@article {pmid42878720,
year = {2026},
author = {Hariharan, A and Vigderman, A and Isaacs, DP and Weir, N and Park, G and Edwards, S and Longden, TA},
title = {Early disruptions in brain capillary blood flow control in a mouse model of Alzheimer's disease.},
journal = {The Journal of general physiology},
volume = {158},
number = {6},
pages = {},
doi = {10.1085/jgp.202614014},
pmid = {42878720},
issn = {1540-7748},
support = {R01AG066645//NIH National Institute on Aging/ ; DP2NS121347/NS/NINDS NIH HHS/United States ; 5F31NS139505/NS/NINDS NIH HHS/United States ; R01NS138179/NS/NINDS NIH HHS/United States ; R21NS142439/NS/NINDS NIH HHS/United States ; CP2-1-0000000385//Chan Zuckerberg Initiative/ ; 830093//American Heart Association/ ; https://doi.org/10.58275/AHA.26CDA1592450.pc.gr.243187//D.C. Women's Board/ ; 26CDA1592450//D.C. Women's Board/ ; },
mesh = {Animals ; *Alzheimer Disease/physiopathology/metabolism ; *Cerebrovascular Circulation/physiology ; Disease Models, Animal ; *Capillaries/physiopathology/metabolism ; *Brain/blood supply/physiopathology/metabolism ; Mice ; Mice, Transgenic ; KATP Channels/metabolism ; Humans ; },
abstract = {In Alzheimer's disease (AD), vascular dysfunction and impaired control of brain blood flow can disrupt cellular bioenergetics decades before cognitive decline. Identifying the earliest vascular changes is therefore critical for developing therapies that intervene before the cascading events leading to neuronal decline. Brain energy supply is dynamically controlled by the cerebral vasculature, where capillary thin-strand pericytes are emerging as key players. We recently identified a central role for ATP-sensitive potassium (K+, KATP) channels in enabling thin-strand pericytes to sense local neuronal activity and generate hyperpolarizing signals that are transmitted via capillary endothelial cells to upstream arterioles, eliciting increases in blood flow. Importantly, thin-strand pericyte KATP channels are the centerpiece of an electro-metabolic "energy switch" mechanism that couples decreases in local glucose to hyperemia, providing a failsafe to ensure continual energy substrate supply to support neuronal function. Disruption of this mechanism could therefore precipitate an imbalance between demand and supply, creating an energy gap for neurons that leads to deleterious consequences. We demonstrate that capillary control of blood flow is disrupted in the early stages of disease progression in mice expressing familial AD mutations (5xFAD). Transgenic 5xFAD mice exhibit early disruption of capillary signaling, beginning with dysfunctional endothelial inward rectifier K+ (Kir)2.1 channels at 2-4 mo, disabling transmission of KATP-mediated signals to upstream blood flow control machinery, followed by direct impairment of pericyte KATP channel function by 6-8 mo. Together, these deficits cause early and sustained failure of electrical signaling from deep capillary pericytes to upstream arterioles and arteriole-capillary transition (ACT) zone vessels, limiting KATP-dependent energy-switch-mediated blood flow control. Our findings define a temporal and mechanistic framework linking familial AD mutations to early capillary signaling dysfunction and highlight preservation of capillary blood flow control as a potential therapeutic target to protect against downstream effects of amyloid β accumulation.},
}

Animals
*Alzheimer Disease/physiopathology/metabolism
*Cerebrovascular Circulation/physiology
Disease Models, Animal
*Capillaries/physiopathology/metabolism
*Brain/blood supply/physiopathology/metabolism
Mice
Mice, Transgenic
KATP Channels/metabolism
Humans

@article {pmid42878916,
year = {2026},
author = {Abbas, T and Rashid, S and Imran, M},
title = {Fractional-order dynamical modelling of neurophysiological reaction-diffusion model of adiposity-induced cognitive decline using physics-informed neural networks.},
journal = {Journal of biological physics},
volume = {52},
number = {1},
pages = {},
pmid = {42878916},
issn = {1573-0689},
mesh = {Diffusion ; *Neural Networks, Computer ; Humans ; *Cognitive Dysfunction/etiology/physiopathology ; *Adiposity ; *Models, Neurological ; },
abstract = {Obesity, hyperglycemia, and aging are major risk factors for dementia-related disorders, particularly Alzheimer's disease. We develop a time-fractional reaction-diffusion mathematical framework integrating nine interacting biological compartments governed by Michaelis-Menten kinetics and Hill functions to characterize the nonlinear interplay between metabolic dysfunction and neurodegeneration. Rigorous analysis establishes boundedness, stability, and the existence of a global attractor describing long-term system behavior. To enhance biological realism and predictive capability, we implement fractional physics-informed neural networks that embed fractional partial differential equations within deep learning architectures. This approach captures memory-dependent and spatiotemporal diffusion dynamics characteristic of neurological disorders while enabling estimation of time-varying parameters, fractional orders, and latent states. Global sensitivity analysis using partial-rank correlation coefficients identifies key drivers of tau pathology, insulin dysregulation, and dementia progression. Simulations reveal heterogeneous diffusion patterns linking obesity to accelerated neurodegenerative processes. An optimal control framework incorporating behavioral interventions and personalized anti-amyloid therapies is proposed to delay obesity-induced cognitive decline. The model highlights the critical roles of neuroinflammation and blood-brain barrier permeability in disease acceleration. The proposed FPI-NN framework achieves high predictive accuracy, with R 2 values of 0.95, 0.93, 0.92, and 0.92 for Y 1 , W β , W τ , and V d , respectively. The corresponding RMSE values are 0.078, 0.094, 0.098, and 0.099, while the MAE values are 0.065, 0.079, 0.082, and 0.084, respectively. The MAPE values are 6.50 % , 7.90 % , 8.20 % , and 8.40 % , respectively. Cross-validation further confirms the stability and robustness of the proposed framework. This work provides a reproducible and interpretable computational platform for modeling fractional-order neurodegenerative dynamics and optimizing therapeutic strategies in obesity-associated dementia.},
}

Diffusion
*Neural Networks, Computer
Humans
*Cognitive Dysfunction/etiology/physiopathology
*Adiposity
*Models, Neurological

@article {pmid42878972,
year = {2026},
author = {Kumar, S and Paswan, SK and Verma, P and Chaturvedi, S and Vishwakarma, VK and Yadav, HN},
title = {Molecular Pathogenesis of Cerebral Amyloid Angiopathy in Alzheimer's Disease: The Role of the Central Fibrinolytic Cascade at the Neurovascular Unit.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42878972},
issn = {1559-1182},
mesh = {Humans ; *Cerebral Amyloid Angiopathy/pathology/metabolism ; *Alzheimer Disease/pathology/metabolism ; Animals ; *Fibrinolysis/physiology ; Amyloid beta-Peptides/metabolism ; Blood-Brain Barrier/pathology/metabolism ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a multifactorial neurodegenerative disorder involving complex neurovascular pathology. Departing from classic neurocentric paradigms, this review provides a conceptually novel perspective on how vascular inflammation and dysfunction actively drive AD progression through the lens of cerebral amyloid angiopathy (CAA) pathology. We evaluate the bidirectional cascade between amyloid-β pathology and the neurovascular unit, highlighted by cerebrovascular alterations and blood-brain barrier disruption. Crucial for cerebral homeostasis, the central nervous system's fibrinolytic pathway plays a dual role in this cascade, where the dysregulation of tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), and plasminogen accelerates CAA. We posit that suppressed fibrinolytic activity impedes amyloid-β clearance, while aberrant plasminogen-amyloid-β interactions paradoxically trigger localized inflammatory and thrombotic cascades that exacerbate vascular injury. By looking beyond traditional, neuron-centered models of Alzheimer's, fibrinolytic regulation and vascular repair offer a powerful new way to intervene. Bringing these discoveries to the clinic means finding a way to clear amyloid-β without tipping the scale toward bleeding risks. If we can map these complex vascular-fibrinolytic links, we can open the door to early intervention to design targeted therapies that prevent vascular damage and fundamentally change the trajectory of CAA and Alzheimer's disease.},
}

Humans
*Cerebral Amyloid Angiopathy/pathology/metabolism
*Alzheimer Disease/pathology/metabolism
Animals
*Fibrinolysis/physiology
Amyloid beta-Peptides/metabolism
Blood-Brain Barrier/pathology/metabolism

@article {pmid42879058,
year = {2026},
author = {Liu, Y and Xu, J and Wang, X and Liu, L and Ren, X and Gong, Y and Miao, C and Sun, M and Zhou, S and Guo, X and Yuan, L},
title = {Docosahexaenoic acid remodels lipid composition of lipid rafts and mitochondrial function in ApoE4/4 mouse brain: a multi-omic investigation.},
journal = {Molecular biomedicine},
volume = {7},
number = {1},
pages = {},
pmid = {42879058},
issn = {2662-8651},
support = {82173508//National Natural Science Foundation of China/ ; CNS-NCL2024-04//Nutrilite Plant Functional Components and Health Research Fund of Chinese Nutrition Society/ ; QY25427//Beijing Natural Science Foundation/ ; },
mesh = {Animals ; *Membrane Microdomains/metabolism/drug effects ; *Docosahexaenoic Acids/pharmacology ; *Brain/metabolism/drug effects/pathology ; *Mitochondria/metabolism/drug effects ; Female ; *Apolipoprotein E4/genetics/metabolism ; Mice ; Lipidomics ; Lipid Metabolism/drug effects ; Alzheimer Disease/metabolism ; Mice, Transgenic ; Humans ; },
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disorder lacking curative therapies, with ApoE4 as the strongest genetic risk factor driving lipid dyshomeostasis and neuronal damage in the central nervous system. Lipid rafts, cholesterol- and sphingolipid-rich membrane microdomains, govern key neuronal signalling, and dysfunction of these microdomains mediates the progression of preclinical pathological lesions in ApoE4 carriers. Dietary docosahexaenoic acid (DHA) is widely reported to mitigate brain lipid disorders, yet how DHA remodels subfractions of lipid raft and non-raft membrane domains to rescue ApoE4-related energy metabolism disorder remains unclear. Most existing studies have only quantified total brain lipids without distinguishing membrane subdomains, and few characterized the liver-brain metabolic axis underlying ApoE4-associated neurodegeneration. We constructed female ApoE3/3 and ApoE4/4 knock-in mice with 6- and 12-month DHA dietary interventions, combining behavioral, histological, lipidomic and proteomic assays to characterize genotype-specific lipid remodelling and downstream mitochondrial changes. Here we show that ApoE4 mice develop severe hepatic steatosis, neuroinflammation and lipid raft rigidification characterized by elevated sulfatides and ceramides levels, DHA upregulates Lpin1, Atgl and nSMase2 while suppressing Acer3 and Sgms2, thereby rebalancing lipids raft and restoring mitochondrial bioenergetics. Our work resolves raft and non-raft lipid profiles in ApoE humanized mice, and links peripheral hepatic metabolic disturbances to cerebral membrane microdomain dysfunction. These multi-omics mechanistic findings advance genotype-specific preventive nutritional strategies for ApoE4 carriers and reveal potential subcellular lipid targets for early AD intervention.},
}

Animals
*Membrane Microdomains/metabolism/drug effects
*Docosahexaenoic Acids/pharmacology
*Brain/metabolism/drug effects/pathology
*Mitochondria/metabolism/drug effects
Female
*Apolipoprotein E4/genetics/metabolism
Mice
Lipidomics
Lipid Metabolism/drug effects
Alzheimer Disease/metabolism
Mice, Transgenic
Humans

@article {pmid42879070,
year = {2026},
author = {Ferrari, RR and Garofalo, M and Di Gerlando, R and Pellegrini, E and Dragoni, F and Rizzo, B and Rossi, M and Calatozzolo, C and Guaita, A and Davin, A and Gagliardi, S and Poloni, TE},
title = {A pattern to rule them all: tracing a human brain map of molecular aspects shared by Alzheimer's disease and dementia with Lewy bodies.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42879070},
issn = {2509-2723},
abstract = {Alzheimer's disease (AD) and dementia with Lewy bodies (LBD) are the most widespread forms of degenerative dementia. However, little is known about the molecular aspects that link these conditions with each other and with aging itself. Whole transcriptome analysis and Gene Set Enrichment Analysis (GSEA) have been carried out on brain samples from hippocampus (HI), temporal and parietal cortex (TC, PC), cingulate cortex (CG), and substantia nigra (SN) of subjects with a neuropathological diagnosis of AD or LBD. According to the Abbiategrasso Brain Bank (ABB) protocol, the neuropathological diagnosis was based on a complete histological characterization, including all the main proteinopathies and vascular scoring. Transcriptomic results show major differences in the number of differentially expressed genes (DEGs) between the two pathologies. In AD, gene expression is more affected compared to LBD. DEGs have peculiar spatial distribution: HI and TC show transcriptomic changes related to synapses, while in CG, SN, and PC, changes are related to proteostasis; in LBD, DEGs are predominant in SN and PC affecting proteostasis, oxidative stress, and inflammation. In AD, GSEA shows that different regions cluster by shared biological processes. AD appears much more complex, and different forms of AD do exist. Nonetheless, the molecular signature of same regions across the two pathologies can be interestingly overlapped. Exploring the molecular processes that occur before the deposition of pathological lesions may reveal individual neurodegeneration trajectory to achieve personalized therapies, which could be much more effective than the mere immunological removal of protein deposits.},
}

@article {pmid42879228,
year = {2026},
author = {Di Domenico, C and Bonarota, S and Caruso, G and Sperati, S and Di Lorenzo, F and Rodini, M and Caltagirone, C and Koch, G and Giove, F and Bozzali, M and Serra, L},
title = {Retrieval-induced forgetting and facilitation across the Alzheimer's disease continuum: Behavioral and neuroanatomical evidence from a recognition-based paradigm.},
journal = {Neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/neu0001126},
pmid = {42879228},
issn = {1931-1559},
support = {//Ministero della Salute/ ; },
abstract = {OBJECTIVE: The aim of the present study was to investigate facilitation (FAC) and retrieval-induced forgetting (RIF) during episodic memory retrieval across the Alzheimer's disease (AD) continuum and to examine their gray matter correlates in verbal and visual recognition tasks.

METHOD: One hundred participants (28 AD, 29 amnestic mild cognitive impairment, 23 subjective cognitive decline [SCD], 20 healthy subjects) completed a modified retrieval-practice paradigm (mRPP) involving verbal and visual recognition tasks, a comprehensive neuropsychological battery, and 3T magnetic resonance imaging. FAC and RIF were computed at the group level and via individual proxy scores, and voxel-based morphometry was used to assess the association between mRPP indices and regional gray matter volumes.

RESULTS: The verbal mRPP showed reduced overall recognition in AD compared with healthy subjects (p = .003 - ηp² = 0.23). A robust FAC effect in AD, amnestic mild cognitive impairment, and SCD was observed, whereas RIF emerged only in SCD, suggesting intact inhibitory control at the earliest stage and its disruption with disease progression (p < .001 - ηp² = 0.48). The visual mRPP showed a strong FAC effect across all groups, with no RIF, indicating modality-specific reliance on recognition-based retrieval (p < .001 - ηp² = 0.63). Voxel-based morphometry analyses revealed distinct gray matter correlates across groups and tasks: Verbal RIF was negatively associated with frontotemporal regions in AD patients and parieto-occipital regions in healthy subjects, while visual indices showed widespread associations with temporal, subcortical, cerebellar, and sensorimotor regions, particularly in amnestic mild cognitive impairment and SCD groups.

CONCLUSIONS: This study shows shared and modality-specific brain mechanisms of retrieval practice across AD stages. Preserved compensatory processes in SCD individuals give way to progressive regional disruption, supporting early, modality-tailored, and multimodal cognitive interventions to enhance cognition and delay cognitive decline. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid42879726,
year = {2026},
author = {Reynolds, EL and Elafros, MA and Muthukumar, L and Shippey, E and Budhu, JA and Terman, SW and Burke, JF and Callaghan, BC},
title = {Predictors of Antiamyloid Medication Utilization and Adherence Among People With Alzheimer Disease and Mild Cognitive Impairment.},
journal = {Neurology},
volume = {107},
number = {9},
pages = {e218594},
doi = {10.1212/WNL.0000000000218594},
pmid = {42879726},
issn = {1526-632X},
mesh = {Humans ; Female ; *Alzheimer Disease/drug therapy ; Male ; Aged ; *Cognitive Dysfunction/drug therapy ; Aged, 80 and over ; Antibodies, Monoclonal, Humanized/therapeutic use ; *Drug Monitoring ; *Medication Adherence ; },
abstract = {BACKGROUND AND OBJECTIVES: From 2021 to 2024, 3 amyloid monoclonal antibody medications (aducanumab, lecanemab, and donanemab) were approved by the US Food and Drug Administration for treatment of mild cognitive impairment (MCI) and mild dementia due to Alzheimer disease (AD). We determined the demographics and social drivers of health associated with utilization and initial adherence of these medications.

METHODS: We used the Vizient database to identify patients with MCI or dementia using an ICD-10 coding definition. Propensity score matching was used to match patients who received an antiamyloid medication to those who did not, based on date of MCI/dementia diagnosis and follow-up. Social drivers of health were assessed using the Vizient Vulnerability Index (VVI), a neighborhood-level measure of socioeconomic vulnerability. Logistic regression determined associations between demographics, Elixhauser comorbidity, and VVI, with utilization of antiamyloid medications. Poisson regression determined associations between demographic, Elixhauser comorbidity, and VVI and initial adherence (measured as days supplied) of antiamyloid medications.

RESULTS: We identified 1,198,362 participants with MCI/dementia, of whom 2,427 (0.2%) were prescribed an antiamyloid medication. Of those prescribed an antiamyloid medication, 1,696 (69.9%) were matched to participants with MCI/dementia that were not prescribed antiamyloid medications (mean age 75.5 [SD 9.5], 56.1% female, 80.1% non-Hispanic White). We found that higher age (odds ratio [OR] 0.93, 95% CI 0.92-0.94), higher Elixhauser comorbidity index (OR 0.56, 95% CI 0.52-0.59), being non-Hispanic Black (OR 0.14, 95% CI 0.09-0.23), and being Hispanic (OR 0.21, 95% CI 0.13-0.36) associated with lower odds of receiving an antiamyloid medication. Furthermore, having greater VVI was associated with lower odds of receiving an antiamyloid medication. By contrast, only higher Elixhauser comorbidity score was associated with lower initial medication adherence (rate ratio 0.94, 95% CI 0.93-0.96), but not age, sex, race/ethnicity, and overall vulnerability.

DISCUSSION: We found that younger, non-Hispanic White patients, with fewer comorbidities, and lower vulnerability, were more likely to receive antiamyloid medications. By contrast, among patients receiving an antiamyloid medication, only higher comorbidity score associated with lower initial medication adherence. These findings indicate a potential disparity in medication access for US patients with MCI/dementia that could become problematic barriers to care as medications for dementia continue to evolve.},
}

Humans
Female
*Alzheimer Disease/drug therapy
Male
Aged
*Cognitive Dysfunction/drug therapy
Aged, 80 and over
Antibodies, Monoclonal, Humanized/therapeutic use
*Drug Monitoring
*Medication Adherence

@article {pmid42879727,
year = {2026},
author = {Planche, V and Bouteloup, V and Pellegrin, I and Mangin, JF and Dubois, B and Ousset, PJ and Pasquier, F and Blanc, F and Paquet, C and Hanon, O and Bennys, K and Ceccaldi, M and Annweiler, C and Krolak-Salmon, P and Godefroy, O and Wallon, D and Sauvee, M and Boutoleau-Bretonnière, C and Bourdel-Marchasson, I and Jalenques, I and Chene, G and Dufouil, C},
title = {Validity and Performance of Blood Biomarkers for Alzheimer Disease to Predict Dementia Risk in a Large Clinic-Based Cohort.},
journal = {Neurology},
volume = {107},
number = {9},
pages = {e218790},
doi = {10.1212/WNL.0000000000218790},
pmid = {42879727},
issn = {1526-632X},
}

@article {pmid42879974,
year = {2026},
author = {Elbatawy, A and Elbanoby, T},
title = {Deep cervical lymphaticovenous anastomosis for Alzheimer disease: A critical narrative assessment and translational framework.},
journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia},
volume = {155},
number = {},
pages = {112349},
doi = {10.1016/j.jocn.2026.112349},
pmid = {42879974},
issn = {1532-2653},
abstract = {Deep cervical lymphaticovenous anastomosis (dcLVA) has been proposed to augment cerebral waste clearance in Alzheimer disease. This critical narrative assessment examines the mechanistic premise, available human reports, registered studies, and governance implications. Experimental loss-of-function and gain-of-function studies support a role for meningeal lymphatics in brain-fluid homeostasis, but they do not establish a rate-limiting cervical outflow abnormality in human Alzheimer disease. The clinical reports identified through this narrative search were uncontrolled single-arm investigations, including patients with severe impairment, substantial attrition, and outcomes vulnerable to floor effects and perioperative influences. Randomised studies are now recruiting. Their value will depend on whether they measure intervention-specific flow, target engagement, clinically meaningful outcomes, and harms. The procedure should remain investigational until studies demonstrate intervention-specific biological target engagement, controlled clinical benefit, and acceptable long-term safety.},
}

@article {pmid42879978,
year = {2026},
author = {Rebord, F and Picciuto, O and Laner, J and Champendal, M and Sá Dos Reis, C},
title = {Behavioural and environmental strategies implemented by radiographers to care for patients with neurocognitive disorders during medical imaging and therapeutic procedures.},
journal = {Radiography (London, England : 1995)},
volume = {32},
number = {8},
pages = {103596},
doi = {10.1016/j.radi.2026.103596},
pmid = {42879978},
issn = {1532-2831},
abstract = {INTRODUCTION: As the population ages, radiographers are increasingly likely to care for patients with dementia, Alzheimer's disease and other neurocognitive disorders in medical imaging or radiation therapy departments. Since the cognitive and behavioural presentation of these patients can vary, radiographers must be prepared to adapt their approach. To investigate behavioural and environmental strategies used by radiographers when caring for patients with neurocognitive disorders (NCDs) during medical imaging and radiation therapy procedures.

METHODS: A cross-sectional survey comprising 18 questions was conducted among radiographers working across medical imaging and radiotherapy modalities. The questionnaire explored attitudes towards patients with NCDs, behavioural communication strategies, environmental adaptations, and institutional support measures. Descriptive statistics and thematic analysis of open-ended responses were performed.

RESULTS: A total of 160 radiographers participated. Most respondents reported positive attitudes toward patients with NCDs, with 94% indicating no fear when interacting with this population. Behavioural communication strategies were frequently used, particularly maintaining eye contact (85%), using simple language (80%), and speaking slowly and clearly (76%). Caregivers were commonly involved to facilitate communication (81%). Despite this, 45% of radiographers reported frustration at not always knowing how to help effectively. Institutional environmental adaptations were limited, with most participants reporting no dementia-specific training (85%) or departmental protocols (78%).

CONCLUSION: Radiographers frequently implement behavioural strategies to support patients with NCDs, but this relies on individual initiative rather than structured organisational support, which remains limited.

IMPLICATIONS FOR PRACTICE: Radiographers should use clear, simple communication strategies with NCD patients, involve caregivers during imaging procedures, and develop dementia-specific training and departmental protocols.},
}

@article {pmid42880003,
year = {2026},
author = {Dharia, SY and Valderrama, CE and Smith, SD},
title = {Cross-cohort transfer of clinical Alzheimer's EEG signatures to cognitively healthy APOE-ε4 and PICALM rs3851179 risk carriers using differentiable logic gate networks.},
journal = {Computers in biology and medicine},
volume = {217},
number = {},
pages = {111981},
doi = {10.1016/j.compbiomed.2026.111981},
pmid = {42880003},
issn = {1879-0534},
abstract = {Neural alterations associated with Alzheimer's disease (AD) may emerge years before clinical diagnosis, and genetic risk factors such as APOE-ε4 and PICALM rs3851179 may identify individuals vulnerable to these shifts. We tested whether electroencephalography (EEG) signatures learned from clinically diagnosed AD patients transfer to cognitively healthy middle-aged adults carrying these variants. Differentiable logic gate networks (Diff-Logic) and neural baselines were trained on log-relative power spectral density features from a clinical cohort of AD patients and cognitively normal (CN) controls. These models were then applied without retraining to an independent genetic-risk cohort of neutral-risk non-carriers (N), APOE-ε4-only carriers (A+P-), and dual APOE-ε4/PICALM G-allele carriers (A+P+), yielding a continuous AD-like EEG signature score per participant. Diff-Logic matched neural baselines in clinical classification (balanced accuracy 0.809±0.028; AUROC 0.845±0.023) while enabling edge inference with a 7.4× model-size reduction and 0.22 ms model-only latency on a 7 W single-core CPU. In the genetic-risk cohort, scores were highest in A+P+ participants (0.393±0.167) relative to N (0.296±0.154) and A+P- (0.285±0.143; subject-level mean ± SD). This elevation was nominally significant before correction (A+P+ vs. A+P-, punc=0.036) but did not survive Holm correction (pHolm=0.109), and the cohort carried no AD pathology or conversion ground truth; the association was therefore exploratory. Integrated gradients attribution of the trained model showed genetic-risk relevance in delta, theta, and alpha, partially overlapping clinical AD topography. These findings support the feasibility of zero-shot EEG transfer in genetically at-risk individuals and highlight the need for replication in larger cohorts. Code is publicly available at https://github.com/Shyamal-Dharia/ad-difflogic-transfer.},
}

@article {pmid42880054,
year = {2026},
author = {Benussi, A and Agosta, F and Agnello, L and Alfano, AR and Altini, M and Antico, A and Basilico, S and Bellelli, G and Bonanni, L and Bottini, G and Bozzali, M and Brignoli, O and Bruno, G and Cagnin, A and Calloni, SF and Cappa, SF and Caraci, F and Cecchin, D and Ciaccio, M and Cocozza, S and Cosottini, M and De Leo, D and Falini, A and Gaetani, L and Gandolfo, N and Gotta, F and Lodi, R and Logroscino, G and Marcello, E and Marra, C and Marrocco, W and Morbelli, S and Mecocci, P and Mossello, E and Palleschi, L and Palumbo, P and Pantoni, L and Parnetti, L and Roccatagliata, L and Sorbi, S and Spadin, P and Splendiani, A and Tessitore, A and Ungar, A and Zappalà, G and Padovani, A},
title = {Updated Italian intersocietal recommendations for the appropriate use of anti-amyloid monoclonal antibodies in Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {10},
pages = {100685},
doi = {10.1016/j.tjpad.2026.100685},
pmid = {42880054},
issn = {2426-0266},
abstract = {With the European authorisation of lecanemab and donanemab, Italy is entering the era of disease-modifying therapy for early symptomatic Alzheimer's disease. The Italian Expert Panel on Alzheimer (EPA), which convened 21 scientific societies and patient associations and published a first set of intersocietal recommendations in 2025, was reconvened in Rome on 24 January 2026 (EPA2) to address the operational gaps that had emerged during the implementation of that document. A modified Delphi process was adopted to formalise consensus on the most controversial points raised during the meeting. Thirty-six declarative statements covering five domains, namely the tiered organisation of the Centres for Cognitive Disorders and Dementia (CDCD), clinical staging and treatment monitoring, eligibility considerations in mild cognitive impairment and atypical phenotypes, composition of the multidisciplinary team, and magnetic resonance imaging thresholds, ARIA monitoring and biomarker pathway, were submitted to a multidisciplinary panel of experts. Strong agreement was reached on the large majority of statements, providing quantitative endorsement for a competence-based reorganisation of the CDCD network, the harmonised use of the Clinical Dementia Rating, an explicit composition of the multidisciplinary team, trial-aligned magnetic resonance imaging eligibility criteria with a move towards risk-adapted ARIA monitoring, and a stepwise biomarker pathway integrating plasma assays, cerebrospinal fluid analysis on automated platforms and amyloid positron emission tomography. The document provides Italian regional and national health systems, prescribing centres and reimbursing authorities with a quantitative blueprint for the appropriate, equitable and sustainable use of anti-amyloid monoclonal antibodies in clinical practice.},
}

