases/metabolism/immunology/therapy
Signal Transduction
*Neuroimmunomodulation

@article {pmid42694660,
year = {2026},
author = {Hur, JY},
title = {Herpes simplex virus infection and Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1858017},
pmid = {42694660},
issn = {1663-4365},
abstract = {Over 95% of Alzheimer's disease (AD) is caused by a complex mixture of genetic and environmental factors. This is called sporadic AD or late-onset AD, and much of its pathological mechanisms remain unclear. There is growing evidence indicating that the viral infection, such as herpes simplex virus type 1 (HSV-1), triggers and worsens the AD progression in combination with the APOE4 genotype in AD patients. The innate immunity of host cells produces proinflammatory cytokines, which further drive neuroinflammation in the brain. Concurrently, Aβ and phosphorylated tau could entrap foreign pathogens such as HSV-1 according to the "antimicrobial protection hypothesis of AD," and accelerate the progression of AD. In this review, growing evidence ranging from HSV-1 infection to the AD progression via the accumulation of Aβ and tau, and neuroinflammation is explored.},
}

@article {pmid42694676,
year = {2026},
author = {Chintalapally, S and Rajanala, K and Upadhyay, A},
title = {Retinoic acid-related orphan receptor alpha (RORα) as a candidate multi-pathway target in Alzheimer's disease: mechanisms and therapeutic prospects.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1912268},
pmid = {42694676},
issn = {1662-4548},
abstract = {The development of Alzheimer disease (AD) involves a cluster of pathogenic processes, including amyloid-beta (Aβ) deposition, tau-mediated neurodegeneration, chronic neuroinflammation, oxidative stress (OS), metabolic dysregulation, and disruption of circadian rhythms. Nuclear hormone receptor, Retinoic Acid-Related Orphan Receptor Alpha (RORα) was shown to regulate multiple neuroprotective pathways such as inflammatory signaling (NF-κB suppression), mitochondrial integrity and mitophagy, redox homeostasis [upregulation of glutathione peroxidase 1 (GPX1), and mitochondrial superoxide dismutase 2, (SOD2)], calcium-dependent synaptic architecture [inositol 1,4,5-trisphosphate receptor type 1 (ITPR1), Purkinje cell protein 4 (PCP4)], and circadian rhythm stability [period 2 (PER2), brain and muscle ARNT-like 1 (BMAL1)]. Multi-omics network analyses place RORα within regulatory networks that are co-associated with key AD-related genes and supports an associational, network-based relationship for RORA. Preclinical gene-augmentation studies using adeno-associated viral vectors report that RORα overexpression reduces APP levels, remodels the complement regulator CD59 glycoprotein (CD59), inhibits OS, and enhances neuronal survival, although these effects were established largely in retinal and other non-AD systems. These findings support the potential of RORA as a therapeutic target through genetic intervention, but direct demonstration of AD-modifying efficacy in-vivo is still lacking. Investigational RORA-focused gene therapy in retinal degenerative diseases provides proof-of-concept for, but does not yet establish, applicability within the central nervous system. Taken together, this evidence nominates RORA as a candidate system-level regulator that may help restore disrupted homeostatic transcriptional networks in AD, a hypothesis that remains to be tested. We propose that RORα functions as a transcriptional hub coupling three homeostatic axes that fail in AD; the circadian, mitochondrial-metabolic, and immune-inflammatory axes, and that its regional expression changes in AD (hippocampal up-regulation vs. suprachiasmatic down-regulation) represent a compensatory response that ultimately fails. Cell-type-specific expression profiling is required to determine in which regions augmentation may be therapeutically appropriate. Restoring RORα is therefore could be network-stabilizing rather than single-pathway intervention.},
}

@article {pmid42695218,
year = {2026},
author = {Nakajima, S and Watanabe, K and Sultanakhmetov, G and Fukuchi, A and Ito, K and Shimizu, S and Saito, T and Asada, A and Ando, K},
title = {MARK4 enhances stress granule formation under oxidative stress and increases tau accumulation.},
journal = {FEBS open bio},
volume = {},
number = {},
pages = {},
doi = {10.1002/2211-5463.70338},
pmid = {42695218},
issn = {2211-5463},
support = {//Takeda Foundation/ ; 24K02860//Japan Society for the Promotion of Science/ ; JP24wm0625509//Japan Agency for Medical Research and Development/ ; JP25wm0625509//Japan Agency for Medical Research and Development/ ; //Tokyo Metropolitan University/ ; },
abstract = {Overactivation of Microtubule affinity regulating kinase 4 (MARK4) is believed to contribute to Alzheimer's disease pathogenesis. MARK4 promotes the accumulation of the microtubule-binding protein tau, thereby enhancing tau-induced neurodegeneration. However, the underlying mechanisms by which MARK4 enhances tau accumulation are not fully understood. T-cell intracellular antigen 1 (TIA1), a critical regulator of stress granule (SG) formation, has been suggested to initiate tau abnormality. Here, we report that MARK4 and TIA1 synergistically induce stress granule (SG) formation. MARK4 is localized in SGs with TIA1 in mammalian cultured cells and primary neurons. MARK4 suppresses TIA1 dimerization and enhances SG formation under oxidative stress. Co-expression of MARK4 and TIA1 promotes tau accumulation, and knockdown of a fly ortholog of TIA1 suppressed tau toxicity in a Drosophila model. These results identify MARK4 as a novel regulator of SG formation and suggest a mechanistic link between oxidative stress and tau pathology.},
}

@article {pmid42695307,
year = {2026},
author = {Mohammadi, L and Baluchnejadmojarad, T and Roghani, M},
title = {Recent Updates on the Neuroprotective Effects of Nobiletin in Neurological Disorders: From Molecular Targets to Clinical Prospects.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673467257260821042739},
pmid = {42695307},
issn = {1875-533X},
abstract = {BACKGROUND: Neurological disorders are a significant and increasing public health concern due to their multifactorial pathogenesis, progressive clinical course, and limited long-term effectiveness of current therapeutic strategies. Recent experimental and clinical studies have increasingly focused on bioactive natural compounds as potential modulators of neuroinflammation, oxidative stress and neuronal apoptosis - processes that play a central role in neurodegeneration. Of these, nobiletin (a polymethoxylated flavonoid found in citrus peels) has attracted particular attention thanks to its reported antioxidant, anti-inflammatory and neuroprotective properties in preclinical models.

OBJECTIVE: We discuss the potential therapeutic role of nobiletin in neurological diseases, examining the relevant molecular mechanisms, preclinical findings, and emerging clinical data.

METHODS: We searched the electronic databases PubMed, Scopus, and Embase to identify studies examining the therapeutic effects of nobiletin on neurological disorders published up to October 2025.

RESULTS: This review discusses the neuroprotective actions of nobiletin, with particular attention to its anti-inflammatory, anti-apoptotic, and antioxidant activities and their involvement in major intracellular signaling pathways. In addition, available preclinical findings and emerging clinical data are examined to assess the therapeutic relevance of nobiletin in experimental and clinical models of neurological disorders.

DISCUSSION: Experimental evidence suggests that nobiletin has neuroprotective properties that could reduce pathological processes associated with neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. However, further well-designed studies are needed to clarify its mechanisms of action and determine whether these effects are beneficial in clinical practice, either as a standalone therapy or in combination with existing treatments.

CONCLUSION: Overall, the available evidence indicates that nobiletin may have beneficial effects on a wide range of neurological conditions, such as Parkinson's disease, Alzheimer's disease, stroke, epilepsy, depression, schizophrenia, multiple sclerosis, glioma, and sciatic nerve injury.},
}

@article {pmid42695325,
year = {2026},
author = {Tiwari, N and Kumar, V and Joshi, BC and Saeedan, AS and Rashid, S and Ansari, MN},
title = {A Systematic Review of the Vascular and Neuronal Role of L-Carnosine: Mechanistic and Pharmacological Perspectives.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X462604260803095102},
pmid = {42695325},
issn = {1875-6190},
abstract = {INTRODUCTION: L-carnosine is a powerful natural antioxidant found in the brain, muscles, and digestive systems of all vertebrates, including humans, that helps fight Reactive Oxygen Species (ROS) and other harmful byproducts of oxidative stress. L-carnosine has antioxidant properties as well as the ability to bind with metal ions and prevent glycation, a process that can damage cells. This review article highlights the protective effects of L-carnosine against a variety of pathological conditions, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), ischemia‒reperfusion injury, Huntington's disease, stroke, depression, traumatic brain injury, cancer, diabetes, ageing, etc. Among these conditions, mitochondrial dysfunction and increased oxidative stress are common. Moreover, methylglyoxal (MG), another metabolic product, and Advanced Glycation End products (AGEs) damage cells through interactions with proteins. Through receptor-mediated endocytosis, macrophages absorb them and release proinflammatory chemicals that induce severe inflammation and lead to cell death.

METHODS: Search engines, including PubMed, ScienceDirect, ProQuest, Scopus, ResearchGate, MDPI, journals, websites, and databases such as Google Scholar, were thoroughly searched and reviewed. The search strategy for articles published between 2000 and 2025 used various combinations of key Medical Subject Headings (MeSH) terms and phrases, including L-carnosine, alanine, histidine, Randomized Controlled Trial (RCT), aging, cancer, cardiovascular disease, diabetes, and neurodegenerative disorders, and various non-MeSH terms.

RESULTS: L-carnosine exhibits protective effects on models of neurological, ischemic, metabolic, and malignant diseases because of its antioxidant, anti-inflammatory, and neuroprotective properties. In Alzheimer's disease, carnosine specifically increases the production of heat shock proteins (Hsps). In Parkinson's disease, it increases dopamine levels and stops alpha-synuclein protein accumulation. In ischemia‒reperfusion injury, L-carnosine inhibits the release of inflammatory mediators such as cytokines and TNF-alpha. In cancer, it inhibits the Mitogen-Activated Protein Kinase (MAPK)/ Extracellular Signal-Related Kinase (ERK) signaling pathway. It mitigates aging-related damage to proteins. Additionally, L-carnosine inhibits the formation of MG and AGEs, suggesting its potential therapeutic efficacy in a range of diseases.

DISCUSSION: L-carnosine shows multitarget therapeutic potential through antioxidant, anti-inflammatory, and antiglycation actions, as well as mitochondrial protection. It influences key pathways involved in neurodegeneration, including protein aggregation and oxidative stress. Evidence from preclinical and early clinical studies suggests benefits in neurological and metabolic disorders. Despite promising outcomes, challenges such as rapid degradation and limited bioavailability affect clinical translation. Further studies are needed to define the optimal dosing and therapeutic use.

CONCLUSION: L-carnosine acts as a cytoprotective molecule in multiple ways, including mitigating oxidative stress, protein glycation, mitochondrial dysfunction, and inflammation, thereby modulating pathways characteristic of chronic illnesses. By altering these interconnected pathways, L-carnosine has the potential for several therapeutic applications as an adjuvant for a range of neurological, metabolic, ischemic, cancer, and aging-related illnesses.},
}

@article {pmid42683795,
year = {2026},
author = {Moon, Y and Jeon, HJ and Kim, HJ and Noh, MY and Kim, SH and Han, SH and Kim, H and Moon, WJ},
title = {Education Moderates the Biomarker-Cortical-Thickness Relationship in Females With Cognitive Decline: A Descriptive Study With Sex Comparisons.},
journal = {Journal of clinical neurology (Seoul, Korea)},
volume = {22},
number = {5},
pages = {552-559},
doi = {10.3988/jcn.2025.0686},
pmid = {42683795},
issn = {1738-6586},
support = {/KU/Konkuk University/Korea ; },
abstract = {BACKGROUND AND PURPOSE: Education is a well-established proxy for cognitive reserve and hence may influence the relationship between Alzheimer's disease pathology and brain structure. This is particularly relevant in South Korea, where historical sex disparities in educational level among current elderly populations create unique cohort characteristics. This study examined how educational level moderates the biomarker-cortical-thickness relationship in females with cognitive decline, with descriptive sex comparisons used to contextualize these findings within a cohort reflecting disparities in the history of educational opportunities in South Korea.

