@article {pmid42607706,
year = {2026},
author = {Lyu, Z and Song, Z and Fu, S and Yu, H and Guo, X},
title = {An explicit functional-map framework for structure-function correspondence in brain connectivity.},
journal = {Journal of neural engineering},
volume = {23},
number = {5},
pages = {},
doi = {10.1088/1741-2552/ae9acb},
pmid = {42607706},
issn = {1741-2552},
mesh = {Humans ; *Brain/physiology/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; *Nerve Net/physiology/diagnostic imaging ; *Brain Mapping/methods ; Female ; Male ; *Connectome/methods ; },
abstract = {Objective. Characterizing the relationship between structural connectivity (SC) and functional connectivity (FC) is a central problem in multimodal neuroimaging. SC-to-FC prediction accuracy is often used to summarize this relationship, but a high score may largely reflect population-level regularities shared across subjects and does not reveal whether regional, network-level, or subject-specific correspondence is preserved. We therefore developed a framework that makes these different levels of SC-FC correspondence explicit and directly testable.Approach.For each subject, we constructed separate spectral representations of SC and FC and estimated an explicit linear map between them. Signal transfer was evaluated against matched controls that disrupted node identity, within-network organization, or subject pairing, allowing aggregate transfer to be distinguished from more specific forms of correspondence. A training-derived reference map was further used to define the functional component expected under a reference SC-FC relationship and the deviation from that expectation for downstream aging and disease-related analyses.Main results.Across four independent datasets, all primary matched-control gaps were positive after false-discovery-rate correction, although their magnitudes varied across cohorts. Strong aggregate transfer did not necessarily imply strong subject-level correspondence. Compared with external baselines, the proposed framework more consistently preserved regional identity, within-network organization, and correct subject pairing. In aging analyses, reduced alignment with a young-reference SC-FC relationship was robust in CamCAN but not significant in NKI, whereas empirical FC magnitude showed no comparable decline. In Alzheimer's Disease Neuroimaging Initiative, reference-conditioned markers showed exploratory disease-related signals, but the associated uncertainty did not support definitive diagnostic or incremental-value claims.Significance.The proposed framework separates the ability to transfer SC-derived signals into FC space from the specificity of the correspondence being preserved. It provides an interpretable basis for testing population-level, network-level, and subject-sensitive SC-FC relationships and for constructing reference-conditioned individual deviation measures without treating prediction accuracy as direct evidence of biological constraint.},
}

Humans
*Brain/physiology/diagnostic imaging
*Magnetic Resonance Imaging/methods
*Nerve Net/physiology/diagnostic imaging
*Brain Mapping/methods
Female
Male
*Connectome/methods

@article {pmid42702638,
year = {2026},
author = {Sfikas, E and Constantinides, V and Koros, C and Smaragdaki, E and Angelopoulou, G and Toulas, P and Stefanis, L and Papageorgiou, S},
title = {Intersecting pathologies in atypical Alzheimer's disease: a case of logopenic PPA with cerebral amyloid angiopathy.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42702638},
issn = {1590-3478},
}

@article {pmid42702643,
year = {2026},
author = {Bergner, A and Musaeus, CS and Simonsen, AH and Munch, TN and Carlsen, JF and Hasselbalch, SG},
title = {Association between p-tau181 in cerebrospinal fluid and shunt response in patients with normal-pressure hydrocephalus.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42702643},
issn = {1590-3478},
mesh = {Humans ; *Hydrocephalus, Normal Pressure/cerebrospinal fluid/surgery ; *tau Proteins/cerebrospinal fluid ; Female ; Male ; Retrospective Studies ; Biomarkers/cerebrospinal fluid ; Aged ; *Cerebrospinal Fluid Shunts ; Amyloid beta-Peptides/cerebrospinal fluid ; Aged, 80 and over ; Phosphorylation ; Peptide Fragments/cerebrospinal fluid ; Treatment Outcome ; },
abstract = {BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a treatable condition, but predicting shunt response remains challenging. Cerebrospinal fluid (CSF) biomarkers, including phosphorylated tau (p-tau181), have been suggested as potential predictors, although existing evidence is inconsistent.

METHODS: In this retrospective single-center study, we included 230 patients with probable or possible iNPH who underwent shunt surgery and had available CSF biomarker data for Amyloid beta42, total tau and phosphorylated tau 181. Patients were divided into two cohorts based on assay method (Innotest[®] and Elecsys[®]). The primary outcome was improvement in gait score. Secondary outcomes included cognition, continence, and overall clinical response. Predictive performance of CSF p-tau181 was evaluated using logistic regression and receiver operating characteristic (ROC) analyses.

RESULTS: Mean CSF p-tau181 levels did not differ significantly between responders and non-responders in either cohort. In multivariable logistic regression analyses adjusted for age and sex, CSF p-tau181 was not associated with shunt response (Innotest[®]: OR 0.997 (0.972-1.024), p = 0.815; Elecsys[®]: OR 1.091 (0.910-1.419), p = 0.429). Findings were consistent across two CSF p-tau181 assay platforms, although the Elecsys[®] cohort was underpowered for calculating AUC with only 14 non-responders. Similar results were observed across secondary outcomes and after exclusion of patients with high CSF p-tau181 levels to reduce potential confounding by concomitant Alzheimer's disease pathology.

CONCLUSION: CSF p-tau181 does not demonstrate clinically meaningful predictive value for shunt response in patients with iNPH and cannot alone guide patient selection for shunt surgery. Future research should focus on multimodal approaches integrating clinical, radiological, and biochemical markers.},
}

Humans
*Hydrocephalus, Normal Pressure/cerebrospinal fluid/surgery
*tau Proteins/cerebrospinal fluid
Female
Male
Retrospective Studies
Biomarkers/cerebrospinal fluid
Aged
*Cerebrospinal Fluid Shunts
Amyloid beta-Peptides/cerebrospinal fluid
Aged, 80 and over
Phosphorylation
Peptide Fragments/cerebrospinal fluid
Treatment Outcome

@article {pmid42702666,
year = {2026},
author = {Elgenidi, A and Shir, D and Piura, YD and Sokol, LL and Duara, R and Lachner, C and Day, GS},
title = {Prion disease mimicking rapidly progressive Alzheimer disease: case series and systematic review.},
journal = {Journal of neurology},
volume = {273},
number = {10},
pages = {},
pmid = {42702666},
issn = {1432-1459},
support = {K23AG064029/AG/NIA NIH HHS/United States ; R01AG089380/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/cerebrospinal fluid ; Diagnosis, Differential ; *Prion Diseases/diagnosis/cerebrospinal fluid ; Female ; Male ; Middle Aged ; Aged ; Disease Progression ; tau Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; },
abstract = {BACKGROUND: Prion disease and Alzheimer disease (AD) are common causes of rapidly progressive dementia (RPD). Although most patients with prion disease are distinguished by MRI and CSF findings, selected cases mimic rapidly progressive AD. We characterized AD-prion disease mimics within a prospective cohort and the extant literature to identify the clinical features and tests that support accurate diagnoses in these patients.

METHODS: Patients with prion disease initially diagnosed as rapidly progressive AD were identified from a prospective cohort study at Mayo Clinic (February 2020-June 2026) and through systematic review of MEDLINE and Embase.

RESULTS: Of 204 patients with RPD, five (2.5%) were initially diagnosed with clinically probable AD but ultimately determined to have prion disease. Systematic review identified 10 additional cases (n=15, median age-at-onset, 59 years; 67% male). Presentations reproduced amnestic (53%), dysexecutive (27%), primary progressive aphasia (13%), and posterior cortical atrophy (7%) AD phenotypes; median time from AD diagnosis to consideration of prion disease was 2 months. Diffusion-weighted MRI abnormalities were absent in Mayo Clinic cases and absent/equivocal (n=2) or overlooked (n=8) in published cases. CSF biomarkers were consistent with AD in 6/9 tested patients, with elevated total tau levels in 11/13 patients and total-tau/p hosphorylated-tau181 ratios in 5/9 patients. Real-time quaking-induced conversion assays for prions were positive in the CSF of 9/12 patients. Prion disease was confirmed by neuropathology (n=7), genetics (n=2), or real-time quaking-induced conversion (n=6) assays.