@article {pmid42880056,
year = {2026},
author = {Wang, M and Li, J and Wang, X and Chai, X and Luo, J and Zhang, Y and Chang, X and Sun, Y and Wang, H},
title = {Harnessing cGAS-STING in neurodegeneration: From mitochondrial DNA leakage and microglial reactivity to species-specific translational barriers.},
journal = {Cytokine & growth factor reviews},
volume = {92},
number = {},
pages = {101537},
doi = {10.1016/j.cytogfr.2026.101537},
pmid = {42880056},
issn = {1879-0305},
abstract = {The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, a cornerstone of innate immunity, has emerged as a critical driver of sterile neuroinflammation in the aging brain. Age-related decline in mitochondrial quality control, coupled with nuclear and lysosomal erosion, fosters the aberrant accumulation of cytosolic self-DNA, establishing a permissive environment for chronic cGAS-STING activation. This review synthesizes recent breakthroughs elucidating how major neurodegenerative diseases-Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease-converge on this pathway through distinct, disease-specific triggers, ranging from PINK1/Parkin deficiency-driven mitochondrial DNA leakage to TDP-43 proteinopathy-associated retrotransposon de-repression. Critically, we evaluate the translational landscape, highlighting the profound challenge posed by species-specific pharmacology, as exemplified by the failure of the covalent inhibitor H-151 to engage human STING. We argue that the future of therapeutic intervention lies not in wholesale pathway ablation, but in nuanced, context-dependent fine-tuning that disentangles its detrimental chronic effects from its indispensable homeostatic functions. This review positions the cGAS-STING axis as a promising yet delicate frontier for combating age-related neurodegeneration.},
}

@article {pmid42880287,
year = {2026},
author = {Akay, LA and Bright, A and Dong, D and Smith, ED and Hurt, RC and Boix, CA and Louderback, K and Medrano, J and Sun, D and Lin, H and King, O and Welch, GM and Nawaid, H and Agbas, E and Jiang, A and Bubnys, A and Cheng, JX and Blanchard, JW and Tsai, LH},
title = {Genome-wide CRISPR screen reveals that Wnt signaling regulates lipid accumulation in APOE4 oligodendrocytes.},
journal = {Cell stem cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.stem.2026.09.012},
pmid = {42880287},
issn = {1875-9777},
abstract = {APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease, yet the cellular mechanisms linking APOE variants to disease risk remain unclear. We previously found that APOE4 expression causes lipid droplet accumulation in oligodendrocytes, reducing myelination, but the underlying mechanisms were unknown. Using a genome-wide CRISPR screen and assay for transposase-accessible chromatin (ATAC) sequencing in human-induced pluripotent stem cell (iPSC)-derived oligodendrocytes, we identified decreased Wnt signaling and overactive glycogen synthase kinase-3 beta (GSK3B) as key regulators of lipid-droplet accumulation. Genetic and pharmacological inhibition of GSK3B reduced lipid droplets in APOE4 oligodendrocytes and increased myelination in three-dimensional iPSC-derived brain organoids. Pharmacological GSK3B inhibition also reduced lipid droplets and improved myelination in APOE4;PS19 tau transgenic mice. Together, these findings establish a mechanistic framework linking Wnt/GSK3B signaling to APOE4-driven disruptions in oligodendrocyte lipid metabolism and myelination, pointing to GSK3B as a potential therapeutic target for APOE4-associated Alzheimer's disease.},
}

@article {pmid42880289,
year = {2026},
author = {Ma, K and Park, K and Honma, PS and Zhang, Y and Brady, E and Qiu, Y and Opitz-Araya, X and Ting, JT and Levi, BP and Akassoglou, K and Palop, JJ},
title = {Parvalbumin cell state dynamics regulate gamma oscillations and are disrupted in Alzheimer's disease.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.09.025},
pmid = {42880289},
issn = {1097-4199},
abstract = {Gamma oscillations are fundamental for cognitive processing, but the cellular and circuit dynamics that generate them remain poorly defined. Establishing a method for simultaneous calcium imaging and electrocorticography recordings in awake mice, we found that spontaneous gamma oscillations are accompanied by dynamic transitions between parvalbumin (PV) interneuron states. Rather than acting as a uniformly synchronized population, PV interneurons showed sequential recruitment, transient inactivation, and frequent transitions between activity states, indicating the formation of dynamic functional networks. In J20 Alzheimer's disease mice, these state transitions became dysregulated, leading to abnormal PV recruitment, impaired coupling between PV activity and gamma oscillations, and network hyperexcitability. Increasing interneuron excitability through expression of the voltage-gated sodium channel Nav1.1 restored PV cell dynamics, gamma oscillations, and network stability. These findings reveal dynamic PV cell states as an organizing feature of gamma oscillations and identify their disruption as a circuit mechanism of network dysfunction in Alzheimer's disease.},
}

@article {pmid42880555,
year = {2026},
author = {Ivantsova, E and Lu, A and Martyniuk, CJ},
title = {A comprehensive review of the neurobehavioral and neurotoxic effects of 6PPD-Q in fish, rodents, and humans.},
journal = {Neurotoxicology and teratology},
volume = {},
number = {},
pages = {107725},
doi = {10.1016/j.ntt.2026.107725},
pmid = {42880555},
issn = {1872-9738},
abstract = {N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) is a widely used tire additive that undergoes environmental transformation to 6PPD-quinone (6PPD-Q), which is ubiquitously detected in environmental matrices. Increasing evidence demonstrates that exposure to 6PPD-Q adversely affects organisms through neurobehavioral disruption and neurotoxicity. While studies document behavioral abnormalities and molecular alterations, a comprehensive synthesis linking these outcomes remains limited. The objective of this review was to synthesize current literature reporting neurobehavioral and neurotoxic effects of 6PPD-Q in fish, rodents, and humans using experimental and computational approaches. Using PRISMA guidelines, a search was conducted in PubMed and Google Scholar using several key phrases related to 6PPD-Q and neurotoxicity, capturing 1874 records. Relevant articles were assessed by full-text review for criteria eligibility, and the final review included 27 articles. In fish, exposure to 6PPD-Q can alter neurobehaviors like locomotor activity, anxiety-like responses, social and aggressive behaviors, and disturbances in circadian-regulated activities. Such behavioral outcomes correspond closely with neurotransmitter imbalance, neuroendocrine disruption, blood-brain barrier dysfunction, and transcriptome changes affecting neural signaling pathways. In rodents, repeated or chronic exposure to 6PPD-Q leads to neuronal damage, cognitive impairment, anxiety-like behavior, and memory deficits. Human biomonitoring and mechanistic studies further associate 6PPD-Q exposure with oxidative stress, mitochondrial dysfunction, and molecular responses relevant to neurological diseases. Leveraging the Comparative Toxicogenomics Database, computational analysis revealed entities associated with 6PPD-Q in the database were related to Alzheimer's disease, dopaminergic synapses, neurotrophin signaling pathways, and Parkinson's disease. Taken together, data suggests that 6PPD-Q may interfere with neuronal signaling, connectivity, and plasticity, leading to behavioral deficits. Based on predictive docking scores using fish, rodent, and human orthologs, 6PPD-Q may interact with tyrosine hydroxylase and L-dopa decarboxylase which can potentially lead to disrupted dopamine biosynthesis pathways. Given the widespread environmental presence of 6PPD-Q and its continuous introduction into aquatic ecosystems, characterizing such mechanisms is critical for improving ecological and human health risk assessments.},
}

@article {pmid42880558,
year = {2026},
author = {Liu, J and Wyatt-Johnson, SK and Chen, J and Chen, J and Liu, Z and Wu, H and Feng, L and Brutkiewicz, RR and Wang, N},
title = {Characterizing age-dependent diamagnetic and paramagnetic susceptibility properties in 5xFAD Alzheimer's mouse brain using high-resolution MRI.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122276},
doi = {10.1016/j.neuroimage.2026.122276},
pmid = {42880558},
issn = {1095-9572},
abstract = {BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is a devastating and progressive neurodegenerative disorder and the most common cause of dementia. This study aimed to characterize magnetic susceptibility changes associated with beta-amyloid (Aβ) plaques during AD progression using diamagnetic and paramagnetic susceptibility measurements in the 5xFAD mouse model.

METHODS: Ex vivo multi-echo gradient-echo imaging (MGRE) with a spatial resolution of 40 × 40 × 40 μm[3] was performed in three age groups of 5xFAD mice (4, 12, and 18 months) using a 9.4T Bruker MRI scanner. Quantitative susceptibility mapping (QSM) was reconstructed, and DECOMPOSE-QSM was applied to derive diamagnetic component susceptibility (DCS) and paramagnetic component susceptibility (PCS). Aβ plaques were automatically detected based on DCS and quantified to assess age-dependent plaque accumulation, changes in plaque burden, and associated susceptibility alterations. Cortical regions were further segmented into plaque-detected and plaque-undetected regions to assess regional susceptibility variations among the three age groups. In addition, Aβ/ferritin immunostaining was performed on the imaged murine brains.

RESULTS: The results demonstrated progressive, spatially heterogeneous, age-dependent accumulation of amyloid plaques, as evidenced by significant increases in plaque burden. In plaque-detected and whole-region cortical areas, DCS consistently shifted toward more negative values (greater diamagnetic susceptibility) with disease progression, while PCS became more positive (greater paramagnetic susceptibility). The concurrent increase in plaque burden, together with progressively more negative DCS and more positive PCS within plaques, is consistent with increasing diamagnetic and paramagnetic tissue contributions associated with amyloid and iron-related pathology, respectively. Histological analysis showed colocalized Aβ aggregation and ferritin deposition within plaques, both of which increased with age.

CONCLUSIONS: The decomposed susceptibility components, DCS and PCS, provide complementary biophysical information beyond conventional QSM, enabling improved characterization of plaque-associated susceptibility changes during AD progression. High-resolution MRI facilitates the visualization and detection of individual plaques, allowing detailed analysis of their susceptibility properties. These findings highlight the importance of high-resolution MRI and the potential of diamagnetic and paramagnetic susceptibility measures as sensitive imaging biomarkers for monitoring neurodegenerative pathology.},
}

@article {pmid42880559,
year = {2026},
author = {Li, Y and Khandelwal, P and Jena, R and Xie, L and Duong, MT and Denning, AE and Brown, CA and Wisse, LEM and Das, SR and Wolk, DA and Yushkevich, PA},
title = {Achieving detailed medial temporal lobe segmentation with upsampled isotropic training from implicit neural representation.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122294},
doi = {10.1016/j.neuroimage.2026.122294},
pmid = {42880559},
issn = {1095-9572},
abstract = {Imaging biomarkers in magnetic resonance imaging (MRI) are important tools for diagnosing, tracking and treating Alzheimer's disease (AD). Neurofibrillary tau pathology in AD is closely linked to neurodegeneration and generally follows a pattern of spread in the brain, with early stages involving subregions of the medial temporal lobe (MTL). Accurate segmentation of MTL subregions is needed to extract granular biomarkers of AD progression. MTL subregions are often imaged using T2-weighted (T2w) MRI scans that are highly anisotropic due to constraints of MRI physics and image acquisition, making it difficult to reliably model MTL subregions geometrically and extract morphological measures, such as thickness. In this study, we propose a segmentation framework for MTL subregions in isotropic space, in which an implicit neural representation is used to construct the isotropic training atlas from the anisotropic low-resolution T2w data, with T1w MRI as an auxiliary modality to support the INR and segmentation. In an independent test set, the morphological measures extracted using this isotropic model showed stronger effect sizes than those from models trained on anisotropic data in distinguishing participants with mild cognitive impairment (MCI) from cognitively unimpaired individuals. In the test-retest analysis, the morphological measures extracted using the isotropic model showed greater stability than those from the anisotropic segmentation. This study demonstrates improved reliability of MRI-derived MTL subregion biomarkers without additional atlas annotation effort, which may more accurately quantify and track the relationship between AD pathology and brain atrophy for monitoring disease progression.},
}

@article {pmid42880601,
year = {2026},
author = {Barberà-Parada, S and Biosca-Brull, J and Gabaldón-Díaz, R and Rodulfo-Cárdenas, R and Guardia-Escoté, L and Blanco, J and Cabré, M and Colomina, MT},
title = {Sex-divergent vulnerability to chronic peripheral LPS challenge in aged ApoE4 mice: Male systemic fragility versus female central neuroinflammation.},
journal = {Behavioural brain research},
volume = {517},
number = {},
pages = {116524},
doi = {10.1016/j.bbr.2026.116524},
pmid = {42880601},
issn = {1872-7549},
abstract = {Inflammageing links chronic inflammation to biological aging, contributing to senescence and multimorbidity common in the elderly. In neurodegenerative diseases, such as Alzheimer's disease, inflammatory processes play a causal role in accelerating neurodegeneration. Interestingly, apolipoprotein E (APOE), particularly the APOEε4 allele, is a major genetic risk factor for neurodegeneration, acting as a key immunomodulator with sex differences. This is especially relevant given the lack of clear prevention strategies for APOEε4 carriers. Therefore, this study characterized the sex-specific neuroinflammatory and cognitive vulnerability of APOE4 genotype under a chronic lipopolysaccharide (LPS) challenge in senescence-transition stage. Male and female homozygous apoE4 mice (15-16 months old) were administered intraperitoneal doses of 0 or 0.25 mg/kg LPS three times per week for a total of 17 doses. Body weight was monitored, and behavioural assessments were conducted from the 12th injection until the 17th. Serum and tissues were collected to assess hippocampal, cortical and systemic markers of inflammation, antioxidant-related genes, genes implied in myelin dynamics, and neurotrophin-related transcripts. Findings revealed basal sex-dependent divergent phenotypes with specific responses under LPS challenge. Under LPS treatment, males exhibited higher systemic fragility, with significantly increased mortality, which may have conditioned cognitive outcomes. Females showed greater central alterations related to neuroinflammation along with altered expression of myelin-related transcripts. However, the results suggest a stablished tolerance to LPS. These results highlight how chronic systemic inflammation during ageing in an APOE4 genotype background shapes sex-divergent pathological trajectories, underscoring the need to address sex-specific therapeutic strategies.},
}

@article {pmid42880847,
year = {2026},
author = {Ma, Y and Chen, KW and DE Jager, P},
title = {Epigenetic mechanisms in brain development and in neurodegeneration.},
journal = {Handbook of clinical neurology},
volume = {219},
number = {},
pages = {361-380},
doi = {10.1016/B978-0-443-19043-8.00030-X},
pmid = {42880847},
issn = {0072-9752},
mesh = {Humans ; *Epigenesis, Genetic/physiology/genetics ; *Brain/growth & development/metabolism ; *Neurodegenerative Diseases/genetics/pathology ; Animals ; DNA Methylation/genetics ; MicroRNAs/genetics ; },
abstract = {Epigenetic mechanisms are important heritable modifications beyond genetic mechanisms. Interindividual epigenetic variants can lead to phenotypic variations even in identical genotypes. Studies on the epigenetic contributions to Alzheimer disease and other neurodegenerative diseases could provide more comprehensive and precise insights into the heritable and nonheritable mechanisms. This knowledge will enable the development of individually tailored preventive and therapeutic pharmacologic interventions. This chapter is divided into three sections. First, we provide a detailed introduction to four epigenetic mechanisms: DNA methylation, histone modifications, chromatin remodeling, and microRNAs. Next, we review published studies that explore the contributions of these epigenetic modifications to Alzheimer disease. Finally, we summarize the current understanding of each epigenetic modification and its influence on the development of the central nervous system.},
}

Humans
*Epigenesis, Genetic/physiology/genetics
*Brain/growth & development/metabolism
*Neurodegenerative Diseases/genetics/pathology
Animals
DNA Methylation/genetics
MicroRNAs/genetics

@article {pmid42880851,
year = {2026},
author = {Pappas, JJ and Khoueiry, R and Godderis, L and Herceg, Z},
title = {The epigenetic mechanisms mediating the long-term impacts of toxicants on brain functions and health.},
journal = {Handbook of clinical neurology},
volume = {219},
number = {},
pages = {449-481},
doi = {10.1016/B978-0-443-19043-8.00021-9},
pmid = {42880851},
issn = {0072-9752},
mesh = {Humans ; Animals ; *Epigenesis, Genetic/drug effects ; *Brain/drug effects ; DNA Methylation/drug effects ; },
abstract = {Recent advances in toxicoepigenetics have significantly enhanced our understanding of epigenetic modifications induced by toxicant exposures. This review synthesizes current knowledge regarding epigenetic alterations - primarily DNA methylation, histone acetylation, and miRNA perturbations - associated with common toxicants, including arsenic, lead, methylmercury, formaldehyde, α-hexabromocyclododecane, bisphenol A, and fluoxetine. While substantial evidence derives from rodent models, human studies have made crucial contributions by characterizing toxicant-specific epigenetic signatures, identifying affected genes and pathways, and establishing epigenetic regulation as a critical mediator of biologic responses. This review highlights parallels between toxicant-induced epigenetic changes and those observed in neurologic disorders, particularly focusing on the potential of epigenetic marks as early diagnostic tools for synaptic dysfunction in Alzheimer disease, but also focusing on Huntington disease and Parkinson disease. It relies on evidence ranging from exposures in vitro and in vivo (mainly in rodents) to human exposures. It also highlights parallels between toxicant-induced epigenetic changes and those observed in brain cancers. The findings underscore the therapeutic potential of targeting epigenetic mechanisms to mitigate toxicant-induced neurologic effects. We conclude by proposing a strategic framework for further advancing toxicoepigenetic research, emphasizing the creation of a centralized databank for toxicant-induced brain epigenetic alterations, the development of validated epigenetic bioassays, and the integration of functional neuroimaging. Our proposed comprehensive approach, combining genetics, toxicology, epidemiology, and environmental science, aims to inform and enhance risk assessment protocols and therapeutic interventions.},
}

Humans
Animals
*Epigenesis, Genetic/drug effects
*Brain/drug effects
DNA Methylation/drug effects

@article {pmid42880986,
year = {2026},
author = {Zhang, X and Li, Z and Zhang, Q and Yin, Z and Lu, Z and Li, Y},
title = {Retraction notice to "A new weakly supervised deep neural network for recognizing Alzheimer's disease" [Computers in Biology and Medicine 163 (2023) 107079].},
journal = {Computers in biology and medicine},
volume = {},
number = {},
pages = {111991},
doi = {10.1016/j.compbiomed.2026.111991},
pmid = {42880986},
issn = {1879-0534},
}

@article {pmid42881131,
year = {2026},
author = {Shimoda, K},
title = {Recognising Mild Cognitive Impairment and Early Alzheimer's Disease in General and Psychiatric Practice: Clinical Clues and Appropriate Referral.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {6},
pages = {e70228},
doi = {10.1111/psyg.70228},
pmid = {42881131},
issn = {1479-8301},
mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; *Referral and Consultation ; *Cognitive Dysfunction/diagnosis/psychology ; Activities of Daily Living ; Aged ; General Practice ; Neuropsychological Tests ; },
abstract = {Early cognitive decline may become evident through changes in daily activities or behaviour before it is apparent in a brief consultation. This selective narrative review supports case-finding and appropriate referral in general and psychiatric practice. Four actions organise the review: identify decline in previously mastered instrumental activities of daily living; recognise new apathy or sustained behavioural change; use a cognitive screen sensitive to mild impairment, such as the Montreal Cognitive Assessment; and refer when clinically meaningful concern remains. Functional and behavioural findings require interpretation alongside medical, psychiatric and social factors. Mild behavioural impairment has reported associations with both amyloid and tau, varying across populations. Depression, medication exposure or a reassuring screening score should not end the assessment of otherwise unexplained decline. Collateral information strengthens the assessment but living alone and lacking a reliable informant are distinct circumstances. Municipal and care services may contribute observations without resolving every gap. Dementia disease medical centres should coordinate assessment and support with referring clinicians and community services.},
}

Humans
*Alzheimer Disease/diagnosis/psychology
*Referral and Consultation
*Cognitive Dysfunction/diagnosis/psychology
Activities of Daily Living
Aged
General Practice
Neuropsychological Tests

@article {pmid42881137,
year = {2026},
author = {Ren, H and Wen, T and Falvey, J and Huang, Y and Chen, C},
title = {A Doubly Robust Approach to Evaluating the Impact of Hospital Length of Stay on Post-Fracture Recovery in Older Adults With Cognitive Impairment.},
journal = {Statistics in medicine},
volume = {45},
number = {23-24},
pages = {e70768},
doi = {10.1002/sim.70768},
pmid = {42881137},
issn = {1097-0258},
support = {R01AG089377/NH/NIH HHS/United States ; P30AG028747/NH/NIH HHS/United States ; },
mesh = {Humans ; *Length of Stay/statistics & numerical data ; *Hip Fractures/rehabilitation/complications ; Computer Simulation ; Aged ; Models, Statistical ; Female ; Aged, 80 and over ; Recovery of Function ; },
abstract = {For older adults diagnosed with Alzheimer's Disease and Related Dementias, recovery outcomes after a hip fracture are often poor, with extended hospital stays and prolonged rehabilitation being common. This paper examines the impact of hospitalization on post-discharge outcomes, focusing on the differential effects of hospital length of stay on recovery, measured by the number of healthy days spent at home (DAH). Our analysis faces important analytical challenges, including baseline confounding, missing outcome, and the complexity of assessing a continuous exposure. To address these issues, we develop a doubly robust estimator that accommodates a continuous exposure and accounts for outcome missingness and provides practical guidance for end-users, including diagnostics for conditional density and missing data models and sensitivity analyses for assumption violation. Extensive simulations demonstrate that our method consistently outperforms existing doubly robust method for continuous exposures when outcome data are missing at random. Application to real-world data suggests that hospital stays longer than 20 days are associated with substantially reduced DAH.},
}

Humans
*Length of Stay/statistics & numerical data
*Hip Fractures/rehabilitation/complications
Computer Simulation
Aged
Models, Statistical
Female
Aged, 80 and over
Recovery of Function

@article {pmid42881165,
year = {2026},
author = {Harvey, J and Imm, J and Kouhsar, M and Smith, AR and Creese, B and Smith, RG and Wheildon, G and Laroche, V and Leung, SK and Chouliaras, L and Shireby, G and Jaunmuktane, Z and De Pablo-Fernández, E and Warner, T and Lett, DJ and Gveric, D and Brooks, H and Attems, J and Thomas, A and Van de Berg, WD and Dempster, E and Ballard, C and T O'Brien, J and Aarsland, D and Mill, J and Pihlstrøm, L and Pishva, E and Lunnon, K},
title = {Interrogating DNA methylation associated with Lewy body pathology in a cross brain-region and multi-cohort study.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42881165},
issn = {2041-1723},
support = {MR/S011625/1//RCUK | Medical Research Council (MRC)/ ; G0400074//RCUK | Medical Research Council (MRC)/ ; MR/M008924/1//RCUK | Medical Research Council (MRC)/ ; R01AG067015//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AS-PG-16b-012/ALZS_/Alzheimer's Society/United Kingdom ; AS-PDF-23-017/ALZS_/Alzheimer's Society/United Kingdom ; ARUK-PG2023A-037//Alzheimer's Research UK (ARUK)/ ; MJFF-023152//Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation)/ ; 733050516//ZonMw (Netherlands Organisation for Health Research and Development)/ ; },
mesh = {*DNA Methylation ; Humans ; Genome-Wide Association Study ; *Lewy Body Disease/genetics/pathology ; Quantitative Trait Loci ; alpha-Synuclein/genetics/metabolism ; *Brain/metabolism/pathology ; *Lewy Bodies/pathology/metabolism ; Parkinson Disease/genetics/pathology ; Epigenesis, Genetic ; Cohort Studies ; Genetic Predisposition to Disease ; },
abstract = {Here, we conduct a large meta-analysis of DNA methylation across multiple cortical brain regions, in relation to increasing burden of Lewy body pathology. Utilizing a dataset of 1205 samples (832 unique donors), we identify 24 false discovery rate significant differentially methylated loci associated with Lewy body pathology, with loci located in UBASH3B and PTAFR, and an intergenic locus passing the genome-wide significance threshold. Ontological enrichment analysis highlights several neurologically relevant traits, including synaptic alterations. We compare methylation signatures between neurodegenerative pathologies and highlight a shared epigenetic profile across Lewy body, Alzheimer's and Huntington's diseases, although the top-ranked loci show disease specificity. Utilizing summary statistics from large-scale genome-wide association studies, we identify significant enrichment of DNA methylation differences with respect to increasing Lewy body pathology in the SNCA genomic region. We also identify specific relationships between genetic risk variants for Lewy body dementia and Parkinson's disease to methylation quantitative trait loci in the SNCA 5' region and expression of alternative transcript isoforms.},
}

*DNA Methylation
Humans
Genome-Wide Association Study
*Lewy Body Disease/genetics/pathology
Quantitative Trait Loci
alpha-Synuclein/genetics/metabolism
*Brain/metabolism/pathology
*Lewy Bodies/pathology/metabolism
Parkinson Disease/genetics/pathology
Epigenesis, Genetic
Cohort Studies
Genetic Predisposition to Disease

@article {pmid42881225,
year = {2026},
author = {Vicidomini, C and Goode, TD and Yu, R and Mehta, I and McAvoy, KM and Beveridge, CH and Randolph, CE and Iyer, SN and Victor, MB and Leary, N and Evans, L and Steinbaugh, MJ and Lai, ZW and Lyon, MC and San Silvestre, MRF and Tosoni, G and Ayyildiz, D and Ho Sui, S and Yamamoto, K and Murakami, M and Salta, E and Tsai, LH and Chopra, G and Sahay, A},
title = {An aging-sensitive secreted phospholipase confers neuroprotection and cognitive resilience.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42881225},
issn = {1546-1726},
abstract = {Cognitive reserve theory posits that compensatory mechanisms during aging stave off cognitive decline and lower risk for Alzheimer's disease. Here, in a screen for hippocampal dentate granule cell (DGC) synapse loss-induced factors in mice, we identified a secreted phospholipase, Pla2g2f, whose expression increases in DGCs during aging and is associated with cognitive resilience in humans. Pla2g2f deletion in DGCs exacerbates aging-associated pathophysiological changes, including synapse loss, inflammatory microglia, reactive astrogliosis, impaired neurogenesis, lipid dysregulation, lipid droplet accumulation and hippocampal-dependent memory loss. Conversely, boosting Pla2g2f in DGCs during aging is sufficient to prevent these pathophysiological alterations in hippocampal-cortical circuits, protect memory and prophylactically modify trajectory of cognitive decline. Mutagenesis of the catalytic site of PLA2G2F prevented lipid droplet mobilization and reduction of reactive gliosis and inflammatory microglia. Neuronal PLA2G2F mediates intercellular signaling to decrease lipid droplet and cholesterol ester load in human induced pluripotent stem cell-derived microglia. Our findings implicate PLA2G2F as a compensatory neuroprotective broadcast signal that maintains lipid homeostasis to counteract aging-associated cognitive decline.},
}

@article {pmid42881935,
year = {2026},
author = {Stafstrom, CE and Shao, LR},
title = {Epilepsy Mechanisms in Down Syndrome: Genetic and Pathophysiological Perspectives Across the Lifespan.},
journal = {Journal of clinical medicine},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/jcm15197471},
pmid = {42881935},
issn = {2077-0383},
support = {FJL 2421_GRT-2025B//Fondation Jérôme-Lejeune/ ; },
abstract = {Down syndrome (trisomy 21) is the most common genetic cause of intellectual disability. Seizures are a frequent comorbidity in individuals with Down syndrome and can exert significant negative consequences on cognitive capacity and quality of life. In Down syndrome, seizures cluster at two extremes of the lifespan. In the first year of life, infantile epileptic spasms syndrome affects 5-10% of children with Down syndrome. The second peak occurs after age 30 years, when myoclonic seizures appear at the time of onset of Down syndrome-related dementia of the Alzheimer type (late-onset myoclonic epilepsy in Down syndrome or LOMEDS). While epilepsy at these two disparate time points has been long recognized in the Down syndrome population, the mechanisms underlying seizure pathogenesis have not been studied in detail. For example, it is not known whether the brain developmental abnormalities that characterize Down syndrome are primarily responsible for the epilepsies or whether distinct mechanisms underlie seizures at the two ages. This narrative review addresses possible mechanisms of seizure propensity across the lifespan, with special reference to potential age-specific treatments.},
}