METHODS: In 80 patients (58 females, 22 males) with cognitive decline, we assessed plasma amyloid-β 42 (Aβ42), phosphorylated tau 181 (p-tau), and total tau levels, p-tau/Aβ42 ratio, regional cortical thickness, and scores on the Mini-Mental State Examination. Given the substantial confounding between sex and educational level in this cohort, moderated mediation analyses examining the biomarker-cortical-thickness-cognition pathway were restricted to females (n=53 with complete data).

RESULTS: Females had a higher p-tau/Aβ42 ratio (p=0.026) and thicker frontal cortex (p=0.049) despite the absence of a significant difference in age-adjusted cognition. No significant sex× educational level interaction was observed for the biomarkers or cognition. In females, educational level moderated the relationship between the p-tau/Aβ42 ratio and cortical thickness (p<0.05 in all five brain regions), with high-educational level females showing the expected cortical thinning with pathology, while low-educational level females exhibited preserved thickness, which did not mediate the cognitive performance.

CONCLUSIONS: Descriptive sex comparisons revealed a higher biomarker burden yet greater cortical thickness in females. Importantly, educational level significantly moderated the biomarker-cortical thickness relationship specifically in females, with lower-educated individuals showing structural preservation despite the presence of pathology. These findings suggest that measurements of the cortical thickness can underestimate the disease burden in lower-educated females, which highlights the need for educational level-stratified interpretations of structural biomarkers.},
}

@article {pmid42683796,
year = {2026},
author = {Yoon, B and Lee, HJ and Hong, YJ and Park, KH and Kim, S and Wang, MJ and Choi, SH and Kang, S and Jeong, JH and Yang, DW},
title = {Comparative Prognostic Performance of Hippocampal Volume and Plasma Biomarkers in Amyloid-Negative Subjective Cognitive Decline: A Four-Year Follow-up.},
journal = {Journal of clinical neurology (Seoul, Korea)},
volume = {22},
number = {5},
pages = {560-572},
doi = {10.3988/jcn.2025.0659},
pmid = {42683796},
issn = {1738-6586},
support = {P0018061/KIAT/Korea Institute for Advancement of Technology/Korea ; HI18C0530/MOHW/Ministry of Health and Welfare/Korea ; },
abstract = {BACKGROUND AND PURPOSE: Subjective cognitive decline (SCD) may precede mild cognitive impairment (MCI) and dementia. However, the prognosis of patients with amyloid-negative (A-) SCD remains unclear. We investigated whether baseline plasma and imaging biomarkers predict four-year clinical progression in A-SCD.

METHODS: Sixty-five individuals with A-SCD were followed for four years. Baseline plasma biomarkers-phosphorylated tau 181 (pTau181), glial fibrillary acidic protein, neurofilament light chain (NfL), and pTau181/Aβ42 ratio-and MRI markers (hippocampal volume and white matter hyperintensity [WMH] grade) were assessed. Outcomes included MCI conversion and cognitive progression defined as ≥1-point (Prog-1) or ≥2-point (Prog-2) decline in Korean Mini-Mental State Examination. Predictive performance was evaluated using multivariable logistic regression and bootstrap-validated receiver operating characteristic analyses.

RESULTS: Fourteen participants (21.5%) converted to MCI, and 24 (36.9%) were classified as Prog-1. Plasma biomarkers did not show consistent predictive performance across predefined endpoints (all p>0.05), although NfL demonstrated modest discrimination for MCI conversion (area under the curve [AUC] 0.686, p=0.008). Hippocampal volume demonstrated significant discriminative performance for MCI conversion (AUC 0.765, p=0.016) and Prog-1 (AUC 0.933, p<0.001). For Prog-2, hippocampal volume showed high discrimination (AUC 0.952, p<0.001). WMH grade also demonstrated significant discrimination for MCI conversion (AUC 0.835, p<0.001) and Prog-1 (AUC 0.857, p<0.001). Bootstrap analyses (1,000 iterations) tended to show higher AUC estimates for imaging markers compared with plasma biomarkers.

CONCLUSIONS: In this A-SCD cohort, hippocampal atrophy demonstrated more consistent prognostic performance than Alzheimer's disease-focused plasma biomarkers for predicting four-year conversion to MCI and cognitive decline, suggesting a potential role for MRI-based neurodegeneration markers in clinical risk stratification.},
}

@article {pmid42683825,
year = {2026},
author = {El-Shiekh, RA and Mandour, AA and Abdel-Sattar, E and Ali, NB},
title = {Phytochemical profiling of Olea europaea subsp. cuspidata aerial parts using LC-DAD-QToF: cholinesterase inhibition and molecular docking insights into potential Alzheimer's disease targets.},
journal = {Natural product research},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/14786419.2026.2727544},
pmid = {42683825},
issn = {1478-6427},
abstract = {Olea europaea subsp. cuspidata is traditionally used in African medicine, but its phytochemical composition and cholinesterase inhibitory activity have not been comprehensively investigated. This study evaluated the cholinesterase inhibitory activity and phytochemical profile of the methanolic extract of O. europaea aerial parts, integrating in vitro assays with LC-DAD-QToF-MS characterisation and molecular modelling. We used the Ellman assay to measure cholinesterase inhibition and LC-DAD-QToF-MS for metabolite profiling, while molecular docking and dynamics simulations helped us understand how specific metabolites interact with human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The extract inhibited AChE (IC50 = 15.99 ± 1.62 μg/mL) to a greater extent than BChE (IC50 = 22.62 ± 2.20 μg/mL). LC-DAD-QToF-MS allowed the tentative identification of 65 metabolites, comprising iridoids, phenylethanoids, flavonoids, phenolic acids, terpenoids, fatty acids, and one alkaloid. Computational predictions support potential interactions only between constituents within the enzyme active sites but do not establish biological activity. These results offer the first detailed phytochemical profile of the aerial parts of O. europaea and confirm its in vitro cholinesterase inhibitory activity. Bioactivity-guided isolation and in vivo studies are required to pinpoint the metabolites responsible for the observed effects and to establish their therapeutic relevance.},
}

@article {pmid42683892,
year = {2026},
author = {Han, P and Dong, P and Zhou, Y and Zhang, L and Mahomed, O},
title = {Stage-Dependent Cognitive Effects of a Multinutrient Intervention in Alzheimer's Disease: A Stage-Stratified Meta-Analysis.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {235},
pages = {},
doi = {10.3791/72385},
pmid = {42683892},
issn = {1940-087X},
mesh = {*Alzheimer Disease/therapy/psychology ; Humans ; Randomized Controlled Trials as Topic ; Cognition ; },
abstract = {A specific multinutrient intervention provides precursors and cofactors for synaptic membrane synthesis. Randomized trials across the Alzheimer's disease (AD) continuum have reported mixed findings. We conducted a systematic review and stage-stratified meta-analysis of randomized, placebo-controlled trials. MEDLINE, Embase, CENTRAL, Web of Science, Scopus, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform were searched through February 28, 2026. Disease stage was prespecified as an effect modifier. Standardized mean differences (SMDs; Hedges' g) were synthesized using restricted maximum likelihood random-effects models. Four trials met the inclusion criteria; three contributed to the quantitative synthesis (analyzed n = 906). Souvenir I was retained for qualitative synthesis because its distinct co-primary outcomes and reporting did not permit a compatible SMD for the prespecified pooled analysis. The exploratory pooled cognitive effect was small and not significant (SMD = 0.08; 95% CI, -0.09 to 0.26; p = 0.35; I[2] = 41.8%). For biomarker-confirmed prodromal AD, the 24-month primary neuropsychological test battery (NTB) 5-item composite endpoint showed a small, nonsignificant effect (SMD = 0.16; 95% CI, -0.08 to 0.41; original trial p = 0.166). The primary NTB memory endpoint in mild, drug-naive AD showed a small effect (SMD = 0.21; 95% CI, -0.06 to 0.49; original longitudinal-model p = 0.023), whereas the primary Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog) endpoint in treated mild-to-moderate AD showed no benefit (SMD = -0.06; 95% CI, -0.25 to 0.13; p = 0.513). At 36 months, the LipiDiDiet extension reported significant differences in the NTB 5-item composite, clinical dementia rating - sum of boxes (CDR-SB), memory, and brain-volume outcomes. The intervention was well tolerated. The evidence is compatible with a potential early-stage signal, but the small evidence base, lack of replication across stages, and manufacturer sponsorship warrant cautious interpretation.},
}

*Alzheimer Disease/therapy/psychology
Humans
Randomized Controlled Trials as Topic
Cognition

@article {pmid42683894,
year = {2026},
author = {Agnello, L and Pilotto, A and Gaetani, L and Bellomo, G and Bessi, V and Bozzali, M and Cagnin, A and Labate, A and Massa, F and Moda, F and Monastero, R and Musso, G and Piccoli, T and Sancesario, G and Parnetti, L and Padovani, A and Ciaccio, M},
title = {Toward harmonized reporting of Alzheimer's disease biomarkers in clinical practice.},
journal = {Clinical chemistry and laboratory medicine},
volume = {},
number = {},
pages = {},
pmid = {42683894},
issn = {1437-4331},
abstract = {Cerebrospinal fluid biomarkers, and more recently blood-based biomarkers, are playing a pivotal role in reshaping the clinical management of neurodegenerative diseases, supporting early detection, biological diagnosis, patient stratification, prognostic assessment, therapeutic decision-making, and longitudinal disease monitoring. To effectively support clinical decision-making, biomarker measurements must be communicated in a standardized, transparent, and clinically interpretable manner. Despite international quality standards, considerable heterogeneity persists in reporting practices, including differences in terminology, units of measurement, analytical descriptions, reference frameworks, and interpretative comments, limiting comparability across laboratories and potentially affecting clinical decision-making. In this article, we discuss the principles of harmonized reporting for Alzheimer's disease biomarkers and propose a structured framework for standardized clinical neurochemistry reports. We describe the essential components of a harmonized report, including report identification, analytical information, specification of analytical method and platform, standardized units of measurement, appropriate use of reference intervals and clinical decision thresholds, documentation of pre-analytical and quality-related factors, and evidence-based interpretative comments. We further discuss the importance of structured multimarker interpretation and the need to contextualize biomarker findings within the clinical scenario. Finally, we examine the role of harmonized reporting in promoting interoperability across healthcare systems, facilitating longitudinal patient monitoring, supporting electronic health records and standardized terminologies, and enabling artificial intelligence-driven clinical decision support. As neurodegenerative disease diagnostics continue to evolve and novel biomarkers and technologies emerge, harmonized reporting should be regarded as a critical component of laboratory quality, ensuring that analytical advances translate into consistent, clinically meaningful, and interoperable information that ultimately improves patient care.},
}

@article {pmid42683906,
year = {2026},
author = {Luca, A and Luca, M and Olgiati, P and Ferri, R and Perry, G and Serretti, A},
title = {Neuropsychiatric characteristics of capgras syndrome in Alzheimer's disease in the CATIE-AD.},
journal = {International journal of psychiatry in clinical practice},
volume = {},
number = {},
pages = {1-5},
doi = {10.1080/13651501.2026.2724972},
pmid = {42683906},
issn = {1471-1788},
abstract = {INTRODUCTION: Capgras syndrome (CS) is a recurrent and transient delusional misidentification disorder in which an individual is firmly convinced that a familiar person has been replaced by an identical impostor. The aim of the study was to evaluate neuropsychiatric characteristics of CS in a cohort of patients with Alzheimer's disease (AD).