CONCLUSIONS: Prion disease may rarely mimic rapidly progressive AD. Disproportionate elevations in CSF total-tau levels or total-tau/p hosphorylated-tau181 ratios should prompt consideration of prion disease.},
}

Humans
*Alzheimer Disease/diagnosis/cerebrospinal fluid
Diagnosis, Differential
*Prion Diseases/diagnosis/cerebrospinal fluid
Female
Male
Middle Aged
Aged
Disease Progression
tau Proteins/cerebrospinal fluid
Biomarkers/cerebrospinal fluid

@article {pmid42702948,
year = {2026},
author = {Zang, W and Vithoulkas, J and Zuo, Z},
title = {Surgery Is Not Associated With Early Presentation of Alzheimer's Disease and Mild Cognitive Impairment or Increased Risk for Both.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {9},
pages = {e71149},
pmid = {42702948},
issn = {1755-5949},
support = {Robert M. Epstein Professorship Endowment//School of Medicine, University of Virginia/ ; },
mesh = {Humans ; *Alzheimer Disease/epidemiology/diagnosis/surgery ; *Cognitive Dysfunction/epidemiology/diagnosis/surgery ; Female ; Aged ; Male ; Retrospective Studies ; Middle Aged ; Aged, 80 and over ; Cohort Studies ; Risk Factors ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia in elderly patients. Mild cognitive impairment (MCI) may be a prodromal status of AD. Previous studies show inconsistent findings on whether surgery increases MCI and AD incidence. Moreover, it remains unknown whether surgery expedites the development of MCI or AD.

METHODS: This was a retrospective propensity score-matched cohort study using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database between September 2005 (ADNI initiation time) and May 2025 (time of data downloaded). Two outcomes were assessed: age at first diagnosis of MCI or AD, and incidence of MCI or AD. Nearest-neighbor matching was used to balance demographic and comorbidity covariates.

RESULTS: The study was composed of 1114 subjects with MCI, 760 subjects with AD, and 397 subjects with normal cognition. Surgery was not associated with a decrease in the age of patients when MCI was diagnosed but was associated with a delayed presentation of AD by 1.7 years. Surgery performed on patients younger than 60 years was associated with a decrease in age when the first diagnosis of MCI or AD was made. Surgery at an age older than 60 years was associated with an increase in the age at MCI or AD diagnosis (mean difference: 5.1 and 5.6 years, respectively). Surgery was not associated with a change in the incidence of MCI or AD.

CONCLUSION: Surgery may be associated with delayed presentation of AD or MCI, except for the surgery performed in patients younger than 60 years. Surgery may not affect the incidence of MCI or AD. These findings do not support deferring clinically indicated surgery for the concern of development of MCI or AD.},
}

Humans
*Alzheimer Disease/epidemiology/diagnosis/surgery
*Cognitive Dysfunction/epidemiology/diagnosis/surgery
Female
Aged
Male
Retrospective Studies
Middle Aged
Aged, 80 and over
Cohort Studies
Risk Factors

@article {pmid42702949,
year = {2026},
author = {Moro, V and Vianello, G and Gambina, G and Gobbetto, V and Gasparini, M and Beccherle, M},
title = {The clinical implications of anosognosia in Alzheimer's disease.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/14737175.2026.2726416},
pmid = {42702949},
issn = {1744-8360},
abstract = {INTRODUCTION: Assessing awareness of patients with Alzheimer's disease (AD) is essential for diagnosis and treatment. Anosognosia, defined as impaired awareness of cognitive and functional deficits, is associated with poorer prognosis, reduced decision-making capacity, increased risk of accidents, and earlier institutionalization.

AREAS COVERED: This narrative review examines 53 studies. After outlining the main theoretical models of awareness in dementia, the multidimensional nature of anosognosia and its impact on patients' autonomy and decision-making abilities are discussed. This review also describes the main instruments available for assessing awareness deficits and highlights their relevance in clinical practice. Particular attention is given to the implications of anosognosia for treatment adherence, patient care, and decision making.

EXPERT OPINION: Taking care of unaware AD patients represents a challenge, and anosognosia is often underestimated in clinical practice. Evidence suggests that awareness deficits may emerge even in the earliest stages of AD, affecting patients' autonomy and capacity to make informed decisions. A two-step assessment process is recommended, consisting of an initial screening followed by a comprehensive evaluation carried out by specialized neuropsychologists. Targeted caregiver training is also essential to address the challenges associated with impaired awareness.},
}

@article {pmid42702988,
year = {2026},
author = {Singh, S and Naithani, D and Raj, G and Narang, J},
title = {High-Performance Screen-Printed OECT-Inspired with Encased Cassette Based on PEDOT:GO for Sensitive and Specific Electrochemical Aptasensing of Aβ-42 in Management of Alzheimer's Disease.},
journal = {ACS applied bio materials},
volume = {9},
number = {17},
pages = {7945-7960},
doi = {10.1021/acsabm.6c00105},
pmid = {42702988},
issn = {2576-6422},
mesh = {*Amyloid beta-Peptides/analysis ; *Alzheimer Disease/diagnosis ; Humans ; *Biosensing Techniques/methods ; *Electrochemical Techniques ; *Polymers/chemistry ; *Peptide Fragments/analysis ; *Bridged Bicyclo Compounds, Heterocyclic/chemistry ; *Graphite/chemistry ; *Biocompatible Materials/chemistry/chemical synthesis ; Materials Testing ; Particle Size ; *Aptamers, Nucleotide/chemistry ; },
abstract = {Recently, substantial interest has emerged in developing point-of-care diagnostic devices for Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by the accumulation of beta-amyloid (Aβ1-42) peptides that act as critical biomarkers for early detection. In response to the growing demand for noninvasive and accessible diagnostic tools, this study presents a highly sensitive organic electrochemical transistor-inspired biosensor for the detection of Aβ-42 in saliva. The device is based on a paper substrate modified with a PEDOT:GO composite and a Ag-Au nanocomposite, which together enhance electrical conductivity and improve the electrochemical response. A highly selective Aβ1-42-binding aptamer is immobilized on the sensor surface. This platform enables real-time signal amplification, allowing the detection of Aβ-42 over a dynamic range of 1 pg/mL to 10 μg/mL. This biosensor demonstrates excellent sensitivity, selectivity, and reproducibility, making it a potential tool for noninvasive, point-of-care detection. The use of artificial saliva as a diagnostic medium further enhances its applicability for early screening, especially in decentralized or resource-limited healthcare environments.},
}

*Amyloid beta-Peptides/analysis
*Alzheimer Disease/diagnosis
Humans
*Biosensing Techniques/methods
*Electrochemical Techniques
*Polymers/chemistry
*Peptide Fragments/analysis
*Bridged Bicyclo Compounds, Heterocyclic/chemistry
*Graphite/chemistry
*Biocompatible Materials/chemistry/chemical synthesis
Materials Testing
Particle Size
*Aptamers, Nucleotide/chemistry

@article {pmid42703295,
year = {2026},
author = {Zhao, J and Li, X and Wu, M and Zhang, Z},
title = {Physical inactivity in preclinical Alzheimer's disease: Risk factor, early symptom, or both?.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70316},
pmid = {42703295},
issn = {2352-8737},
abstract = {Physical inactivity is a key modifiable risk factor for Alzheimer's disease (AD). However, emerging evidence suggests a bidirectional relationship where inactivity also serves as an early manifestation of AD pathology. This perspective synthesizes recent findings from long-term epidemiological cohorts, brainstem neuropathology, and digital phenotyping to reconceptualize the role of inactivity in preclinical AD. Early tau accumulation in catecholaminergic nuclei (locus coeruleus and ventral tegmental area) disrupts circuits essential for reward valuation and effort calculation. We hypothesize that this neurobiological failure may manifest as prodromal apathy and declining physical activity years before cognitive impairment. Standard metrics like step counts fail to capture these nuances. We propose a multidimensional digital phenotype - incorporating temporal complexity, circadian rhythms, and life-space mobility - to distinguish "behavioral" from "biologically constrained" inactivity. This framework has critical implications for trial enrichment and the design of personalized lifestyle interventions.},
}