@article {pmid42882298,
year = {2026},
author = {Prieur-Coloma, Y and Prado, P and El-Deredy, W and Weinstein, A},
title = {An Interpretable Framework for Identifying EEG Spectral Biomarkers of Pathological Brain Aging.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {19},
pages = {},
doi = {10.3390/diagnostics16193143},
pmid = {42882298},
issn = {2075-4418},
support = {FONDECYT 3260279//Agencia Nacional de Investigación y Desarrollo/ ; BASAL CIA250006//Agencia Nacional de Investigación y Desarrollo/ ; FONDECYT 1231132//Agencia Nacional de Investigación y Desarrollo/ ; FONDECYT 1241695//Agencia Nacional de Investigación y Desarrollo/ ; FONDECYT 1260530//Agencia Nacional de Investigación y Desarrollo/ ; 13240064//Agencia Nacional de Investigación y Desarrollo/ ; },
abstract = {Background: Normal aging involves gradual declines in brain function, whereas neurodegenerative disorders show accelerated deterioration. Electroencephalography (EEG) captures alterations in brain oscillatory activity, making it promising for detecting neurodegenerative disorders. However, existing approaches often emphasize classification performance over spectral biomarker identification, limiting clinical translation. Methods: We propose an EEG-based framework integrating explainable machine learning, analyses of inter-subject heterogeneity and temporal stability, and probabilistic modeling to identify reproducible spectral biomarkers of pathological brain aging. Two independent public EEG datasets comprising cognitively normal (CN) individuals and patients with Alzheimer's disease (AD), Parkinson's disease (PD), and frontotemporal dementia (FTD) were analyzed. Spectral features from canonical frequency bands were analyzed using SHAP to identify reproducible biomarkers in two datasets. The identified biomarker was subsequently characterized through inter-subject heterogeneity, temporal stability, and empirical distributions to assess disease-related alterations in oscillatory activity. Results: Several spectral features showed consistent disease-related associations across classification tasks. The θ/α ratio emerged as a representative biomarker, showing reduced temporal stability and broader empirical distributions in most neurodegenerative groups than in CN. Conclusions: Reduced temporal stability of reproducible EEG spectral biomarkers may represent an observable signature of disrupted oscillatory brain organization during pathological aging. The proposed framework characterizes a dimension of EEG spectral biomarkers that static summaries discard, offering an interpretable basis on which future longitudinal studies may build diagnostic and monitoring tools.},
}

@article {pmid42882419,
year = {2026},
author = {Mao, J and Zhang, Y and Wang, P and Qin, D},
title = {Clockophagy in Alzheimer's Disease: An Emerging Hypothesis Linking Circadian Dysfunction to Ferroptotic Vulnerability.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191721},
pmid = {42882419},
issn = {2073-4409},
support = {82374425//National Natural Science Foundation of China/ ; 82474377//National Natural Science Foundation of China/ ; 202501AZ070001-033//Yunnan Provincial Department of Finance/ ; D20230035//Enshi Science and Technology Program - Qihang Special Project/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/physiopathology/pathology ; *Autophagy ; *Circadian Rhythm/physiology ; *Ferroptosis ; Animals ; ARNTL Transcription Factors/metabolism ; Oxidative Stress ; Lipid Peroxidation ; },
abstract = {Alzheimer's disease (AD) is frequently associated with sleep disturbances and circadian dysfunction, which may precede or accompany clinical manifestations and have been associated with amyloid-β (Aβ) pathology, tau abnormalities, oxidative stress, lipid peroxidation, and neuronal vulnerability. Increasing evidence suggests that circadian regulation intersects with multiple cellular processes implicated in AD pathogenesis, including autophagy and ferroptosis. Among these mechanisms, clockophagy, an SQSTM1/p62-mediated selective autophagic process involved in BMAL1 degradation, has recently emerged as a potential molecular link between circadian regulation and cellular stress responses. In this review, we summarize current evidence connecting sleep disruption, circadian dysfunction, lipid peroxidation, and ferroptotic susceptibility in AD, while highlighting the current limitations of mechanistic evidence. We further discuss the molecular basis of clockophagy and its potential relationship with BMAL1 regulation, oxidative lipid damage, and ferroptosis. Collectively, clockophagy is currently viewed as an emerging hypothesis that may contribute to AD-related pathological processes. Finally, we discuss potential therapeutic implications, including approaches targeting sleep and circadian organization, BMAL1-associated regulatory pathways, and lipid oxidative stress. Further studies are required to determine whether modulation of clockophagy can influence AD-related neurodegenerative processes.},
}

Humans
*Alzheimer Disease/metabolism/physiopathology/pathology
*Autophagy
*Circadian Rhythm/physiology
*Ferroptosis
Animals
ARNTL Transcription Factors/metabolism
Oxidative Stress
Lipid Peroxidation

@article {pmid42882436,
year = {2026},
author = {Chmiel, J and Leszek, J},
title = {Skull Bone Marrow as a Cranial Neuroimmune Reservoir in Alzheimer's Disease: Amyloid, Osteoimmune Remodeling, and Translational Imaging Evidence.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191738},
pmid = {42882436},
issn = {2073-4409},
mesh = {*Alzheimer Disease/immunology/pathology/diagnostic imaging ; Humans ; *Skull/immunology/pathology/diagnostic imaging ; *Bone Marrow/immunology/pathology/diagnostic imaging ; Animals ; *Translational Research, Biomedical ; Amyloid beta-Peptides/metabolism ; *Amyloid/metabolism ; },
abstract = {Alzheimer's disease (AD) has traditionally been conceptualized as a disorder driven primarily by cerebral amyloid-β accumulation, tau pathology, synaptic failure, vascular dysfunction, and chronic neuroinflammation. However, emerging evidence suggests that AD pathobiology may also involve extracerebral cranial compartments positioned at the interface between the brain, meninges, cerebrospinal fluid, and skull bone marrow. Recent anatomical and experimental studies have identified direct vascular and osseous channels connecting skull bone marrow with the dura mater, allowing bidirectional exchange of immune cells, soluble mediators, and cerebrospinal fluid-derived signals. These findings support the concept that skull bone marrow functions as a specialized cranial immune reservoir capable of sensing central nervous system-derived molecular cues and supplying myeloid and lymphoid cells to meningeal and brain-border compartments. In AD models and human imaging studies, amyloid-β-related signals have been detected in skull marrow, where they may promote IL-6-dependent B lymphopoiesis, expansion of age-associated B cells, microglial activation, and amplification of cerebral amyloid pathology. In parallel, AD-related amyloid precursor protein and amyloid-β signaling may remodel the skull marrow niche through osteoblast dysfunction, altered osteoclast activity, vascular channel expansion, marrow adiposity, and inflammatory reprogramming. Human PET and MRI studies indicate that skull marrow-associated inflammatory, amyloid-related, and cerebrospinal-fluid drainage signals can be detected in vivo; however, these observations remain indirect, method-dependent, and insufficiently validated for diagnostic or prognostic use. Importantly, much of the anatomical foundation for skull marrow-meninges-brain communication derives from non-AD studies of CNS-border physiology, stroke, meningitis, spinal cord injury, and infection, whereas the strongest AD-specific mechanistic evidence is currently derived from transgenic mouse models. Accordingly, we frame the skull marrow-meninges-brain axis as a testable conceptual model rather than an established causal pathway in human AD. This review integrates anatomical, immunological, osteoimmune, and imaging evidence while explicitly distinguishing AD-specific findings from evidence extrapolated from other neurological or inflammatory contexts. Determining whether skull marrow alterations represent a cause, consequence, compensatory response, or amplifier of AD pathology will require longitudinal, biomarker-defined human studies and further mechanistic validation. The review also compares the principal in vivo strategies used to distinguish skull-marrow-derived immune cells from circulating leukocytes and examines ischemic stroke and brain tumors as comparator CNS conditions. These disease models demonstrate that cranial marrow responses can be rapid, spatially organized, and either protective or pathogenic depending on cellular phenotype and disease context, reinforcing the interpretation of skull marrow as a general CNS-border immune organ rather than an AD-specific compartment.},
}

*Alzheimer Disease/immunology/pathology/diagnostic imaging
Humans
*Skull/immunology/pathology/diagnostic imaging
*Bone Marrow/immunology/pathology/diagnostic imaging
Animals
*Translational Research, Biomedical
Amyloid beta-Peptides/metabolism
*Amyloid/metabolism

@article {pmid42882446,
year = {2026},
author = {Janković, T and Pilipović, K and Gržeta Krpan, N and Rajič Bumber, J and Mežnarić, S and Pelčić, A and Dolenec, P and Ćelić, T and Mršić-Pelčić, J},
title = {1,8-Cineole (Eucalyptol) in Neurodegeneration: From Pharmacological Mechanisms to Therapeutic Applications.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191748},
pmid = {42882446},
issn = {2073-4409},
support = {100.24.0009 to T.J.//Researcher support fund of the Faculty of Medicine, Rijeka/ ; },
mesh = {Humans ; *Eucalyptol/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; },
abstract = {Neurodegenerative diseases represent an enormous global burden, and due to the lack of effective therapies, the number of affected individuals continues to rise, placing a significant pressure on patients and their families. Phytochemicals such as terpenes are a group of compounds that have the potential to provide long-term neuroprotective effects by targeting multiple pathobiological pathways and supporting the brain's natural defense mechanisms. 1,8-cineole (eucalyptol) is a monoterpene known for its anti-inflammatory and antioxidant properties, mainly utilized in the respiratory system. However, due to its ability to cross the blood-brain barrier, beneficial effects have been observed in the central nervous system. Here we examine the pharmacological mechanisms and neuroprotective potential of 1,8-cineole in the nervous tissue. Studies have shown that 1,8-cineole has the potential to suppress neuroinflammation and reduce glial activation, activate antioxidant defense mechanisms and scavenge reactive oxygen species. Additionally, 1,8-cineole has been shown to modulate central neurotransmission and synaptic plasticity, inhibit apoptotic neuronal death and regulate ion channels involved in pain modulation. This review aims to examine the therapeutic potential of 1,8-cineole in the most prevalent neurodegenerative diseases in the population, such as Alzheimer's and Parkinson's diseases, as well as brain injuries, including ischemic stroke and traumatic brain injury, which may lead to neurodegeneration. We also explore the potential benefits of 1,8-cineole for anxiety and depression, which occur as early symptoms or common complications of neurodegenerative diseases. Given the need for novel therapeutic approaches, combination therapies that utilize the therapeutic potential of phytochemicals, such as 1,8-cineole, may enable more effective targeting of the multiple, interconnected pathobiological processes underlying neurodegenerative diseases.},
}

Humans
*Eucalyptol/therapeutic use/pharmacology
*Neurodegenerative Diseases/drug therapy
Animals
*Neuroprotective Agents/therapeutic use/pharmacology

@article {pmid42882466,
year = {2026},
author = {Burdman, G and Hanna, M and Arias, AY and Vashist, A and Lakshmana, MK},
title = {Human iPSC-Derived Brain Cells, Organoids, and Organoids-on-Chips: Advancing Neurological Disease Modeling to Improve Clinical Outcome.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191768},
pmid = {42882466},
issn = {2073-4409},
support = {1R21DA060111, 1R61AG086971, R03AG08475//National Institute of Health (NIH)/ ; },
mesh = {Humans ; *Induced Pluripotent Stem Cells/cytology/metabolism ; *Brain/pathology/cytology ; *Organoids/pathology/cytology ; *Nervous System Diseases/pathology ; Animals ; Microphysiological Systems ; Neurons/pathology ; Models, Biological ; },
abstract = {Neurological disorders are the leading cause of overall disease and disability worldwide, affecting more than 3.4 billion people globally and over 180 million Americans. Yet there are no curative treatments available for any of the cardinal neurological diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) and Huntington's disease (HD). Many compounds that demonstrate excellent activity in preclinical models fail in clinical trials. The most compelling reason for this failure is attributed to inherent limitations of rodent models that fail to replicate complex human biology. The transformation of patient-derived somatic cells into induced pluripotent stem cells (iPSCs) that can become functional human neurons is an emerging technology that is expected to revolutionize medical treatments and personal medicine. Here, we review the available evidence for the efficacy of iPSC-derived neurons, organoids, assembloids and organ-on-chip in models of AD, PD, ALS-FTD and HD. We focus on how these human-relevant iPSC-derived brain cells are crucial for understanding neurological disease pathogenesis and accelerating drug discovery. We also discuss the current limitations of this technology and how alternative models such as induced neurons (iNs) are generated by directly reprogramming fibroblasts that preserve age-associated epigenetic signatures and may serve as better models for neurological disorders.},
}

Humans
*Induced Pluripotent Stem Cells/cytology/metabolism
*Brain/pathology/cytology
*Organoids/pathology/cytology
*Nervous System Diseases/pathology
Animals
Microphysiological Systems
Neurons/pathology
Models, Biological

@article {pmid42882491,
year = {2026},
author = {Colasuonno, F and Valenza, A and Rossin, F and Moreno, S},
title = {From Amyloid Exposure to Genetic Causality: Converging hiPSC-Based Models of Alzheimer's Disease.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191793},
pmid = {42882491},
issn = {2073-4409},
support = {AGYR2020//Italian Alzheimer Research Association Onlus/ ; PRIN 2022, CUP E53D23007150006//Ministry of Universities and Research/ ; PNRR-MAC2-II.3 project PE6 "Heal Italia" CUP E83C22004670001//Ministry of Universities and Research/ ; PNRR (DM 629) CUP: F81J24000490006//Ministry of Universities and Research/ ; 27116//Italian Association for Cancer Research/ ; Grant of Excellence Department 2023-2027//Ministero dell'università e della ricerca/ ; PNRR-MAD-2022-12375639//Ministero della Salute/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Animals ; *Models, Biological ; Neuroglia/metabolism/pathology ; *Amyloid/metabolism ; Organoids/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder in which genetic susceptibility, aging, protein aggregation, and neuroglial dysfunction converge to drive progressive neuronal loss. Although animal models and conventional cell systems have provided fundamental insights into pathomechanisms, they only partially reproduce the human-specific and multifactorial nature of AD. Human induced pluripotent stem cell (hiPSC)-based models have emerged as a powerful platform to investigate disease-relevant processes within a patient-specific genetic background while enabling the generation of multiple neural cell types and multicellular systems. In this review, we present the evolution of hiPSC-based AD modeling, from reductionist paradigms based on exogenous amyloid-β exposure to CRISPR-engineered isogenic models addressing causal mutations and genetic risk variants associated with either familial or sporadic forms. We examine the contribution of three-dimensional brain organoids and neuroglial co-culture systems in recapitulating cell-cell interactions, neuroinflammatory responses, and tissue-level pathological processes. We focus on current challenges, including the limited representation of neuronal aging, variability among organoids, and the need for standardized protocols. Finally, we discuss the translational potential of hiPSC-derived systems for target identification, drug discovery, and regenerative medicine. Collectively, these advances position hiPSC-based platforms as essential complementary models for elucidating AD pathogenesis and accelerating the development of precision therapeutic strategies.},
}

Humans
*Alzheimer Disease/genetics/pathology/metabolism
*Induced Pluripotent Stem Cells/metabolism/pathology
*Amyloid beta-Peptides/metabolism
Animals
*Models, Biological
Neuroglia/metabolism/pathology
*Amyloid/metabolism
Organoids/metabolism/pathology

@article {pmid42882500,
year = {2026},
author = {Alam, JJ and Germann, UA and Maruff, P},
title = {Targeting Pro-Inflammatory Interleukin-1 Beta Signaling to Modulate Neuroinflammatory Processes Associated with Cognitive Decline in Dementia with Lewy Bodies.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191803},
pmid = {42882500},
issn = {2073-4409},
support = {//CervoMed Inc/ ; #R01AG080536/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Interleukin-1beta/metabolism ; *Lewy Body Disease/drug therapy/complications/metabolism ; *Signal Transduction/drug effects ; *Neuroinflammatory Diseases/metabolism/drug therapy ; *Cognitive Dysfunction/drug therapy/complications/metabolism ; Amyloid beta-Peptides ; Female ; Alzheimer Disease/drug therapy ; Male ; Interleukin-6/metabolism ; },
abstract = {Interleukin-1 beta (IL-1β) is implicated as a molecular driver of cognitive decline in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), potentially through activation of pro-inflammatory pathways within the neuron that impair synaptic function. Because pro-inflammatory IL-1β signaling depends on p38α kinase, the oral brain-penetrant p38α inhibitor neflamapimod has the potential to reverse synaptic dysfunction and treat cognitive decline in these contexts. Neflamapimod has also shown positive effects in animal models and in clinical studies in AD and DLB. Herein we evaluated neflamapimod effects on pro-inflammatory IL-1β signaling in vitro and in patients with AD or DLB. In human PBMCs, neflamapimod inhibited IL-1β-induced IL-6 and IL-8 production with EC50 values of 6.3 ± 1.3 nM and 7.1 ± 3.2 nM, respectively. In AD, six weeks of neflamapimod 40 mg BID treatment reduced CSF levels of IL-6 and IL-8, with maximal effects at trough drug concentration ≥4 ng/mL (9 nM). In DLB, neflamapimod 40 mg TID increased the plasma Aβ42/40 ratio and reduced plasma GFAP levels, treatment effects consistent with reduced pro-inflammatory IL-1β signaling. Collectively, these results support the hypothesis that inhibition of p38α-dependent IL-1β signaling may beneficially modulate neuroinflammatory processes that otherwise are associated with cognitive decline in DLB, and potentially in AD.},
}

Humans
*Interleukin-1beta/metabolism
*Lewy Body Disease/drug therapy/complications/metabolism
*Signal Transduction/drug effects
*Neuroinflammatory Diseases/metabolism/drug therapy
*Cognitive Dysfunction/drug therapy/complications/metabolism
Amyloid beta-Peptides
Female
Alzheimer Disease/drug therapy
Male
Interleukin-6/metabolism

@article {pmid42882520,
year = {2026},
author = {Yang, T and Tran, KC and Leng, A and Langness, VF and Massa, SM and Longo, FM},
title = {A Small-Molecule TrkB Agonist Promotes Synaptic Resilience Against Aβ and Tau Oligomers and Mitigates Alterations in TrkB-Akt and Fyn Signaling.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191822},
pmid = {42882520},
issn = {2073-4409},
support = {//Scully Initiative/ ; //Taube Family Foundation/ ; //Jean Perkins Foundation/ ; //Horngren Family/ ; },
mesh = {Animals ; *Proto-Oncogene Proteins c-fyn/metabolism ; *Amyloid beta-Peptides/metabolism ; *tau Proteins/metabolism ; *Receptor, trkB/agonists/metabolism ; Signal Transduction/drug effects ; *Proto-Oncogene Proteins c-akt/metabolism ; *Synapses/metabolism/drug effects ; Mice ; Hippocampus/metabolism ; Dendritic Spines/metabolism/drug effects ; Neurons/metabolism/drug effects ; Phosphorylation/drug effects ; Alzheimer Disease/metabolism/drug therapy/pathology ; *Membrane Glycoproteins/metabolism/agonists ; Male ; },
abstract = {BACKGROUND: Pathogenic amyloid-beta and tau oligomers (oAβ, oTau) drive synaptic degeneration and cognitive decline in Alzheimer's disease (AD). Tropomyosin receptor kinase B (TrkB), expressed in neurons and glia, supports synaptic integrity in AD-affected regions. We tested whether PTX-BD4-3, a small-molecule TrkB partial agonist, promotes neuroprotective signaling, reduces degenerative signaling, and prevents synaptic loss in an AD mouse model and hippocampal neurons exposed to oAβ or oTau.

METHODS: Cultured hippocampal neurons were treated with oAβ or oTau ± PTX-BD4-3. Effects on synaptic proteins (±TrkB-blocking antibody), spine density, and Fyn, NR2B, and tau phosphorylation as well as tau oligomerization were assessed. Two cohorts of APP[L/S] mice, 5 and 12 months of age, received intraperitoneal PTX-BD4-3 or vehicle for 3 months, followed by assessment of synaptic proteins, dendritic spines, TrkB signaling, and Y-maze analysis.

RESULTS: In vitro, PTX-BD4-3 prevented oAβ-induced synaptic marker loss in a TrkB-dependent manner, reduced phosphorylation of Fyn, NR2B, and tau, suppressed oligomeric tau formation, and attenuated oTau-induced spine loss. In APP[L/S] mice, PTX-BD4-3 mitigated deficient TrkB/Akt signaling, reduced phosphorylation of Fyn and tau, preserved synaptic markers and dendritic spines, and improved Y-maze performance.

CONCLUSIONS: Small-molecule TrkB partial agonists may normalize TrkB signaling and promote synaptic resilience, supporting their potential as AD therapeutics.},
}

Animals
*Proto-Oncogene Proteins c-fyn/metabolism
*Amyloid beta-Peptides/metabolism
*tau Proteins/metabolism
*Receptor, trkB/agonists/metabolism
Signal Transduction/drug effects
*Proto-Oncogene Proteins c-akt/metabolism
*Synapses/metabolism/drug effects
Mice
Hippocampus/metabolism
Dendritic Spines/metabolism/drug effects
Neurons/metabolism/drug effects
Phosphorylation/drug effects
Alzheimer Disease/metabolism/drug therapy/pathology
*Membrane Glycoproteins/metabolism/agonists
Male

@article {pmid42883264,
year = {2026},
author = {Sun, L and Apweiler, M and Schulzki, R and Grathwol, CW and Normann, C and Bräse, S and Fiebich, BL},
title = {Anti-Neuroinflammatory Effects of Cardenolides in IL-1β-Activated SK-N-SH Cells.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {19},
pages = {},
doi = {10.3390/molecules31193501},
pmid = {42883264},
issn = {1420-3049},
support = {284178167//Deutsche Forschungsgemeinschaft/ ; 266379491//Deutsche Forschungsgemeinschaft/ ; //Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg/ ; },
mesh = {Humans ; *Interleukin-1beta/metabolism/pharmacology ; *Anti-Inflammatory Agents/pharmacology/chemistry ; NF-kappa B/metabolism ; *Cardenolides/pharmacology/chemistry ; Cyclooxygenase 2/metabolism ; Cell Line, Tumor ; Dinoprostone/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; Signal Transduction/drug effects ; Cell Survival/drug effects ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Interleukin-6/metabolism ; Prostaglandin-E Synthases/metabolism ; },
abstract = {Neuroinflammation is a key feature of neurological disorders such as Alzheimer's or Parkinson's disease, depression or amyotrophic lateral sclerosis. This study investigates the anti-neuroinflammatory effects of three cardenolide derivatives, digitoxigenin, digitoxigenone, and coroglaucigenin (all at concentrations of 1, 5, 10, and 25 µM), in IL-1β-stimulated human neuroblastoma SK-N-SH cells. All compounds significantly reduced PGE2 production without affecting cell viability by downregulation of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthases (mPGES)-1 expression and synthesis. Among them, digitoxigenin notably inhibited phosphorylation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) and suppressed interleukin (IL)-6 and IL-8 expression and release. These findings demonstrate that cardenolide derivatives exert potent anti-neuroinflammatory effects by at least partially targeting key enzymes of the arachidonic acid pathway and modulating MAPK/NF-κB signaling, highlighting their potential as novel therapeutic candidates for neuroinflammatory diseases. Future research should focus on effects of the cardenolides in mixed-cell cultures, organoids and in vivo experiments, to evaluate possible side effects and the potential in disease models.},
}

Humans
*Interleukin-1beta/metabolism/pharmacology
*Anti-Inflammatory Agents/pharmacology/chemistry
NF-kappa B/metabolism
*Cardenolides/pharmacology/chemistry
Cyclooxygenase 2/metabolism
Cell Line, Tumor
Dinoprostone/metabolism
p38 Mitogen-Activated Protein Kinases/metabolism
Signal Transduction/drug effects
Cell Survival/drug effects
*Neuroinflammatory Diseases/drug therapy/metabolism
Interleukin-6/metabolism
Prostaglandin-E Synthases/metabolism

@article {pmid42883292,
year = {2026},
author = {McDermott, C and Cole, MH and Pearson, M and Winberg, P and Fernandez, F},
title = {Targeting Specific Sirtuin Modulation: Emerging Therapeutic Strategies for Healthy Cognitive Ageing and Potential Implications for Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {19},
pages = {},
doi = {10.3390/molecules31193528},
pmid = {42883292},
issn = {1420-3049},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Sirtuins/metabolism ; Animals ; *Cognitive Aging ; Aging ; *Healthy Aging ; },
abstract = {Nicotinamide adenine dinucleotide (+)-dependent class III histone deacetylases, widely known as sirtuins (SIRTs), have been found to play key functions in a wide range of biological processes implicated in ageing processes. The downregulation of some specific SIRTs was reported in ageing and in some neurological diseases such as Alzheimer's disease. SIRT modulator factors, such as diet, exercise and various natural compounds, have recently emerged as a potential new avenue of therapy to modify the progression of Alzheimer's disease and delay some ageing effects. This review synthesises recent advances in the understanding of the modulatory effects of SIRTs in the context of healthy ageing with a particular focus on cognitive function and implications for Alzheimer's disease.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy
*Sirtuins/metabolism
Animals
*Cognitive Aging
Aging
*Healthy Aging

@article {pmid42883328,
year = {2026},
author = {Garbarek, J and Hys, O and Woźniak, A and Szewczyk-Golec, K and Nuszkiewicz, J},
title = {Bee-Derived Products in Neurodegenerative Diseases: Bioactive Constituents, Redox-Modulating Mechanisms, Evidence, and Translational Perspectives.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {19},
pages = {},
doi = {10.3390/molecules31193564},
pmid = {42883328},
issn = {1420-3049},
mesh = {Humans ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; Oxidation-Reduction/drug effects ; Antioxidants/pharmacology/chemistry/therapeutic use ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; Bees/chemistry ; Propolis/chemistry/therapeutic use ; Oxidative Stress/drug effects ; Royal Jelly ; *Bee Venoms/chemistry/therapeutic use/pharmacology ; Anti-Inflammatory Agents/pharmacology/chemistry/therapeutic use ; Signal Transduction/drug effects ; Honey/analysis ; },
abstract = {Oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation are closely interconnected processes involved in the pathogenesis and progression of neurodegenerative diseases. Bee-derived products, including honey, propolis, royal jelly, bee pollen, bee bread, and bee venom, contain diverse bioactive constituents with antioxidant, anti-inflammatory, immunomodulatory, and redox-modulating properties. This narrative review summarizes the major bioactive compounds present in bee-derived products and evaluates their potential relevance to neuroprotection. Particular attention is given to mechanisms involving activation of the Nrf2/ARE antioxidant response, inhibition of NF-κB-dependent inflammatory signaling, modulation of the NLRP3 inflammasome, mitochondrial protection, regulation of apoptosis, and maintenance of proteostasis. Available evidence from cellular and animal models, together with the limited clinical data, is discussed primarily in the context of Alzheimer's and Parkinson's diseases, with additional consideration of amyotrophic lateral sclerosis and other neurodegenerative or neuroinflammatory conditions. Although several bee-derived products and isolated constituents show promising biological effects, their therapeutic translation remains limited by variable chemical composition, insufficient standardization, low or uncertain bioavailability, limited evidence of central nervous system exposure, and safety concerns. Further mechanistic, pharmacokinetic, and well-controlled clinical studies are therefore required before their potential neuroprotective applications can be reliably established.},
}