METHODS: 150 participants [84 (56.0%) women, mean age 77.4 ± 7.5 years)] were collected within the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer disease (CATIE-AD). According to the Neuropsychiatric Inventory, patients were classified into Capgras[+] and Capgras[-].

RESULTS: Fifty-five (36.7%) AD patients were Capgras[+]. CS was strongly associated with other misidentification syndromes including phantom boarder (p < 0.001) and misidentification of places (p < 0.001). Moreover, Capgras[+] were presented more frequently with agitation (p = 0.036), depressive (p = 0.018) and anxious (p = 0.004) symptoms, and aberrant motor behaviours (p = 0.020).

CONCLUSIONS: According to our findings, CS was not an 'isolated' phenomenon but rather a complex neuropsychiatric syndrome frequently associated with other misidentification syndromes and specific behavioural disturbances.},
}

@article {pmid42684699,
year = {2026},
author = {Aaronson, A and Nosek, SB and Abdolmohammadi, B and Hadley, J and Labonte, J and Uretsky, M and Mosaheb, S and Nowinski, CJ and Altaras, C and Asken, BM and Banks, SJ and Barr, WB and Dams-O'Connor, K and Hromas, G and Ly, MT and Wethe, JV and Martin, BM and Palmisano, JN and Stern, RA and Tripodis, Y and Stein, TD and McKee, AC and Mez, J and Alosco, ML},
title = {Neuropsychological Profile of Autopsy-Confirmed Chronic Traumatic Encephalopathy.},
journal = {JAMA network open},
volume = {9},
number = {9},
pages = {e2631754},
pmid = {42684699},
issn = {2574-3805},
mesh = {Humans ; *Chronic Traumatic Encephalopathy/diagnosis/pathology/psychology/physiopathology ; Male ; Retrospective Studies ; *Neuropsychological Tests ; Autopsy ; Middle Aged ; Aged ; *Football/injuries ; Female ; Brain/pathology ; tau Proteins/metabolism ; },
abstract = {IMPORTANCE: Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact exposure. CTE can only be diagnosed post mortem, and the antemortem neuropsychological profile is poorly understood, hindering accurate diagnosis before death.

OBJECTIVE: To characterize antemortem neuropsychological test performance of former National Football League (NFL) players with autopsy-confirmed CTE.

This retrospective case series included former NFL players who completed an antemortem neuropsychological evaluation and had autopsy-confirmed CTE. Data were collected between January 1, 2017, and April 30, 2025. Statistical analysis was performed from September 2025 to June 2026.

EXPOSURE: CTE neuropathology, defined by the National Institute of Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering consensus panel.

MAIN OUTCOMES AND MEASURES: Neuropsychological test performance, neuropathologic diagnoses, and semiquantitative phosphorylated tau (p-tau) pathology across 11 brain regions were examined. Raw scores were converted to z scores using age, sex, and/or education level-based normative data. Test results with z scores of -1.5 or less were categorized as impaired; domains with 2 or more impaired test results were considered impaired.

RESULTS: The primary analytic sample included 33 men (mean [SD] age at death, 65.4 [13.3] years; mean [SD] time between testing and death, 2.4 [1.6] years), 25 with high- and 8 with low-stage CTE. Learning and memory was most impaired (17 of 27 [63.0%]), followed by executive function (15 of 29 [51.7%]) and language (12 of 29 [41.4%]). High-stage CTE participants generally had worse scores than low-stage CTE participants. Greater global p-tau burden was associated with worse learning and memory performance (B = -0.40; 95% CI, -0.70 to -0.09; P = .01). Findings were similar after excluding 9 participants with co-occurring Alzheimer disease or frontotemporal lobar degeneration tau.

CONCLUSIONS AND RELEVANCE: In this retrospective case series of NFL players with autopsy-confirmed CTE, memory, executive function, and language impairments were common, and p-tau burden was associated with worse memory performance. Findings provide insight into the expected CTE neuropsychological profile and may help advance diagnosis before death.},
}

Humans
*Chronic Traumatic Encephalopathy/diagnosis/pathology/psychology/physiopathology
Male
Retrospective Studies
*Neuropsychological Tests
Autopsy
Middle Aged
Aged
*Football/injuries
Female
Brain/pathology
tau Proteins/metabolism

@article {pmid42684813,
year = {2026},
author = {Unger, RH and Rohatgi, S and Ferraciolli, SF and Kako, B and Omid-Fard, N and Imbett, REM and Dowling, T and Zhu, S and Romero, JM and Ford, JN},
title = {Real-World Challenges in the MRI Detection and Classification of Amyloid-Related Imaging Abnormalities.},
journal = {AJR. American journal of roentgenology},
volume = {},
number = {},
pages = {},
doi = {10.2214/AJR.26.35478},
pmid = {42684813},
issn = {1546-3141},
abstract = {Anti-amyloid monoclonal antibody therapies (AATs) are increasingly used for the treatment of early symptomatic Alzheimer disease. Safe implementation of AATs relies on accurate assessment for exclusionary findings on baseline brain MRI and reliable longitudinal detection of amyloid-related imaging abnormalities (ARIA), including ARIA-H (hemosiderin or hemorrhage) and ARIA-E (edema or effusion). In routine clinical practice, MRI findings encountered during baseline screening and ARIA surveillance sometimes fall into borderline or ambiguous categories that do not clearly conform to trial-defined criteria. For example, subtle or artifactual FLAIR signal abnormality, equivocal microhemorrhage counts, and overlapping features of ARIA-E and ARIA-H can create uncertainty with direct implications for treatment management. Given limited practical guidance addressing these and other gray zones, this imaging-focused review synthesizes common interpretive challenges encountered in a high-volume AAT program and offers practical management-oriented recommendations. Key issues addressed include recognizing technical factors that affect interpretation of susceptibility-weighted and FLAIR images, managing variability in lesion detection across serial examinations, and accurately reporting the temporal evolution of ARIA-related findings. As AAT use expands, recognition of the presented pitfalls can improve diagnostic confidence and help avoid misclassification of findings that may influence therapeutic decisions.},
}

@article {pmid42684942,
year = {2026},
author = {Huang, D and Zhang, Z and Gong, X},
title = {Context-dependent roles of osteopontin in aging-related neurological disorders.},
journal = {The Journal of international medical research},
volume = {54},
number = {9},
pages = {3000605261476190},
pmid = {42684942},
issn = {1473-2300},
mesh = {Humans ; *Osteopontin/metabolism ; *Aging/pathology/metabolism ; Animals ; *Nervous System Diseases/metabolism/pathology ; Brain/pathology/metabolism ; Alzheimer Disease ; Microglia/metabolism ; },
abstract = {Osteopontin (encoded by secreted phosphoprotein 1) is a multifunctional matricellular phosphoglycoprotein that has emerged as an important mediator in the aging nervous system. During aging, osteopontin interacts with microglial priming, vascular remodeling, myelin repair, and innate immune responses and is consistently implicated in major late-life neurological disorders. However, its biological effects are highly context dependent. Depending on its cellular source, proteolytic processing, receptor interactions, anatomical distribution, and disease stage, osteopontin may either exacerbate chronic neuroinflammation and tissue injury or promote phagocytic clearance, neuronal survival, remyelination, neuroplasticity, and tissue repair. This review critically synthesizes studies indexed in PubMed and Google Scholar through 3 April 2026 on the role of osteopontin in brain aging, Alzheimer's disease and related dementias, Parkinson's disease and Lewy body disorders, cerebrovascular disease, vascular cognitive impairment, cerebral small vessel disease, and amyotrophic lateral sclerosis. In Alzheimer's disease, cerebrospinal fluid and plasma osteopontin concentrations increase from the prodromal to symptomatic stages, whereas microglial or perivascular secreted phosphoprotein 1 expression correlates with amyloid pathology, synaptic remodeling, and cognitive decline. However, under specific conditions, osteopontin also enhances macrophage-mediated amyloid-beta clearance. In stroke, elevated circulating osteopontin predicts poor clinical outcomes, whereas experimental studies demonstrate that appropriately timed exogenous osteopontin, regulatory T cell-derived osteopontin, and osteopontin-mediated autophagic and reparative pathways promote white-matter repair, peri-infarct plasticity, and blood-brain barrier integrity. Evidence from Parkinson's disease, Lewy body disease, frontotemporal dementia, and amyotrophic lateral sclerosis further supports the role of osteopontin as both a candidate biomarker and a regulator of selective neuronal vulnerability. Rather than being uniformly detrimental or protective, osteopontin should be regarded as a context-dependent regulator of age-related neuroimmune remodeling. This perspective reconciles seemingly conflicting findings and supports the development of therapeutic strategies that are tailored to disease stage, protein fragment, and cell type rather than broadly targeting osteopontin.},
}

Humans
*Osteopontin/metabolism
*Aging/pathology/metabolism
Animals
*Nervous System Diseases/metabolism/pathology
Brain/pathology/metabolism
Alzheimer Disease
Microglia/metabolism

@article {pmid42684969,
year = {2026},
author = {Chen, L and Xiao, L and Li, Y},
title = {Multi-trajectories of activity participation and risk of mild cognitive impairment in China: A national longitudinal cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261483186},
doi = {10.1177/13872877261483186},
pmid = {42684969},
issn = {1875-8908},
abstract = {BackgroundEngagement in physical, social, and intellectual activities is associated with cognitive health in later life, but how their long-term combinations relate to mild cognitive impairment (MCI), a key preclinical stage of Alzheimer's disease, remains unclear.ObjectiveTo identify multi-activity trajectories and examine their associations with MCI.MethodsData were from the China Health and Retirement Longitudinal Study (CHARLS), a nationally representative biennial survey collecting demographic, socioeconomic, health, cognitive, and activity-related information. We included 1884 participants aged ≥60 years in 2020. Group-based multi-trajectory modeling identified physical, social, and intellectual activity patterns using the 2011, 2013, 2015, and 2018 waves. Multivariable logistic regression examined associations with MCI in 2020, with subgroup analyses by sex, baseline age, education, and residence.ResultsFour distinct trajectory groups were identified: Moderate PA-low SI (social and intellectual activity), High PA-low SI, Moderate PA-higher SI, and High PA-moderate SI. The Moderate PA-higher SI group had the lowest MCI prevalence (9.47%) and served as the reference. In the fully adjusted model, MCI odds were highest in the High PA-low SI group (OR = 2.05, 95% CI: 1.34-3.15), followed by the Moderate PA-low SI group (OR = 1.57, 95% CI: 1.08-2.30). The High PA-moderate SI group was not significantly associated with MCI (OR = 1.38, 95% CI: 0.72-2.58).ConclusionsModerate physical activity combined with higher social and intellectual engagement was associated with more favorable cognitive outcomes, supporting integrated, pattern-based lifestyle strategies for early prevention of MCI and Alzheimer's disease.},
}