@article {pmid42703487,
year = {2026},
author = {Boşgelmez, Iİ and Mertaş, B and Deliser, H},
title = {Exposome influences: a multi-omics perspective on the combined toxic effects of pharmaceuticals and personal care products in Alzheimer's disease.},
journal = {Frontiers in toxicology},
volume = {8},
number = {},
pages = {1871830},
pmid = {42703487},
issn = {2673-3080},
abstract = {According to WHO data, approximately 57 million people worldwide were affected by dementia in 2021, with prevalence projected to rise. Alzheimer's disease (AD), responsible for 60%-80% of dementia cases, continues to be a leading cause of mortality, with current treatments offering limited efficacy and disease-modifying therapies lacking widespread adoption or conclusive safety evidence, shifting the focus toward prevention and risk modification. Risk factors for AD include both non-modifiable elements, such as age, genetics, and gender, and modifiable factors, like environmental pollution, health status, and diet. While age remains the primary non-modifiable risk factor, early-onset dementia represents only up to 9% of cases. Addressing modifiable factors is essential, as it could prevent or delay almost half of dementia cases, with interventions-such as increased physical activity, smoking cessation, alcohol limitation, and overall health management-being significantly associated with a reduced risk. In this context, the exposome approach offers a comprehensive, integrative framework in which both modifiable and non-modifiable risk factors interact to influence individual susceptibility. Within the neural exposome, chronic low-dose exposure to xenobiotics-such as industrial chemicals, pesticides, metals, pharmaceuticals and personal care products (PPCPs), and air pollutants-may induce neurodegeneration via mechanisms including oxidative stress, neuroinflammation, proteinopathies, and epigenetic modifications, although establishing causality remains challenging. Integration of genomics, transcriptomics, proteomics, metabolomics, and lipidomics, combined with artificial intelligence (AI) techniques such as machine learning (ML) and deep learning (DL), provides promising avenues for biomarker discovery, enhanced preventive strategies, early non-invasive diagnosis, and therapeutic target identification by integrating multi-layered biological data with exposure profiles. This review highlights emerging AD risk factors-including PPCPs-underscoring complex, multifactorial nature of AD and exposome, and the requirement for an interdisciplinary research approach, while also addressing several critical research gaps and methodological limitations.},
}

@article {pmid42704084,
year = {2026},
author = {Sassi, KLM and Thomson, A and Young, VM and Rocha, NP and Teixeira, AL},
title = {Mild behavioral impairment and risk of incident dementia: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261480315},
doi = {10.1177/13872877261480315},
pmid = {42704084},
issn = {1875-8908},
abstract = {BackgroundLate-life emergence of persistent behavioral changes has been recognized as a clinically meaningful sign of neurodegeneration. These neuropsychiatric symptoms, operationalized as mild behavioral impairment (MBI), represent a unique pathway through which early dementia symptoms may become observable. By capturing this neurobehavioral dimension of risk, MBI expands the traditional focus on cognitive decline and may provide a complementary framework for understanding the early manifestations of neurodegeneration.ObjectiveThis systematic review evaluated longitudinal evidence on the association between MBI and incident dementia, including conversion rates, dementia subtypes, domain-specific risk patterns, and biomarker correlates.MethodsWe systematically searched five databases up to November 2025. Eligible studies were longitudinal prospective or retrospective cohorts including adults ≥ 50 years without dementia at baseline, assessing MBI using ISTAART-aligned instruments and reporting incident dementia outcomes. Two reviewers independently screened studies and extracted data. Hazard ratios were synthesized using random-effects meta-analysis, with heterogeneity and publication bias formally assessed.ResultsDespite significant study heterogeneity, MBI was associated with increased risk of incident dementia. Alzheimer's disease was the most frequently reported outcome. Among different neurobehavioral domains, apathy and affective dysregulation emerged as particularly strong predictors of dementia risk. A few biomarker studies linked MBI to greater amyloid burden, elevated plasma phosphorylated tau, and structural brain changes, supporting a biological connection between MBI and early neurodegeneration.ConclusionsMBI seems to represent a clinically meaningful syndrome that identifies individuals at elevated risk for dementia. Future studies must confirm the clinical and epidemiological value of MBI and/or its subdomains, exploring their biological substrates.},
}

@article {pmid42704086,
year = {2026},
author = {Jung, HE and Heo, SJ and Lee, YJ and Han, TH and Kwon, YJ and Lee, JW},
title = {Association between oxidative balance score and cardiovascular risk factors, aging, and incidence of dementia risk score: A prospective cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261485588},
doi = {10.1177/13872877261485588},
pmid = {42704086},
issn = {1875-8908},
abstract = {BackgroundOxidative stress is a key contributor to the pathogenesis of Alzheimer's disease and other dementias. The oxidative balance score (OBS), which reflects combined dietary and lifestyle exposure to pro-oxidant and antioxidant factors, serves as an integrated measure of oxidative stress burden.ObjectiveTo investigate the association between OBS and predicted late-life dementia risk using the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score.MethodsWe analyzed data from 5088 participants aged 40-69 years without dementia at baseline from the Korean Genome and Epidemiology Study. Participants were categorized by OBS tertiles. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for developing a high risk of late-life dementia, defined by a CAIDE score ≥8. Longitudinal changes in CAIDE scores were assessed using linear mixed-effects models.ResultsDuring a mean follow-up of 12.8 years, 1468 participants (28.9%) progressed to CAIDE-predicted high risk for late-life dementia. Compared with the lowest OBS tertile (T1), participants in the highest tertile (T3) had a significantly lower risk for developing high-risk late-life dementia (HR 0.74, 95% CI 0.65-0.84) and exhibited the lowest CAIDE scores (p < 0.001). Each one-point increase in the OBS was associated with a 3% reduction in CAIDE-predicted dementia risk.ConclusionsA higher OBS was significantly associated with a lower predicted risk of late-life dementia. These findings suggest that maintaining an antioxidant-rich diet and a healthy lifestyle during midlife may be effective strategies for dementia prevention.},
}

@article {pmid42704090,
year = {2026},
author = {Fu, X and Cui, M and Yue, A and He, Q and Nan, H and Ye, H and Rosa-Neto, P and Wu, L and Nie, B and Chu, M},
title = {Disease-specific hypometabolic epicenters in dementia: Neural networks and clinical correlations.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261481091},
doi = {10.1177/13872877261481091},
pmid = {42704090},
issn = {1875-8908},
abstract = {BackgroundIn dementia, it remains unclear how the hypometabolism pattern relates to the intrinsic network, where the disease-specific hypometabolism epicenters are located, and what the epicenter's clinical effects are.ObjectiveIn this cross-sectional study, we aim to identify disease-specific hypometabolism epicenters in Alzheimer's disease (AD), posterior cortical atrophy (PCA), and frontotemporal dementia (FTD) using a data-driven network-based approach; to determine whether intrinsic structural and functional brain networks shape the spatial distribution of hypometabolism; and to examine the clinical relevance of epicenter hypometabolism by assessing its association with network disruption and disease-related clinical features.MethodsDisease-specific epicenters were identified using data-driven analysis in AD (n = 98), PCA (n = 40), and FTD (n = 71). Hypometabolism was measured by [[18]F]-fluorodeoxyglucose positron emission tomography (FDG-PET). Brain regions with reduced network connectivity to the epicenter were identified, and the correlation between changes in the epicenter and clinical features was examined.ResultsRegional hypometabolism was significantly correlated with that of the network-connected neighbors. The disease-specific hypometabolism epicenters were the bilateral angular gyrus in AD, the angular and middle occipital gyri in PCA, and the rectus and anterior cingulate gyri in FTD. The hypometabolism of the epicenters contributed to the disruption of the network and was correlated with clinical features.ConclusionsThe hypometabolism epicenters are disease-specific and correlated with clinical features in dementia, providing insight into neuromodulation targets.},
}

@article {pmid42704398,
year = {2026},
author = {Zhu, Z and Jiang, X and Huang, R and Guo, X and Wang, Y and Liu, T and Wang, J and Huang, J and Huang, W and Zhang, D and Li, Q and Chen, S and Yang, Z and Liu, Q and Wei, Z},
title = {Deferiprone Modulates Ferroptosis to Protect Macrophages and Liver during Neospora caninum Infection.},
journal = {Acta parasitologica},
volume = {71},
number = {5},
pages = {},
pmid = {42704398},
issn = {1896-1851},
support = {32002309//the National Natural Science Foundation of China/ ; 2022A1515010960//Guangdong Basic and Applied Basic Research Foundation/ ; NJTG20240253//Guangdong Provincial Department of Agriculture and Rural Affairs - Guangdong Agricultural Technical Service "Light Cavalry" Project 2024/ ; SWU-KQ24021//Central University Basic Scientific Research Program of Southwest University/ ; },
mesh = {Animals ; *Ferroptosis/drug effects ; *Neospora/drug effects/physiology ; *Deferiprone/pharmacology/administration & dosage ; *Coccidiosis/drug therapy/parasitology ; *Liver/parasitology/drug effects ; Mice ; *Macrophages/drug effects/parasitology ; Mice, Inbred C57BL ; Iron/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress/drug effects ; Female ; },
abstract = {BACKGROUND: Neospora caninum (N. caninum), an obligate intracellular apicomplexan parasite, infects nucleated cells across diverse mammalian hosts, resulting in severe clinical outcomes, including reproductive failure (abortion, stillbirth) and neurological impairment. Ferroptosis, an iron-dependent, non-apoptotic cell death pathway characterized by excessive lipid peroxidation, is closely associated with disrupted iron metabolism and oxidative stress. Deferiprone (DFP), a clinically approved iron chelator, is widely used in the treatment of iron overload disorders such as β-thalassemia, Alzheimer's disease, and superficial hemosiderosis. While ferroptosis has been implicated in various disease states, its role in N. caninum infection remains unknown.