Humans
Animals
*Neurodegenerative Diseases/drug therapy/metabolism
Oxidation-Reduction/drug effects
Antioxidants/pharmacology/chemistry/therapeutic use
*Neuroprotective Agents/pharmacology/chemistry/therapeutic use
Bees/chemistry
Propolis/chemistry/therapeutic use
Oxidative Stress/drug effects
Royal Jelly
*Bee Venoms/chemistry/therapeutic use/pharmacology
Anti-Inflammatory Agents/pharmacology/chemistry/therapeutic use
Signal Transduction/drug effects
Honey/analysis

@article {pmid42883332,
year = {2026},
author = {Işık, M and Syla, GH and Karakaya, A and Çevik, UA and Daoud, NE and Fırat, M and Öğünç Keçeci, Y and Özkay, Y and Kaplancıklı, ZA and Beydemir, Ş},
title = {Design and Synthesis of New Thiazole Derivatives for Alzheimer's Disease Therapy as a Potential Cholinesterase Inhibitor; Toxicity Prediction and Molecular Docking Studies and Biological Evaluation.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {19},
pages = {},
doi = {10.3390/molecules31193568},
pmid = {42883332},
issn = {1420-3049},
support = {//Anadolu University/ ; },
mesh = {*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology ; Molecular Docking Simulation ; *Thiazoles/chemistry/chemical synthesis/pharmacology ; *Alzheimer Disease/drug therapy/enzymology ; Humans ; Butyrylcholinesterase/chemistry/metabolism ; Acetylcholinesterase/chemistry/metabolism ; *Drug Design ; Structure-Activity Relationship ; Molecular Structure ; Animals ; },
abstract = {In this study, thiazole derivatives 13-23 were synthesized as novel cholinesterase inhibitors. Their structures were elucidated using [1]H-NMR, [13]C-NMR, and elemental analysis techniques. The binding positions and efficiencies of the designed compounds on the enzyme were investigated through molecular docking studies, and the properties of ADMET were examined using computational methods. Cytotoxicity analyses of the synthesized compounds were performed to screen their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro. It has been determined that these compounds do not exhibit a significant cytotoxic effect on healthy endothelial cells. Although the compounds showed lower efficacy in AChE inhibition compared to the reference compound tacrine (IC50: 0.136 μM; KI: 0.46 ± 0.01 nM), they exhibited moderate inhibitory effects. Among these, compounds 16 and 23 were found to be the most potent AChE inhibitors, with IC50 values of 36.47 µM and 34.65 µM, and KI values of 22.20 ± 1.23 and 21.10 ± 1.58 µM, respectively, while compounds 15 and 20 were found to be the most potent BChE inhibitors, with IC50 values of 17.76 µM and 16.90 µM, and KI values of 14.10 ± 0.58 and 13.40 ± 0.48 µM, respectively, on other cholinesterases. These tested compounds can be considered potential candidates for further research in the treatment of Alzheimer's disease (AD).},
}

*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology
Molecular Docking Simulation
*Thiazoles/chemistry/chemical synthesis/pharmacology
*Alzheimer Disease/drug therapy/enzymology
Humans
Butyrylcholinesterase/chemistry/metabolism
Acetylcholinesterase/chemistry/metabolism
*Drug Design
Structure-Activity Relationship
Molecular Structure
Animals

@article {pmid42883433,
year = {2026},
author = {Li, P and Qi, ZM and Wu, JZ and Liu, J and Yu, P},
title = {Targeting Ferroptosis in Neurodegenerative Diseases: Therapeutic Potential and Mechanistic Insights of Traditional Chinese Medicine.},
journal = {Biology},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/biology15191760},
pmid = {42883433},
issn = {2079-7737},
support = {NO.20250204060YY//Jilin Province Science and Technology Department/ ; },
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are characterized by progressive and irreversible neuronal loss, whereas current treatments remain largely symptomatic. Ferroptosis is an iron-dependent form of regulated cell death whose execution is defined by iron-enabled phospholipid peroxidation and failure of cellular ferroptosis-defense systems. Mitochondrial metabolism can modify ferroptosis susceptibility, but its contribution varies with cell type and initiating stimulus. Converging evidence implicates ferroptosis in multiple NDs, in which affected regions commonly show iron accumulation, glutathione depletion, and increased lipid peroxidation. With their multi-component and multi-target properties, traditional Chinese medicine (TCM) interventions may modulate several nodes in this network. This review summarizes the core execution and defense mechanisms of ferroptosis, evaluates their roles in major NDs, and critically appraises bioactive herbal compounds, compound formulas, acupuncture, electroacupuncture, and moxibustion. The reported interventions mainly engage the Nrf2/GPX4 antioxidant axis, TFR1/FPN1/FTH1/NCOA4-mediated iron handling, ACSL4-dependent lipid peroxidation, and GPX4-independent defense systems. Because most studies are preclinical and many infer ferroptosis from non-specific markers, the evidence is graded here as direct, supportive, indirect, mixed, or complementary. Translation will require standardized formulations, causal ferroptosis validation, pharmacokinetic and brain-exposure data, validated human biomarkers, and rigorously designed clinical trials.},
}

@article {pmid42883782,
year = {2026},
author = {Hashioka, S},
title = {Minocycline-Mediated Inhibition of Microglial Activation in Neuroinflammation-Related Neuropsychiatric Disorders: Preclinical Promise and Clinical Limitations.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198533},
pmid = {42883782},
issn = {1422-0067},
support = {JP22H02999//Japan Society for the Promotion of Science/ ; },
mesh = {*Minocycline/therapeutic use/pharmacology ; Humans ; *Microglia/drug effects/metabolism/pathology ; Animals ; *Neuroinflammatory Diseases/drug therapy ; *Mental Disorders/drug therapy ; Alzheimer Disease/drug therapy ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; Schizophrenia/drug therapy ; Major Depressive Disorder/drug therapy ; },
abstract = {Minocycline, a second-generation tetracycline antibiotic, has attracted interest as a CNS-active anti-inflammatory agent because it crosses the blood-brain barrier and inhibits microglial activation. This review summarizes preclinical and clinical evidence for minocycline in neuroinflammation-related neuropsychiatric disorders, focusing on Alzheimer's disease (AD), Lewy body disease (LBD), schizophrenia, and major depressive disorder (MDD). Across these disorders, preclinical studies have generally shown that minocycline attenuates microglial activation or maladaptive microglial responses and improves disease-relevant behavioral, synaptic, or neuropathological outcomes. However, clinical translation has been inconsistent. Clinical trials in AD, related parkinsonian disorders, schizophrenia, and MDD have failed to demonstrate robust and reproducible efficacy, despite encouraging preclinical findings. Moreover, direct clinical evidence that minocycline suppresses microglial activation in the human brain remains very limited. These discrepancies between preclinical findings and clinical evidence may reflect heterogeneity in disease stage and microglial states, suboptimal timing of intervention, lack of direct evidence that minocycline suppresses microglial activation in the human brain, and its non-selective anti-inflammatory actions. Future studies should incorporate biomarker-based patient stratification and direct measures of central microglial target engagement.},
}

*Minocycline/therapeutic use/pharmacology
Humans
*Microglia/drug effects/metabolism/pathology
Animals
*Neuroinflammatory Diseases/drug therapy
*Mental Disorders/drug therapy
Alzheimer Disease/drug therapy
*Anti-Inflammatory Agents/therapeutic use/pharmacology
Schizophrenia/drug therapy
Major Depressive Disorder/drug therapy

@article {pmid42883821,
year = {2026},
author = {Kim, KY and Shin, KY and Chang, KA},
title = {Plasma Neurofilament Light Chain as a Complementary Biomarker for Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198574},
pmid = {42883821},
issn = {1422-0067},
support = {RS-2026-25481253//National Research Foundation of Korea/ ; RS-2025-02292973//Korea Institute of Marine Science and Technology Promotion/ ; RS-2026-25474868//National Research Foundation of Korea/ ; },
mesh = {Humans ; *Neurofilament Proteins/blood ; *Alzheimer Disease/blood/diagnosis ; *Biomarkers/blood ; *Cognitive Dysfunction/blood/diagnosis ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss, ultimately leading to a loss of independence and reduced quality of life. As current treatments are most effective in the early stages, reliable blood-based biomarkers are required for early diagnosis, therapeutic monitoring, and disease staging. Plasma neurofilament light chain (NfL), a marker of neuroaxonal injury, is a candidate biomarker; its value relative to established amyloid- and tau-based biomarkers is unclear. A systematic review and meta-analysis comparing plasma NfL with Aβ42, Aβ40, the Aβ42/Aβ40 ratio, and p-tau217 across cognitively normal (control, Con), mild cognitive impairment (MCI), and AD groups was conducted. Fourteen studies that met specific criteria were included. Plasma NfL and p-tau217 increased across disease stages. Aβ42 and Aβ42/Aβ40 were lower in AD/MCI than in Con; Aβ40 was similar across groups. Heterogeneity (I[2] < 99%) was observed across biomarkers. Plasma NfL reliably reflected neuroaxonal injury and disease severity from the earliest clinically detectable stage of AD. Plasma NfL may be most valuable when combined with p-tau217/Aβ-based assays to provide a more comprehensive, blood-based assessment of both AD-specific pathology and neurodegeneration. Further studies are needed to validate its prognostic utility and establish clinically applicable cut-off values.},
}

Humans
*Neurofilament Proteins/blood
*Alzheimer Disease/blood/diagnosis
*Biomarkers/blood
*Cognitive Dysfunction/blood/diagnosis
Amyloid beta-Peptides/blood
tau Proteins/blood

@article {pmid42883839,
year = {2026},
author = {Acosta-Martínez, M and Carter, V and Nessim, A and Murphy, S and Dhawan, J and Beach, TG and Serrano, GE and Sundermann, EE and Biegon, A},
title = {Sex-Divergent Patterns in Hippocampal and Cortical NMDA Receptor Density Across the Alzheimer's Disease Continuum.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198590},
pmid = {42883839},
issn = {1422-0067},
support = {R01 AG074221-01//E.E. Sundermann/ ; U24 NS072026/NS/NINDS NIH HHS/United States ; P30 AG019610 and P30 AG072980/AG/NIA NIH HHS/United States ; contract 211002//Arizona Department of Health Services/ ; contracts 4001, 0011, 05-901 and 1001//Arizona Biomedical Research Commission/ ; MJFF-020402//Michael J. Fox Foundation for Parkinson's Research./ ; },
mesh = {Humans ; *Receptors, N-Methyl-D-Aspartate/metabolism ; *Alzheimer Disease/metabolism/pathology ; Female ; Male ; *Hippocampus/metabolism ; Aged ; tau Proteins/metabolism ; Cognitive Dysfunction/metabolism ; Aged, 80 and over ; Entorhinal Cortex/metabolism ; Sex Characteristics ; },
abstract = {While the loss of NMDA receptors (NMDARs) is associated with Alzheimer's disease (AD) severity, the effect of sex or the relationship between regional NMDAR density and antemortem cognitive status across the AD spectrum has not been examined. We performed quantitative in vitro autoradiography of the hippocampus, entorhinal cortex (EC), and parietal cortex using NMDAR and tau radioligands. Relationships between regional NMDAR density and cognitive status assessed by the Mini Mental State Examination (MMSE), and between NMDAR and tau density, were examined by bivariate correlations. In both sexes, the largest AD-related decreases in NMDAR density were observed in the cornu ammonis 1 (CA1) field. However, there was a significant diagnosis by sex interaction driven by sex-specific differences in the mild cognitive impairment (MCI) stage, with lower NMDAR density in MCI women, but not MCI men relative to same-sex controls. Within diagnosis analyses revealed positive correlations between NMDAR density and MMSE scores and significant negative correlations between EC NMDAR and tau density, which was significant only in AD men. Our data show that differences in hippocampal NMDAR density across the AD continuum are modulated by sex and may contribute to the known sex differences in the clinical trajectory of the disease.},
}

Humans
*Receptors, N-Methyl-D-Aspartate/metabolism
*Alzheimer Disease/metabolism/pathology
Female
Male
*Hippocampus/metabolism
Aged
tau Proteins/metabolism
Cognitive Dysfunction/metabolism
Aged, 80 and over
Entorhinal Cortex/metabolism
Sex Characteristics

@article {pmid42883891,
year = {2026},
author = {Ali, MY and Park, SE and Jung, HA and Choi, JS},
title = {In Vitro Screening of Sargassum spp. Ethanolic Extracts for Antioxidant Activity and Inhibition of Disease-Associated Enzymatic Targets Related to Diabetes, Alzheimer's Disease, and Parkinson's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198643},
pmid = {42883891},
issn = {1422-0067},
mesh = {*Sargassum/chemistry ; *Antioxidants/pharmacology/chemistry ; *Alzheimer Disease/drug therapy/enzymology ; Humans ; *Parkinson Disease/drug therapy/enzymology ; *Diabetes Mellitus/drug therapy/enzymology ; Ethanol/chemistry ; Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; *Enzyme Inhibitors/pharmacology/chemistry ; Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors/metabolism ; Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism ; *Plant Extracts/pharmacology/chemistry ; },
abstract = {Sargassum is a large and diversified genus of marine brown algae that is distributed widely in tropical and subtropical areas. They have been used for centuries in Asian countries, and have demonstrated a variety of health advantages, including anti-cardiovascular disease, anti-osteoarthritis, anti-cancer, anti-inflammatory, antioxidant, and hypopigmentation effects. However, the putative anti-diabetic, anti-Alzheimer's, and anti-Parkinson's diseases activities of various Sargassum spp. have not been investigated and compared thoroughly. Thus, the purpose of this study was to examine the anti-diabetic, anti-Alzheimer's, and anti-Parkinson's diseases' activities of ten Sargassum and one myagroides species collected off the Korean coast. In this study, we examined the inhibitory activity of 70% ethanolic extract of the Sargassum and myagroides species against protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, peroxynitrite (ONOO[-]), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), BACE1, MAO-A, and MAO-B. Among the Sargassum and myagroides species tested, S. hemiphyllum, S. filicinum, and S. miyabei showed potent PTP1B inhibitory activity (IC50 values of 2.11, 1.87, and 6.49 μg/mL, respectively), α-glucosidase inhibitory activity (IC50 values of 3.67, 2.30, and 11.12 μg/mL, respectively), and ONOO[-] scavenging activity, with IC50 values of 2.07, 4.49, and 2.46 μg/mL, respectively. Moreover, S. miyabei exhibited the highest BACE1 and BChE inhibitory activity, with IC50 values of 3.38 and 39.76 μg/mL, respectively. The highest MAO-A inhibitory activity was seen in S. miyabei, S. serratifolium, and S. macrocarpum, with IC50 values of 16.91, 12.46, and 14.02 μg/mL, respectively. Therefore, our findings showed that Sargassum species have health benefits and may be useful in treating diabetes and neurological disorders.},
}

*Sargassum/chemistry
*Antioxidants/pharmacology/chemistry
*Alzheimer Disease/drug therapy/enzymology
Humans
*Parkinson Disease/drug therapy/enzymology
*Diabetes Mellitus/drug therapy/enzymology
Ethanol/chemistry
Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism
*Enzyme Inhibitors/pharmacology/chemistry
Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors/metabolism
Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism
*Plant Extracts/pharmacology/chemistry

@article {pmid42883894,
year = {2026},
author = {Melrose, J},
title = {The Glyco-Code Molecular Template Instructively Guides Skeletal and Neural Development, Tissue Regeneration and Dynamic Repair Responses Following Trauma and Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198646},
pmid = {42883894},
issn = {1422-0067},
support = {//The University of Sydney/ ; },
mesh = {Humans ; Animals ; *Glycosaminoglycans/metabolism/chemistry ; *Nerve Regeneration ; Tissue Engineering/methods ; },
abstract = {Glycosaminoglycans encode instructional information that cells can decipher to regulate tissue development, repair responses, regeneration and recovery of tissue function following trauma or disease. This information has been termed the glyco-code and is a road map for tissue development and repair. This review shows that a clearer understanding of the glyco-code will support improved strategies in repair biology, particularly in skeletal and neural repair, regeneration, and therapeutic biomaterial design. Emerging therapeutic approaches for peripheral nerve repair increasingly combine multimodal delivery, microenvironmental control, and biomimetic structural support; however, the electroconductive properties of glycosaminoglycans have not yet been fully incorporated into these strategies. This gap is clinically important because neurological disorders affect more than 40% of the global population, representing approximately three billion people across conditions such as stroke, migraine, Alzheimer's disease, and diabetic neuropathy. Nanoparticle-engineered platforms and glyco-code-driven biomaterials may, therefore, provide future regenerative therapies that integrate glycosaminoglycan structure, charge, ligand-binding capacity, informational functions, and electroconductive control of resident cell populations to drive neural recovery. Multifunctional glycosaminoglycan interactions with a diverse range of binding proteins orchestrate tissue form and function in a diverse range of tissues in health and disease and have been widely used in tissue engineering protocols in repair biology. Tissue atlases, advanced glycomics, and molecular dynamics binding studies are now identifying roles for glycosaminoglycan binding proteins in therapeutic repair processes at the single-cell level, aiding in the identification of molecular targets for more effective recovery of tissue function. DynamicBind and SurfDock are deep learning methods that accurately demonstrate state-of-the-art performance in understanding the docking of potential therapeutic drugs with prospective targets, identifying cryptic pockets in unseen protein targets, and accelerating the development of small molecules for previously undruggable targets, potentially expanding the horizons of computational drug discovery with glycan structures.},
}

Humans
Animals
*Glycosaminoglycans/metabolism/chemistry
*Nerve Regeneration
Tissue Engineering/methods

@article {pmid42883911,
year = {2026},
author = {Rojas-Sánchez, I and Cortes-Flores, E and Camacho-Concha, N and Almazán, JL and Ramírez-Lugo, L and Crivelli-Galindo, E and Ramirez-Serrano, CE and Pedraza-Alva, G and Pérez-Martínez, L},
title = {Therapeutic Administration of Malva parviflora Hydroalcoholic Extract Restores Cognitive Function Consistent with a Resilient Phenotype in Female 5XFAD.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198665},
pmid = {42883911},
issn = {1422-0067},
support = {PAPIIT IN217822//Dirección General de Asuntos del Personal Académico (DGAPA), Universidad Nacional Autónoma de México (UNAM)/ ; PAPIIT IN222925//Dirección General de Asuntos del Personal Académico (DGAPA), Universidad Nacional Autónoma de México (UNAM)/ ; PAPIIT IN216922//Dirección General de Asuntos del Personal Académico (DGAPA), Universidad Nacional Autónoma de México (UNAM)/ ; CBF2023-2024-878//Consejo Nacional de Humanidades, Ciencias y Tecnologías/ ; IFC 2016-2282//Consejo Nacional de Humanidades, Ciencias y Tecnologías/ ; },
mesh = {Animals ; Female ; *Plant Extracts/pharmacology/chemistry/administration & dosage ; *Cognition/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; Hippocampus/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; *Malva/chemistry ; Mice, Transgenic ; Long-Term Potentiation/drug effects ; Phenotype ; Disease Models, Animal ; Glial Fibrillary Acidic Protein/metabolism ; Neuronal Plasticity/drug effects ; },
abstract = {The remarkable increase in human life expectancy has been accompanied by a rising global incidence of neurodegenerative disorders, particularly Alzheimer's disease. This condition is characterized by progressive accumulation of soluble and insoluble amyloid-beta peptides, neuroinflammation, and synaptic dysfunction in the hippocampus, leading to impaired higher-order cognition. Epidemiological evidence indicates that women are disproportionately affected; however, female-specific pathology remains understudied. Here, we evaluated the therapeutic potential of a hydroalcoholic extract of Malva parviflora in female 5XFAD mice following prolonged intragastric administration initiated after disease establishment. Long-term treatment shifted cognitive performance toward a phenotype comparable to wild-type littermates, an improvement associated with reduced soluble amyloid-beta levels in the hippocampus and peripheral circulation, and significant attenuation of reactive astrogliosis as evidenced by reduced hippocampal glial fibrillary acidic protein levels. Because reactive astrocytes impair synaptic activity and metabolic homeostasis during disease progression, we examined the direct effects of Malva parviflora on synaptic plasticity ex vivo. Incubation of hippocampal synaptosomes from adult female 5XFAD mice with the extract restored chemically induced long-term potentiation. These findings demonstrate that Malva parviflora attenuates key pathological hallmarks of Alzheimer's disease and promotes cognitive recovery, supporting its potential as a plant-derived therapeutic candidate, particularly in females most affected by Alzheimer's disease. Future studies including both sexes under a therapeutic paradigm are needed to determine the generalizability of these findings.},
}

Animals
Female
*Plant Extracts/pharmacology/chemistry/administration & dosage
*Cognition/drug effects
*Alzheimer Disease/drug therapy/metabolism
Mice
Hippocampus/drug effects/metabolism
Amyloid beta-Peptides/metabolism
*Malva/chemistry
Mice, Transgenic
Long-Term Potentiation/drug effects
Phenotype
Disease Models, Animal
Glial Fibrillary Acidic Protein/metabolism
Neuronal Plasticity/drug effects

@article {pmid42883925,
year = {2026},
author = {Seol, SI and Kim, JE and Davaanyam, D and Park, SY and Lee, EH and Han, PL and Kim, TK and Lee, JK},
title = {HMGB1 in Amyloid-Beta Pathology: Mechanistic Insights and Therapeutic Implications for Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198681},
pmid = {42883925},
issn = {1422-0067},
support = {2021R1A2C2010920//Mid-carrier Research Grant (2021R1A2C2010920) for J.-K.L. from the National Research Foun-dation (NRF), Republic of Korea/ ; },
mesh = {Humans ; *HMGB1 Protein/metabolism/genetics ; *Alzheimer Disease/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Animals ; Microglia/metabolism/pathology ; Neurons/metabolism/pathology ; Phagocytosis ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles. Beyond these hallmark pathological features, the complex pathogenesis of AD involves cellular dysfunctions associated with chronic oxidative stress and neuroinflammation. Central to these inflammatory pathways is the extracellular release of the nuclear protein high-mobility group box 1 (HMGB1) from neurons and microglia. Extracellular HMGB1 disrupts homeostatic and reparative microglial functions, impairing the phagocytic clearance of amyloid-beta and driving neuroinflammation to accelerate AD pathogenesis. Consequently, targeting HMGB1 offers a promising therapeutic strategy for AD. This review examines recent progress and key insights regarding HMGB1-associated neuroinflammatory pathology in AD. We evaluate its regulation across transcriptional upregulation, cellular redistribution, age-related alterations, and Aβ-associated pathology. We further detail the pleiotropic effects of extracellular HMGB1, including neuroinflammation, defective Aβ phagocytic clearance, and genomic instability. Finally, we discuss the potential clinical utility of targeting HMGB1 to mitigate AD progression and provide HMGB1-related perspectives for future studies.},
}

Humans
*HMGB1 Protein/metabolism/genetics
*Alzheimer Disease/metabolism/pathology
*Amyloid beta-Peptides/metabolism
Animals
Microglia/metabolism/pathology
Neurons/metabolism/pathology
Phagocytosis

@article {pmid42883945,
year = {2026},
author = {Bellver-Sanchis, A and Griñán-Ferré, C and Sutour, S and Marchev, AS},
title = {Effect of Rhodiola rosea L. Extract on Alzheimer's Disease-like Symptoms in Caenorhabditis elegans.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198701},
pmid = {42883945},
issn = {1422-0067},
support = {KП-06-КОСТ/14//Bulgarian National Science Fund/ ; },
mesh = {Animals ; *Caenorhabditis elegans/drug effects/metabolism ; *Rhodiola/chemistry ; *Plant Extracts/pharmacology/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress/drug effects ; Glucosides/pharmacology ; Phenols/pharmacology ; Amyloid beta-Peptides/metabolism ; Antioxidants/pharmacology ; *Neuroprotective Agents/pharmacology/chemistry ; Disease Models, Animal ; Caenorhabditis elegans Proteins/metabolism/genetics ; Locomotion/drug effects ; Disaccharides ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, oxidative stress, and amyloid-beta accumulation. Natural products with antioxidant and stress-response-modulating properties are increasingly being investigated as candidate neuroprotective agents. In this study, we evaluated the effects of Rhodiola rosea L. extract, salidroside, and rosavin in Caenorhabditis elegans models of AD. Phenotypic, behavioral, biochemical, and molecular assays were used to assess locomotion, egg laying, chemotaxis, reactive oxygen species (ROS), gene expression, and amyloid-like aggregation. The extract and its related compounds improved locomotor performance, partially rescued reproductive and sensory defects, reduced ROS accumulation, modulated stress-response genes including skn-1/nrf2, daf-2, and sod-1, and decreased thioflavin-S-positive aggregates. Together, these findings support the potential neuroprotective effect of R. rosea extract and its key marker compounds, suggesting the involvement of conserved antioxidant pathways.},
}

Animals
*Caenorhabditis elegans/drug effects/metabolism
*Rhodiola/chemistry
*Plant Extracts/pharmacology/chemistry
*Alzheimer Disease/drug therapy/metabolism
Reactive Oxygen Species/metabolism
Oxidative Stress/drug effects
Glucosides/pharmacology
Phenols/pharmacology
Amyloid beta-Peptides/metabolism
Antioxidants/pharmacology
*Neuroprotective Agents/pharmacology/chemistry
Disease Models, Animal
Caenorhabditis elegans Proteins/metabolism/genetics
Locomotion/drug effects
Disaccharides

@article {pmid42883949,
year = {2026},
author = {Delgado-Minjares, KM and Flores-Maldonado, C and Campos-Blázquez, JP and Díaz-Miranda, SY and Andrade-Guerrero, J and Colín-García, W and León-Arcia, K and Martinez-Fong, D and Contreras, RG and Soto-Rojas, LO},
title = {Age-Stratified Analysis of Blood-Brain Barrier Proteins Identifies Lower Occludin Abundance in the 3xTg-AD Model.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198705},
pmid = {42883949},
issn = {1422-0067},
support = {20932//Universidad Nacional Autónoma de México through the Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica/ ; IN227026//the Universidad Nacional Autónoma de México through the Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica/ ; CBF-2025-G35//Ciencia básica y de Frontera/ ; 2019/7357//Ciencia básica y de Frontera/ ; },
mesh = {Animals ; *Blood-Brain Barrier/metabolism ; *Occludin/metabolism/genetics ; *Alzheimer Disease/metabolism/pathology/genetics ; Male ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Cadherins/metabolism ; Pericytes/metabolism ; Humans ; Endothelial Cells/metabolism ; Aging/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which blood-brain barrier (BBB) dysfunction may arise early. We performed an age-stratified, cross-sectional analysis of pericyte- and endothelial-associated markers and junctional proteins (claudin-1, -3, -5, occludin, and VE-cadherin) in cerebral capillary-enriched fractions from male Non-Tg and 3xTg-AD mice at asymptomatic, early, and advanced stages (3, 6, 12, and 16 months of age). Protein abundance was assessed by Western blot, and BBB permeability to 3-5 kDa FITC-dextran was evaluated at 3 months in an independent cohort. At 3 months, the pSRC/SRC ratio and an MMP-9-immunoreactive band were also evaluated in a separate cohort as candidate signaling markers related to occludin dysregulation. We detected no significant age or genotype effects for the pericyte- and endothelial-associated markers or for most junctional protein outcomes. Occludin was the only protein outcome with a significant overall genotype effect, with the largest mean reductions observed at 3 (~80%) and 6 months (~68%). A small exploratory cohort showed a higher hemisphere-derived permeability index in 3xTg-AD mice at 3 months. Neither pSRC/SRC nor the abundance of the MMP-9-immunoreactive band differed significantly between genotypes. These findings identify lower occludin abundance as the principal BBB-associated protein alteration in the 3xTg-AD model and provide exploratory evidence of increased BBB permeability at 3 months. These independent observations warrant longitudinal and translational evaluation to determine whether occludin abundance and BBB permeability could serve as indicators of early neurovascular dysfunction in AD.},
}