@article {pmid42684971,
year = {2026},
author = {Freitag, JM and Konen, FF and Heck, J and Jahn, K and Groba, S and Klietz, M and Skripuletz, T and Wegner, F and Schulze Westhoff, M and Schröder, S},
title = {Memory, social cognition, and beyond: Neuropsychological markers differentiating Alzheimer's disease and frontotemporal dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261480113},
doi = {10.1177/13872877261480113},
pmid = {42684971},
issn = {1875-8908},
abstract = {BackgroundDistinguishing Alzheimer's disease (AD) from frontotemporal dementia (FTD) remains a major clinical challenge, particularly in early disease stages due to overlapping symptoms. Although neuropsychological assessment is central to diagnosis, brief cognitive screening instruments often emphasize episodic memory, whereas comprehensive neuropsychological assessment encompasses multiple cognitive domains. Nevertheless, social cognition and other relevant functions may remain underrepresented in routine clinical assessment.ObjectiveTo identify neuropsychological domains and test procedures that reliably differentiate AD from FTD and support differential diagnosis.MethodsA systematic PubMed literature search was conducted using predefined inclusion and exclusion criteria. Original studies directly comparing neuropsychological performance in patients with AD and FTD were included. Owing to methodological heterogeneity, findings were synthesized narratively.ResultsA total of 322 records were identified, of which 80 studies met the inclusion criteria. A clear domain-specific pattern emerged. Episodic memory impairment, particularly delayed recall deficits, consistently distinguished AD from FTD, with poorer performance in AD. In contrast, deficits in social cognition, including theory of mind and emotion recognition, were more pronounced in FTD and were often detectable early in the disease course. Executive functions and language showed heterogeneous findings, with discriminative value depending on specific subdomains and FTD subtypes. Visuospatial functions and attention provided supportive but less consistent differentiation, while global screening instruments showed limited diagnostic specificity.ConclusionsDifferentiation between AD and FTD should not rely on single cognitive domains. The most clinically meaningful distinction is achieved through a multidimensional assessment integrating episodic memory, social cognition, and selected executive and behavioral measures.},
}

@article {pmid42684984,
year = {2026},
author = {Singh, RK and Bekena, S and Walker, AIB and Taylor, K and Zhu, Y and Pal, S and Mohamed, EA and Trani, JF and Kaplan, I and Babulal, GM},
title = {Exploratory factor and network analysis of 43 inflammatory plasma biomarkers and cognitive performance in Black adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261481701},
doi = {10.1177/13872877261481701},
pmid = {42684984},
issn = {1875-8908},
abstract = {BackgroundSystemic inflammation has been implicated in cognitive aging and neurodegeneration; however, inflammatory biomarkers are expressed in coordinated patterns rather than as isolated markers.ObjectiveTo identify latent inflammatory biomarker groupings and evaluate their associations with cognitive performance among midlife and older adults.MethodsThis cross-sectional study included 334 participants from the Aging Research Characterizing Health Exposome via Social Drivers (ARCHES) study. Cognitive performance was assessed using the Preclinical Alzheimer Cognitive Composite (PACC). Plasma inflammatory biomarkers were quantified using the NuLISA™ multiplex immunoassay platform. Exploratory factor analysis (EFA) (minimum residual extraction, oblimin rotation) identified latent inflammatory factors, retaining biomarkers with loadings ≥0.40. Factor scores were evaluated in multivariable linear regression models adjusted for age, sex, education, and genotype status; sensitivity analyses adjusted for socioeconomic context, medication use, BMI, lifestyle factors, and clinical diagnoses. Age-stratified and nonlinear spline analyses were conducted.Results27 of 43 biomarkers formed an eight-factor structure explaining 43% of variance. Two factors were significantly associated with cognitive performance after FDR correction. Factor 4 (CCL4, CXCL1, S100A12) and Factor 5 (IL2, IL5, IL13, IL10, CSF2) were inversely associated with PACC scores. These associations remained consistent across sensitivity analyses. Age-stratified analyses showed that several inflammatory factors were associated with cognitive performance among participants aged 45-<65 years, whereas no factors remained significant among participants aged ≥65 years after FDR correction. Nonlinear modeling indicated a non-linear age-cognitive performance relationship.ConclusionsEFA identified clusters of correlated inflammatory biomarkers associated with cognitive performance in this cohort of midlife and older adults.},
}

@article {pmid42685496,
year = {2026},
author = {Basir, HS and Rashno, M and Gholipour, P and Faraji, N and Tork, YJ and Naseri, E and Komaki, A and Ghaderi, S},
title = {L-carnitine attenuates Aβ1-42-induced spatial cognitive deficits and hippocampal dysfunction in a rat model of Alzheimer's disease.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {203},
number = {},
pages = {119884},
doi = {10.1016/j.biopha.2026.119884},
pmid = {42685496},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction and impaired synaptic plasticity. This study evaluated whether chronic L-carnitine (LC) attenuates amyloid-beta 1-42 (Aβ1-42)-induced spatial learning and memory deficits following intracerebroventricular (ICV) Aβ1-42 infusion. Forty adult male Wistar rats were randomly assigned to four groups (n = 10/group): Sham + Vehicle, Sham + LC, AD + Vehicle, and AD + LC. Following ICV Aβ1-42 infusion, LC (100 mg/kg/day, i.p.) or vehicle was administered for 28 days. Spatial learning and memory, hippocampal long-term potentiation (LTP), oxidative stress markers, Aβ plaque density, and neuronal integrity were evaluated. Compared with the AD + Vehicle-treated rats, LC attenuated Aβ1-42-induced impairments in spatial learning and memory, as indicated by reduced escape latency on training days 3-4 (both p < 0.01) and increased time spent in the target quadrant (p < 0.01). LC also improved hippocampal LTP, as reflected by a 58.4% increase in population spike (PS) amplitude potentiation (p < 0.01). Additionally, LC increased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities by 40.3%, 34.4%, and 37.4%, respectively, while reducing malondialdehyde (MDA) levels by 22.0% (all p < 0.01). LC also decreased Aβ plaque density by 36.6% and increased intact pyramidal neurons by 58.3% (both p < 0.01). These findings indicate that LC mitigates Aβ1-42-induced spatial learning and memory deficits and is associated with improved hippocampal LTP, enhanced antioxidant enzyme activities, reduced lipid peroxidation and Aβ plaque density, and preserved neuronal integrity.},
}

@article {pmid42685603,
year = {2026},
author = {Aurore, MD and Sarah, M and Perrine, S and Agnès, D and Lionel, T and Amandine, G and Coline, C and Nathalie, F and Stéphanie, D and Anaëlle, M and Maxime, B and Mélanie, J and Jérémie, P and Lola, D and Thibaud, L and Mai, TT},
title = {Progression of language profiles in primary progressive aphasia: A bicentric longitudinal study.},
journal = {Cortex; a journal devoted to the study of the nervous system and behavior},
volume = {204},
number = {},
pages = {271-287},
doi = {10.1016/j.cortex.2026.08.004},
pmid = {42685603},
issn = {1973-8102},
abstract = {BACKGROUND: Primary progressive aphasias (PPA) are syndromes characterised by a progressive loss of language functions. To date, four main variants have been identified: semantic (svPPA), non-fluent/agrammatic (nfvPPA), logopenic (lvPPA) and Primary Progressive Apraxia of Speech (PPAoS). Currently, little is known about their clinical course, especially in French-speaking populations, though such data could aid prognosis and guide therapy.

OBJECTIVE: To characterise longitudinal changes in the language profiles in PPA using the GRÉMOTS, a French language assessment tool specifically developed for neurodegenerative disorders.

METHODS: We retrospectively included PPA patients, as well as patients with typical amnesic Alzheimer's disease (AD) and behavioural variant frontotemporal degeneration (bvFTD), from the Lille and Toulouse Memory Centres, who underwent longitudinal assessment ≥6 months with the GRÉMOTS. We performed between-groups comparisons and within-group paired analyses of GRÉMOTS subscores.

RESULTS: Eighty-two patients were included: 20 svPPA, 9 lvPPA, 12 nfvPPA, 9 PPAoS, 20 AD and 12 bvFTD. svPPA patients showed a predominant decline in lexico-semantic domains. nfvPPA patients deteriorated mainly in phonetics and syntactic production. Apraxia remained the prominent symptom in PPAoS patients, although mild agrammatical aphasia emerged at follow-up. lvPPA patients exhibited a significant decline in lexical oral comprehension alongside their core impairments. Language impairments remained modest in AD and bvFTD.

CONCLUSION: Our results highlighted a progression of core language impairments across PPA variants, with lvPPA additionally showing significant decline beyond its defining criteria. These results support the development of tailored speech-language interventions that anticipate the evolving needs of PPA patients in French-speaking settings.},
}

@article {pmid42685677,
year = {2026},
author = {Sassano, ML and De Strooper, B},
title = {Glucose hypometabolism gates tau-dependent necroptosis.},
journal = {Neuron},
volume = {114},
number = {17},
pages = {3130-3132},
doi = {10.1016/j.neuron.2026.07.011},
pmid = {42685677},
issn = {1097-4199},
mesh = {*tau Proteins/metabolism ; *Glucose/metabolism ; Humans ; *Necroptosis/physiology ; Animals ; Phosphorylation ; Neurons/metabolism ; Alzheimer Disease/metabolism/pathology ; },
abstract = {Tau pathology closely tracks neuronal loss in Alzheimer's disease, but how phosphorylated tau becomes lethal has remained unclear. Chen et al. identify a dual-hit mechanism: glucose hypometabolism removes a protective A20-mediated brake on necroptosis while phosphorylated tau scaffolds RIPK1 activation, driving tau-associated neuronal death.[1].},
}

*tau Proteins/metabolism
*Glucose/metabolism
Humans
*Necroptosis/physiology
Animals
Phosphorylation
Neurons/metabolism
Alzheimer Disease/metabolism/pathology

@article {pmid42685684,
year = {2026},
author = {Matallana Rincón, S and Orozco López, F and Galindo, JF},
title = {Computational identification of novel acetylcholinesterase inhibitors as potential treatments for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261483260},
doi = {10.1177/13872877261483260},
pmid = {42685684},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease represents a major public health issue that affects millions of people worldwide. Although symptomatic treatments are available, they neither prevent nor halt disease progression; therefore, it is necessary to develop new therapeutic alternatives.ObjectiveTo identify acetylcholinesterase inhibitors with potential biological activity through a computational protocol.MethodsIn this study, a computational approach based on virtual screening, molecular docking, and molecular dynamics simulations was applied to identify new potential acetylcholinesterase inhibitors.ResultsThe results allowed the identification of three compounds with higher binding affinities than donepezil, which was used as a reference. Among them, ligand code 24771824 stood out for establishing hydrophobic and aromatic interactions that maximize dispersive contributions and promote a rigid and stable conformation within the active site. In contrast, ligand codes 151171 and 21081761 were favored by more directional polar contacts, which increased specificity but limited the overall affinity toward the enzyme.ConclusionsAltogether, the free energy, structural fluctuation, hydrogen bond occupancy, and molecular clustering analyses suggest that 24771824 exhibits the most favorable energetic and dynamic behavior, consolidating it as the best candidate for future experimental validation.},
}