METHODS: This study established in vitro and in vivo infection models to investigate the role of ferroptosis in N. caninum pathogenesis and the protective mechanism of DFP. In vitro, RAW 264.7 were infected with N. caninum and treated with DFP, followed by comprehensive assessment of reactive oxygen species (ROS), glutathione (GSH) levels, intracellular iron content, GPX4 expression, and parasite proliferation via qPCR. In vivo, C57BL/6 mice were intraperitoneally inoculated with 1 × 10[^7] tachyzoites and orally administered DFP for seven days. Body weight, food intake, hepatic pathology, oxidative stress markers (GSH and MDA), iron levels, and ferroptosis-related gene expression (GPX4, FTH1, and TRF) were monitored.

RESULTS: Our in vitro findings demonstrated that N. caninum infection significantly elevated ROS production and intracellular iron accumulation while depleting GSH and suppressing GPX4 transcription-hallmarks of ferroptosis. Remarkably, DFP treatment reversed these effects, restoring redox balance and protecting host tissue, not host control of infection. In vivo, DFP alleviated N. caninum-induced hepatic ferroptosis, as evidenced by normalized iron homeostasis, upregulated GPX4 and ferritin expression, and reduced histopathological damage. However, DFP exacerbated weight loss, suggesting a potential trade-off between ferroptosis inhibition and metabolic adaptation.

CONCLUSIONS: In summary, these results establish ferroptosis as a critical pathogenic mechanism in N. caninum infection and highlight DFP's dual role in mitigating oxidative injury while possibly impairing host metabolic responses. Our findings provide novel insights into iron-targeted therapeutic strategies for combating intracellular parasitic infections, paving the way for future investigations into optimizing host-directed antiparasitic interventions.},
}

Animals
*Ferroptosis/drug effects
*Neospora/drug effects/physiology
*Deferiprone/pharmacology/administration & dosage
*Coccidiosis/drug therapy/parasitology
*Liver/parasitology/drug effects
Mice
*Macrophages/drug effects/parasitology
Mice, Inbred C57BL
Iron/metabolism
Reactive Oxygen Species/metabolism
Oxidative Stress/drug effects
Female

@article {pmid42704497,
year = {2026},
author = {Tudella, GCN and Klostermann, AU and Menegucci, G and Fernandes, JVA and Pacheco, JPG},
title = {Efficacy and safety of cannabinoid-based interventions for behavioral and cognitive symptoms in dementia: systematic review and meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42704497},
issn = {1590-3478},
mesh = {Humans ; *Cannabinoids/therapeutic use/adverse effects ; *Dementia/drug therapy/complications ; *Psychomotor Agitation/drug therapy ; },
abstract = {BACKGROUND: Behavioral and cognitive symptoms are frequent in Alzheimer's disease and dementia, and available pharmacological options offer limited benefit. Cannabinoid-based therapies have been proposed as alternatives, but evidence remains inconclusive.

METHODS: We systematically searched PubMed, Embase, Web of Science, and the Cochrane Library through November 2025 for randomized controlled trials evaluating cannabinoids in Alzheimer's disease or dementia. Primary outcomes were agitation measured by the Cohen-Mansfield Agitation Inventory (CMAI) and neuropsychiatric symptoms assessed by the Neuropsychiatric Inventory-Nursing Home version (NPI-NH). Secondary outcomes included cognition using the Mini-Mental State Examination (MMSE) and adverse events. Standardized Mean Differences (SMDs) and Risk Ratios (RRs) were synthesized using random-effects (REML) and Bayesian random-effects models. Risk of bias was evaluated with RoB 2, and certainty of evidence with GRADE.

RESULTS: Nine trials (334 participants) met inclusion criteria. Cannabinoids did not improve CMAI (SMD -0.58, 95% CI -1.71 to 0.55; I2 = 84%), NPI-NH total (SMD -0.02, 95% CI -1.00 to 0.96; I2 = 67%), NPI-NH agitation (SMD -0.44, 95% CI -1.45 to 0.57; I2 = 48%), or MMSE (SMD 0.86, 95% CI -16.33 to 18.06; I2 = 96%). Bayesian posterior estimates were close to zero, supporting the absence of effect. Leave-one-out analyses reduced heterogeneity only after excluding influential trials but did not alter results. Certainty of evidence was moderate for behavioral outcomes and low for cognition. Overall adverse events were similar to placebo, while somnolence was more frequent with cannabinoids (RR 2.03, 95% CI 1.29-3.20).

CONCLUSIONS: Cannabinoid-based therapies do not improve agitation, neuropsychiatric symptoms, or cognition in Alzheimer's disease and increase somnolence.},
}

Humans
*Cannabinoids/therapeutic use/adverse effects
*Dementia/drug therapy/complications
*Psychomotor Agitation/drug therapy

@article {pmid42704522,
year = {2026},
author = {Joshi, A and Salunkhe, J and Ugale, V},
title = {UPS-mediated P-glycoprotein regulation in Alzheimer's disease: pharmacological implications for the amyloid pathology.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42704522},
issn = {1573-4978},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; *ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Blood-Brain Barrier/metabolism ; *Proteasome Endopeptidase Complex/metabolism ; Ubiquitin/metabolism ; Animals ; Oxidative Stress ; Ubiquitination ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid β (Aβ), tau pathology, neuroinflammation, oxidative stress, and neurovascular dysfunction. Growing evidence suggests that impaired clearance of Aβ across the blood-brain barrier (BBB), rather than overproduction alone, is a key factor driving progression of AD. P-glycoprotein (P-gp) plays a crucial role in Aβ removal and is consistently reduced in AD. This review focuses on the mechanisms underlying P-gp dysfunction, particularly its regulation by the ubiquitin-proteasome system. Herein, we have discussed multiple factors associated with the AD, such as Aβ, oxidative stress, and inflammatory signaling, contributing to the phosphorylation, ubiquitination, internalization, and degradation of P-gp. These processes result in impaired transporter function and a compromised integrity of the BBB. The review further examines experimental and clinical evidence linking altered P-gp turnover with defective Aβ clearance in AD.},
}

Humans
*Alzheimer Disease/metabolism/pathology
Amyloid beta-Peptides/metabolism
*ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
Blood-Brain Barrier/metabolism
*Proteasome Endopeptidase Complex/metabolism
Ubiquitin/metabolism
Animals
Oxidative Stress
Ubiquitination

@article {pmid42704561,
year = {2026},
author = {Huang, T and Hao, Z and Shen, J and Lai, T and Wu, Y and Zhu, X and Wu, H and Bao, C},
title = {Microbiota-Gut-Brain Axis Mechanisms in Cognitive Impairment Associated with Central Obesity.},
journal = {Current obesity reports},
volume = {15},
number = {1},
pages = {},
pmid = {42704561},
issn = {2162-4968},
support = {No. 202310268066//Shanghai College Students Innovation and Entrepreneurship Training Program Project/ ; No. SHUTCM2023010//the 16th Batch of Science and Technology Innovation Projects of Shanghai University of Traditional Chinese Medicine/ ; },
mesh = {Humans ; *Obesity, Abdominal/complications/microbiology/psychology/physiopathology ; *Gastrointestinal Microbiome/physiology ; *Cognitive Dysfunction/etiology/microbiology/physiopathology ; *Brain/physiopathology ; Intra-Abdominal Fat ; Risk Factors ; Dysbiosis ; *Brain-Gut Axis ; Animals ; },
abstract = {PURPOSE OF REVIEW: Central obesity (CO), characterized by excessive visceral adipose tissue (VAT) accumulation, is increasingly recognized as a risk factor for cognitive decline, dementia, and Alzheimer's disease (AD). This review summarizes current evidence linking CO, particularly VAT accumulation, to cognitive impairment and discusses the microbiota-gut-brain axis as a mechanistic framework for interpreting this association.