Animals
*Blood-Brain Barrier/metabolism
*Occludin/metabolism/genetics
*Alzheimer Disease/metabolism/pathology/genetics
Male
Mice
Mice, Transgenic
Disease Models, Animal
Cadherins/metabolism
Pericytes/metabolism
Humans
Endothelial Cells/metabolism
Aging/metabolism

@article {pmid42883986,
year = {2026},
author = {Popa, E and Popa, AE and Poroch, V and Schreiner, TG and Slanina, AM and Poroch, M and Hatneanu, AM and Ungureanu, MI and Petroaie, AD and Bacusca, AI and Coman, EA},
title = {GLP-1, GIP, and Glucagon Receptor Agonism at the Obesity-Neurodegeneration Interface: A Narrative Review.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198738},
pmid = {42883986},
issn = {1422-0067},
mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Receptors, Gastrointestinal Hormone/agonists/metabolism ; Animals ; *Receptors, Glucagon/agonists/metabolism ; *Obesity/metabolism/drug therapy ; *Neurodegenerative Diseases/drug therapy/metabolism ; Semaglutide ; *Glucagon-Like Peptide 1/metabolism ; Tirzepatide ; *Gastric Inhibitory Polypeptide/metabolism ; },
abstract = {Glucagon-like peptide-1 receptor agonism has attracted interest in neurodegeneration because of its effects on metabolic and inflammatory pathways implicated in neuronal dysfunction. This narrative review examines the molecular rationale and neurological evidence for selective glucagon-like peptide-1 receptor agonists, dual agonists additionally targeting the glucose-dependent insulinotropic polypeptide receptor, and triple agonists also engaging the glucagon receptor. English-language literature retrieved from PubMed, Scopus, and Web of Science was synthesized according to study design and neurological relevance. Preclinical findings indicate modulation of insulin signaling, synaptic function, mitochondrial homeostasis, and neuroinflammation, but responses vary across compounds and experimental models. In Alzheimer's disease, liraglutide did not meet its primary trial endpoint, and semaglutide did not slow clinical progression. Parkinson's disease trials have yielded mixed results without establishing disease modification. Observational associations with reduced dementia risk remain susceptible to confounding. Neurological evidence for tirzepatide and retatrutide remains predominantly observational or preclinical. Greater metabolic efficacy does not establish neuroprotection, while nutritional vulnerability may constrain therapeutic applicability. Dedicated randomized trials integrating clinical outcomes with pharmacological exposure, target engagement, and metabolic mediation are required to distinguish systemic effects from direct neural actions and determine whether these therapies can prevent cognitive decline or modify established neurodegenerative disease.},
}

Humans
*Glucagon-Like Peptide-1 Receptor Agonists
*Receptors, Gastrointestinal Hormone/agonists/metabolism
Animals
*Receptors, Glucagon/agonists/metabolism
*Obesity/metabolism/drug therapy
*Neurodegenerative Diseases/drug therapy/metabolism
Semaglutide
*Glucagon-Like Peptide 1/metabolism
Tirzepatide
*Gastric Inhibitory Polypeptide/metabolism

@article {pmid42884007,
year = {2026},
author = {Gu, T and Wei, X and Hua, S},
title = {Cuproptosis: New Mechanisms Linking Endothelial Dysfunction to Neurodegenerative Diseases and Therapeutic Prospects.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198765},
pmid = {42884007},
issn = {1422-0067},
mesh = {Humans ; *Cuproptosis ; *Neurodegenerative Diseases/metabolism/pathology/etiology/therapy ; Animals ; *Copper/metabolism ; Mitochondria/metabolism ; Oxidative Stress ; *Endothelium, Vascular/metabolism/pathology/physiopathology ; Homeostasis ; },
abstract = {Cuproptosis is a copper-dependent form of regulated cell death driven by disrupted copper homeostasis and mitochondrial metabolic reprogramming. It is distinct from other cell death pathways and has been increasingly linked to vascular endothelial dysfunction and neurodegenerative diseases such as Alzheimer's and Parkinson's disease. This article comprehensively reviews the core molecular mechanisms of cuproptosis and its emerging roles in endothelial dysfunction and neurodegeneration, synthesizing recent findings from cellular, animal, and human studies. Cuproptosis exacerbates vascular pathology by impairing endothelial barrier function, inducing oxidative stress, and promoting inflammation and senescence. In the brain, it drives neurodegeneration both directly-via mitochondrial damage and neuronal loss-and indirectly by interacting with pathological proteins such as amyloid-beta and α-synuclein, creating a vicious cycle of copper dysregulation and protein aggregation. This review provides new insights into the pathophysiology of vascular endothelial dysfunction and neurodegenerative diseases by highlighting the pivotal role of cuproptosis. Understanding how cuproptosis links copper metabolism to cell death pathways opens avenues for identifying novel therapeutic targets. Interventions that restore copper homeostasis or block cuproptosis-specific molecular events may offer promising strategies for treating these devastating diseases.},
}

Humans
*Cuproptosis
*Neurodegenerative Diseases/metabolism/pathology/etiology/therapy
Animals
*Copper/metabolism
Mitochondria/metabolism
Oxidative Stress
*Endothelium, Vascular/metabolism/pathology/physiopathology
Homeostasis

@article {pmid42884019,
year = {2026},
author = {Abbate, C},
title = {The Adult Neurogenesis Theory of Alzheimer's Disease Predicts Where Tauopathy Develops in the Brain.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198776},
pmid = {42884019},
issn = {1422-0067},
support = {Ricerca Corrente 2026; RRC-2026-23687902//Fondazione Don Carlo Gnocchi ETS/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/physiopathology ; *Neurogenesis ; *Tauopathies/pathology/metabolism/physiopathology ; *Brain/pathology/metabolism ; tau Proteins/metabolism ; Animals ; Neurons/metabolism/pathology ; },
abstract = {Adult neurogenesis is impaired in Alzheimer's disease (AD) and contributes to neuronal and cognitive dysfunction. Furthermore, efficient neurogenesis promotes cognitive resilience. I recently proposed a theory suggesting that neurogenesis plays a more central role in the pathogenesis of AD. The main hypothesis posits that new neurons harboring tau seeds propagate tauopathy as they mature and integrate into the brain. The aim of this study is to demonstrate that the theory successfully predicts the distribution of the earliest foci of tauopathy in AD. To this end, I synthesized data from the literature regarding the earliest localizations of tauopathy in AD. I then indicated where one would expect to find the earliest seeds of tauopathy if the theory were true. Finally, I compared the localization data with the theory's predictions. Overall, the theory's predictions were entirely consistent with the initial localization of tauopathy. Specifically, the theory is consistent with the exclusively neuronal and somatodendritic involvement of tauopathy; the preference for layer II and the transentorhinal/entorhinal complex; the early involvement of subcortical nuclei; phenotypic heterogeneity; differences between early- and late-onset AD; hemispheric asymmetries; and clinical-anatomical convergence. The theory demonstrates predictive power, economicity, compatibility with other theories, and generalizability to other diseases.},
}

Humans
*Alzheimer Disease/pathology/metabolism/physiopathology
*Neurogenesis
*Tauopathies/pathology/metabolism/physiopathology
*Brain/pathology/metabolism
tau Proteins/metabolism
Animals
Neurons/metabolism/pathology

@article {pmid42884062,
year = {2026},
author = {Kuikel, K and McEwen, A and Mathiske, TJ and Wojtaszak, L and John, JAS and Delbaz, A},
title = {Combined Effects of Chlamydia pneumoniae Infection and Hypoxia on Glial Metabolism and Alzheimer's Disease-Related Pathways.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198820},
pmid = {42884062},
issn = {1422-0067},
support = {//Clem Jones Foundation/ ; //Goda Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/microbiology/pathology ; *Chlamydophila pneumoniae ; Amyloid beta-Peptides/metabolism ; *Neuroglia/metabolism ; Astrocytes/metabolism/microbiology ; Cell Hypoxia ; *Hypoxia/metabolism ; Microglia/metabolism/microbiology ; Cell Line ; Proteomics/methods ; *Chlamydophila Infections/metabolism ; *Chlamydia Infections/metabolism ; },
abstract = {Alzheimer's disease involves complex interactions among neuroinflammation and metabolic dysfunction. Emerging evidence implicates microbial pathogens and hypoxia as converging stressors, yet their combined impact on glial function remains poorly understood. Human astrocyte and microglial cell lines were exposed to four experimental conditions: (i) normoxic control, (ii) Chlamydia pneumoniae infection under normoxia, (iii) hypoxia control and (iv) Chlamydia pneumoniae infection under hypoxic conditions. Hypoxia was induced at 3% oxygen for 72 h. Cellular responses were assessed using NanoString nCounter transcriptomics using the Alzheimer's Disease and Metabolic Pathways panels, Tandem Mass Tag proteomics, MTT reduction, glucose uptake, intracellular ATP quantification and amyloid beta quantification by ELISA. Combined exposure to infection and hypoxia was associated with cell-type-specific alterations in glial metabolic and transcriptional responses. Factorial transcriptomic analysis identified significant infection × oxygen interactions across both NanoString panels and glial cell types. Proteomic responses differed according to cell type and oxygen availability. Aβ40 and Aβ42 measurements demonstrated treatment-associated alterations in the extracellular Aβ peptide profile, including increased Aβ42/Aβ40 ratios following infection. Together, these findings demonstrate distinct and interacting effects of infection and hypoxia on glial metabolic and molecular responses and identify Alzheimer's disease-related cellular changes warranting further investigation in physiologically relevant models.},
}

Humans
*Alzheimer Disease/metabolism/microbiology/pathology
*Chlamydophila pneumoniae
Amyloid beta-Peptides/metabolism
*Neuroglia/metabolism
Astrocytes/metabolism/microbiology
Cell Hypoxia
*Hypoxia/metabolism
Microglia/metabolism/microbiology
Cell Line
Proteomics/methods
*Chlamydophila Infections/metabolism
*Chlamydia Infections/metabolism

@article {pmid42884579,
year = {2026},
author = {Intharuksa, A and Prasansuklab, A and Techarang, T and Chaikhong, K and Arunotayanun, W and Jenraumjit, R},
title = {The Role of Herbal Medicines in Cognitive Impairment: A Narrative Review of Neuroprotective Mechanisms and Therapeutic Perspectives.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
doi = {10.3390/nu18193126},
pmid = {42884579},
issn = {2072-6643},
mesh = {Humans ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; *Cognitive Dysfunction/drug therapy ; *Phytotherapy/methods ; *Plant Preparations/therapeutic use/pharmacology ; Plant Extracts/pharmacology/therapeutic use ; Plants, Medicinal ; Cognition/drug effects ; },
abstract = {Cognitive impairment encompasses a clinical spectrum ranging from mild cognitive impairment to dementia, particularly Alzheimer's disease (AD), and involves interconnected pathological processes including cholinergic dysfunction, oxidative stress, neuroinflammation, mitochondrial impairment, amyloid-β accumulation, tau hyperphosphorylation, and synaptic loss. Herbal medicines have attracted increasing attention because their complex phytochemical composition may provide multi-target neuroprotective effects. This narrative review aimed to summarize current preclinical and clinical evidence on herbal medicines and traditional herbal formulations for cognitive impairment, with emphasis on their mechanisms, therapeutic potential, safety, and translational limitations. Relevant evidence from in vitro studies, animal models, randomized clinical trials, systematic reviews, and meta-analyses was narratively synthesized. The review considered single herbal medicines, standardized extracts, isolated phytochemicals, and traditional multi-herbal formulations, together with their reported cognitive outcomes and molecular targets. Preclinical studies suggest that selected herbal preparations may modulate pathways implicated in cognitive impairment through acetylcholinesterase and butyrylcholinesterase inhibition, antioxidant and mitochondrial protection, suppression of neuroinflammatory signaling, modulation of amyloidogenic and tau-related pathways, and enhancement of BDNF/TrkB- and CREB-associated neuroplasticit; however, clinical evidence remains limited and heterogeneous. Clinical studies of Bacopa monnieri, Panax ginseng, Crocus sativus, and several traditional Chinese, Korean, and Persian formulations have reported improvements in memory and global cognitive measures, including MMSE, MoCA, and ADAS-cog scores. However, evidence remains constrained by heterogeneity of products, small sample sizes, short treatment periods, inconsistent outcome measures, limited biomarker integration, and incomplete long-term safety assessment. Herbal medicines show potential as preventive, complementary, or adjunctive approaches for cognitive impairment, but they cannot yet be considered established replacements for conventional therapy. Standardized products, rigorous pharmacokinetic and toxicological evaluation, disease-relevant models, and adequately powered multicenter trials are required to support evidence-based clinical application.},
}

Humans
*Neuroprotective Agents/therapeutic use/pharmacology
Animals
*Cognitive Dysfunction/drug therapy
*Phytotherapy/methods
*Plant Preparations/therapeutic use/pharmacology
Plant Extracts/pharmacology/therapeutic use
Plants, Medicinal
Cognition/drug effects

@article {pmid42884593,
year = {2026},
author = {Chen, R},
title = {Association of Nut Consumption with Dementia and Alzheimer's Disease.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
doi = {10.3390/nu18193143},
pmid = {42884593},
issn = {2072-6643},
mesh = {Humans ; *Nuts ; Aged ; Male ; Female ; *Alzheimer Disease/epidemiology/prevention & control ; Case-Control Studies ; Middle Aged ; *Dementia/epidemiology/prevention & control ; Aged, 80 and over ; China/epidemiology ; Risk Factors ; *Diet ; Odds Ratio ; Logistic Models ; },
abstract = {Background: Nut consumption reduces risks of cardiovascular disease, respiratory disease and depression. However, its association with dementia and Alzheimer's disease (AD) remains unclear. Methods: A population-based case-control study was conducted in China, including 466 participants aged 52-100 years (233 with dementia). Data on socio-demographic characteristics, lifestyle factors, comorbidities, and dietary intake over the past two years were collected through structured face-to-face interviews. Nut consumption was categorised as non-consumption or }

Humans
*Nuts
Aged
Male
Female
*Alzheimer Disease/epidemiology/prevention & control
Case-Control Studies
Middle Aged
*Dementia/epidemiology/prevention & control
Aged, 80 and over
China/epidemiology
Risk Factors
*Diet
Odds Ratio
Logistic Models

@article {pmid42884594,
year = {2026},
author = {Ben Mohamed, A and Vauzour, D},
title = {Do Grape- and Wine-Derived (Poly)Phenols Contribute to the Hallmarks of Healthy Brain Ageing?.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
doi = {10.3390/nu18193144},
pmid = {42884594},
issn = {2072-6643},
mesh = {Humans ; *Wine/analysis ; *Vitis/chemistry ; *Brain/drug effects/physiology ; *Polyphenols/pharmacology/pharmacokinetics ; *Aging/drug effects ; Gastrointestinal Microbiome/drug effects ; Animals ; Biological Availability ; Antioxidants/pharmacology ; Cognitive Aging ; Neuroprotective Agents/pharmacology ; *Phenols/pharmacology ; },
abstract = {Population ageing is associated with a rising burden of cognitive decline, dementia and late-life affective disorders. Grape- and wine-derived (poly)phenols represent a chemically diverse group of bioactives whose biological relevance is shaped by structural complexity, the intervention matrix, host conjugation and gut microbial metabolism. Rather than acting as simple antioxidants, these compounds and their derived metabolites may influence interrelated pathways implicated in brain ageing, including neuroinflammation, endothelial function, synaptic plasticity, oxidative stress and gut-brain axis signalling. The gut microbiota is central to this framework as it converts poorly absorbed parent compounds into smaller phenolic metabolites and is modulated by (poly)phenol exposure. This review summarises the chemical and bioavailability features that determine intestinal and colonic availability, evaluates preclinical evidence concerning the neuroprotective potential of grape- and wine-derived (poly)phenols, and integrates clinical evidence from studies of cognitive ageing, mild cognitive impairment and Alzheimer's disease. Current evidence supports biological plausibility and justifies further investigation, but clinical findings remain heterogeneous. Future studies should prioritise chemically standardised preparations, metabolomic profiling, functional microbiome readouts, and integrated cognitive, vascular and inflammatory endpoints.},
}

Humans
*Wine/analysis
*Vitis/chemistry
*Brain/drug effects/physiology
*Polyphenols/pharmacology/pharmacokinetics
*Aging/drug effects
Gastrointestinal Microbiome/drug effects
Animals
Biological Availability
Antioxidants/pharmacology
Cognitive Aging
Neuroprotective Agents/pharmacology
*Phenols/pharmacology

@article {pmid42884597,
year = {2026},
author = {Kamalakar, K and Akerele, C and Lafont, E and Koralnik, LR and Gilman, C and Litran, JC and Lee, J and Robinson-Papp, J and Malaspina, D},
title = {Gut Microbiome-Mediated Neuroprotective Effect of the Mediterranean Diet: A Narrative Review of Cognitive Aging, Alzheimer's Disease, and Parkinson's Disease.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
doi = {10.3390/nu18193146},
pmid = {42884597},
issn = {2072-6643},
mesh = {Humans ; *Diet, Mediterranean ; *Gastrointestinal Microbiome/physiology ; *Parkinson Disease/microbiology/prevention & control ; *Alzheimer Disease/prevention & control/microbiology ; *Cognitive Aging/physiology ; *Neuroprotection ; Animals ; },
abstract = {Background: Alzheimer's disease (AD) and Parkinson's disease (PD) are major neurodegenerative disorders for which disease-modifying therapies are limited. Increasingly, evidence suggests that diet influences neurodegenerative risk through interactions among the gut microbiome, immune system, and brain. The Mediterranean diet (MD) is associated with improved cognitive health, but the mechanisms underlying its potential neuroprotective effects remain incompletely understood. Objective: In this narrative review, evidence on microbiome-mediated mechanisms linking MD adherence to neuroprotection was synthesized, and how Mediterranean dietary components influence microbial ecology, metabolites, immune regulation, and neuroinflammation relevant to cognitive aging, AD, and PD was evaluated. Methods: Evidence from experimental, observational, and clinical studies was reviewed, focusing on microbial metabolites, intestinal barrier integrity, immune regulation, and inflammatory pathways. Discussion: Mediterranean dietary components, including fiber, polyphenols, whole grains, legumes, nuts, extra-virgin olive oil, and omega-3 fatty acids, may promote beneficial microbial communities and metabolite production. Short-chain fatty acids, secondary bile acids, indole derivatives, and phenolic metabolites may strengthen the intestinal and blood-brain barriers, regulate immune responses, and suppress neuroinflammation. Conversely, dysbiosis may increase intestinal permeability, lipopolysaccharide translocation, systemic inflammation, and microglial activation. However, evidence remains heterogeneous and largely observational or experimental. Conclusions: The MD may promote neuroprotection through interconnected diet-microbiome-immune pathways. Longitudinal and intervention studies integrating microbiome, metabolomic, inflammatory, neuroimaging, and cognitive measures are needed to establish causality and advance precision nutrition strategies to prevent neurodegenerative disease.},
}

Humans
*Diet, Mediterranean
*Gastrointestinal Microbiome/physiology
*Parkinson Disease/microbiology/prevention & control
*Alzheimer Disease/prevention & control/microbiology
*Cognitive Aging/physiology
*Neuroprotection
Animals

@article {pmid42884661,
year = {2026},
author = {Yue, M and Zhou, L and He, W and Li, B and Yang, Z and Liu, Y and Chen, L and Chen, C and Zhang, Y},
title = {Neuroprotective Potential of the Edible Seaweed Pterocladiella capillacea: Bioactivity Coupled LC-MS/MS, Metabolomics Annotation, Validation, and Network Pharmacology.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
doi = {10.3390/nu18193210},
pmid = {42884661},
issn = {2072-6643},
support = {2025A1515010941//Guangdong Provincial Natural Science Foundation/ ; KCXFZ20240903093925033//the Sustainable Development Program of Shenzhen Science and Technology Major Program/ ; 2025KCJS_057//Guangdong Provincial Graduate Student Course Construction Project/ ; 2024ZDZX2086//Special Project in Key Fields of Guangdong Provincial Higher Education Institutions/ ; 2024B01265//Zhanjiang Science and Technology Plan Projects/ ; 2024A1515110066//Guangdong Provincial Natural Science Foundation/ ; GDOU2025092//Guangdong Provincial College Student Innovation & Entrepreneurship Training Project/ ; },
mesh = {*Neuroprotective Agents/pharmacology/chemistry ; Tandem Mass Spectrometry ; Metabolomics/methods ; *Edible Seaweeds/chemistry ; Antioxidants/pharmacology ; Network Pharmacology ; Liquid Chromatography-Mass Spectrometry ; Humans ; Animals ; Chromatography, Liquid ; *Rhodophyta/chemistry ; Molecular Docking Simulation ; Neurons/drug effects ; *Plant Extracts/pharmacology ; Cell Survival/drug effects ; },
abstract = {Background: Alzheimer's disease (AD) is a complex neurodegenerative disorder with a global impact, highlighting an urgent need for effective dietary therapeutic agents for the development of brain-healthy functional foods and medicines. This study focuses on the edible red alga Pterocladiella capillacea from Zhanjiang, China, investigating its anti-neuronal injury activity, active principles, and underlying mechanisms. Methods: Based on antioxidant and neuroprotection evaluations and column fractioning, bioactivity-coupled liquid chromatography-tandem mass spectrometry (Bio-LC-MS/MS) was employed to recognize the neuroprotective compounds, which were further annotated by comprehensive metabolomics analysis. The annotated compounds were validated by LC-MS/MS and bioassay. Computational prediction techniques were further used to reveal their mechanism of action. Results: The study demonstrated that P. capillacea extract and fractions exhibited significant antioxidant and anti-neuronal injury activities. Among the annotated and MS-validated potential compounds, erucamide standard exhibited the strongest neuroprotective effect, maintaining cell viability above 85% at low concentrations. Network pharmacology and molecular docking revealed that erucamide may exert neuroprotective effects by modulating the AKT1 and BCL2 targets. ADMET prediction suggested a low risk of central side effects. Conclusions: The neuroprotective potential of P. capillacea provides a primary foundation for new brain-healthy functional foods and drug development in future.},
}

*Neuroprotective Agents/pharmacology/chemistry
Tandem Mass Spectrometry
Metabolomics/methods
*Edible Seaweeds/chemistry
Antioxidants/pharmacology
Network Pharmacology
Liquid Chromatography-Mass Spectrometry
Humans
Animals
Chromatography, Liquid
*Rhodophyta/chemistry
Molecular Docking Simulation
Neurons/drug effects
*Plant Extracts/pharmacology
Cell Survival/drug effects

@article {pmid42884668,
year = {2026},
author = {Choe, YM and Kim, JH and Choi, HJ and Lee, BC and Suh, GH and Kim, SG and Kim, HS and Hwang, J and Yi, D and Kim, JW},
title = {Nutritional Status and Cognition in Older Adults: Modification by Apolipoprotein E ε4.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
doi = {10.3390/nu18193217},
pmid = {42884668},
issn = {2072-6643},
support = {HURF-2023-36//Hallym University/ ; RS-2023-00210820//National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (MSIT)/ ; },
mesh = {Humans ; *Apolipoprotein E4/genetics ; *Nutritional Status/genetics ; *Cognition ; Aged ; Cross-Sectional Studies ; Female ; Male ; Nutrition Assessment ; Aged, 80 and over ; *Malnutrition/genetics ; Republic of Korea ; Risk Factors ; },
abstract = {Background: Malnutrition is a modifiable risk factor for late-life cognitive decline, but whether its cognitive correlates vary by genetic risk is unclear. We examined whether the apolipoprotein E ε4 allele (APOE4) modifies associations of the Mini-Nutritional Assessment (MNA) and its subscales with global cognition. Methods: In this cross-sectional analysis of 196 non-demented older Korean adults from the General Lifestyle and Alzheimer's Disease (GLAD) cohort, multiple linear regression tested associations of MNA total (MNA-T), screening (MNA-S), and assessment (MNA-A) scores with the CERAD total score (TS), including MNA × APOE4 interactions. Exploratory analyses examined one representative item per a priori nutritional domain. Results: After adjustment, MNA-T (p = 0.006) and MNA-A (p = 0.003), but not MNA-S (p = 0.065), were associated with TS. APOE4 carrier status modified these associations (interaction p = 0.005 and 0.007, respectively); associations were evident in non-carriers but not in carriers, an underpowered subgroup (n = 40). Among the domain-representative items, only self-rated health survived Bonferroni correction (p = 0.006); protein intake (p = 0.025) and calf circumference (p = 0.043) showed nominal associations only. Conclusions: Better nutritional status was associated with better global cognition, predominantly in APOE4 non-carriers. These hypothesis-generating findings require confirmation in larger longitudinal and interventional studies.},
}

Humans
*Apolipoprotein E4/genetics
*Nutritional Status/genetics
*Cognition
Aged
Cross-Sectional Studies
Female
Male
Nutrition Assessment
Aged, 80 and over
*Malnutrition/genetics
Republic of Korea
Risk Factors

@article {pmid42884681,
year = {2026},
author = {Cornelis, MC and van Dam, RM and Bennett, DA and Schneider, JA},
title = {Interaction Between COMT Genotype and MIND Diet, Cognitive Decline, and Incident Dementia: A Prospective Cohort Study.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
doi = {10.3390/nu18193232},
pmid = {42884681},
issn = {2072-6643},
support = {R01AG065398/AG/NIA NIH HHS/United States ; R01AG17917/AG/NIA NIH HHS/United States ; R01AG054476/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Catechol O-Methyltransferase/genetics ; *Dementia/genetics/epidemiology ; Female ; Prospective Studies ; Male ; Genotype ; Aged, 80 and over ; Aged ; *Diet, Mediterranean ; *Cognitive Dysfunction/genetics/epidemiology ; Cognition ; Incidence ; Proportional Hazards Models ; },
abstract = {Background: Catechol-O-methyltransferase (COMT) metabolizes catecholamines and polyphenols unique to the Mediterranean-DASH Diet Intervention for Neurodegenerative Delay (MIND). The COMT Val158Met variant modified the effect of MIND on change in perceptual speed after 3 years in a randomized controlled trial. We aimed to evaluate and extend these findings to dementia incidence in a community-based prospective cohort. Methods: We included 745 older adults (mean age 80.0 years) from the Rush Memory and Aging Project. MIND adherence was estimated using a validated food-frequency questionnaire (0-15 points). Repeated cognitive assessments and dementia diagnoses were based on standardized clinical neurological examinations and criteria. Linear regression, linear mixed-effects, and Cox proportional hazards models examined associations of COMT Val158Met and its interactions with MIND with baseline cognition, cognitive decline, and incident dementia. Associations with neuropathology and COMT protein were also explored. Results: Significant COMT × MIND interactions were observed for Alzheimer's (p = 0.003) and all-cause (p = 0.004) dementia and for COMT × MIND × time interactions with declines in global cognition (p = 0.008), episodic memory (p = 0.009), and visuospatial ability (p = 0.01). Cognitive benefits associated with MIND adherence were greater among Met/Met carriers (lower COMT activity). The hazard ratio (95% CI) per MIND point for Alzheimer's dementia was 0.82 (0.69-0.98) for Met/Met, 1.00 (0.87-1.15) for Met/Val, and 1.05 (0.84-1.33) for Val/Val. Greater MIND adherence was associated with lower plasma COMT (p = 0.01), while each additional Val allele was associated with higher brain COMT (p < 0.0001). Conclusions: Individuals with genetically reduced COMT activity may be especially responsive to cognitive benefits of the MIND diet. Further study is needed to determine whether these effects differ across cognitive domains.},
}

Humans
*Catechol O-Methyltransferase/genetics
*Dementia/genetics/epidemiology
Female
Prospective Studies
Male
Genotype
Aged, 80 and over
Aged
*Diet, Mediterranean
*Cognitive Dysfunction/genetics/epidemiology
Cognition
Incidence
Proportional Hazards Models

@article {pmid42884722,
year = {2026},
author = {Dube, K and Stoinescu, A and Sadler, J and Truong, M and Malakoti-Negad, N and Chaudhry, M and Talukdar, R and Cohen, J and Pandey, S},
title = {Multidimensional Neuroprotective Effects of Combined Ubisol-Q10 and Ashwagandha (Withania somnifera) in Male and Female 5XFAD Mice.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
doi = {10.3390/nu18193270},
pmid = {42884722},
issn = {2072-6643},
support = {809194//This work was supported through donations from the Szecsei and Dhar families (grant # 809194)./ ; },
mesh = {Animals ; Male ; Female ; *Neuroprotective Agents/pharmacology ; *Withania/chemistry ; *Alzheimer Disease/drug therapy/pathology ; *Plant Extracts/pharmacology ; Mice ; Disease Models, Animal ; Autophagy/drug effects ; Mice, Transgenic ; Brain/drug effects/pathology ; },
abstract = {BACKGROUND/OBJECTIVES: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by interconnected pathological processes including mitochondrial dysfunction, oxidative stress, impaired autophagic processes, neuroinflammation, neuronal degeneration, and progressive functional decline. Natural health products (NHPs), coenzyme-Q10 (CoQ10) and Ashwagandha (Withania somnifera) (ASH), have been previously reported to possess antioxidant, anti-inflammatory, mitochondrial-supportive, neuroprotective, and neurotrophic properties. This work investigates the neuroprotective effects of a bioavailability-enhanced formulation, Ubisol-Q10 (UQ), and ethanolic ASH extract, combined as a "Tonic," across multiple domains of AD pathology.