@article {pmid42685685,
year = {2026},
author = {Yang, X and Li, X and Wang, C and Duan, A and Zhou, J and Wang, J and Jiang, Z and Li, M},
title = {A dual-branch time-frequency fusion network for EEG-based classification of Alzheimer's disease and frontotemporal dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261483197},
doi = {10.1177/13872877261483197},
pmid = {42685685},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) and frontotemporal dementia (FTD) exhibit substantial overlap in clinical manifestations and patterns of brain functional degeneration, which poses significant challenges for automated classification based on electroencephalography (EEG).ObjectiveThis study aims to develop an EEG-based framework capable of simultaneously capturing temporal dynamics and frequency-related characteristics of EEG signals for discrimination among AD, FTD, and cognitively normal (CN) subjects.MethodsA Dual-Branch Time-Frequency Fusion Network (DBTF-Net) based on routine clinical resting-state EEG recordings acquired under eyes-closed conditions is proposed. The model employs parallel temporal and frequency branches to process raw EEG time-series signals and their corresponding time-frequency representations. A global temporal dependency construction mechanism is introduced in the temporal branch to capture both local temporal patterns and long-range temporal dependencies. Feature-level fusion is then performed across the two branches to achieve a collaborative representation of multidimensional brain functional information. The proposed method was systematically evaluated on one three-class classification task (AD versus FTD versus CN) and multiple binary classification tasks.ResultsExperimental results from five-fold cross-validation at the epoch level show the classification accuracies of DBTF-Net as 86.36%±4.28%, 83.01%±6.15%, 92.13%±10.35%, and 88.74%±7.69%% for AD versus FTD versus CN, AD versus CN, FTD versus CN, and AD versus FTD, respectively.ConclusionsThe proposed DBTF-Net leverages temporal and time-frequency information in EEG signals and provides classification of AD and FTD. Visualization analysis further indicates that the model attends to disease-relevant discriminative patterns in time-frequency representations, enhancing the interpretability of its classification decisions.},
}

@article {pmid42685686,
year = {2026},
author = {Sahuquillo, R and García-Pérez, E and Navarro, B and Fernández-Aguilar, L and Martínez-Sáez, MC and Ros, L and Borja, AL and Latorre, JM},
title = {Machine learning classification of mild Alzheimer's disease using EEG during emotional processing.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261483280},
doi = {10.1177/13872877261483280},
pmid = {42685686},
issn = {1875-8908},
abstract = {BackgroundMild Alzheimer's disease (AD) is associated with alterations in brain activity, which can be detected using electroencephalography (EEG). Investigating these changes during emotional processing may help identify neurophysiological patterns that differentiate patients with mild AD from healthy controls (HCs).ObjectiveTo investigate whether EEG responses elicited during emotional processing provide biomarkers capable of discriminating patients with AD from HCs. Additionally, to identify the emotional contexts, brain regions, frequency bands, and machine learning models that maximize this discriminative capacity.MethodsA sample of 39 AD patients and 54 HCs watched brief movie clips designed to elicit tenderness, amusement, anger, fear, and sadness, along with an Alzheimer's-related clip, together with neutral clips used as control, baseline, and recovery conditions, while cortical activity was recorded using EEG. The signals were then classified across emotional contexts using LASSO, Random Forest, SVM-RBF, XGBoost, and CatBoost ML models.ResultsEEG signals allowed for discrimination between AD patients and HCs across different emotional contexts, including individual emotions, grouped by valence or arousal, and the Alzheimer's-related stimulus. LASSO achieved the best performance for positive and neutral conditions in the parietal and posterior gamma bands, whereas CatBoost performed best for high-arousal negative emotions such as anger and fear, particularly in frontal gamma and theta bands, respectively.ConclusionsPatients with mild AD show EEG signal patterns that differ from those of HCs across different emotional contexts. These findings highlight the potential of EEG recorded during emotional processing to support the development of objective biomarkers for mild AD.},
}

@article {pmid42685709,
year = {2026},
author = {Zarhin, D and Bregman, N and Shiner, T and Mirelman, A and Alcalay, RN and Thaler, A},
title = {Cognitive and motor profiles in biologically defined Parkinson's and Alzheimer's disease.},
journal = {Journal of Parkinson's disease},
volume = {},
number = {},
pages = {1877718X261477521},
pmid = {42685709},
issn = {1877-718X},
abstract = {BackgroundParkinson's disease (PD) patients may harbor coexisting Alzheimer's disease (AD) pathology that accelerates cognitive and motor decline. Defining biomarker-defined AD in PD is important for prognosis, patient counseling, and trial stratification.ObjectiveTo determine the prevalence of AD biomarker positivity in α-synuclein seed amplification assay (αSyn-SAA) positive PD and assess its impact on cognitive and motor progression.MethodsWe analyzed data from the Parkinson's Progression Markers Initiative, a multinational prospective cohort of de novo PD patients. Baseline CSF biomarkers included αSyn-SAA, amyloid-β1-42 (Aβ1-42), and phosphorylated tau181 (p-tau181). AD biomarker positivity was defined by a low Aβ1-42/high p-tau181 profile using the CSF Aβ1-42/p-tau181 ratio (<39.2). αSyn-SAA-positive PD participants with and without AD biomarker positivity were compared. Outcomes included cognition, Montreal Cognitive Assessment (MoCA), neuropsychological testing, and MDS-UPDRS motor scores over follow-up.ResultsAmong 449 αSyn-SAA-positive PD patients, 42 (9.3%) met AD biomarker criteria (PD-AD). Baseline cognition and motor scores did not differ between PD-AD and PD without AD biomarkers (PD-nonAD). Over time, PD-AD patients showed greater cognitive decline, with lower MoCA scores and higher MCI prevalence at 5 years. At 8 years, PD-AD patients also demonstrated worse motor outcomes. MoCA <24 predicted AD biomarker positivity (PPV 15%; OR 6.1). APOE ε4 status was not associated with cognition.ConclusionsBiomarker-defined AD identifies a distinct PD subgroup with accelerated cognitive and motor decline, independent of APOE ε4. A ratio-based CSF Aβ1-42/p-tau181 framework offers a practical approach to detect AD copathology in PD and refine prognostic stratification.},
}

@article {pmid42686546,
year = {2026},
author = {Shigetomi, E and Koizumi, S},
title = {[Gq-GPCR upregulation in reactive astrocytes: implication for neurological disorders].},
journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica},
volume = {161},
number = {5},
pages = {313-318},
doi = {10.1254/fpj.26045},
pmid = {42686546},
issn = {0015-5691},
mesh = {*Astrocytes/metabolism ; Animals ; *Up-Regulation ; Humans ; *Nervous System Diseases/metabolism/genetics ; *Receptors, Purinergic P2Y1/metabolism/genetics ; Mice ; Insulin-Like Growth Factor Binding Protein 2/metabolism ; *GTP-Binding Protein alpha Subunits, Gq-G11/metabolism ; },
abstract = {Astrocytes are essential glial cells that maintain brain homeostasis. Upon brain injury, they become reactive astrocytes with altered morphology, gene expression, and function, including dysregulated Ca[2+] signaling implicated in disease development and progression. P2Y1 receptor (P2Y1R), one of Gq-GPCRs, is upregulated in reactive astrocytes across multiple brain disorders, including Alzheimer's disease, epilepsy, and stroke; however, how this upregulation contributes to pathology has remained unclear. To address this question, we generated astrocyte-specific P2Y1R-overexpressing transgenic mice. P2Y1R overexpression in astrocytes induced neuronal hyperexcitability, as evidenced by increased hippocampal neuronal firing, abnormal EEG spikes, and heightened susceptibility to pilocarpine-induced seizures. Dual-color Ca[2+] imaging of neurons and astrocytes, electrophysiology, transcriptome analysis of astrocytes, immunohistochemistry, and CRISPR/Cas9-mediated astrocyte-specific knockdown revealed that P2Y1R overexpression amplified both neuron-to-neuron and neuron-to-astrocyte signaling, with astrocytes becoming hypersensitive to neuronal activity-derived ATP. Astrocyte-specific transcriptomic analysis identified insulin-like growth factor binding protein 2 (IGFBP2) as a key downstream effector. IGFBP2, a secreted protein selectively expressed in astrocytes, enhanced glutamatergic synaptic transmission. Furthermore, co-upregulation of P2Y1R and IGFBP2 was confirmed in reactive astrocytes in both kainate-induced epilepsy and middle cerebral artery occlusion stroke models. These findings identify the P2Y1R-IGFBP2 signaling axis as a common pathological feature of reactive astrocytes across brain diseases and establish IGFBP2 as a novel glial-derived factor that could promote neuronal hyperexcitability.},
}

*Astrocytes/metabolism
Animals
*Up-Regulation
Humans
*Nervous System Diseases/metabolism/genetics
*Receptors, Purinergic P2Y1/metabolism/genetics
Mice
Insulin-Like Growth Factor Binding Protein 2/metabolism
*GTP-Binding Protein alpha Subunits, Gq-G11/metabolism

@article {pmid42686563,
year = {2026},
author = {Nishikubo, K and Muramatsu, R},
title = {[Metal homeostasis dysregulation and pharmacological modulation in Alzheimer's disease].},
journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica},
volume = {161},
number = {5},
pages = {410},
doi = {10.1254/fpj.26043},
pmid = {42686563},
issn = {0015-5691},
}

@article {pmid42686621,
year = {2026},
author = {Shirotani, K and Hatta, D and Watanabe, K and Saito, T and Saido, TC and Iwata, N},
title = {Stepwise Upregulation of Microglial Genes through the Slow Progression of Amyloid Pathology in Alzheimer's Disease Model Mice.},
journal = {Biological & pharmaceutical bulletin},
volume = {49},
number = {9},
pages = {1409-1415},
doi = {10.1248/bpb.b26-00310},
pmid = {42686621},
issn = {1347-5215},
mesh = {Animals ; *Microglia/metabolism ; *Alzheimer Disease/genetics/metabolism/pathology ; Up-Regulation ; Disease Models, Animal ; Brain/metabolism/pathology ; Amyloid beta-Protein Precursor/genetics ; Mice, Transgenic ; *Amyloid beta-Peptides/metabolism ; Receptors, Immunologic/genetics ; Membrane Glycoproteins/genetics ; Disease Progression ; Mice ; Mice, Inbred C57BL ; },
abstract = {The mechanistic role of microglial activation in Alzheimer's disease pathology is typically investigated using mouse models with aggressive amyloid accumulation, leaving the dynamics of microglial responses under the relatively slow deposition of amyloid-β (Aβ) characteristic of the early stages of the disease poorly understood. In this study, we examined microglial gene expression in the brains of App[NL-F] knock-in mice, which gradually develop Aβ pathology in an aging-dependent manner without amyloid-β precursor protein overexpression. Quantitative PCR (qPCR) analysis revealed that microglial gene expression presents a stepwise activation pattern: early-induced genes increased at 12 months, whereas late-induced genes emerged at 18 months. Notably, neither group showed further induction at 24 months despite continued Aβ accumulation, indicating that microglial activation does not scale proportionally with the amyloid burden. Several canonical components of the disease-associated microglia program were not induced in App[NL-F] mice, whereas a set of previously unrecognized microglial genes (Ly86, Snx20, and Pram1) was upregulated. The induction of these novel genes was preserved in the brains of Trem2 R47H knock-in mice, corroborating that the R47H variant exhibits only mild, if any, phenotype. Immunoblotting of selected proteins confirmed these qPCR-based findings. Together, these results reveal a stepwise mode of microglial gene activation under slow amyloid progression and identify novel genes that may be relevant to the early stages of Alzheimer's disease.},
}

Animals
*Microglia/metabolism
*Alzheimer Disease/genetics/metabolism/pathology
Up-Regulation
Disease Models, Animal
Brain/metabolism/pathology
Amyloid beta-Protein Precursor/genetics
Mice, Transgenic
*Amyloid beta-Peptides/metabolism
Receptors, Immunologic/genetics
Membrane Glycoproteins/genetics
Disease Progression
Mice
Mice, Inbred C57BL