RECENT FINDINGS: Studies published in recent years suggest that VAT-related indices, such as waist circumference, waist-to-hip ratio, and imaging-derived VAT measures, are more closely associated with cognitive dysfunction than body mass index. Recent neuroimaging studies have linked VAT accumulation with brain atrophy, white matter abnormalities, altered functional connectivity, and increased AD-related pathological burden. Emerging multi-omics evidence further indicates that VAT expansion shows an association with gut microbial dysbiosis, altered microbial metabolites, impaired intestinal barrier function, systemic low-grade inflammation, insulin resistance, and neuroendocrine disturbances. These findings support a model in which VAT-related metabolic and inflammatory alterations may influence brain structure and function through microbiota-mediated, immune, endocrine, and barrier-related pathways. Current evidence is consistent with a VAT-centered model in which CO is associated with cognitive impairment through interconnected inflammatory, metabolic, endocrine, and microbiota-mediated mechanisms. The microbiota-gut-brain axis may provide a useful mechanistic framework linking peripheral metabolic dysfunction with AD vulnerability. Future longitudinal cohort studies and mechanistically informed intervention studies are needed to clarify temporal relationships and to determine whether VAT reduction or microbiota-targeted strategies can improve cognitive or neuroimaging outcomes.},
}

Humans
*Obesity, Abdominal/complications/microbiology/psychology/physiopathology
*Gastrointestinal Microbiome/physiology
*Cognitive Dysfunction/etiology/microbiology/physiopathology
*Brain/physiopathology
Intra-Abdominal Fat
Risk Factors
Dysbiosis
*Brain-Gut Axis
Animals

@article {pmid42704803,
year = {2026},
author = {Yang, L and Cui, X and Li, T and Zhang, X and Chang, R and Lu, J and Li, D and Wang, B},
title = {NDIB-Sim: A Multimodal Bidirectional PINN Model for Simulating Brain Dynamics.},
journal = {IEEE transactions on neural networks and learning systems},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TNNLS.2026.3728665},
pmid = {42704803},
issn = {2162-2388},
abstract = {Constructing dynamic virtual brain models is essential for understanding brain functions and pathological mechanisms, crucial in computational neuroscience. Current modeling methods can be grouped into two paradigms: deep learning models for accurate simulation, and neural dynamics models emphasizing physiological interpretability. However, these methods entail a fundamental tradeoff between accuracy and interpretability. To address this challenge, we introduce the neurodynamics-informed brain simulator (NDIB-Sim), a multimodal bidirectional physics-informed neural network (PINN) model. NDIB-Sim is a unified framework integrating a data-driven module constrained by multimodal data and a multiscale neural dynamics mechanism module, jointly optimized under a composite loss function. It contains two data loss and two physical constraint terms. This design ensures that the generated brain signals adhere to fundamental neurophysiological principles while achieving high fidelity to empirical data. We also designed a dynamic weighting strategy to adaptively balance these objectives during optimization. This framework simultaneously addresses the forward problem of predicting long-term brain activity and the inverse problem of estimating individual-specific neurophysiological parameters. Extensive experiments demonstrate that NDIB-Sim can achieve high-fidelity long-term brain activity prediction from short-term observations, with an average functional connectivity similarity above 0.97. The inferred effective connectivity (EC) shows excellent reliability and strong alignment with underlying structural and functional architecture. When applied to Alzheimer's disease (AD) classification, these subject-specific parameters achieve high accuracy in distinguishing cognitively normal (CN) individuals from AD patients. This work presents a powerful computational framework that effectively reconciles mechanistic interpretability with data-driven performance, offering a novel approach for exploring brain dynamics and identifying potential disease biomarkers.},
}

@article {pmid42705087,
year = {2026},
author = {Kong, X and Jiang, H and Hu, B and Shu, Q and Luo, X and Pan, F and Hu, J and Wang, Z},
title = {A signal-locked clamped hybridization chain reaction nanoamplifier for rapid and highly sensitive analysis of Aβ42.},
journal = {Talanta},
volume = {312},
number = {Pt C},
pages = {130596},
doi = {10.1016/j.talanta.2026.130596},
pmid = {42705087},
issn = {1873-3573},
abstract = {Amyloid-beta 42 (Aβ42) is a core biomarker associated with Alzheimer's disease (AD), but accurate quantification of low-abundance plasma Aβ42 remains challenging because of matrix interference, limited assay sensitivity, and time-consuming procedures in conventional methods. Herein, we developed an enzyme-free fluorescence biosensing platform integrating a triple-helix aptamer probe (THAP) with clamped hybridization chain reaction (cHCR), termed T-cHCR, for sensitive Aβ42 analysis. In this system, Aβ42 recognition induces controlled release of a trigger probe from the triplex-locked THAP module, which subsequently initiates a two-hairpin cHCR cascade for low-background signal amplification. Under optimized conditions, the T-cHCR assay exhibited a linear response to Aβ42 from 1 to 1000 pg/mL with a limit of detection of 1.16 pg/mL, showing an 8.1-fold lower LOD than the manufacturer-reported minimum detectable dose of the ELISA kit used in this study. The assay also displayed acceptable specificity, reproducibility, and storage stability. Preliminary analysis of clinical plasma samples showed significantly different Aβ42 levels between AD patients and age-matched healthy controls, supporting the potential of T-cHCR for further validation in plasma AD biomarker analysis. Overall, this integrated THAP-cHCR strategy provides a rapid, enzyme-free, and low-background approach for ultrasensitive plasma Aβ42 detection.},
}

@article {pmid42705121,
year = {2026},
author = {Yang, MT and Temkin-Greener, H and Cai, S},
title = {Pattern of Audio Telehealth Among Medicare Beneficiaries With Alzheimer's Disease and Related Dementias.},
journal = {Journal of the American Medical Directors Association},
volume = {27},
number = {11},
pages = {106471},
doi = {10.1016/j.jamda.2026.106471},
pmid = {42705121},
issn = {1538-9375},
abstract = {OBJECTIVES: The Medicare telehealth expansion increased telehealth use, but the utilization patterns of audio-only telehealth remain unclear among those with Alzheimer's disease and related dementias (ADRDs). We aimed to describe 2020 to 2022 trends in audio-only telehealth utilization and provider specialty and to examine variations in utilization patterns by patient characteristics within the ADRD population.

DESIGN: Cohort study.

SETTING AND PARTICIPANTS: We identified 5,021,632 Medicare beneficiaries with a diagnosis of ADRD enrolled in Medicare fee-for-service plans between 2020 and 2022.

METHODS: Using Medicare fee-for-service claims data from 2020 to 2022, we described the modality of evaluation and management (E&M) visits. We calculated the proportion of E&M visits delivered via telehealth and audio-only and described the provider specialty. To further explore the pattern of telehealth use during the later stages of the pandemic, we used 2022 data to classify telehealth users into audio-only, supplementary, and video-only categories. We examined its association with individual race, ethnicity, socioeconomic status, and rurality using a linear probability model and a multinomial logistic regression. Average marginal effects were estimated.

RESULTS: Overall, E&M telehealth visits among beneficiaries with ADRD declined from 21% in 2020 to 8% in 2022, whereas the audio-only share remained stable at around 20%. Over half of audio-only visits were furnished by primary care providers. Among telehealth users, traditionally underserved populations were significantly more likely to rely exclusively on audio-only visits and less likely to use them as supplemental care. For example, higher adjusted probabilities of exclusive audio-only use were observed among Black individuals (+0.4 percentage points; P < .01) and rural beneficiaries (+0.8 percentage points; P < .01).