METHODS: The effects of long-term administration were evaluated in male and female 5XFAD mice from 2.5 to 11 months of age. Longitudinal magnetic resonance imaging assessed hippocampal and white matter volumes, a frailty index assessed physiological resilience, Novel Object and Novel Location Recognition testing assessed spatial and non-spatial memory, while post-mortem Nissl, Golgi-Cox, and immunofluorescence evaluated cellular density, dendritic morphology, amyloid pathology, neuroinflammation, autophagy-associated signaling, and astrocytic activity.

RESULTS: Across these measures, Tonic treatment preserved brain volumes, reduced amyloid pathology and inflammation, and modulated autophagy-associated pathways. Treatment also preserved dendritic architecture, frailty progression, and novelty-recognition behavior. Females demonstrated particularly pronounced preservation of white matter structure and increased dendritic density, whereas males showed strong modulation of inflammatory and autophagy-associated markers. Astrocytic immunoreactivity also demonstrated sex- and region-specific patterns, suggesting that glial responses may contribute differently to structural preservation in males and females.

CONCLUSIONS: Together, these findings support that UQ + ASH may provide diverse protection against AD neurodegeneration. The observed sex-specific responses emphasize the importance of incorporating sex into preclinical evaluation of novel interventions for neurodegenerative diseases.},
}

Animals
Male
Female
*Neuroprotective Agents/pharmacology
*Withania/chemistry
*Alzheimer Disease/drug therapy/pathology
*Plant Extracts/pharmacology
Mice
Disease Models, Animal
Autophagy/drug effects
Mice, Transgenic
Brain/drug effects/pathology

@article {pmid42884726,
year = {2026},
author = {Cai, H and Chen, C and Cai, H and Zhang, D and Huang, Q},
title = {Planetary Health Diet and the Gut-Liver-Brain Axis: Implications for MASLD and Cognitive Aging.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
doi = {10.3390/nu18193275},
pmid = {42884726},
issn = {2072-6643},
mesh = {Humans ; Gastrointestinal Microbiome/physiology ; *Brain/metabolism ; *Cognitive Aging/physiology ; *Liver/metabolism ; *Diet, Healthy ; Animals ; *Fatty Liver ; *Brain-Gut Axis/physiology ; },
abstract = {Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) and cognitive aging are prevalent, interrelated conditions that share gut-derived pathomechanisms. The Planetary Health Diet (PHD), a sustainable plant-forward framework proposed by the EAT-Lancet Commission, may offer dual-target benefits for hepatic and neurological health through the gut-liver-brain axis. Methods: A structured narrative literature search of PubMed, Web of Science, and Scopus (2015-2026) was conducted to identify observational, mechanistic, and interventional studies addressing PHD adherence in relation to MASLD, cognitive aging, and gut-liver-brain axis pathways. Results: Epidemiological evidence from large cohorts links higher PHD adherence to lower MASLD prevalence and severity, slower cognitive decline, reduced dementia incidence, and more favorable Alzheimer's disease neuropathology. Mechanistically, PHD components may modulate gut microbiota composition and diversity, enhance short-chain fatty acid production, regulate bile acid signaling through farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5), reinforce intestinal barrier integrity, and attenuate metabolic endotoxemia and neuroinflammation. Conclusions: Although current evidence remains predominantly observational, the PHD is a promising dietary framework for simultaneously supporting liver and brain health. Future research should prioritize randomized controlled trials integrating liver imaging, cognitive assessment, microbiome profiling, and culturally adapted dietary interventions.},
}

Humans
Gastrointestinal Microbiome/physiology
*Brain/metabolism
*Cognitive Aging/physiology
*Liver/metabolism
*Diet, Healthy
Animals
*Fatty Liver
*Brain-Gut Axis/physiology

@article {pmid42885145,
year = {2026},
author = {Blessing, E},
title = {The right temperature at the right time: A framework for understanding thermoregulatory pathophysiology in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71847},
doi = {10.1002/alz.71847},
pmid = {42885145},
issn = {1552-5279},
support = {5R01AG070866/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/physiopathology ; Humans ; *Body Temperature Regulation/physiology ; Animals ; Neurons/physiology ; *Brain/physiopathology ; tau Proteins/metabolism ; Circadian Rhythm/physiology ; },
abstract = {The neuromodulatory subcortical system (NSS) includes thermoregulatory neurons that maintain core body temperature (Tb) and brain temperature within a narrow, diurnally varying range. Cellular pathways in NSS neurons implicated in Alzheimer's disease (AD) may be vulnerable to Tb rhythm disturbance because of their sensitivity to temperature and their thermoregulatory function. This review evaluates a framework for pathophysiological interactions between thermoregulation and AD anchored in the functional anatomy of thermoregulatory neurons. Findings in humans show that thermoregulatory neurons exhibit tau pathology in early AD, and abnormal Tb rhythm is seen in advanced AD. In rodents, cellular risk pathways for tau aggregation are both modulated by diurnal range temperature change and involved in thermoregulation. Further research is needed to bridge human and rodent findings, to understand how sex differences in Tb impact AD risk, and to identify modifiable causal links between Tb disturbance and pathophysiology toward improving clinical outcomes in early AD.},
}

*Alzheimer Disease/physiopathology
Humans
*Body Temperature Regulation/physiology
Animals
Neurons/physiology
*Brain/physiopathology
tau Proteins/metabolism
Circadian Rhythm/physiology

@article {pmid42885186,
year = {2026},
author = {Joseph, JM and Rachel, J and Han, G and Smith, ML},
title = {Comparing Health Care Utilization Between Medicare Advantage and Traditional Medicare by Dementia Status: A Propensity-Weighted Analysis.},
journal = {Health services research},
volume = {61},
number = {5},
pages = {e70174},
doi = {10.1111/1475-6773.70174},
pmid = {42885186},
issn = {1475-6773},
mesh = {Humans ; United States ; Female ; Aged ; *Medicare Part C/statistics & numerical data ; Male ; Cross-Sectional Studies ; *Patient Acceptance of Health Care/statistics & numerical data ; *Dementia/epidemiology/therapy ; *Medicare/statistics & numerical data ; Aged, 80 and over ; Propensity Score ; Alzheimer Disease ; },
abstract = {OBJECTIVE: To compare health care utilization between Medicare Advantage (MA) and Traditional Medicare (TM) beneficiaries, stratified by Alzheimer's disease and related dementias (ADRD) status.

STUDY SETTING AND DESIGN: Repeated cross-sectional observational analysis of community-dwelling Medicare beneficiaries aged ≥ 65 years continuously enrolled in MA or TM. Eight self- or proxy-reported binary utilization outcomes over a 12-month reference period were estimated by survey-weighted linear probability models stratified by ADRD status.

Secondary analysis of pooled 2018-2022 Medicare Current Beneficiary Survey (MCBS) public use files (N = 43,995: 974 TM and 954 MA with ADRD; 23,050 TM and 19,017 MA without ADRD), excluding beneficiaries entitled through disability or end-stage renal disease and records with missing covariates. Dual-eligible beneficiaries were retained and dual eligibility included as a covariate. Stabilized inverse probability of treatment weights multiplied by MCBS full-sample weights addressed non-random MA enrollment.

PRINCIPAL FINDINGS: Among beneficiaries with ADRD, seven of eight adjusted MA - TM differences were not statistically significant. Specialist visits were more common among MA beneficiaries with ADRD (5.2 percentage points; 95% CI, -0.1 to 10.2). Among beneficiaries without ADRD, MA was associated with lower outpatient hospital visits (-2.6; -3.7 to -1.6) and lower reported need for home health visits (-0.9; -1.5 to -0.3). Effect modification by ADRD status was significant only for specialist visits (interaction 6.3 percentage points; p = 0.004).

CONCLUSIONS: Adjusted health care utilization was broadly comparable between MA and TM for beneficiaries with ADRD, with the exception of higher specialist use in MA. Among beneficiaries without ADRD, MA was associated with lower outpatient hospital use. Plan-type differences were smaller and fewer for beneficiaries with ADRD.},
}

Humans
United States
Female
Aged
*Medicare Part C/statistics & numerical data
Male
Cross-Sectional Studies
*Patient Acceptance of Health Care/statistics & numerical data
*Dementia/epidemiology/therapy
*Medicare/statistics & numerical data
Aged, 80 and over
Propensity Score
Alzheimer Disease

@article {pmid42885191,
year = {2026},
author = {Lee, S and Kim, K and Kim, H and Oh, MS and Yoon, K and Kwak, S and Kim, J and Lee, GH and Kim, Y and Kim, J},
title = {Focused Ultrasound as a Plasma Protein Binding-targeted Strategy to Enhance Brain Uptake of Donepezil.},
journal = {Experimental neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.5607/en26028},
pmid = {42885191},
issn = {1226-2560},
abstract = {Donepezil, a reversible acetylcholinesterase inhibitor, is widely used for the symptomatic treatment of Alzheimer's disease (AD). Although higherdose donepezil has been shown to provide additional clinical benefit, dose escalation is often limited by cholinergic adverse effects. Given that approximately 96% of circulating donepezil is bound to plasma proteins, especially albumin, we hypothesized that increasing its unbound fraction from albumin may improve brain delivery without increasing the administered dose. To achieve this goal, herein we examined whether the donepezil-albumin complex can be dissociated by low-intensity focused ultrasound (FUS) in vitro. Then brain uptake of donepezil was evaluated in mice receiving intravenous donepezil followed by targeted brain FUS stimulation. As a result, FUS significantly increased unbound fraction of donepezil at the targeted region in vitro, resulting in a 41.1% increase of donepezil diffusion into dialysis cassettes compared with non-sonicated controls. In mice receiving intravenous donepezil, targeted brain FUS stimulation increased brain donepezil concentrations by 52.7% at 15-min post-administration time. These findings suggest that low-intensity FUS enhances brain uptake of donepezil, potentially through modulation of donepezil-albumin binding, and support further investigation of plasma protein binding-targeted brain drug delivery.},
}

@article {pmid42885249,
year = {2026},
author = {Wang, YC and Yeh, HC and Islam, MM and Kung, WM},
title = {Machine Learning in Dementia Research: Trends, Biomarkers, Prediction Goals, and Data Modalities.},
journal = {Brain and behavior},
volume = {16},
number = {10},
pages = {e71847},
doi = {10.1002/brb3.71847},
pmid = {42885249},
issn = {2162-3279},
support = {115-2320-B-038-072-MY2//National Science and Technology Council/ ; },
mesh = {*Dementia/diagnosis/metabolism ; *Machine Learning/trends ; Humans ; Biomarkers ; Large Language Models ; Predictive Learning Models ; Bibliometrics ; *Biomedical Research/trends ; },
abstract = {OBJECTIVE: Machine learning (ML) is increasingly used in dementia research for diagnosis, early detection, prognosis, biomarker characterization, and disease phenotyping. This study aimed to provide a bibliometric and thematic overview of ML applications in dementia, emphasizing biological mechanisms, prediction goals, data modalities, collaborative networks, and emerging computational approaches.

METHODS: A title-field search of the Web of Science Core Collection identified 3,833 records related to ML and dementia. After restricting publications to 2000 onward and excluding non-analytic document types, 3,479 records were included in the bibliometric analysis. A subset of 3,223 original articles was used for thematic analyses. Publication trends, authorship, institutional collaboration, keywords, biomarker themes, ML objectives, data modalities, methods, shared research resources, and large language model (LLM) applications were evaluated.

RESULTS: ML-related dementia research increased substantially over time. Diagnostic classification was the predominant ML objective (55.0%), followed by early detection or screening (10.3%), progression or cognitive-decline prediction (6.8%), and biomarker or feature discovery (4.7%). Structural magnetic resonance imaging was the most frequently identified modality (42.6%), followed by clinical or cognitive data (22.4%), positron emission tomography/single photon emission computerized tomography (10.3%), and genetic or genomic data (10.2%). Prominent biological themes included hippocampal measures, amyloid/Aβ, electroencephalogram, tau/p-tau, and cerebrospinal fluid biomarkers. Institutional networks showed distinct international collaboration clusters and frequent use of shared infrastructures. Transformer-based and LLM approaches emerged in recent years.

CONCLUSIONS: ML research in dementia has expanded beyond diagnostic neuroimaging toward multimodal, biomarker, prognostic, and language model applications, although diagnostic classification and structural imaging remain dominant. Emphasis on biological integration, longitudinal validation, and clinical translation are needed.},
}

*Dementia/diagnosis/metabolism
*Machine Learning/trends
Humans
Biomarkers
Large Language Models
Predictive Learning Models
Bibliometrics
*Biomedical Research/trends

@article {pmid42885665,
year = {2026},
author = {Gifani, M and Chambers, LC and Fernandez, Z and Beck, JS and Wiseman, RW and Qian, C and Dorrance, AM and Counts, SE},
title = {Locus coeruleus degeneration impairs forebrain arteriole physiology and perfusion in a rat model of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261496548},
doi = {10.1177/13872877261496548},
pmid = {42885665},
issn = {1875-8908},
abstract = {The locus coeruleus (LC) provides forebrain norepinephrine (NE) and degenerates early in Alzheimer's disease (AD). We have shown that experimental LC lesions in the Tg344-19 AD rat model result in parenchymal arteriole (PA) stenosis, blood-brain barrier permeability, amyloid angiopathy, and cognitive impairment. Here, we show that PAs from LC-lesioned Tg344-19 AD rats displayed increased myogenic tone and decreased responsiveness to TRPV4 channel agonists, which was reversible by NE replacement. MRI studies indicated reduced forebrain perfusion and fractional anisotropy in LC-lesioned animals compared to controls. Targeting LC-mediated effects on cerebral hemodynamics presents a compelling AD therapeutic target.},
}

@article {pmid42885673,
year = {2026},
author = {Peterson, AJ and Sun, Y and Liu, D and Pechman, KR and Cambronero, FE and Moore, EE and Gupta, DK and Hohman, TJ and Zetterberg, H and Jefferson, AL},
title = {Lower cardiac output is associated with longitudinal decreases in cerebrospinal fluid amyloid-β42, a core Alzheimer's disease biomarker, in women but not men.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261497236},
doi = {10.1177/13872877261497236},
pmid = {42885673},
issn = {1875-8908},
abstract = {Subclinical reductions in cardiac output relate to cognitive decline. We examined the relationship between cardiac output and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease pathologies in 153 participants from the Vanderbilt Memory and Aging Project. Linear regression and linear mixed effects regression models related baseline cardiac output, assessed using echocardiogram, to CSF amyloid-β42 (Aβ42), Aβ42/Aβ40, and phosphorylated tau-181 cross-sectionally and longitudinally. Cardiac output interacted with sex on Aβ42 levels longitudinally. Lower cardiac output was associated with lower Aβ42 over time in women but not men. This may reflect cerebral Aβ accumulation or a more general change in Aβ production.},
}

@article {pmid42885674,
year = {2026},
author = {Atee, M and Lloyd, R and Morris, T and Macfarlane, S},
title = {Terminal agitation in dementia: Challenges and opportunities.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261496316},
doi = {10.1177/13872877261496316},
pmid = {42885674},
issn = {1875-8908},
abstract = {Terminal agitation (TA), also referred to as terminal restlessness or terminal delirium, is a complex, multifactorial clinical syndrome that occurs at the end of life. While TA is evident in dementia (including Alzheimer's disease), it is not exclusive to the condition and also occurs in other terminal illnesses, e.g., cancer. Currently, no clinical tools exist or have been validated to assess TA in dementia. This may hinder the correct identification of TA and further contribute to the incorrect estimation of TA prevalence. Due to the complex diagnostic profile of TA, it may be frequently underrecognized in individuals with dementia. There is also a lack of consensus on clinical terminology, operational definition (e.g., temporality, symptomology) and conceptualization of TA. This may be attributed in part to cultural context and the variability in describing the final stages of dementia. Thus, reported prevalence rates of TA in dementia are heterogeneous in the literature. Further, using multiple descriptions or terms for TA in the literature suggests that the syndrome may occur in groups, or clusters of symptoms. There is an association between pain, agitation, and delirium in various stages of dementia, particularly at the end of life. Differentiating TA, or delirium from behavioral and psychological symptoms of dementia (BPSD) is often difficult. The complex interaction between TA, dementia, and overlapping BPSD remains poorly understood and underresearched. Therefore, we outline priorities for future action and research, including the development of diagnostic and assessment tools to identify TA in dementia, and the establishment of consistent criteria for defining this syndrome.},
}

@article {pmid42885677,
year = {2026},
author = {Pandey, JP},
title = {Immunoglobulin GM (γ marker) allotypes as potential genetic markers of efficacy of lecanemab therapy in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500140},
doi = {10.1177/13872877261500140},
pmid = {42885677},
issn = {1875-8908},
abstract = {Lecanemab is a humanized IgG1 monoclonal antibody that targets amyloid-β (Aβ) aggregates, a pathological hallmark of Alzheimer's disease (AD). In the largest clinical trial of its kind to date, lecanemab slowed cognitive decline by 27% in patients with early-stage AD. Lecanemab has also been shown to reduce cerebral Aβ deposition. Lecanemab expresses the immunoglobulin GM 3 allotype, which is defined by an arginine residue in the CH1 region of the γ1 chain and is potentially immunogenic in individuals who lack this allotype. I hypothesize that anti-GM 3 antibodies, generated either following lecanemab administration or acquired previously through maternal-fetal incompatibility or transfusion of allotype-incompatible blood products, may form immune complexes with the therapeutic antibody. These immune complexes could be cleared by phagocytic cells, including microglia, thereby reducing the availability and efficacy of lecanemab and contributing to therapeutic nonresponsiveness. If validated, GM allotypes could serve as genetic markers for predicting response to lecanemab therapy and may help guide personalized treatment strategies in AD.},
}

@article {pmid42885680,
year = {2026},
author = {Li, J and Woo, J and Yang, Y and Ye, Z and Li, J},
title = {Evening chronotype and incidence of all-cause dementia and subtypes after accounting for other sleep traits: A prospective cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261498357},
doi = {10.1177/13872877261498357},
pmid = {42885680},
issn = {1875-8908},
abstract = {BackgroundChronotype may affect neurophysiology, but whether its association with dementia persists independent of other sleep traits remains uncertain.ObjectiveTo examine associations of chronotype with incident dementia subtypes and potential modification by metabolic and social factors.MethodsIn 443,906 dementia-free participants, Cox models estimated dementia risk after adjustment for sociodemographic, lifestyle, clinical, apolipoprotein E (APOE) genotype, and sleep-related factors. We tested baseline interactions and robustness using multiple imputation, competing-risk models, and landmark analyses.ResultsOver a mean follow-up of 12.5 years, 6355 incident dementia cases were documented. Evening chronotype was associated with a small increased risk of all-cause dementia compared with morning types (HR, 1.07; 95% CI, 1.01-1.14). This association was observed primarily in "other dementias" (HR, 1.12; 1.04-1.21), with no significant association with Alzheimer's disease or vascular dementia (VaD).Exploratory subgroup analyses identified two interactions that remained significant after false discovery rate (FDR) correction: social visit frequency for all-cause dementia and napping for VaD (FDR-adjusted p for interaction is 0.024 for both). Evening chronotype was associated with higher all-cause dementia risk among participants reporting infrequent social visits and with higher VaD risk among those reporting usual napping.ConclusionsEvening chronotype was associated with a small increase in the hazard of all-cause dementia after multivariable adjustment. Given the modest magnitude and observational design, evening chronotype may be considered a potential risk marker rather than an independent or causal risk factor. These findings require independent replication.},
}

@article {pmid42885682,
year = {2026},
author = {Ogawa, Y and Chen, R and Ross, GW and Donlon, T and Fujikami, G and Takenaka, C and Willcox, B and Masaki, K},
title = {Association between late-life blood pressure and incident dementia in older men: The Kuakini Honolulu-Asia aging study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261498372},
doi = {10.1177/13872877261498372},
pmid = {42885682},
issn = {1875-8908},
abstract = {BackgroundThe relationship between late-life blood pressure and incident dementia (including Alzheimer's disease and vascular dementia) remains controversial.ObjectiveTo examine whether late-life blood pressure is associated with incidence of dementia.MethodsWe analyzed 2649 participants aged 71 to 93 years without prevalent dementia at baseline in a prospective cohort of Japanese-American men (the Kuakini Honolulu Heart Program). Diagnosis of dementia was conducted based on standardized protocols and participants were followed for up to 20 years. Cox proportional hazards models were applied to estimate hazard ratios (HR) for incident dementia across blood pressure categories, adjusting for demographic, medical, lifestyle, and genetic factors.ResultsDuring follow-up, 716 cases of incident dementia were identified (519 cases of Alzheimer's disease and 88 cases of vascular dementia). After adjustment, high late-life systolic blood pressure (≥160 mmHg) was associated with a lower risk of Alzheimer's disease [HR 0.72 (95% confidence interval: 0.56-0.93)] and a higher risk of vascular dementia [HR 1.95 (95% confidence interval: 1.03-3.68)] compared to the reference (120 to <140 mmHg) group. The protective effect of high late-life systolic blood pressure (≥160 mmHg) on Alzheimer's disease was seen only in participants with the protective version of the FOXO3 genotype. No significant associations were found between diastolic blood pressure and incidence of dementia.ConclusionsHigh late-life systolic blood pressure was associated with a protective effect against Alzheimer's disease, after adjusting for confounders, including the FOXO3 longevity genotype, and an increased risk of vascular dementia in older men aged over 71 years.},
}

@article {pmid42885687,
year = {2026},
author = {Meléndez, JC and Escudero, J and Satorres, E and Delhom, I and Martí-Hoyos, I and González-Moreno, J},
title = {Home-delivered transcranial direct current stimulation with or without cognitive training in mild dementia due to Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261498210},
doi = {10.1177/13872877261498210},
pmid = {42885687},
issn = {1875-8908},
abstract = {BackgroundTranscranial direct current stimulation (tDCS) and cognitive training are non-pharmacological interventions for cognitive impairment in Alzheimer's disease (AD), but evidence on combined protocols in mild dementia remains limited.ObjectiveTo evaluate home-delivered active tDCS combined with cognitive training and active tDCS alone versus sham tDCS in mild dementia due to AD, and explore whether the combined intervention showed changes across a broader range of cognitive outcomes.MethodsForty participants with mild dementia due to AD and evidence of amyloid-β pathology were randomized to tDCS combined with cognitive training (n = 14), active tDCS alone (n = 14), or sham tDCS (n = 12). The 10-day intervention was delivered at participants' homes by trained study personnel. Cognitive outcomes were assessed at baseline, post-intervention, and 1-month follow-up using linear mixed-effects models.ResultsSignificant Group × Time interactions were observed for the primary cognitive outcome, Mini-Mental State Examination (MMSE), and for all secondary cognitive outcomes except Backward Digit Span. Both active conditions showed greater change from baseline than sham tDCS in MMSE, Memory Alteration Test, verbal learning, total verbal recall, and delayed recall. The combined condition also showed greater change than sham tDCS in initial immediate recall and Forward Digit Span. No significant differences were observed between the two active conditions.ConclusionsActive tDCS, with or without cognitive training, was associated with more favorable short-term cognitive change than sham stimulation. The combined condition differed from sham across more outcomes, but not from active tDCS alone; therefore, this exploratory pattern does not establish a broader benefit of the combined intervention.},
}

@article {pmid42885688,
year = {2026},
author = {Chen, C and Huentelman, M and Chen, K},
title = {Association between handedness and Alzheimer's disease: Results from a large MindCrowd observational study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261498845},
doi = {10.1177/13872877261498845},
pmid = {42885688},
issn = {1875-8908},
abstract = {BackgroundHandedness is tied to the lateralization of brain functions and significantly affects cognitive function and brain activity. Alzheimer's disease (AD) is a progressive brain disorder that leads to declines in memory, thinking skills, and to behavioral changes, which also exhibits lateralized patterns of brain involvement. Understanding the relationship between handedness and AD may provide useful context for interpreting findings in AD research.ObjectivePrevious findings on the relationship between AD and handedness are inconsistent.We used the large MindCrowd dataset, comprising with over 150,000 participants, study the association between AD and handedness.MethodsWe applied logistic regression models to the data with and without adjustment for other covariates to estimate the association between handedness and AD. We also performed similar analyses for samples stratified by ages. We estimated the unadjusted and adjusted odds ratios (ORs) of having AD among left- and mixed-handed participants compared with right- handed participants.ResultsOur results showed that compared with right-handed participants, left- and mixed-handed participants had higher odds of self-reported AD (the overall adjusted OR: 2.08, 95% CI: (1.69, 2.53), p < 0.001)) being larger than that for left-handers (the overall adjusted OR: 1.42, 95% CI: (1.23, 1.64), p < 0.001)). Furthermore, for each age group considered, the estimated adjusted and unadjusted ORs for mixed-handers were consistently greater than that for left-handers; all were greater than 1.0.ConclusionsOur study confirmed that there is a significant association between handedness and AD. Our findings also indicate that mixed-handedness has a stronger association with AD than left-handedness.},
}

@article {pmid42885690,
year = {2026},
author = {Vidyanti, AN and Prawiroharjo, P and Syafrita, Y and Prodjohardjono, A and Rahmadini, A and Istiqomah Rizki Hidayatun, P and Rahman, RH and Divina, E and Permata, R and Tazkia, AA and Fadhilah, N and Putri, NS},
title = {Diagnostic accuracy of plasma amyloid-β42 and Montreal Cognitive Assessment score as composite index for Alzheimer's disease in resource-limited settings: An exploratory study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261497299},
doi = {10.1177/13872877261497299},
pmid = {42885690},
issn = {1875-8908},
abstract = {BackgroundAccurate diagnosis of Alzheimer's disease (AD) in Indonesia remains challenging due to limited access to cerebrospinal fluid (CSF) analysis and PET imaging. Plasma amyloid-β42 (Aβ42) may offer a less-invasive and affordable alternative, particularly when combined with cognitive assessment. However, its diagnostic performance in Indonesian populations is not well established.ObjectiveTo exploratorily assess the diagnostic accuracy of plasma Aβ42, alone and as a composite index combined with Montreal Cognitive Assessment-Indonesian version (MoCA-INA) scores, as potential alternatives to CSF biomarkers for AD diagnosis in a resource-limited setting.MethodsA cross-sectional study was conducted involving 25 AD patients and 20 cognitively normal controls. Plasma and CSF biomarker levels were measured using ultrasensitive immunoassay. Cognitive function was evaluated using MoCA-INA. Receiver operating characteristic curve analysis was used to assess diagnostic accuracy.ResultsPlasma Aβ42 with the level of 9.6 pg/ml showed moderate diagnostic accuracy (AUC = 0.78, sensitivity = 69.2%, specificity = 70.6%), while its combination with MoCA-INA Score improved accuracy (adjusted AUC = 0.93, sensitivity = 80.0%, specificity = 84.0%). No significant correlation was found between plasma and CSF biomarkers. Plasma p-tau181 was excluded from the final composite index because it showed an unexpected direction of change.ConclusionsPlasma Aβ42 combined with MoCA-INA as a composite index, demonstrated potential diagnostic performance for AD in resource-limited settings. However, these exploratory findings should be interpreted cautiously and require further validation in larger and independent cohorts before clinical application.},
}