@article {pmid42686898,
year = {2026},
author = {Belk, JA and Zhang, Y and Reilly, EE and Shi, Q and Liu, DD and Womack-Gambrel, N and van der Linde, M and Ma, L and Paul, D and Enciso, AM and Kalluru, R and Weiss, J and Li, R and Eastman, AE and Zhu, C and Chakravarthy, A and Bukhari, S and Bhattacharya, D and Raj, S and Richard, D and Brioschi, S and Chrostek, MR and Nachun, DC and Arends, CM and Gopakumar, J and Tengesdal, IW and Bynum, A and Mitchell, S and Sandor, K and Zhang, W and Vardarajan, BN and Cobos, I and Born, DE and West, RB and Brunet, A and Colonna, M and Bharani, KL and Vogel, H and Montine, TJ and Latimer, CS and Weissman, IL and Matusiak, M and Hooper, JE and Keene, CD and Chang, HY and Jaiswal, S},
title = {Somatic mutations reveal the ontogeny of microglia in human ageing.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {42686898},
issn = {1476-4687},
abstract = {Microglia are the resident macrophages of the central nervous system[1]. In mice, microglia seed the brain during embryogenesis and can be maintained throughout life with minimal input from adult haematopoiesis[2-4]. The origins of human microglia are less clear, but recent evidence suggests that bone-marrow-derived cells contribute to the human microglial pool in certain individuals[5-9]. Here, to investigate the ontogeny of human microglia, we develop an approach that uses the collection of accumulated somatic mutations that uniquely labels each clone of cells to track the infiltration of bone-marrow-derived cells into the human brain. Applying this approach to 20 older individuals, we find evidence of an influx of bone-marrow-derived cells into the brain in all examined individuals. Single-cell analysis, including single-cell lineage tracing using mitochondrial DNA variants, demonstrates that these infiltrating cells are similar to microglia and can comprise a large fraction of the microglial pool. Analysis of human cohort data demonstrates a protective association between most types of clonal haematopoiesis and Alzheimer's disease. Together, we identify a widespread influx of myeloid cells into the healthy human brain that contributes to the pool of human microglia and becomes common with ageing.},
}

@article {pmid42686946,
year = {2026},
author = {Trushin, S and Nguyen, TKO and Ostroot, M and Nesbitt, JJ and Kovalenko, T and Galkin, A and Nambara, T and Lu, W and Kanekiyo, T and Johnson, G and Trushina, E},
title = {Discovery and preclinical validation of a translationally optimized mitochondrial complex I modulator for Alzheimer's disease.},
journal = {npj drug discovery},
volume = {3},
number = {1},
pages = {},
pmid = {42686946},
issn = {3005-1452},
support = {23AARF-1027342/ALZ/Alzheimer's Association/United States ; U19 AG069701/AG/NIA NIH HHS/United States ; R01AG 55549//NIH/ ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive metabolic failure, impaired mitochondrial function, and diminished adaptive stress responses, highlighting the need for disease-modifying therapies that restore cellular resilience rather than target downstream pathology. Here, we report the discovery and preclinical validation of C273, a translationally optimized, brain-penetrant mitochondrial complex I (mtCI) modulator developed through medicinal chemistry optimization of our first-generation compounds. C273 retained nanomolar neuroprotective activity against Aβ-induced toxicity while exhibiting favorable drug-like properties, including high oral bioavailability, efficient brain penetration, microsomal stability, minimal CYP and off-target pharmacology liabilities, and selective mild modulation of mtCI. Mechanistic studies demonstrated that C273 activated AMP-activated protein kinase (AMPK) and coordinated antioxidant, autophagic, anti-inflammatory, and mitochondrial quality-control pathways in cultured cells and mouse brain. These responses were absent in AMPKα1/α2-deficient cells, establishing AMPK as an essential mediator, while rotenone pretreatment abolished C273-mediated neuroprotection, supporting engagement of the mtCI quinone-binding site. Repeated administration to wild-type mice for 30 days produced no detectable cardiac or hepatic toxicity. Importantly, C273 activated the same neuroprotective pathways and reduced Aβ and p-Tau levels in induced pluripotent stem cell-derived cerebral organoids from patients with sporadic AD. Together, these findings establish mild modulation of mtCI as a therapeutic strategy to restore metabolic resilience and identify C273 as a promising disease-modifying candidate for AD treatment.},
}

@article {pmid42686974,
year = {2026},
author = {Sharma, V and Vashisht, K and Choudhary, G and Choudhay, V and Bhatia, V and Ashawat, MS and Baldi, A and Kushawaha, SK},
title = {Acitretin shows promising potential in Alzheimer's disease: retinoid-driven modulation of amyloid processing, neuroinflammation, and translational prospects.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42686974},
issn = {1568-5608},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder driven by the convergence of amyloid-β (Aβ) accumulation, tau hyperphosphorylation, synaptic failure, and chronic neuroinflammation, for which effective disease-modifying therapies remain elusive. Increasing evidence identifies dysregulated retinoid signaling as a critical yet underexplored contributor to AD pathogenesis. Retinoic acid, acting through retinoic acid receptors (RARs) and retinoid X receptors (RXRs), is essential for maintaining neuronal homeostasis, synaptic plasticity, and neuroimmune equilibrium in the adult central nervous system. In AD, impairment of RAR/RXR signaling shifts amyloid precursor protein (APP) processing toward amyloidogenic pathways, sustains NF-κB-driven inflammatory cascades, and promotes microglial dysfunction, thereby accelerating the progression of neurodegenerative processes. This review integrates mechanistic, preclinical, and translational evidence supporting acitretin, a second-generation synthetic retinoid, as a multi-target therapeutic candidate for AD. Acitretin enhances ADAM10-mediated non-amyloidogenic APP cleavage, increases soluble APP-α production, and reduces Aβ generation in transgenic AD models, while concurrently modulating microglial activation to attenuate pro-inflammatory cytokine signaling, including IL-6 and TNF-α, and preserve synaptic integrity. Importantly, biomarker-based clinical studies demonstrate increased cerebrospinal fluid APP-α following acitretin administration, confirming central target engagement in humans. Although definitive clinical efficacy remains to be established, acitretin's pleiotropic mechanism, established pharmacological profile, and biomarker responsiveness position it as a promising repurposed candidate within biomarker-guided and combination-based therapeutic strategies for AD.},
}

@article {pmid42686992,
year = {2026},
author = {Wang, Y and Smith, GE and Lipori, GP and Sun, RC and Shenkman, EA and Liu, M and Wu, Y and Guo, Y},
title = {Structural requirements for intelligent clinical digital twins in feedback-driven care.},
journal = {npj health systems},
volume = {3},
number = {1},
pages = {},
pmid = {42686992},
issn = {3005-1959},
abstract = {Clinical digital twins are increasingly promoted for decision support, yet most are designed and validated for prediction under observed care rather than decision-support validity. We identify four structural requirements for intelligent clinical digital twins used in bidirectional clinical care. Using Alzheimer's disease and related dementias as an example, we show how routine deployment can induce care-path-dependent epistemic drift despite stable predictive performance.},
}

@article {pmid42686999,
year = {2026},
author = {Akhter, F and Akhter, A and Guo, X and Zhu, X and Zhao, Z and Zhu, D},
title = {Advanced glycation end products drive blood-brain barrier lipid dysregulation via RAGE-ABCA1 signaling to promote neurovascular dysfunction in Alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42686999},
issn = {1476-5578},
support = {R01HL140562//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01DK129493//U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)/ ; R01AG064798//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Neurovascular dysfunction is an early and critical contributor to Alzheimer's disease (AD), yet the molecular mechanisms linking vascular pathology to metabolic dysregulation remain incompletely understood. Advanced glycation end products (AGEs), which accumulate during aging and metabolic stress, have been implicated in AD pathology; however, their role in cerebrovascular lipid homeostasis is unclear. Here, we demonstrate that AGE accumulation within cerebral microvessels promotes lipid droplet (LD) formation in endothelial cells through receptor for AGE (RAGE)-dependent disruption of cholesterol efflux pathways. In aged APP transgenic mice and human AD brains, we observe increased AGE deposition concomitant with elevated RAGE, DGAT1, and perilipin expression, alongside reduced ABCA1 levels. In human brain endothelial cells, AGE exposure induces lipid metabolic reprogramming characterized by enhanced LD accumulation, upregulation of lipogenic machinery, and suppression of cholesterol efflux. Mechanistically, RAGE silencing restores ABCA1 expression and attenuates LD formation, identifying RAGE as a key upstream regulator. Pharmacological activation of ABCA1 reverses AGE-induced lipid accumulation and reduces RAGE expression, highlighting a therapeutic axis. Furthermore, AGE exposure disrupts blood-brain barrier (BBB) integrity and impairs amyloid-β transport in an in vitro BBB model. In vivo, aging is associated with progressive microvascular LD accumulation, linking metabolic dysfunction to vascular pathology. Together, our findings establish an AGE-RAGE-ABCA1 signaling axis that drives endothelial lipid dysregulation and BBB impairment, providing a mechanistic framework connecting metabolic stress to neurovascular dysfunction in AD.},
}

@article {pmid42687000,
year = {2026},
author = {Liu, J and Peng, F and Li, P and Yao, C and Jin, S and Wu, G and Zhang, T and Liang, Q and Wang, X and Du, X},
title = {Correction: Mechanistic insights into cannabidiol-mediated TrkB activation via FRS2 interaction in attenuating Alzheimer's disease pathology and cognitive impairment.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41380-026-03864-1},
pmid = {42687000},
issn = {1476-5578},
}

@article {pmid42687124,
year = {2026},
author = {Ghosh, P and Mukhopadhyay, S and Rati, S and Ghosh, SS and Krishnan Iyer, P},
title = {Sustainably Synthesized Small Molecule Therapeutic Aggregates Attenuate Aβ-Induced ROS-Mitochondrial-Apoptotic Cascade in Alzheimer's Disease.},
journal = {ACS applied bio materials},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsabm.6c01210},
pmid = {42687124},
issn = {2576-6422},
support = {DST/CRG/2019/002614//Department of Science and Technology, Ministry of Science and Technology, India/ ; 5/3/8/20/2019-ITR//Indian Council of Medical Research/ ; PMRF ID: 1900819//Ministry of Education, India/ ; 5(1)/2022-NANO//Ministry of Electronics and Information technology/ ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) aggregation, oxidative stress, mitochondrial dysfunction, and progressive neuronal loss, yet effective disease-modifying therapeutics remain limited. Herein, we report the sustainable synthesis of two triphenylamine-based donor-acceptor (D-A) scaffolds, TPA-IM (triphenylamine-indanonemalononitrile) and TPA-FM (triphenylamine-furanmalononitrile), via a catalyst-free ethanol-mediated Knoevenagel condensation under mild conditions, yielding high yields (>80%). Integrated photophysical, computational, biophysical, and cellular investigations revealed that acceptor engineering critically governs supramolecular assembly, amyloid-binding behavior, and neuroprotective efficacy. Among the two molecules, TPA-IM exhibited superior inhibition of Aβ40 fibrillogenesis and a stronger fibril-binding affinity, as evidenced by ThT kinetics, ITC, docking, and molecular dynamics simulations. Aggregate simulations and FETEM analyses further demonstrated distinct supramolecular assembly behavior associated with enhanced amyloid interactions. Importantly, TPA-IM effectively suppressed intracellular ROS generation, restored mitochondrial membrane potential, and attenuated Aβ-induced apoptosis in neuronal cells. Favorable BBB permeability and ADMET profiles further support its therapeutic potential. Collectively, this work establishes a mechanistic framework linking acceptor-controlled supramolecular organization with amyloid modulation and mitochondrial neuroprotection for AD therapeutics.},
}