CONCLUSIONS AND IMPLICATIONS: Audio-only telehealth services were consistently used by Medicare beneficiaries with ADRD during the study period. Continued coverage for audio-only services could be a potential approach to promote digital health equity for older adults with ADRD.},
}

@article {pmid42705154,
year = {2026},
author = {Li, JN and Zhang, SW and Zhang, TH},
title = {Diagnosis-guided multimodal adversarial graph masked autoencoder network for association analysis between brain imaging and gene expression in Alzheimer's disease.},
journal = {Computer methods and programs in biomedicine},
volume = {287},
number = {},
pages = {109620},
doi = {10.1016/j.cmpb.2026.109620},
pmid = {42705154},
issn = {1872-7565},
abstract = {Identifying the associations between brain imaging and gene expression data is crucial for uncovering potential biomarkers of Alzheimer's disease (AD). Although various methods have been developed for association analysis using imaging genetics data, most rely on single nucleotide polymorphisms (SNPs) that reflect genetic variation, while overlooking gene expression data that reflect the impact of environmental factors on the progression of AD. Moreover, existing imaging-genetics association methods rely on unsupervised learning, thus fail to utilize the diagnostic information related to AD. To address these limitations, we propose a novel diagnosis-guided Multimodal Adversarial Graph Masked Autoencoder network (MAGMA), an end-to-end deep learning framework to integrate functional magnetic resonance imaging (fMRI) and gene expression data for association analysis between brain imaging and gene expression in AD. MAGMA comprises two major components: (1) a multimodal graph representation module, which is designed to extract the diagnosis-guided latent embeddings of brain fMRI and gene expression data by employing two Adversarial Graph Masked Autoencoders (AGMAs) with random feature masking, and the diagnosis information is incorporated to guide the learning of disease-relevant representations; and (2) An association analysis module, which models nonlinear relationships between brain imaging and gene expression data by nonlinearly mapping gene representations to imaging representations. To demonstrate the validity of MAGMA, we conducted experiments on Alzheimer's Disease Neuroimaging Initiative dataset and analyzed the results from diverse perspectives. Experimental results demonstrate that MAGMA can identify potential disease-related biomarkers, many of which are biologically interpretable and supported by existing AD-related studies. These findings suggest that MAGMA may offer new insights into the pathological mechanisms of AD and contribute to its early diagnosis.},
}

@article {pmid42705162,
year = {2026},
author = {Guarneri, L and Beh, C and de Campo, L and Whitten, AE and Moir, M and Hung, A and Clulow, AJ and Conn, CE and van 't Hag, L},
title = {Nanoscale localisation of memantine governs structural modulation and loading in bicontinuous cubic phase systems.},
journal = {Journal of colloid and interface science},
volume = {726},
number = {},
pages = {141405},
doi = {10.1016/j.jcis.2026.141405},
pmid = {42705162},
issn = {1095-7103},
abstract = {Memantine is a primary pharmacological treatment for moderate-to-severe Alzheimer's disease but its efficacy and brain delivery remain limited. Lipid bicontinuous cubic phases and their nanoparticle dispersions (cubosomes) offer platforms for enhancing central nervous system drug delivery, yet the rigid adamantane scaffold of memantine can destabilise lipid organisation. This study resolves how an amphiphilic, adamantane-containing drug interacts with non-lamellar lipid bilayers using monoolein-based bulk cubic mesophases and cubosomes formulated with biomimetic lipid compositions and multiple stabilisers. SAXS revealed that lipid composition primarily governed mesophase structure, while memantine induced only modest structural changes in bulk cubic phases. Following memantine incorporation, cubosomes retained cubic symmetry and colloidal stability across stabilisers, although they were more susceptible than bulk phases to additive-induced disorder, with cryo-TEM showing transitions toward less ordered, lower curvature sponge-like structures. Bulk mesophases exhibited 3-5-fold higher apparent drug retention than nanoparticle dispersions. Under excess hydration, however, even bulk phases released memantine rapidly, losing ∼65% of the drug within 24 h. SANS and molecular dynamics simulations revealed a mobile state of memantine with predominantly interfacial localisation rather than stable burial within the hydrophobic tails, providing a mechanistic explanation for its mesophase-dependent structural effects and its limited retention. These findings show that the adamantane scaffold alone is insufficient to ensure efficient incorporation into cubic phases. Localisation, accommodation, and retention are governed by the balance between hydrophobic anchoring and the hydration demands of attached functionalities, establishing a mechanistic framework for predicting the behaviour of amphiphilic adamantane-containing therapeutics in non-lamellar lipid nanocarriers.},
}

@article {pmid42705844,
year = {2026},
author = {Zhou, Q and Yang, MX and Zhang, QQ and Li, YQ and Wang, ZQ},
title = {Efficacy and Durability of Repetitive Transcranial Magnetic Stimulation on Cognitive Function in Patients With Mild-to-Moderate Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70199},
doi = {10.1111/psyg.70199},
pmid = {42705844},
issn = {1479-8301},
support = {2022ZD0208506//STI 2030-Major Projects/ ; 82201628//National Natural Sciencen Foundation of China/ ; U24A20274//National Natural Sciencen Foundation of China/ ; S23042//SiChuan Province Medical Research Project Program/ ; 513//2024 Annual Specialized Research Project on Traditional Chinese Medicine of SiChuan Provincial Administration of Traditional Chinese Medicine/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; *Transcranial Magnetic Stimulation/methods ; *Cognition/physiology ; Treatment Outcome ; Cognitive Enhancement ; Randomized Controlled Trials as Topic ; Aged ; },
abstract = {Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has shown potential for improving cognitive function in Alzheimer's disease (AD), though findings remain inconsistent. This meta-analysis evaluated the efficacy and durability of rTMS in patients with mild to moderate AD and explored potential moderating factors. Randomised controlled trials (RCTs) comparing active rTMS with sham stimulation were identified through systematic searches of major databases. Effect sizes were calculated using Hedges' g, with random-effects models applied. Risk of bias was assessed using the Cochrane RoB 2 tool. Five RCTs (N = 143) were included in the primary analysis. rTMS showed a small-to-moderate improvement in MMSE scores (g = 0.41, 95% CI [0.06, 0.75], p = 0.021, I[2] = 6.5%). Excluding two studies with methodological concerns yielded a similar effect (g = 0.46), though with wider confidence intervals. Sensitivity analysis including studies with change scores confirmed the robustness of results (g = 0.48). Given the limited number of studies (k < 10), formal publication bias tests and trim-and-fill adjustment were not applied, in line with current methodological guidance. Notably, all five studies employed excitatory stimulation protocols (high-frequency rTMS or iTBS), with four of five targeting the left dorsolateral prefrontal cortex (DLPFC), suggesting that excitatory stimulation of key cognitive network hubs represents the most consistent evidence base to date. Meta-regression identified treatment duration as a significant moderator (β = -0.193, p = 0.034), suggesting shorter, more intensive protocols may be more effective. Follow-up analyses indicated a nonsignificant trend towards sustained benefits (g = 0.25), while time-trend analysis demonstrated a stable overall effect (g = 0.38). In conclusion, rTMS provides modest cognitive benefits in mild to moderate AD, with excitatory protocols targeting the left DLPFC showing the most consistent efficacy and treatment duration influencing outcomes. However, evidence remains limited, highlighting the need for larger, standardised, multi-centre trials with long-term follow-up.},
}

Humans
*Alzheimer Disease/therapy/psychology
*Transcranial Magnetic Stimulation/methods
*Cognition/physiology
Treatment Outcome
Cognitive Enhancement
Randomized Controlled Trials as Topic
Aged

@article {pmid42705860,
year = {2026},
author = {Matsui, H and Omori, Y and Furuta, K},
title = {Improvement in Delusional Jealousy and Caregiver Distress After Switching From Oral Galantamine to a Donepezil Transdermal Patch in Alzheimer's Disease: A Case Report.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70217},
doi = {10.1111/psyg.70217},
pmid = {42705860},
issn = {1479-8301},
mesh = {Humans ; Female ; *Donepezil/administration & dosage ; *Galantamine/administration & dosage/therapeutic use ; *Alzheimer Disease/drug therapy/psychology ; *Caregivers/psychology ; Transdermal Patch ; *Cholinesterase Inhibitors/administration & dosage/therapeutic use ; Aged ; *Jealousy ; *Delusions/psychology/drug therapy ; Middle Aged ; Treatment Outcome ; Administration, Oral ; *Indans/administration & dosage ; Nootropic Agents/administration & dosage ; *Piperidines/administration & dosage ; },
abstract = {BACKGROUND: Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are common and strongly associated with caregiver distress. Switching cholinesterase inhibitors (ChEIs) may be considered when NPS remain clinically problematic. Although switching ChEIs may improve NPS in some patients, published reports describing improvement in delusional jealousy after switching to a donepezil transdermal patch remain limited.