@article {pmid42885691,
year = {2026},
author = {Alavi, A and Høilund-Carlsen, PF},
title = {The critical role of PET-based assessment of cerebrovascular disease in the management of patients with cognitive impairment and dementias.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261497232},
doi = {10.1177/13872877261497232},
pmid = {42885691},
issn = {1875-8908},
abstract = {A recent survey provides valuable insights into French practitioners' preparedness for implementing anti-amyloid immunotherapy (AAI) for Alzheimer's disease. It highlights the need for education but also underscores a broader challenge: clinicians must understand not only treatment protocols but also unresolved issues regarding diagnostic specificity, efficacy, safety, and cost-effectiveness. Amyloid biomarkers should not be considered definitive indicators of disease causality or treatment response. Greater attention should also be given to functional imaging approaches and cerebrovascular pathology, which may contribute to a more comprehensive understanding of cognitive decline. A balanced, evidence-based approach is essential before widespread adoption of AAI.},
}

@article {pmid42885693,
year = {2026},
author = {Choi, YJ and Han, JW and Kim, KW},
title = {Concurrent diagnostic efficiency and 8-year measurement stability of the weighted subjective memory complaints questionnaire-revised.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261498376},
doi = {10.1177/13872877261498376},
pmid = {42885693},
issn = {1875-8908},
abstract = {BackgroundSubjective memory complaints (SMC) are a potential early indicator of dementia, but whether their measurement properties hold over years of repeated assessment is unexamined. The weighted Subjective Memory Complaints Questionnaire-Revised (SMCQ-R) showed higher cross-sectional accuracy than the original SMCQ, but its performance over extended follow-up requires verification.ObjectiveTo evaluate whether SMCQ-R maintains measurement fidelity over 8 years relative to SMCQ and Mini-Mental State Examination (MMSE).MethodsWe analyzed 2057 community-dwelling older adults without baseline major depressive disorder from the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD), followed biennially for 8 years (5 assessments). Concurrent discriminative performance was evaluated via AUC, Cohen's d, signal-to-noise ratio (SNR). Sensitivity analysis excluded participants with incident depression during follow-up, and separately used all available data.ResultsAll three measures demonstrated excellent cross-sectional validity (mean AUC: SMCQ-R = 0.883, SMCQ = 0.889, MMSE = 0.884). SMCQ-R showed numerically larger effect sizes than SMCQ (Cohen's |d|: 1.884 versus 1.742, p = 0.154) and higher SNR (1.659 versus 1.485, p = 0.327), neither significant. Both subjective measures showed significant SNR reductions with incident depression, whereas MMSE remained robust.ConclusionsSMCQ-R showed a significant AUC decline over 8 years (slope = -0.0079/year, p = 0.024), but maintained clinically adequate accuracy (AUC ≥ 0.844), similar to SMCQ (0.883 vresus 0.889), despite a 36% reduction in item burden. Using all available data, this decline was not an artifact of the complete case restriction, and the MMSE discriminated at least as well as SMCQ-R at every assessment. SMCQ-R is regarded as an efficient complement to the MMSE rather than evidence of its superiority.},
}

@article {pmid42341744,
year = {2026},
author = {Marth, L and Lund, A and Höglinger, G and Levin, J},
title = {[Dementia with Lewy bodies].},
journal = {Fortschritte der Neurologie-Psychiatrie},
volume = {94},
number = {9},
pages = {340-350},
pmid = {42341744},
issn = {1439-3522},
support = {EXC 2145 SyNergy ID 390857198//Deutsche Forschungsgemeinschaft/ ; },
mesh = {Humans ; *Lewy Body Disease/diagnosis/therapy/psychology/pathology/epidemiology ; alpha-Synuclein/metabolism ; Biomarkers ; Lewy Bodies/pathology ; },
abstract = {Dementia with Lewy bodies (DLB) is the second most common neurodegenerative type of dementia after Alzheimer’s disease and belongs to the atypical parkinsonian syndromes. It is characterized by cognitive fluctuations, visual hallucinations, REM sleep behavior disorder, and parkinsonism. Typically, cognitive impairment appears before or within one year after the onset of motor symptoms (“one-year rule”). Neuropathologically, DLB is an α-synucleinopathy with neuronal Lewy bodies, often accompanied by copathologies. Diagnosis is based on clinical McKeith criteria and often supported by imaging biomarkers. Treatment is mainly symptomatic. Disease-modifying therapies are not yet available but are being investigated in clinical trials. The development of biologically defined diagnostic criteria and molecular biomarkers is crucial for future therapeutic studies.},
}

Humans
*Lewy Body Disease/diagnosis/therapy/psychology/pathology/epidemiology
alpha-Synuclein/metabolism
Biomarkers
Lewy Bodies/pathology

@article {pmid42872646,
year = {2026},
author = {Budak Savaş, A and Yeşilyurt, F and Hacimuftuoglu, A},
title = {From Hypothesis to Clinical Validation: A Bibliometric Mapping of Immunotherapy for Neurodegenerative Proteinopathies (2000-2025).},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273531307261012100737},
pmid = {42872646},
issn = {1996-3181},
abstract = {INTRODUCTION/OBJECTIVE: For twenty-five years, despite persistent challenges, the field of neurodegenerative disease has remained committed to a single hypothesis: targeting the immune system directly against misfolded proteins accumulating in the brain. Today, this approach has produced a clinical counterpart, with three monoclonal antibodies now approved, although the field is still progressing toward clinical validation. However, the research lines, countries, institutions, and journals through which this point was reached, and how far that validation has actually progressed, have remained largely unexamined.

METHODS: This study analyzes 9,863 articles published between 2000 and 2025 using bibliometric methods to map the field's intellectual structure, productivity patterns, and the thematic evolution shaped around four turning points.

RESULTS: The findings reveal a nonlinear trajectory. Annual output rose from a steady pace in the early 2000s to a sudden surge after 2019, exceeding 900 publications per year. Research output is heavily concentrated in the United States, while impact is concentrated among a small number of core journals and prolific authors. Only 47 journals account for one-third of the literature, and roughly four out of five authors have contributed only a single publication to the field. While the amyloid hypothesis continues to rest on strong genetic foundations, which protein species is actually neurotoxic, soluble oligomers or deposited plaques, remains an open question, and this keeps alive the debate over what clinical trials are truly measuring. The safety of approved drugs, particularly ARIA-related imaging abnormalities, and the challenge of delivering treatment across the blood-brain barrier stand out as fronts the field has yet to overcome.

DISCUSSION: Perhaps the most notable signal is that this accumulated progress now appears to be extending beyond Alzheimer's disease: thematic patterns suggest the same immunotherapeutic logic is beginning to extend toward Parkinson's disease and other proteinopathies.

CONCLUSION: The study presents, within a single framework, the critical periods the field has passed through, who has led this journey, and which questions remain unanswered.},
}

@article {pmid42872652,
year = {2026},
author = {Watson, D and Neam, MG and Stafford, M and Bouchard, C and Ranney, V and Werner, S},
title = {Transitioning from Clinical Trial to Clinical Practice for Long-Term Lecanemab Treatment in Early Alzheimer's Disease: Perspectives from a Cohort Study from the Alzheimer's Research and Treatment Center.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050525938260923072703},
pmid = {42872652},
issn = {1875-5828},
abstract = {INTRODUCTION/BACKGROUND: Lecanemab, an anti-amyloid monoclonal antibody, significantly reduces amyloid markers and slows clinical decline in early Alzheimer's disease (AD) clinical trials. We assessed our single-center experience with lecanemab, including evaluating efficacy and safety data as well as patient-reported outcomes of individuals from our single center treated with intravenous or subcutaneous lecanemab.

MATERIALS AND METHODS: We conducted a single-center, nested cohort study of early AD subjects on lecanemab (intravenous or subcutaneous) at our center. Participants had been initiated on lecanemab therapy as part of lecanemab Study 201 or Clarity AD, and then continued lecanemab treatment in our center. Data collection included patient demographic characteristics, efficacy (eg, CDR-SB), safety, and patient-reported outcomes from surveys.

RESULTS: At our center, 136 people were randomized to receive either lecanemab or placebo in either lecanemab Study 201 (lecanemab:53; placebo:16) or Clarity AD (lecanemab:37; placebo:30). Patients receiving lecanemab were more likely to have higher rates of stable or improved disease across efficacy assessments relative to placebo. There were no new long-term safety signals, and the most common adverse events for lecanemab patients were infusion-related reactions (36.2%), ARIA-H (25.9%), and ARIA-E (13.8%). Survey responses demonstrated high satisfaction with the subcutaneous lecanemab administration, including with treatment satisfaction (97%) and convenience (97%). All patients preferred subcutaneous over IV dosing, citing quickness, ease, and comfort.

DISCUSSION: Our single-center experience with long-term lecanemab treatment was similar to that observed in clinical trials.

CONCLUSION: The subcutaneous lecanemab formulation was highly preferred by patients and care partners, with feedback highlighting reduced treatment burden and strong acceptability.},
}

@article {pmid42872679,
year = {2026},
author = {Li, M and Lv, S and Cui, L and Fang, S},
title = {Tetrachloro-1,4-benzoquinone Exerts Neurotoxicity through Neuroinflammation and the TLR4 Signaling Pathway, which is a Risk Factor for Alzheimer's Disease: An Integrated Network and Mendelian Randomization Analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050502048260925094031},
pmid = {42872679},
issn = {1875-5828},
abstract = {INTRODUCTION: Research has found that the disinfection byproduct Tetrachloro-1,4- Benzoquinone (TCBQ) in drinking water increases the risk of Alzheimer's Disease (AD). However, the mechanism by which TCBQ increases the risk of AD remains unclear.

METHODS: This study employs a comprehensive approach that includes network toxicology (PPI network, hub genes, KEGG analysis), Mendelian randomization, computational simulations (molecular docking and dynamics), and cellular experiments to systematically elucidate the neurotoxic mechanisms of TCBQ.

RESULTS: Key findings indicate that TCBQ induces neurotoxicity by activating the Toll-like receptor signaling pathway, AD, and the apoptosis pathway. All ligand-receptor docking energies are recorded at ≤ -1.8 kcal/mol, suggesting that TCBQ demonstrates a stable interaction with the targets. Molecular simulations confirm that TCBQ tightly binds to targets such as Caspase3 and TLR4. Mendelian randomization found that XDH, FABP3, IMPDH1, ACBD7, and CASP3 are common targets and play a potential role in AD. Immunofluorescence experiments revealed that APP expression increased after TCBQ treatment. Cellular experiments verified that TCBQ significantly upregulates the expression of inflammation- and apoptosis-related proteins, including IL-1B, MyD88, NFκB, TLR4, Cleaved-Caspase3, and Cyt C, leading to neuronal cell death. Notably, the TLR4 inhibitor effectively reversed the expression of these proteins and alleviated cell death.

DISCUSSION: The discussion indicates that TCBQ induces neurotoxicity by activating the TLR4 pathway and apoptotic signals, and Caspase3 is a potential co-target. TLR4 inhibitors can reverse protein alterations and cell death, suggesting that intervention in this pathway may alleviate TCBQrelated nerve damage.

CONCLUSION: Our research provides a theoretical basis for the clinical assessment of potential neurotoxicity risks in populations exposed to TCBQ.},
}

@article {pmid42872680,
year = {2026},
author = {Jiang, Y and Li, X and Yue, P and Hu, Y and Lan, X and Yang, X and Chen, M and Li, Y and Luo, G and Liu, M and Wu, J},
title = {Global Dynamics and Emerging Trends in Alzheimer's Disease and Apoptosis from 2007 to 2025: A Bibliometric Analysis of Scholarly Evolution.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050512147260928102334},
pmid = {42872680},
issn = {1875-5828},
abstract = {INTRODUCTION: To conduct the first systematic bibliometric analysis of global research on the relationship between Alzheimer's disease (AD) and apoptosis from 2007 to 2025.

METHODS: This study utilized the Web of Science Core Collection (WoSCC) and Scopus to retrieve literature from 2007 to 2025 concerning the role of apoptosis in Alzheimer's disease. Bibliometric analysis and visualization were performed using the CiteSpace, VOSviewer, SCImago Graphica, and Bibliometrix R software packages.

RESULTS: China produced the most papers (n=823), though co-authorship led to duplicate counting. Leading institutions included China Medical University and Huazhong University of Science and Technology; Harvard University had the highest academic impact. The Journal of Biochemistry was the most active and cited journal. Dr. Zhang Y was the most prolific author, and Dr. Wang H the most cited.

DISCUSSION: China and the United States are dominant contributors, but Chinese research remains domestically oriented with lower international citation impact. The Journal of Alzheimer's Disease serves as a key dissemination platform. Major research themes include Aβ-induced mitochondrial dysfunction, oxidative stress, tau hyperphosphorylation synergizing with apoptosis, and emerging multi-target therapies. Recent attention has shifted towards inflammation, synaptic impairment, and combined strategies. The vicious cycles between Aβ and oxidative stress, and between tau pathology and apoptosis, warrant further mechanistic investigation.

CONCLUSIONS: This study provides a systematic summary of research on AD and apoptosis. β- amyloid (Aβ) and abnormal Tau phosphorylation are likely to remain central areas of focus for future research.},
}

@article {pmid42873092,
year = {2026},
author = {Bedel, A and Bouaziz-Amar, E and Bousiges, O and Delaby, C and Fogli, A and Hanin, A and Lamari, F and Lefranc, E and Le Gouellec, A and Lehmann, S and Malaplate, C and Puravet, A and Quadrio, I and Rusu, PM and Schraen-Maschke, S},
title = {[The blood biomarker breakthrough in Alzheimer's disease: what applications in 2026? Part I: Blood biomarkers transitioning to clinical practice].},
journal = {Annales de biologie clinique},
volume = {84},
number = {5},
pages = {0},
doi = {10.1684/abc.2026.2068},
pmid = {42873092},
issn = {1950-6112},
abstract = {Alzheimer's disease (AD) is the leading cause of cognitive decline, and its diagnosis increasingly relies on a clinicobiological approach combining cognitive assessment with disease-specific biomarkers. Until recently, these biomarkers were mainly measured in cerebrospinal fluid (CSF), requiring lumbar puncture. Advances in ultrasensitive analytical technologies now enable their detection in blood, providing a less invasive, more accessible, and potentially earlier diagnostic alternative. This review summarizes the current state of blood-based biomarkers available for clinical use, focusing on markers of the amyloid pathway (Aβ1-42, Aβ1-40, and their ratio) and the Tau pathway (pTau181, pTau217, pTau231, and BD-Tau). Amyloid peptides reflect early amyloid pathology but show limited diagnostic performance when used alone. In contrast, phosphorylated Tau biomarkers, particularly pTau217 and the pTau217/Aβ1-42 ratio, demonstrate excellent diagnostic accuracy and strong correlations with established CSF and amyloid PET biomarkers. These blood biomarkers have recently been incorporated into national and international diagnostic recommendations and are progressively entering routine clinical practice. Their implementation represents a major advance in the diagnosis, patient stratification, and therapeutic monitoring of AD. Despite these promising developments, challenges remain regarding analytical standardization, interpretation thresholds, and ethical considerations related to very early diagnosis. Nevertheless, blood-based biomarkers are expected to play a central role in future Alzheimer's disease management and precision medicine strategies.},
}

@article {pmid42873210,
year = {2026},
author = {Ye, Z and Xie, X and Wang, S and Chen, J and Zhang, B and Chen, J and Teng, B and Wei, R and Li, B and Zhang, Q and Huang, S and Weng, Y and Yang, D},
title = {Cross-sectional associations of insulin resistance surrogate indices with cognitive disorders and cognitive performance in UK Biobank.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261494125},
doi = {10.1177/13872877261494125},
pmid = {42873210},
issn = {1875-8908},
abstract = {BackgroundWhile systemic insulin resistance (IR) is a well-established risk factor for Alzheimer's disease (AD), its connections to broader cognitive conditions, particularly mild cognitive impairment (MCI) and specific cognitive domains, remain unclear.ObjectiveThis study aims to explore the associations between IR surrogates and cognitive status, including AD, MCI, and normal cognition (NC) group, and to assess their association with domain-specific cognitive functions.MethodsData from 381,818 UK Biobank participants were analyzed. Logistic regression was used to assess relationships between IR surrogates-the triglyceride-glucose (TyG) index, TyG-waist-to-height ratio (TyG-WHtR), and triglyceride-to-high-density lipoprotein cholesterol (TG/HDL-C) ratio-and cognitive groups (AD, MCI, NC). Domain-specific cognitive functions, including prospective memory (PM) and reaction time (RT), were evaluated using multivariable linear regression, logistic models, and restricted cubic splines.ResultsTyG-WHtR was independently associated with MCI (adjusted odds ratio [OR] = 1.166, 95% CI: 1.084-1.255, p < 0.001). Elevated TG/HDL-C and TyG-WHtR were both linked to slower RT (ORs > 1, p < 0.05), whereas RCS analysis revealed an inverted M-shaped nonlinear association between TyG and mean RT. All IR surrogates were significantly associated with poorer PM performance (ORs < 1, p < 0.05).ConclusionsThis study suggests that elevated TyG-WHtR levels are independently associated with MCI. Higher TG/HDL-C and TyG-WHtR correlate with slower processing speed, with TyG showing a unique nonlinear progression. All IR indices are also associated with poorer PM performance, suggesting potential metabolic markers linked with cognitive performance.},
}

@article {pmid42873344,
year = {2026},
author = {Lee, M and Lee, S and Kim, JH and Oh, MS},
title = {Rheum undulatum Linné Exerts Neuroprotective Effects Against Aβ Oligomer-Induced Neuronal Damage by Modulating p53-Mediated Signaling.},
journal = {Neurochemical research},
volume = {51},
number = {5},
pages = {},
pmid = {42873344},
issn = {1573-6903},
support = {RS-2023-KH138733//Korea Health Industry Development Institute/ ; RS-2023-KH138733//Korea Health Industry Development Institute/ ; RS-2023-KH138733//Korea Health Industry Development Institute/ ; RS-2023-KH138733//Korea Health Industry Development Institute/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/toxicity ; *Neuroprotective Agents/pharmacology/therapeutic use/isolation & purification ; *Signal Transduction/drug effects/physiology ; *Tumor Suppressor Protein p53/metabolism ; *Rheum/chemistry ; *Neurons/drug effects/metabolism ; Mice ; Male ; Peptide Fragments/toxicity ; Mice, Inbred C57BL ; *Plant Extracts/pharmacology/therapeutic use ; Hippocampus/drug effects/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and synaptic dysfunction. Accumulating evidence indicates that β-amyloid oligomers (AβO), the most neurotoxic form of β-amyloid, play a critical role in the pathogenesis of AD by inducing synaptic loss, neuronal death, and neuroinflammation. Therefore, targeting AβO-driven pathological processes through multi-target therapeutic strategies represents a promising approach to treating AD. This study aimed to investigate the neuroprotective effects of Rheum undulatum Linné rhizome (RUL) and the underlying mechanisms of its action against AβO-induced neurotoxicity using integrated in vitro, in vivo, and in silico approaches. RUL treatment protected HT22 and N2a neuronal cells from AβO-induced neurotoxicity and reduced extracellular AβO levels. In AβO-injected mice, oral administration of RUL alleviated memory impairment, preserved synaptic integrity, as evidenced by increased PSD95 and SYP expression, and suppressed microglial and astrocytic activation, as indicated by reduced Iba-1 and GFAP immunoreactivity in the hippocampus. Mechanistically, systems-level network analysis identified p53-related signaling as a central regulatory axis in the AD-associated pathway. These network-level insights were experimentally validated by demonstrating that RUL suppressed p53 phosphorylation, increased the BCL2/Bax ratio, inhibited caspase-3 activation, and reduced pro-inflammatory cytokines, including TNF-α and IL-1β, in the hippocampus. Collectively, these findings demonstrate that RUL exerts neuroprotective effects by preserving synaptic integrity and concurrently suppressing apoptotic and neuroinflammatory pathways through the network-level modulation of AβO-driven pathology, supporting its potential as a multi-target therapeutic candidate for AD.},
}

Animals
*Amyloid beta-Peptides/toxicity
*Neuroprotective Agents/pharmacology/therapeutic use/isolation & purification
*Signal Transduction/drug effects/physiology
*Tumor Suppressor Protein p53/metabolism
*Rheum/chemistry
*Neurons/drug effects/metabolism
Mice
Male
Peptide Fragments/toxicity
Mice, Inbred C57BL
*Plant Extracts/pharmacology/therapeutic use
Hippocampus/drug effects/metabolism

@article {pmid42873357,
year = {2026},
author = {Gündoğdu, AA and Özkan, NG and Adapınar, DÖ},
title = {The small giant actor in the pathogenesis of neurodegenerative diseases: Microtubules.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42873357},
issn = {1573-7365},
mesh = {Humans ; *Microtubules/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; tau Proteins/metabolism ; Axonal Transport/physiology ; },
abstract = {Neurodegenerative diseases are a clinically and pathologically diverse group of disorders characterized by progressive neuronal dysfunction, synaptic impairment, and neuronal loss. Although research has traditionally focused on disease-associated protein misfolding and aggregation, increasing evidence implicates abnormalities of cytoskeletal organization and intracellular transport in several neurodegenerative conditions. Microtubules contribute to neuronal polarity, axonal and dendritic transport, organelle distribution, and synaptic maintenance. These functions are regulated in part by tubulin isotypes, post-translational modifications collectively described as the tubulin code, microtubule-associated proteins, and molecular motors. This narrative review examines evidence linking alterations in these processes with Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. We summarize proposed interactions among microtubule instability, impaired axonal transport, mitochondrial dysfunction, and disease-associated proteins, including tau, α-synuclein, mutant huntingtin, TDP-43, and prion protein. Evidence connecting tau pathology with microtubule dysfunction is comparatively well established in Alzheimer's disease and MAPT-related tauopathies, whereas findings in other disorders are more heterogeneous and are frequently derived from cellular or animal models. We also discuss emerging experimental approaches, candidate biomarkers, and investigational microtubule-directed treatments. However, no tubulin-specific biomarker or microtubule-targeted disease-modifying treatment discussed in this review has yet been clinically validated. Overall, microtubule dysfunction may represent one component of broader, disease-specific pathological networks rather than a universal primary cause of neurodegeneration. Further longitudinal and clinical studies are needed to determine whether microtubule-related alterations act as causes, consequences, or modifiers of disease progression.},
}

Humans
*Microtubules/metabolism/pathology
*Neurodegenerative Diseases/metabolism/pathology
Animals
tau Proteins/metabolism
Axonal Transport/physiology

@article {pmid42873408,
year = {2026},
author = {León-Arcia, K and Martínez-Orozco, H and Guerra-Crespo, M and Díaz-Miranda, SY and Soto-Rojas, LO},
title = {"Morphological, Functional, and Molecular Progression of Blood-Brain Barrier Dysfunction in Alzheimer's Disease".},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {4},
pages = {},
pmid = {42873408},
issn = {1559-1166},
support = {IN205726//UNAM-PAPIIT/ ; IN209325//UNAM-PAPIIT/ ; IN227026//UNAM-PAPIIT/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Blood-Brain Barrier/metabolism/pathology/physiopathology ; Animals ; Pericytes/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; },
abstract = {Blood-brain barrier (BBB) dysfunction is increasingly recognized as an early pathological event in sporadic Alzheimer's disease (AD), which represents over 95% of cases. Vascular risk factors and cerebral insulin resistance are considered potential contributors to its initiation. This review synthesizes evidence available through March 2026 on the temporal progression of morphological, functional, and molecular BBB alterations in AD patients and experimental models. This review emphasizes the proposed role of BBB disruption in perpetuating neurodegeneration through feedback loops involving pericyte damage, hypoxia, perivascular inflammation, and dysregulation of amyloid-β transport systems. By integrating data from neuroimaging, fluid biomarkers, and post-mortem studies, available evidence suggests that BBB alterations can be detected from preclinical stages, most consistently in the hippocampus, and may exhibit sex-specific differences. The review compares findings from familial transgenic models with the more limited characterization available in sporadic AD models (notably the intracerebroventricular streptozotocin model), and highlights key knowledge gaps regarding temporal dynamics. This synthesis supports further exploration of strategies to preserve BBB integrity. An integrated vascular approach may usefully complement current amyloid- and tau-centered therapies, particularly in sporadic AD.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Blood-Brain Barrier/metabolism/pathology/physiopathology
Animals
Pericytes/metabolism/pathology
Amyloid beta-Peptides/metabolism

@article {pmid42873451,
year = {2026},
author = {von Alvensleben, AC and Kim, E and Kurth, T and LeBoff, MS and Anderson, AK and Yang, T and Xu, YR and Ostaszewski, BL and Selkoe, DJ and Sesso, HD and Manson, JE and Rist, PM},
title = {Plasma biomarkers of neurodegeneration and physical performance in older adults.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42873451},
issn = {2509-2723},
support = {Women's Brain Initiative//Brigham and Women's Hospital/ ; },
abstract = {Physical performance declines with age, but its association with circulating neurodegeneration biomarkers remains unclear. Blood biomarkers including NT1, NfL, oAβ, and pTau217 may reflect early neurodegenerative changes linked to physical performance decline. Evidence linking these biomarkers to physical performance is limited. We analyzed older adults in the COSMOS Clinic substudy with baseline and two-year follow-up assessments of plasma NT1, NfL, and oAβ and a single assessment of pTau217. Physical performance was assessed using walking speed, grip strength, and the Short Physical Performance Battery (SPPB). The primary analysis examined associations between baseline biomarker levels and two-year changes in physical performance. Secondary analyses examined longitudinal associations between two-year changes in biomarkers and concurrent changes in physical performance. Models were adjusted for demographics, cardiovascular risk profile, body mass index, and the baseline value of the physical performance measures, and we considered all biomarkers jointly. We included 506 participants; the mean age was 69.7 years, and 49.3% were women. In the primary analysis, we found no statistically significant associations between baseline NT1, NfL, or oAβ and two-year changes in physical performance. In fully adjusted models, baseline NfL was not associated with 2-year changes in physical performance, with estimates ranging from β = -0.046 (p = 0.69) for SPPB to β = 0.350 (p = 0.48) for grip strength. Similarly, estimates for NT1 ranged from β = -0.097 (p = 0.50) for SPPB to β = 0.267 (p = 0.67) for grip strength, and those for oAβ ranged from β = -0.124 (p = 0.39) for grip strength to β = 0.008 (p = 0.25) for fast walking speed. In the secondary longitudinal analysis, two-year change in NT1 was statistically significantly associated with change in grip strength (β = 1.408, p = 0.01). No other significant associations were observed. Baseline NT1, NfL, or oAβ were not associated with changes in physical performance measures over two years. Changes in NT1 were associated with changes in grip strength. Overall, these biomarkers provided limited information on short-term physical performance decline.},
}

@article {pmid42873606,
year = {2026},
author = {Ziontz, J and Blazhenets, G and Visani, A and Chiotis, K and Maiti, P and Lin, Z and Hills, AR and Yballa, C and Rocha, S and Shankar, R and Sturm, VE and Vemuri, P and Hammers, DB and Eloyan, A and Carrillo, MC and Dickerson, BC and Apostolova, LG and Rabinovici, GD and La Joie, R and , },
title = {Hemispheric Asymmetry of Neuroimaging Biomarkers in Early Onset Alzheimer's Disease: Clinical and Cognitive Outcomes.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78391},
pmid = {42873606},
issn = {1531-8249},
abstract = {OBJECTIVE: Individuals diagnosed with Alzheimer's disease (AD) often exhibit amyloid, tau, and atrophy predominantly in the left or right hemisphere, but group-level analyses typically ignore inter-individual variability and changing asymmetry patterns when averaging data across participants in phenotypically diverse cohorts.