@article {pmid42687127,
year = {2026},
author = {Yu, P and Jiang, M and Qiu, Z and Fu, Y and Yu, Y and Luo, Y and Deng, X and Li, J and Chen, X and Zhang, J and Huang, M and Cui, X and Yang, X},
title = {Cerium-Rutin Coordination Polymer Nanoparticles for Scavenging ROS and Inhibiting Amyloid-β Fibrillation in Alzheimer's Disease.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.6c12785},
pmid = {42687127},
issn = {1944-8252},
support = {2023CXQD049//Central South University/ ; 82403717//National Natural Science Foundation of China/ ; },
abstract = {The abnormal accumulation of amyloid-beta (Aβ) triggers cellular dysfunction and tissue damage through processes including reactive oxygen species (ROS) and neuroinflammation, ultimately leading to the manifestation of AD symptoms. However, existing studies have revealed that the isolated clearance of amyloid-beta (Aβ), reactive oxygen species (ROS), or neuroinflammation confers no significant benefit on cognitive and memory function in AD patients. Thus, given the complex pathogenic mechanisms underlying AD, multitarget synergistic therapy represents a promising therapeutic strategy. Herein, we reported coordination polymer nanoparticles, Ce-Ru@Trf NPs, composed of cerium (Ce), rutin (Ru), and transferrin (Trf), which efficiently scavenge various ROS and anti-neuroinflammation and inhibit Aβ fibrillization. Owing to Trf modification, its accumulation in brain tissues increased significantly. The Ce-Ru@Trf NPs also dampened neuroinflammation by redirecting microglia toward the M2 phenotype and curtailing proinflammatory factor release. In an AD APP/PS1 model, it significantly achieved a neuroprotective effect and improved cognitive function. The findings suggest that biocompatible coordination polymers composed of metals and natural products may offer a viable therapeutic strategy for Alzheimer's disease.},
}

@article {pmid42687401,
year = {2026},
author = {Hooper, C and González, E and Nogueira, L and Delrieu, J and Coley, N and Soto, M and Vellas, B and Guyonnet, S and , },
title = {Cross-sectional associations of loneliness with plasma p-tau217 and neurofilament light chain in dementia-free older adults in the INSPIRE-T baseline cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261482077},
doi = {10.1177/13872877261482077},
pmid = {42687401},
issn = {1875-8908},
abstract = {BackgroundLoneliness is the subjective feeling of social isolation and evidence suggests that it increases the risk for cognitive decline and Alzheimer's disease (AD). However, studies examining the associations between loneliness and AD biomarkers are limited and inconclusive.ObjectiveWe sought to investigate the relationships between loneliness and plasma tau phosphorylated at threonine 217 (p-tau217) and plasma neurofilament light chain (NfL): peripheral biomarkers of central AD pathology.MethodsThis is a cross-sectional analysis of the 'INStitute for Prevention' 'healthy agIng' and 'medicine REjuvenative' 'Translational' (INSPIRE-T) baseline data. Participants were dementia-free (Mini-Mental State Exam score ≥ 24) community-dwellers aged ≥ 65 years (n = 434). Loneliness was assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS[®]) Item Bank v2.0, Short Form 8a questionnaire and plasma p-tau217 and plasma NfL were measured using Lumipulse immunoassays. Multiple linear regression was conducted to evaluate the relationships between loneliness (exposure) and plasma biomarkers (outcomes).ResultsLoneliness was not associated with plasma p-tau217 (β = 0.00458 [95% CI: -0.00328, 0.01243], p = 0.253) or plasma NfL (β = 0.00138 [95% CI: -0.00418, 0.00693], p = 0.626) in multiple linear regression models adjusted for age, sex, education, cognitive performance, depressive score, eyesight, hearing, and apolipoprotein ε4 (APOE ε4) status (model 2). There was no significant moderating effect of sex, depression, eyesight, hearing or APOE ε4 on these associations.ConclusionsOur findings suggest that loneliness is not associated with plasma p-tau217 or plasma NfL in dementia-free older adults. Perspective studies are warranted to examine these associations further.},
}

@article {pmid42687894,
year = {2026},
author = {Mitchell, BA and Hausle, I and Smith, S and Thropp, P and Sirota, M and Tosun, D},
title = {Peripheral blood microarray-based transcriptomic and epigenetic analyses identify immune, inflammation, and metabolic dysregulation in Alzheimer's disease.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {74},
pmid = {42687894},
issn = {3005-1940},
abstract = {Leveraging multi-omics to better understand the molecular signatures and pathways underlying Alzheimer's disease (AD) pathogenesis is critical for early diagnosis and disease modifying interventions. We performed peripheral blood transcriptome (N = 669) and epigenome microarray analyses (N = 553) on non-Hispanic white participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to identify molecular signatures of AD. We identified specific transcripts (e.g., MAPK14, GM2A, CD177) and co-expression networks that were dysregulated in AD, marked by a strong influence of APOE ε4 genotype, and characterized by a consistent pattern of immune activation, inflammation, and metabolic suppression. Further, these peripheral signatures were linked to central AD pathology (amyloid PET, CSF p-tau181) and neurodegeneration (plasma NfL, regional atrophy), with two genes, MXD3 and NR4A1, identified as protective against progression from MCI to AD. Our work emphasizes the importance of APOE genotypes in AD pathophysiology and highlights potential targets for biomarker discovery and personalized therapeutic strategies.},
}

@article {pmid42687896,
year = {2026},
author = {Afifi, T and Collins, N and Rand, K and Stamps, J and Naffziger, E and Truscelli, N and Harris, P and Neumann, T and Mazur, A and Rosen, Y and Salehuddin, A and Gonzales, C and Otmar, C and Wilson, V and Salmon, J and Fujiwara, K and Monin, J and Lou, Y},
title = {The effects of virtual reality and video conferencing on personal and relational well-being among older adults with cognitive impairments and their adult children: The Thrive randomized controlled trial.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10584186/v1},
pmid = {42687896},
issn = {2693-5015},
abstract = {Older adults in senior living communities (SLCs) often face barriers to maintaining emotional well-being and family ties. This stratified, unblinded, parallel-group randomized controlled trial tested a four-week virtual reality (VR) intervention (Thrive) designed to improve well-being for older adults with cognitive impairment and their adult children living at a distance, compared to an active video conferencing (VC) control. A total of 186 dyads - each comprising a parent with mild cognitive impairment (MCI) or mild-to-moderate Alzheimer's disease and related dementias (ADRD) and an adult child - were recruited from 23 SLCs and randomized 1:1 to VR (n=90) or VC (n=96). Primary outcomes - including personal, social, and relational well-being for parents and adult children, and perceived stress and caregiver guilt for adult children - were assessed at baseline, one week post-intervention (primary endpoint), and one and three months post-intervention using intention-to-treat linear mixed models; secondary outcomes captured session engagement via self-report and behavioral coding. Retention was high (89% at post-intervention). Parents with ADRD showed significantly greater improvement in VR than VC for psychological well-being, social connection, and relationship quality, while parents with MCI showed a comparable pattern favoring VC for relationship quality and social connection. Adult children in both conditions reported improved personal, social, and relational well-being, with VR showing more sustained reductions in caregiver guilt through three months. Overall, VR sessions elicited more engagement than VC. These findings indicate that both VR and VC improved well-being and family connection, with VR conferring additional benefits for parents living with dementia and a sustained caregiver-guilt benefit for adult children, suggesting that tailoring technology to cognitive abilities may enhance outcomes in senior care settings.},
}

@article {pmid42687900,
year = {2026},
author = {McClarty, B and Monteiro, R and Dong, H},
title = {Histone Deacetylase Inhibitors Improve Memory Function and Decrease Neuropathology in APP/PS1 Mice.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10816126/v1},
pmid = {42687900},
issn = {2693-5015},
abstract = {Although histone deacetylase (HDAC) inhibitors have shown therapeutic potential in aging and Alzheimer's disease (AD), direct comparisons of nonselective and selective HDAC inhibitors across aging and AD models are lacking. We compared the effects of the broad-spectrum HDAC inhibitor valproic acid (VPA) and the selective class I HDAC inhibitors entinostat (MS-275) and tacedinaline (CI-994) in 3-, 12-, and 18-month-old wild-type and APP/PS1 mice. Mice received 30 days of treatment, followed by a series of behavioral tests assessing different memory domains. Brain tissue was then analyzed for molecular and pathological changes. Both MS-275 and CI-994 improved recognition memory and short-term working memory in 12- and 18-month-old APP/PS1 mice, whereas only CI-994 restored long-term spatial reference memory. CI-994 increased hippocampal synapse-related gene expression and H3K9 acetylation at their promoters, consistent with improved hippocampus-dependent memory. In contrast, MS-275 enhanced synapse-related gene expression and H3K9 acetylation, in the prefrontal cortex (PFC), corresponding to improvements in recognition and working memory. MS-275 also significantly reduced amyloid plaque burden in the hippocampus and PFC, whereas both MS-275 and CI-994 decreased microglial density in APP/PS1 mice. These findings demonstrate distinct spatial and functional effects of selective HDAC inhibition in AD. CI-994 primarily targets hippocampal synaptic plasticity to improve long-term spatial memory, whereas MS-275 preferentially modulates PFC synaptic function and reduces amyloid pathology, leading to improved recognition and working memory. Together, these results identify region-specific HDAC mechanisms that differentially regulate cognitive function and AD pathology, supporting selective HDAC inhibition as a promising therapeutic strategy for AD.},
}

@article {pmid42687915,
year = {2026},
author = {Javanray, M and Gallego-Rudolf, J and Yakoub, Y and Qiu, T and St-Onge, F and Remz, J and Soucy, JP and Misic, B and Bellec, L and Vogel, J and Group, PR and Villeneuve, S},
title = {Network-level functional connectivity is associated with longitudinal tau accumulation and amyloid-dependent cognitive decline in preclinical Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10282950/v1},
pmid = {42687915},
issn = {2693-5015},
abstract = {Amyloid-β and tau, pathological hallmarks of AD, silently accumulate years before clinical symptoms' onset and are associated with neuronal dysfunction and cognitive impairment. Although functional connectivity has shown promise in tracking AD proteinopathy, how large-scale brain functional connections and their temporal variability relate to longitudinal pathological and cognitive changes during the preclinical stage remains unclear. Here, we examined both static and time-varying functional connectivity across brain networks in cognitively unimpaired older adults with a family history of AD, who underwent resting-state fMRI, longitudinal amyloid- and tau-PET imaging, and decade-long neuropsychological assessments. We found that lower static connectivity across multiple large-scale networks was associated with faster longitudinal tau accumulation and, selectively in individuals with elevated amyloid burden, with accelerated cognitive decline. These associations were not observed for time-varying connectivity. Together, our results demonstrate a role of static functional network organization in early pathological and cognitive progression of AD.},
}