CASE PRESENTATION: We report a woman in her 60s with probable AD who developed caregiver-reported delusional jealousy and near-daily marital conflicts during oral galantamine therapy. NPS were assessed using the caregiver-rated Neuropsychiatric Inventory Questionnaire (NPI-Q) at three time points: prior to initiating galantamine (baseline symptoms were predominantly non-psychotic), immediately prior to switching and 6 months after switching. Total NPI-Q severity increased from 4 to 20 and then decreased to 11; total caregiver distress increased from 3 to 31 and then decreased to 13. After switching from oral galantamine, 16 mg/day, to a donepezil transdermal patch, 27.5 mg/day, improvements in domain-level severity were observed in the delusions domain, driven mainly by reduced caregiver-rated delusional jealousy, as well as in agitation/aggression, disinhibition and irritability/lability. Clinically, the conviction of delusional jealousy gradually diminished with a reduction in conflict frequency; at 6 months, delusional jealousy had almost completely resolved, whereas caregiver-attributed negative self-appraisals (e.g., a persistent belief that she was useless, perceived by the caregiver as delusional) persisted. No psychotropic medications were initiated or dose-adjusted from immediately prior to switching through the 6-month follow-up. Subsequently, the patient became able to attend day care services.

CONCLUSION: This case suggests that switching from oral galantamine to a donepezil transdermal patch may be associated with improvement in delusional jealousy, selected caregiver-rated NPS domains and caregiver distress in some patients, although causal inference is not possible in a single case and responses may vary.},
}

Humans
Female
*Donepezil/administration & dosage
*Galantamine/administration & dosage/therapeutic use
*Alzheimer Disease/drug therapy/psychology
*Caregivers/psychology
Transdermal Patch
*Cholinesterase Inhibitors/administration & dosage/therapeutic use
Aged
*Jealousy
*Delusions/psychology/drug therapy
Middle Aged
Treatment Outcome
Administration, Oral
*Indans/administration & dosage
Nootropic Agents/administration & dosage
*Piperidines/administration & dosage

@article {pmid42706463,
year = {2026},
author = {Hunt, JN and Kortagere, S},
title = {When Pathologies Collide: The Intersection of Tau and Alpha-Synuclein in Neurodegenerative Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42706463},
issn = {1559-1182},
mesh = {*alpha-Synuclein/metabolism ; Humans ; *tau Proteins/metabolism ; *Neurodegenerative Diseases/pathology/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are becoming increasingly prevalent in today's aging population and with significant cost to society. While these diseases were traditionally defined by distinct protein aggregates, namely, tau tangles and amyloid-β (Aβ) plaques in AD and α-synuclein (α-syn) inclusions in PD, substantial evidence reveals frequent mixed pathologies, with tau, α-syn, and Aβ aggregates coexisting in patients. This copathology complicates understanding disease mechanisms, classification, and progression, highlighting the need to examine mixed pathologies in neurodegenerative diseases to develop disease-modifying therapies. The presence of mixed proteinopathies suggests shared or converging pathological mechanisms, including synergistic aggregation, enhanced seeding capabilities, and shared protein-protein interactions. Understanding these molecular mechanisms is essential for identifying disease modifiers and refining experimental models. This review explores the pathogenic mechanisms of α-syn and tau individually, followed by exploration of their molecular interactions and potential mechanisms of coaggregation and exacerbation of pathology. By recognizing the intersection of these pathologies, further research can refine disease classifications for neurodegenerative diseases.},
}

*alpha-Synuclein/metabolism
Humans
*tau Proteins/metabolism
*Neurodegenerative Diseases/pathology/metabolism
Animals
Amyloid beta-Peptides/metabolism

@article {pmid42706500,
year = {2026},
author = {Ding, J and Miao, J and Zhang, L and Liu, Q and Zhang, Y and Li, J and Li, Y},
title = {Cognitive safety of statin use in the elderly: Evidence from a nationally representative sample.},
journal = {Journal of internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1111/joim.70159},
pmid = {42706500},
issn = {1365-2796},
support = {SCYG2025-1//Sichuan Hospital Management and Development Research Center/ ; YF25-Y15//Sichuan Medical and Health Rule of Law Research Center-Chinese Society of Health Law Joint Project/ ; scsyxh202502//Hospital Pharmaceutical Research Funding Project of 'Yue·Stealth' of Sichuan Province Pharmaceutical Association/ ; 26MSZX599//Special Science and Technology Research Project of the Sichuan Province Administration of Traditional Chinese Medicine/ ; 26MSZX601//Special Science and Technology Research Project of the Sichuan Province Administration of Traditional Chinese Medicine/ ; CSXL-26209//Foundation of the Sichuan Research Center of Applied Psychology/ ; MZSJ202602//Mianyang Key Laboratory of Anesthesia and Neuroregulation/ ; 17PJ332//Sichuan Province Health Commission Project/ ; },
abstract = {OBJECTIVE: To systematically evaluate the association between current statin use and global cognitive impairment in US older adults and examine potential variations across treatment intensity, duration, and specific cognitive domains to guide clinical cardiometabolic management.

METHODS: This survey-weighted cross-sectional study included 3137 National Health and Nutrition Examination Survey 2011-2014 participants aged ≥60 years. Cognitive performance across Consortium to Establish a Registry for Alzheimer's Disease, animal fluency, and digit symbol substitution test (DSST) was composite-summarized to define impairment (Z-score ← 1.5 standard deviation). Survey-weighted multivariable models adjusted for sociodemographic, lifestyle, cardiometabolic, psychotropic medication, polypharmacy, and substance-use proxies, supplemented by inverse probability of treatment weighting (IPTW) and multiple imputation.

RESULTS: In the primary fully adjusted model, current statin use was not associated with global cognitive impairment (odds ratio [OR] = 0.90, 95% confidence interval: 0.48-1.67, p = 0.736). Results remained consistent across psychotropic-adjusted (OR = 0.91), IPTW (OR = 1.03), and multiply imputed models (OR = 0.86). Domain-specific analyses showed statin use was associated with lower odds of DSST impairment (OR = 0.51, p = 0.009), with no clear trend across statin intensity or duration categories.

CONCLUSION: Current statin use was not significantly associated with global cognitive impairment in older adults. Although cross-sectional observational neutrality precludes inferring long-term safety, indicated statin therapy should not be routinely withheld over cognitive concerns, with prescribing remaining firmly guided by established atherosclerotic cardiovascular disease risk guidelines.},
}

@article {pmid42706501,
year = {2026},
author = {Chai, L and Huang, Y and Ni, J and Zuo, S and Huang, J and Lin, B},
title = {A meta-refined human Alzheimer's disease-associated gene subset shows partial mouse-model pathway correspondence and limited cross-cohort machine-learning transportability.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71804},
doi = {10.1002/alz.71804},
pmid = {42706501},
issn = {1552-5279},
support = {2023J01876//Natural Science Foundation of Fujian Province/ ; 2025Y9599//Joint Funds for the Innovation of Science and Technology/ ; },
mesh = {*Alzheimer Disease/genetics ; Animals ; Humans ; Mice ; *Disease Models, Animal ; *Machine Learning ; Brain/metabolism/pathology ; Cohort Studies ; },
abstract = {INTRODUCTION: Common Alzheimer's disease (AD) mouse models are widely used, but their molecular correspondence with human AD remains uncertain.

METHODS: We analyzed 15 post mortem human brain datasets, four human non-brain or in vitro sensitivity datasets, and nine AD-related mouse-model molecular-profiling datasets; GSE222494 was analyzed separately for single-nucleus localization. Refined107, a meta-refined 107-gene human AD-associated gene subset, was evaluated using recurrence-matched control sampling, independent pathway-level comparison, within cohort out-of-fold (OOF) classification, and ordered cross-cohort transportability.

RESULTS: Refined107 comprised 37 Tier 1 and 70 Tier 2 genes and showed greater statistical consistency than recurrence-matched controls. Functional annotation implicated inflammatory, blood-brain barrier, metabolic, neuronal, and developmental programs. Among 636 recurrent human pathways, 226 showed same-direction support in at least one evaluated mouse-model family, indicating partial and model-dependent human-mouse correspondence. Post-selection within-cohort OOF areas under the curve (AUCs) were 0.833 to 0.980, whereas ordered cross-cohort AUCs were 0.288 to 0.720.