METHODS: We examined left/right hemispheric asymmetry in amyloid positron emission tomography (PET), tau PET, and cortical atrophy in sporadic early-onset AD from 585 deeply phenotyped individuals across 2 cohorts to investigate its clinical correlates. For each imaging biomarker, we computed a global asymmetry index reflecting left/right hemisphere signal difference, and an analogous asymmetry value for PET/magnetic resonance imaging (MRI) voxels. We examined clinical and cognitive correlates of this asymmetry across phenotypes cross-sectionally and longitudinally in a subset of 218 participants.

RESULTS: Both left and right asymmetry were common for all clinical phenotypes and was correlated between imaging biomarkers. Asymmetry patterns varied spatially within phenotypes, and asymmetry in tau PET and MRI volumes was related to hemisphere-dependent cognitive deficits and neuropsychiatric symptoms. Longitudinal analyses revealed stable amyloid PET asymmetry, decreasing tau PET asymmetry, and increasing MRI volume asymmetry.

INTERPRETATION: Hemispheric asymmetry is common in early onset AD and correlates with clinical outcomes. Our longitudinal findings suggest a time-lagged asymmetry peak in amyloid, then tau, then atrophy. Taken together, our results position asymmetry as an important feature of AD heterogeneity, as it provides insight into disease mechanisms and trajectories. ANN NEUROL 2026.},
}

@article {pmid42873658,
year = {2026},
author = {Pylkkö, E and Paakinaho, A and Hartikainen, S and Kaasinen, V and Tolppanen, AM},
title = {Identifying drugs associated with Alzheimer's disease risk using machine learning-assisted signal detection.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261498381},
doi = {10.1177/13872877261498381},
pmid = {42873658},
issn = {1875-8908},
abstract = {BackgroundSeveral Alzheimer's disease (AD) clinical trials currently focus on drug repurposing. Machine learning (ML)-based pharmacoepidemiological approaches may help identify candidate drugs for trials.ObjectiveWe applied an ML-based signal detection method to identify drugs associated with AD risk.MethodsUsing Finnish nationwide register-based data, we defined drug exposure at both subgroup and drug substance levels according to the Anatomical Therapeutic Chemical classification. Three binary embedded variables were calculated for each drug based on the frequency of dispensations over three years, starting 10 years before the index date. An algorithm combining subsampling and lasso-logistic regression was applied, with 500 replications for each drug exposure variable. Drug variables with a selection percentage (SP) ≥ 70% across replications were considered as signals. The average beta describes the direction and strength of the association.ResultsThe study population comprised 43,926 AD cases and 43,926 matched controls. The mean age was 80.3 years in both groups, and 65% of participants were women. Four drug subgroups and three individual drugs were associated with a lower risk of AD, whereas 14 subgroups and 11 individual drugs were associated with a higher risk. Drugs associated with decreased AD risk belonged to cardiovascular drugs: antihypertensives affecting the renin-angiotensin and diuretics.ConclusionsThe identified associations are consistent with established risk factors of AD and support the importance of effective hypertension management in AD prevention. Further studies are needed to evaluate whether antihypertensive drugs may exert neuroprotective effects and represent viable candidates for drug repurposing in AD.},
}

@article {pmid42873676,
year = {2026},
author = {Nguyen, N and Huynh, S and Mroczko, B and Glodzik, L},
title = {The role of matrix metalloproteinases in Alzheimer's disease and small vessel disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261494579},
doi = {10.1177/13872877261494579},
pmid = {42873676},
issn = {1875-8908},
abstract = {Matrix metalloproteinases (MMPs) are a family of enzymes participating in maintenance and remodeling of the extracellular matrix. Their many types are involved in diverse, sometimes contrasting physiological processes, and they are ubiquitously present throughout the CNS. In this mini-review we focused on MMP-2, MMP-3, MMP-9, and MMP-14, highlighting their importance in pathways linked to Alzheimer's disease and small vessel disease. Despite overlapping roles in modulating brain-blood barrier impairment, neuroinflammation, and the accumulation of disease-specific proteins like amyloid-β and tau, they show somewhat distinct expression patterns in different cells and differ in their primary influences on disease mechanisms. Although our knowledge is still very limited, there is evidence linking them to imaging manifestations of cerebral vessel disease and suggesting they could be a target for therapeutic interventions.},
}

@article {pmid42873864,
year = {2026},
author = {Lemon, NL and Canepa, E and Vázquez-Torres, R and Parodi-Rullán, R and Hirt, T and Petersohn, LM and Rifat, T and Abyaneh, MH and Ilies, MA and Fossati, S},
title = {Mitochondrial carbonic anhydrase-VB inhibition rescues brain endothelial stress and memory in Alzheimer's disease models.},
journal = {Science advances},
volume = {12},
number = {42},
pages = {eady1161},
pmid = {42873864},
issn = {2375-2548},
mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Animals ; Humans ; *Mitochondria/metabolism/drug effects ; Disease Models, Animal ; Mice ; *Brain/metabolism/drug effects/pathology ; *Endothelial Cells/metabolism/drug effects ; *Carbonic Anhydrase Inhibitors/pharmacology ; *Carbonic Anhydrases/metabolism/genetics ; Mice, Transgenic ; *Memory/drug effects ; Amyloid beta-Peptides/metabolism ; Apoptosis/drug effects ; },
abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no effective cure, characterized by the cerebral parenchymal and vascular accumulation of aggregated amyloid-β (Aβ) and hyperphosphorylated tau. Cerebrovascular and mitochondria dysfunction are early causal events in the progression of AD. Previous studies support that inhibiting carbonic anhydrases (CAs) may prevent mitochondrial and cerebrovascular dysfunction in AD models. Here, we selectively target the mitochondrial CA isoform CA-VB by pharmacological and genetic manipulation in human cerebral microvascular endothelial cells (hCMEC), and we confirm the protective effects of the CA-V inhibitor in AD mice. CA-V inhibition and CA-VB KO prevent Aβ induced mitochondria-mediated endothelial apoptosis, loss of barrier resistance, and hCMEC inflammatory activation. Strikingly, CA-V inhibition also mitigates caspase activation and endothelial cell activation in the brains of 3xTg AD mice, resulting in preserved memory function. Our results demonstrate that selective CA-V inhibition is an effective and promising strategy against AD-mediated cerebrovascular pathology, neuroinflammation and cognitive impairment.},
}

*Alzheimer Disease/drug therapy/metabolism/pathology
Animals
Humans
*Mitochondria/metabolism/drug effects
Disease Models, Animal
Mice
*Brain/metabolism/drug effects/pathology
*Endothelial Cells/metabolism/drug effects
*Carbonic Anhydrase Inhibitors/pharmacology
*Carbonic Anhydrases/metabolism/genetics
Mice, Transgenic
*Memory/drug effects
Amyloid beta-Peptides/metabolism
Apoptosis/drug effects

@article {pmid42873892,
year = {2026},
author = {Dejanovic, B and Figley, MD and Weisman, E and Kiragasi, B and Gergits, FW and Larson, K and Renoux, A and Rajagovindan, R and Pandya, B and Houze, J and Huang, L and Gaudreault, F and O'Mara, R and Clarkson, JH and Turnbull, MT and Meier, A and Colonna, M and Stromme, J and Gray, D and Thackaberry, EA and Kaufmann, P and Mirescu, C},
title = {Preclinical and first-in-human evaluation of VG-3927/SAR448851, an oral small-molecule TREM2 agonist for Alzheimer's disease.},
journal = {Science translational medicine},
volume = {18},
number = {871},
pages = {eaec5740},
doi = {10.1126/scitranslmed.aec5740},
pmid = {42873892},
issn = {1946-6242},
mesh = {Animals ; Female ; Humans ; Male ; Mice ; Administration, Oral ; *Alzheimer Disease/drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; Drug Evaluation, Preclinical ; *Membrane Glycoproteins/agonists/metabolism ; Mice, Transgenic ; Microglia/metabolism/drug effects/pathology ; Neurons/drug effects/metabolism ; *Receptors, Immunologic/agonists/metabolism ; Signal Transduction/drug effects ; },
abstract = {Microglial dysfunction is increasingly implicated in Alzheimer's disease (AD) pathogenesis, with loss-of-function variants in the microglial receptor TREM2 as major risk factors for late-onset AD. We report VG-3927, an oral, CNS-penetrant small-molecule TREM2 agonist that engages the transmembrane domains of TREM2 and its adaptor DAP12 to promote higher-order receptor complex formation and downstream signaling. VG-3927 and tool compound VG-3909 exhibited (sub)nanomolar potency, cooperated with endogenous ligands including amyloid-β (Aβ), and restored signaling in disease-associated TREM2 variants. In human iPSC-derived neuron-microglia-astrocyte cultures, VG-3927 reduced inflammatory cytokines and markers of neuronal damage. In 5xFAD amyloidosis mice expressing the common variant of hTREM2 (5xFAD;hTREM2[CV]), VG-3909 induced neuroprotective transcriptional reprogramming of microglia, particularly in the plaque niche; enhanced Aβ phagocytosis; and boosted brain glucose metabolism. By contrast, a TREM2 agonist antibody, which may be sequestered by soluble TREM2 (sTREM2), failed to engage plaque microglia. In a first-in-human, randomized, double-blind, placebo-controlled phase 1 trial (NCT06343636, n = 115), VG-3927 was well tolerated across single and multiple ascending doses of up to 140 milligrams. Pharmacokinetics supported once-daily dosing with high CNS penetration (CSF-to-unbound plasma ratio of 0.91). VG-3927 induced dose-dependent reductions in CSF sTREM2, a biomarker of target engagement, consistent across healthy and elderly participants and participants with AD, supporting further clinical development in AD under the new designation SAR448851.},
}

Animals
Female
Humans
Male
Mice
Administration, Oral
*Alzheimer Disease/drug therapy/metabolism
Amyloid beta-Peptides/metabolism
Drug Evaluation, Preclinical
*Membrane Glycoproteins/agonists/metabolism
Mice, Transgenic
Microglia/metabolism/drug effects/pathology
Neurons/drug effects/metabolism
*Receptors, Immunologic/agonists/metabolism
Signal Transduction/drug effects

@article {pmid42874179,
year = {2026},
author = {Qu, L and Wang, Y and Ren, L and Zhang, C and Guo, Z and Zhang, L and Pang, X and Sha, S},
title = {Advancing early detection of Alzheimer's disease: from established biomarkers to future innovations.},
journal = {International immunopharmacology},
volume = {190},
number = {},
pages = {117537},
doi = {10.1016/j.intimp.2026.117537},
pmid = {42874179},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) is a major form of dementia, imposes an escalating global burden on public health and social care. Pathological changes in AD occur years before clinical symptoms, defining a prolonged preclinical phase. Currently, there is no effective treatment exist for late-stage AD, making early diagnosis and intervention indispensable, in which biomarkers play a pivotal role. While cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers improved AD diagnostic accuracy, their clinical application is limited by invasiveness, high costs. Advances in ultrasensitive immunoassay technologies has rendered peripheral blood biomarkers easily accessible, cost-effective, minimally invasive, and suitable for continuous monitoring, offering noval opportunities for AD screening, diagnosis and progression tracking. Additionally, non-invasive body fluids including saliva, urine and tears are being explored as potential biomarkers. Artificial intelligence (AI)-driven multimodal fusion, integrated with large-scale multimodal computing frameworks, significantly improve the accuracy of early AD diagnosis. Recent studies have identified a series of promising synaptic and neuronal biomarkers, such as neurofilament light chain (NFL), neurogranin (Ng), β-secretase 1 (BACE1) and synaptosomal-associated protein 25 (SNAP-25). Inflammatory mediators and genetic factors also contribute to AD pathological evaluation. This review systematically characterizes biomarker profiles of emerging non-invasive carriers (saliva, urine and tears). It further synthesizes cohort-derived quantitative diagnostic metrics (AUC, sensitivity, specificity) of multimodal AD biomarkers and conducts head-to-head comparison to clarify their respective strengths and translational limitations, aiming to provide evidence-based insights for optimizing early AD screening and diagnostic strategies.},
}

@article {pmid42874250,
year = {2026},
author = {Xu, W and Cao, J and Liu, Y and Wei, Z and Zha, X and Xie, S and Liu, X and Wang, W and Zhang, C},
title = {Corrigendum to "LPI alleviates Alzheimer's disease pathology via the GPR55 receptor" [Neuroscience 611 (2026) 99-110].},
journal = {Neuroscience},
volume = {618},
number = {},
pages = {80},
doi = {10.1016/j.neuroscience.2026.09.017},
pmid = {42874250},
issn = {1873-7544},
}

@article {pmid42874293,
year = {2026},
author = {Garloff, V and Grimmel, M and Maroofian, R and Efthymiou, S and Stengel, S and Bello, D and Tille, C and Ghait, M and Ohlenschläger, O and Dieckmann, A and de Vries, H and Waginger, M and Nadeef, S and Barkhordari, E and Kaiyrzhanov, R and Bühler, S and Pjeci, I and Beck-Wödl, S and Alvi, JR and Sultan, T and Chassevent, A and Smith-Hicks, C and Mishina, I and Rodríguez-Palmero, A and Wassmer, E and Vogt, J and Meudt, CM and Jamra, RA and Abbaszadegan, MR and Ajami, N and Azizimalamiri, R and Galehdari, H and Chamanrou, N and Zamani, M and Shariati, G and Nourbakhsh, P and Ali, FB and Fatima, A and Hashmi, SN and Iqbal, Z and Kaleem, S and Toft, M and Afzal, E and Maqbool, S and Rahman, F and Salpietro, V and Grisval, M and Racine, C and Januel, L and Cheillan, D and Acquaviva-Bourdain, C and Al Alam, C and Alfadhel, M and Umair, M and Oehl-Jaschkowitz, B and Haider, S and Jain, V and Narang, B and Amer, F and Elkhateeb, N and Alvarez, C and Pérez-Palma, E and Ríos-Pohl, L and Møller, RS and Baruah, D and Lingappa, L and Farooq, A and Zaki, MS and Svyatova, G and Murtazalieva, A and Burabayeva, A and Salayev, K and Guliyeva, U and Kahrizi, K and Najmabadi, H and Revah-Politi, A and Mulhern, MS and Sands, TT and Mustafa, HM and Rao, HA and Oprea, G and Rad, A and Miryounesi, M and Mardi, A and Gowda, VK and Srinivasan, VM and Alanazi, RM and Abumansour, IS and Alhaddad, B and Bakur, K and Bauer, M and Alkuraya, FS and Huppke, P and Houlden, H and Haack, TB and Rubio, I and Husain, RA},
title = {CNPY3 variants associated with a recessive developmental and epileptic encephalopathy affect inflammasome and TLR function.},
journal = {EBioMedicine},
volume = {133},
number = {},
pages = {106506},
doi = {10.1016/j.ebiom.2026.106506},
pmid = {42874293},
issn = {2352-3964},
abstract = {BACKGROUND: Canopy FGF signalling regulator 3 (CNPY3) is an endoplasmic reticulum (ER)-resident chaperone essential for toll-like receptor (TLR) folding, trafficking and inflammasome activation. In rare paediatric cases, biallelic CNPY3 variants have been associated with developmental and epileptic encephalopathy (DEE), but available data remain sparse.

METHODS: 50 individuals from 38 unrelated families with biallelic CNPY3 variants and DEE were evaluated for exome and genome findings, standardised clinical phenotype descriptions, EEG results, and neuroimaging data. A selection of variants underwent functional analysis focussing on protein stability and localisation, TLR2 function, NLPR3 inflammasome activation, and structural conformation.

FINDINGS: Disease onset occurred in early infancy (median age at onset 68 days), with a clinical phenotype comprising global developmental delay (100%) and intractable epilepsy (86%), accompanied by microcephaly (70%), spasticity (77%), growth faltering (63%), stridor (48%), and early mortality (38%). Epileptic spasms and tonic seizures (46% each) were the most frequent seizure types, and EEG findings included suppression-burst (37%) and hypsarrhythmia (28%). Phenotypic severity varied substantially, with most patients being severely affected (median score 16, range 2-20). Most variants occurred in the homozygous state (95%), including 13 missense changes and 7 truncating alleles. Variants were classified as of uncertain significance (71%), followed by likely pathogenic (23%) and pathogenic (6%) according to ACMG/AMP criteria. Genotype-phenotype correlation showed that individuals with truncating variants were, on average, more severely affected than those with non-truncating variants (median score 18 vs 14.5). Protein modelling predicted conformational effects for most missense variants. In cells, frameshift alleles abolished CNPY3 protein expression, whereas nonsense alleles markedly reduced protein levels. ER localisation of CNPY3 remained preserved across tested genotypes; however, capacity to support TLR2 maturation and processing varied substantially. Remarkably, some missense variants permitted TLR2 surface expression but impaired downstream signalling and inflammasome activation, uncoupling trafficking from signal transduction.

INTERPRETATION: CNPY3-associated DEE is a severe early-onset disorder with genotype-dependent phenotypic severity, accompanied by allele-specific disruption of innate immune pathways. Our findings reveal separable effects on TLR trafficking, downstream signalling and inflammasome activation, identifying CNPY3 as a key regulator of multiple cellular pathways involved in inflammatory responses and neurodevelopment.

FUNDING: Interdisciplinary Center of Clinical Research and Jena School of Molecular Medicine, Jena University Hospital; Friedrich Schiller University Jena; The Wellcome Trust; The Medical Research Council; The MSA Trust; The National Institute for Health Research University College London Hospitals Biomedical Research Centre; The Michael J Fox Foundation; Biotechnology and Biological Sciences Research Council; The Fidelity Trust; Rosetrees Trust; Ataxia UK; Brain Research UK; Sparks GOSH Charity; Alzheimer's Research UK; CureDRPLA; UK Dementia Research Institute; Parkinson's UK; South-Eastern Norway Regional Health Authority, Norway; France Genomic Medicine Plan 2025; Deutsche Forschungsgemeinschaft; European Commission; Federal Government of Germany; State of Thuringia; Pakistan Science Foundation; King Abdullah International Medical Research Center; Science and Technology Development Fund; King Salman Center for Disability Research.},
}

@article {pmid42874425,
year = {2026},
author = {Le Scouarnec, L and Bouteloup, V and Grasset, L and Planche, V and Chêne, G and Dufouil, C and , },
title = {Estimating the eligible population for amyloid-targeting monoclonal antibody therapy in memory clinics: Application to lecanemab in France.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {10},
pages = {100683},
doi = {10.1016/j.tjpad.2026.100683},
pmid = {42874425},
issn = {2426-0266},
abstract = {Lecanemab was the first amyloid-targeting monoclonal antibody approved by the European Commission for treating patients with mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease (AD). While this marketing authorization led to heterogeneous situations across European countries, France declined reimbursement, citing limited clinical benefit and concerns about the healthcare system's capacity to implement this new care pathway. This capacity depends directly on the number of eligible patients, yet robust estimates remain limited and highly variable across studies. Our objective was therefore to estimate the population eligible for lecanemab in France. Using transportability methods based on inverse odds of selection weighting, we articulated the nationwide consultation data from the French National Alzheimer Database (BNA) with the deeply phenotyped MEMENTO clinical cohort. Eligibility for lecanemab followed the French appropriate use recommendations: 1) clinical eligibility (age 50-90 years, MCI with common AD phenotype or mild AD dementia, MMSE ≥22), 2) biological eligibility (amyloid confirmation determined sequentially using plasma p-tau217, cerebrospinal fluid biomarkers and amyloid-PET), 3) absence of contraindications (APOEε4 homozygosity, anticoagulant use, MRI risk markers for ARIA). Among patients consulting French memory clinics, 19.5% met clinical eligibility criteria. Of these, 73.0% (95%CI: 67.6-77.9) were amyloid-positive, and 49.7% (95%CI: 44.0-55.5) remained eligible after applying safety criteria. Overall, 9.7% (95%CI: 8.6-10.8) of patients consulting memory clinics were estimated to be eligible for lecanemab, representing approximately 18,200 individuals nationally (annual average, 2022-2024). These results inform healthcare planning for disease-modifying therapy implementation in France and comparable countries.},
}

@article {pmid42874468,
year = {2026},
author = {Donner, A and Chung, K and Bobowski, N and Hovling, T and Kurian, A and Monichan, AC and Hackert, VD and Ali, MM and Wilson, AJ and Durisile, BC and Neuwirth, LS and Yokoyama, K},
title = {Nanoparticle size-dependent structural observability revealed by surface-enhanced Raman scattering in Alzheimer's disease rat hippocampal tissue.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {367},
number = {Pt 1},
pages = {128965},
doi = {10.1016/j.saa.2026.128965},
pmid = {42874468},
issn = {1873-3557},
abstract = {Understanding the structural heterogeneity of protein aggregation in complex biological environments remains a central challenge in biophysical chemistry. Transient and partially ordered aggregation intermediates are particularly difficult to characterize because they exhibit structural diversity, low abundance, and weak spectroscopic signatures. The present within-subject repeated-measures study investigated how gold nanoparticle (AuNP) size influences plasmon-enhanced vibrational spectroscopy used to probe amyloid aggregation in situ. Hippocampal tissue sections from an Alzheimer's disease (AD) rat model were examined using AuNPs of two distinct diameters (20 nm and 80 nm). Surface-enhanced Raman scattering (SERS) spectroscopy combined with three-dimensional (3D) Raman imaging was used to investigate nanoparticle aggregation behavior, spectral enhancement, and structural observability within a heterogeneous biological matrix. The present study builds upon our previous observations that Aβ-coated 20 nm AuNPs exhibit nanoparticle-size-dependent quasi-reversible aggregation behavior, suggesting that nanoparticle size influences the structural states accessible during protein assembly. Accordingly, the primary objective of the present work was to clarify how nanoparticle size governs structural observability and molecular selectivity during in situ SERS analysis of amyloid aggregation. The results reveal a pronounced nanoparticle-size dependence in the SERS response. Smaller nanoparticles preferentially enhance vibrational features associated with dynamic and weakly ordered protein conformations characteristic of aggregation intermediates. The preferential observation of several localized vibrational modes in the 20 nm AuNP datasets further indicates that the reduced spectral occupancy should not be interpreted as reduced analytical sensitivity. Rather, it implies selective access to conformationally diverse and dynamically evolving molecular environments that are not strongly represented in the 80 nm datasets, consistent with previously reported nanoparticle-size-dependent quasi-reversible aggregation behavior. In contrast, 80 nm nanoparticles preferentially enhance vibrational features associated with more extended and highly ordered aggregate structures. Three-dimensional Raman imaging further demonstrated that these distinct structural states are associated with markedly different aggregate architectures and spatial extents within hippocampal tissue from the AD rat model, consistent with nanoparticle-size-dependent structural observability. These findings establish nanoparticle size as a key physical parameter governing plasmon-molecule coupling and structural observability in SERS. The use of multiple nanoparticle sizes therefore provides a practical strategy for resolving weakly ordered aggregation-associated states in situ and establishes a spectroscopic framework for investigating protein assembly pathways in complex biological environments.},
}

@article {pmid42874747,
year = {2026},
author = {Xiao, X and Gao, F and Xie, J and Lu, Y and Lv, K and Mo, H and Chen, J and Liu, J and Meng, Q and Guan, Y and Chen, Q},
title = {Fucosylated Chondroitin Sulfate Modulates Microglia-Associated Responses and Reduces Aβ Burden with ERK1/2-Related Signaling Changes.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106278},
doi = {10.1016/j.neuint.2026.106278},
pmid = {42874747},
issn = {1872-9754},
abstract = {INTRODUCTION: Fucosylated chondroitin sulfate (FCS) is a sulfated polysaccharide derived from the marine organism Apostichopus japonicus. This study aimed to investigate its neuroprotective potential, specifically focusing on microglial modulation and ERK1/2 signaling, in Alzheimer's disease (AD) models.

METHODS: An integrated in vitro and in vivo approach was employed. In vitro, Aβ42-stimulated BV2 microglia were treated with FCS, and the broad protein kinase C activator TPA was used as a pharmacological perturbation to examine whether the FCS-associated ERK1/2 signaling changes were reversible. Cytokine levels, microglial phenotype markers (CD86, CD206, iNOS, Arg-1), Aβ handling, and MAPK pathway proteins (p-ERK1/2, p38, JNK) were analyzed. In vivo, 5xFAD transgenic mice received intraperitoneal FCS for 28 days. Aβ plaque burden, soluble/insoluble Aβ levels, cognitive performance (Morris water maze, Y-maze), cortical Iba1-positive cell counts, activation state (Iba1[+]CD86[+], Iba1[+]CD206[+]), and expression of p-ERK1/2, iNOS, and Arg-1 were assessed.

RESULTS: In vitro, FCS attenuated Aβ42-induced pro-inflammatory responses (reduced IL-6, TNF-α; increased IL-10), modulated phenotype (decreased CD86/iNOS; increased CD206/Arg-1), and increased the cell-associated Aβ fraction while reducing supernatant Aβ. FCS reduced Aβ42-associated ERK1/2 phosphorylation and the nuclear-to-cytoplasmic p-ERK1/2 fluorescence signal ratio, and these changes were partially attenuated by TPA. In vivo, FCS treatment reduced cerebral Aβ burden, improved spatial and working memory, decreased the number and proportion of cortical Iba1[+]CD86[+] microglia, and increased the Iba1[+]CD206[+] subset. Cortical p-ERK1/2/total ERK1/2 and iNOS expression were downregulated, while Arg-1 was upregulated.

CONCLUSION: FCS reduced Aβ-related pathological burden, improved selected behavioral outcomes, and modulated microglia-associated inflammatory and phenotype-related readouts in AD models. These effects were accompanied by ERK1/2-related signaling changes, supporting a pathway-associated interpretation rather than definitive proof of ERK1/2 causality in vivo.},
}

@article {pmid42874875,
year = {2026},
author = {Liu, KW and Pang, RTE and Durongbhan, P},
title = {Analysis choices can produce apparent rich-club differences: an Alzheimer's disease EEG case study.},
journal = {Journal of neuroscience methods},
volume = {},
number = {},
pages = {110927},
doi = {10.1016/j.jneumeth.2026.110927},
pmid = {42874875},
issn = {1872-678X},
abstract = {BACKGROUND: The weighted rich-club coefficient tests whether a network's most strongly connected nodes are preferentially interconnected. Its interpretation depends on two often-implicit choices: how the randomised comparison networks are constructed, and whether the hubs are re-identified in each comparison network or held fixed at those of the observed network. When hubs are defined by connection strength, these choices change what the coefficient tests.

NEW METHOD: We examined how these choices affect inference using resting-state EEG from 20 people with Alzheimer's disease and 20 controls. Holding the data fixed, we compared four analysis pipelines, crossing two ways of building the comparison networks (global weight reshuffle or strength-conditioned null) with the two hub choices, and ran a calibration study using data constructed to contain no preferential hub coupling beyond nodal strength.

RESULTS: An apparent eyes-open group difference in rich-club organisation appeared only under the pipeline combining a global weight reshuffle with re-identified hubs. Under the empirical resampling ensemble, that pipeline reported a group difference in 43% of pseudo-studies, always higher in the Alzheimer's disease group, while the other three stayed near the expected 5%.

Unlike global weight reshuffling, strength-conditioned nulls approximately preserve nodal strengths; fixing observed hubs also retains the identity of the core being tested.

CONCLUSIONS: The same data can support or dissolve an apparent rich-club difference depending on these choices. No single choice is universally correct, but reporting which were made, and why they fit the question being asked, is essential to interpreting the result.},
}