@article {pmid42687927,
year = {2026},
author = {Duche, A and Chandnra, DV and Han, D and Sumbria, RK and Rahman, M},
title = {Hepatic and Brain Spatial Gene Expression Changes in Intragastric Alcohol Fed APP/PS1 Alzheimer's Disease Mouse Model.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10760512/v1},
pmid = {42687927},
issn = {2693-5015},
abstract = {Background Alcohol use is increasingly recognized as a significant modifier of Alzheimer's disease (AD) risk and progression. Two key organs, the liver and the brain, are central to understanding the impact of alcohol intake on AD. This is due to the liver being the primary site of alcohol detoxification and a major target of alcohol-induced injury, while the brain harbors the neuropathological hallmarks of AD. Although growing literature now links liver dysfunction to AD pathogenesis, the molecular mechanisms linking peripheral alcohol-induced liver injury to brain pathology remain poorly defined. To address this gap, we performed what is, to the best of our knowledge, the first integrated, multi-organ spatial transcriptomic analysis of liver and brain tissue from APP/PS1 AD mice subjected to chronic intragastric alcohol feeding. Methods Following five-weeks of either control- or alcohol-diet feeding of APP/PS1 mice, differentially expressed genes (DEGs) were quantified in postmortem tissue across regions of interest (ROIs) spanning periportal and perivenous liver zones, along with Aβ plaque-bearing and Aβ plaque-free regions of the cortex and hippocampus in the brain. Pathway and network analyses were then used to identify candidate hub genes and biological processes altered within and across ROIs, followed by in silico nomination of therapeutic targets and drug repurposing compounds. Results Following alcohol exposure, the most prominent transcriptional changes in the liver occurred in the perivenous zone, followed by the periportal zone. Among brain ROIs, the strongest differential expression occurred in the plaque-bearing hippocampus, with few or no DEGs detected in the remaining ROIs. These findings highlight Aβ pathology-dependent and region-selective tissue vulnerability to alcohol in the brain and liver during AD. Accordingly, cross-tissue comparisons focused on the plaque-bearing hippocampus and liver ROIs. This revealed coordinated molecular perturbations, including shared downregulation of S100a8 and Tmem267 , as well as opposing regulation of Lrp1 , Osgin1 , and Cpsf7 between the plaque-bearing hippocampus and perivenous liver ROIs, respectively. Enrichment analyses indicated convergent dysregulation of cytoplasmic processes, metal ion homeostasis, redox/oxidative stress responses, mitochondrial pathways, and immune signaling. Although no gene-level overlap was observed, identified candidate therapeutic compounds and targets converged on pathways regulating metabolic sensing, kinase and phosphatase balance, proteostasis, inflammation, autophagy, and neurovascular signaling, which are central to aging biology, chronic alcohol exposure, and AD. Conclusion These findings implicate significant liver-brain crosstalk through which chronic alcohol exposure may modulate AD-relevant pathology and reinforce the growing recognition of the liver as a critical organ in AD pathogenesis. Furthermore, these results reveal key alcohol-driven hepatic and brain gene perturbations and dysregulated pathways relevant to AD along with actionable therapeutic targets for future investigation.},
}

@article {pmid42687952,
year = {2026},
author = {Illán-Gala, I and Vera, E and Selma-González, J and Rodríguez-Baz, Í and Abdelnour, C and Rodriguez-Porcel, F and Wyman-Chick, K and Toledo, J and Ferreira, D and Habich, A and Sala-Matevera, I and Peris-Subiza, J and García-Castro, J and Rubio-Guerra, S and Dols-Icardo, O and Belbin, O and Fortea, J and Lleó, A and Alcolea, D},
title = {Pre-dementia clinical trajectories associated with neuronal α-synuclein neuropathologic change: a retrospective cohort study.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10788306/v1},
pmid = {42687952},
issn = {2693-5015},
abstract = {Biological definitions of neuronal α-synuclein disease are advancing diagnosis beyond traditional clinical syndromes, but the trajectories preceding dementia and the influence of concomitant Alzheimer pathology remain uncertain. We analyzed longitudinal data from 1,543 participants without dementia at baseline who underwent repeated cognitive, functional, neuropsychiatric, and motor assessments and had neuropathological characterization at autopsy. Participants were classified as having neuronal α-synuclein neuropathologic change (NSNC), Alzheimer's disease neuropathologic change (ADNC), or both. NSNC without intermediate or high ADNC was associated with the greatest motor burden. Among participants without mild cognitive impairment at baseline, concomitant ADNC was associated with earlier cognitive impairment and faster cognitive decline; mixed NSNC/ADNC also showed faster functional worsening than NSNC alone. Across participants with NSNC, baseline mild cognitive impairment, neuropsychiatric manifestations and concomitant ADNC predicted progression to dementia, whereas prespecified motor signs did not. These findings reveal heterogeneous pre-dementia trajectories and support combining α-synuclein detection with Alzheimer biomarkers, cognitive staging and multidomain clinical measures to improve prognosis and trial design.},
}

@article {pmid42687965,
year = {2026},
author = {Zeidan, HM and Shah, GH and Zeidan, IH and Samawi, HM and Jones, JA},
title = {Association between Internet Use for Health Information and Self-reported Alzheimer's Disease Diagnosis among Older Adults in the United States: Racial and Gender Disparities.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10570409/v1},
pmid = {42687965},
issn = {2693-5015},
abstract = {UNLABELLED: Background Alzheimer's disease (AD) disproportionately affects racial and ethnic minority populations, reflecting broader inequities in access to diagnosis, treatment, and long-term care. As digital health technologies become increasingly widespread, understanding whether internet use for health information is associated with Alzheimer's disease diagnosis may inform strategies to address disparities in aging populations.

AIM: This study examined the association between internet use for health or medical information and AD diagnosis among older adults in the United States and assessed whether this association varied by race/ethnicity, gender, and socioeconomic status.

SUBJECT AND METHODS: Data were drawn from Round 13 (2024) of the National Health and Aging Trends Study, a nationally representative survey of adults aged 65 years and older. Internet use for health information was assessed via self-report, binary and multivariable logistic regression models estimated adjusted odds ratios for AD diagnosis, controlling for sociodemographic characteristics.

RESULTS: Internet use for health information was significantly associated with Alzheimer's disease diagnosis. Stratified analyses by race/ethnicity and gender showed consistent patterns, although no statistically significant interaction effects were observed.

CONCLUSION: These findings suggest that digital health engagement is associated with Alzheimer's disease diagnosis among older adults and underscore the importance of equitable and culturally responsive access to digital health resources to address persistent disparities in cognitive aging.},
}

@article {pmid42687999,
year = {2026},
author = {Hai, H and Li, M and Hu, X and Peng, J and He, Z},
title = {Targeting cellular senescence with Traditional Chinese Medicine: advances in neurodegenerative disorder treatment.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1875385},
pmid = {42687999},
issn = {1664-2295},
mesh = {Humans ; *Cellular Senescence/drug effects/physiology ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Medicine, Chinese Traditional/methods ; Animals ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; Signal Transduction/drug effects ; },
abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), represent formidable health challenges, particularly within aging populations. Cellular senescence, marked by irreversible cell cycle arrest and the secretion of pro-inflammatory cytokines, has emerged as a crucial factor in the pathogenesis of these disorders. The accumulation of senescent cells in the nervous system exacerbates neuroinflammation, impairs neuronal function, and accelerates tissue degeneration, all of which are key features of NDDs. In this context, bioactive components derived from Traditional Chinese Medicine (TCM) have attracted significant attention for their potential to modulate cellular senescence and alleviate neurodegeneration. This review examines the shared molecular signaling pathways linking cellular senescence to NDDs, explores the mechanisms by which TCM-derived compounds-such as ginsenosides, ginkgo biloba extract, and curcumin-intervene in senescence-related processes, and discusses the translational potential of these natural compounds for clinical application.},
}

Humans
*Cellular Senescence/drug effects/physiology
*Neurodegenerative Diseases/drug therapy/metabolism
*Medicine, Chinese Traditional/methods
Animals
*Drugs, Chinese Herbal/therapeutic use/pharmacology
Signal Transduction/drug effects

@article {pmid42688049,
year = {2026},
author = {Hu, M and Sun, Z and Mao, D and Tian, X and Shang, Q},
title = {Temporal trends in the prevalence of Alzheimer's disease, 1980-2024: a systematic review and meta-analysis.},
journal = {Frontiers in public health},
volume = {14},
number = {},
pages = {1884058},
pmid = {42688049},
issn = {2296-2565},
mesh = {*Alzheimer Disease/epidemiology ; Humans ; Prevalence ; Female ; Male ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the primary cause of dementia and represents a significant public health concern in aging populations. Existing evidence indicates geographic and sex-related differences in AD prevalence; however, comparability across time periods and diagnostic criteria is limited, and data from lower-resource regions remain scarce. This study synthesized evidence on reported AD prevalence from 1980 to 2024 and examined temporal, geographic, demographic, and methodological variation.

METHODS: PubMed, Web of Science, and Embase were systematically searched from inception to December 31, 2024, for observational studies reporting AD prevalence in general or community-based populations. Eligible studies reported prevalence estimates with 95% confidence intervals or provided sufficient data for calculation. Studies with sample sizes below 100 and non-original reports were excluded. Two reviewers independently screened studies and extracted data; disagreements were resolved by a third reviewer. Pooled reported prevalence was estimated using a random-effects model. The review was prospectively registered in PROSPERO (CRD420251111597).

RESULTS: Fifty-two studies from 19 countries met the inclusion criteria. The pooled reported prevalence of AD was 4.43 per 100 population (95% CI 3.47-5.50). Prevalence was higher among females (4.65 per 100, 95% CI 3.37-6.13) than males (2.30 per 100, 95% CI 1.71-2.97). By survey period, reported prevalence was 3.52 per 100 for 1980-1989, 4.21 for 1990-1999, 4.12 for 2000-2009, and 6.78 for 2010-2024. Adjusted meta-regression did not identify a significant association between survey year and reported prevalence. Estimates also varied by WHO region, Human Development Index (HDI) level, sample size, and study design.

CONCLUSIONS: Reported AD prevalence was substantial and varied by demographic, geographic, and methodological factors. Although prevalence was highest in the most recent survey period, meta-regression did not indicate a consistent global increase over time. Given the extremely high between-study heterogeneity, these findings should be interpreted with caution. More standardized, age-comparable, and geographically representative studies are needed, particularly in underrepresented and lower-resource settings.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251111597, identifier CRD420251111597.},
}

*Alzheimer Disease/epidemiology
Humans
Prevalence
Female
Male

@article {pmid42688072,
year = {2026},
author = {Chen, J and Chen, X and Yu, W and Chen, T and Liu, Z and Hu, J},
title = {Multi-omics integration identifies a gut-microbiota-associated plasma metabolite signature for alzheimer disease diagnosis and metabolic pathway targeting.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1933454},
pmid = {42688072},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia, with early diagnosis remaining constrained by the invasiveness and limited accessibility of current biomarkers. The gut-brain axis has emerged as a critical communication network linking intestinal homeostasis with central nervous system function, yet the diagnostic utility of gut-microbiota-associated circulating metabolites in AD remains largely unexplored.

METHODS: In this case-control study, 85 participants (37 AD patients and 48 cognitively normal controls) were enrolled. Targeted plasma metabolomics using four complementary UPLC-MS/MS assays covering 375 endogenous metabolites was integrated with fecal metagenomic sequencing in 72 participants with paired samples. Differential metabolites were screened using the Mann-Whitney U test, orthogonal partial least squares discriminant analysis, and fold-change thresholds. Gut-microbiota-associated plasma metabolites were defined through Spearman correlation with linear discriminant analysis effect size-identified differential bacterial species. A diagnostic panel was constructed using least absolute shrinkage and selection operator logistic regression with stability selection, and its performance was evaluated by support vector machine with repeated cross-validation, with age and sex evaluated as covariates.

METHODS: We identified 27 differential plasma metabolites enriched in tricarboxylic acid cycle and amino acid metabolic pathways. Correlation analysis identified 10 gut-microbiota-associated plasma metabolites significantly associated with gut microbial alterations. A three-metabolite panel (citric acid, 3-hydroxyoctanoic acid, and glyoxylic acid) achieved a cross-validated area under the curve of 0.865, with a modest sensitivity of 62.2% and specificity of 100.0%, positioning it as a confirmatory auxiliary tool rather than a broad screening instrument. The panel score correlated negatively with Mini-Mental State Examination scores (r = -0.544, P < 0.001), and integration with clinical cognitive assessment yielded an area under the curve of 0.978.

CONCLUSION: These findings potentially advance the translational understanding of the gut-brain metabolic axis in neurodegeneration and support the exploratory clinical utility of microbiota-linked peripheral metabolic signatures as non-invasive auxiliary diagnostic tools for AD, awaiting external validation in larger, multi-center cohorts.},
}