DISCUSSION: Refined107 represents a statistically consistent, meta-refined human AD-associated gene subset rather than a comprehensive disease signature. Human-mouse pathway correspondence was partial and model-dependent, and within-cohort classification did not translate into robust cross-cohort transportability.},
}

*Alzheimer Disease/genetics
Animals
Humans
Mice
*Disease Models, Animal
*Machine Learning
Brain/metabolism/pathology
Cohort Studies

@article {pmid42706510,
year = {2026},
author = {Ilardi, A and Ilardi, CR},
title = {Thyroid dysfunction: Another piece in the complex puzzle of Alzheimer's disease?.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261485579},
doi = {10.1177/13872877261485579},
pmid = {42706510},
issn = {1875-8908},
abstract = {An expanding body of evidence suggests that thyroid dysfunction may be clinically relevant in Alzheimer's disease (AD), although the significance of this association remains unsettled. Rather than reflecting a single biological pathway, thyroid hormone alterations in AD may involve downstream systemic adaptations related to inflammation and frailty, central dysregulation of thyroid hormone bioavailability and signaling, and upstream vulnerability mechanisms. Clarifying how these pathways intersect with cognitive and functional decline may help refine the biological interpretation of clinical heterogeneity in patients with AD.},
}

@article {pmid42706511,
year = {2026},
author = {Islam, AS and Saif, R and Alghalyini, B and Zia Zaidi, AR},
title = {Epidemiology, risk determinants, and research trends of dementia in Saudi Arabia: A systematic review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261485493},
doi = {10.1177/13872877261485493},
pmid = {42706511},
issn = {1875-8908},
abstract = {BackgroundDementia is an emerging public health priority in Saudi Arabia, driven by population aging and a high prevalence of vascular and metabolic disease. Despite increasing research activity, evidence remains fragmented, limiting understanding of the national burden and determinants of dementia.ObjectiveTo synthesize evidence on dementia epidemiology, risk factors, awareness, comorbidities, caregiving challenges, and research trends in Saudi Arabia.MethodsA systematic review was conducted following PRISMA 2020 guidelines. PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar were searched for studies reporting dementia-related outcomes in Saudi populations. Given heterogeneity in study designs, sampling methods, and diagnostic criteria, findings were narratively synthesized.ResultsFifty-five studies met the inclusion criteria. Alzheimer's disease was the most common dementia subtype. Prevalence estimates among adults aged 60 years and older ranged from 3.8% to 6.3%, reflecting differences in diagnostic approaches and sampling methods. Diabetes and hypertension were the most consistently identified risk factors, while depression and anxiety were also associated with dementia. Public awareness was low, with stigma contributing to delayed recognition and underdiagnosis. Caregiving was family-based and associated with significant burden. Dementia commonly co-occurs with cardiometabolic, neuropsychiatric, and other chronic conditions. Research activity increased after 2020, with over half of the included studies published between 2020 and 2024; however, methodological inconsistencies and limited rural representation remain.ConclusionsDementia research in Saudi Arabia has expanded, yet epidemiological estimates remain inconsistent. Standardized diagnostic practices, enhanced surveillance, and public health strategies addressing risk reduction, awareness, and caregiver support are needed to address the dementia burden.},
}

@article {pmid42706564,
year = {2026},
author = {Zhang, Z and Cao, L and Liu, P and Yang, S and Yan, Y and Kwapong, WR and He, Y and Yang, M and Wang, H and Wang, Y and Feng, Z and Zhou, J and Liu, M and Lei, P and Wu, B and Zhang, S},
title = {Distinct ocular microvascular alterations in Alzheimer's disease and cerebral small vessel disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71809},
doi = {10.1002/alz.71809},
pmid = {42706564},
issn = {1552-5279},
support = {82371210 U24A20690 U25A2073//National Natural Science Foundation of China/ ; ZYGXQNJSKYCXNLZCXM-H14//Scientific Research Innovation Capability Support Project for Young Faculty/ ; 2025B-07-11//Changping Laboratory/ ; 2026NSFSC1623//Sichuan Science and Technology Program/ ; 2023YFC2506603//National Key R&D Program of China/ ; HXQMX0052//Qimingxing Research Fund for Young Talents/ ; 2024HXFH023 ZYYC23016//West China Hospital, Sichuan University/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; *Cerebral Small Vessel Diseases/diagnostic imaging/pathology ; Female ; Cross-Sectional Studies ; Male ; Tomography, Optical Coherence ; Aged ; *Retinal Vessels/diagnostic imaging/pathology ; *Microvessels/pathology/diagnostic imaging ; Aged, 80 and over ; *Choroid/blood supply ; },
abstract = {INTRODUCTION: While both Alzheimer's disease (AD) and cerebral small vessel disease (CSVD) involve vascular dysfunction, the ocular microvascular differences between them remain largely underinvestigated.

METHODS: This cross-sectional study included 650 participants (149 AD, 276 CSVD, and 225 cognitively unimpaired individuals). Optical coherence tomography angiography (OCTA) metrics were analyzed to characterize ocular microvascular alterations.

RESULTS: CSVD patients exhibited a higher burden of retinal ischemic perivascular lesions (RIPLs) than AD patients (all p < 0.05), whereas AD patients showed reduced choriocapillaris (CC) density (p = 0.031). In the CSVD group, RIPLs were associated with total CSVD score (p = 0.049), while reduced CC density was associated with elevated phosphorylated tau 181 in the AD group (p = 0.001). Machine learning models integrating OCTA metrics effectively differentiated AD from CSVD (area under the curve = 0.86).

DISCUSSION: AD and CSVD exhibit distinct ocular microvascular alterations, supporting OCTA-derived measures as potential non-invasive biomarkers.

TRIAL REGISTRATION NUMBER: ChiCTR2000041386.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology
*Cerebral Small Vessel Diseases/diagnostic imaging/pathology
Female
Cross-Sectional Studies
Male
Tomography, Optical Coherence
Aged
*Retinal Vessels/diagnostic imaging/pathology
*Microvessels/pathology/diagnostic imaging
Aged, 80 and over
*Choroid/blood supply

@article {pmid42706570,
year = {2026},
author = {Müller, L and Köhler, C and Lindner, T and Polei, S and Vollmar, B and Weber, MA and Krause, BJ and Kirschstein, T and Porath, K and Engel, N and Teipel, S and Radbruch, A and Deike, K and Kuhla, A},
title = {No evidence of major integrative brain clearance impairment in an Alzheimer´s disease model of transgenic APPswe/PS1dE9 mice.},
journal = {Fluids and barriers of the CNS},
volume = {23},
number = {1},
pages = {},
pmid = {42706570},
issn = {2045-8118},
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics ; Mice, Transgenic ; Disease Models, Animal ; Mice ; *Brain/metabolism/pathology ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Male ; Contrast Media/pharmacokinetics ; Mice, Inbred C57BL ; Plaque, Amyloid/pathology/metabolism ; Microglia/metabolism/pathology ; },
abstract = {BACKGROUND: Brain clearance pathways via the interstitial fluid and cerebrospinal fluid are essential for maintaining homeostasis and removing metabolic waste. Disruptions in these processes are linked to neurodegenerative diseases, particularly Alzheimer's Disease (AD), where an imbalance between amyloid β (Aβ) production and clearance leads to cerebral amyloidosis. Although AD research continues to rely heavily on murine models, including APPswe/PS1dE9 mice, it remains unclear to what extent these models replicate the deficits in brain clearance observed in human AD.

METHODS: We examined AD pathology in transgenic APPswe/PS1dE9 (tg) mice and wildtype (wt) littermates at six, nine and twelve months using immunohistochemistry for Aβ plaques (6E10[+]) and activated microglia (Iba1[+]). To assess integrative parameters contributing to brain clearance, we applied two complementary approaches. First, we performed daytime-dependent intrahippocampal injections of a fluorescent tracer in six-month-old tg and wt mice, followed by histological analysis of tracer dispersion 1 h and 3 h after injection. Second, we present a novel, longitudinal and non-invasive approach utilizing washout kinetics of intravenously administered gadolinium-based contrast agents (GBCA) as an integrative proxy to assess brain clearance dynamics. In this novel approach DOTAREM[®] was administered intravenously and imaging was done with anesthetized tg and wt mice at nine and twelve months of age. Integrity of the blood-brain-barrier was further evaluated via western blot analysis of occludin protein expression.

RESULTS: Despite tg mice displayed characteristic AD-like phenotype, with significant, age-dependent Aβ plaque deposition and neuroinflammation no significant differences in the integrative GBCA washout kinetics were detected between wt and tg mice, suggesting that no major deficits in the combined clearance pathways are present. However, contrast-agent uptake showed a general age-dependent increase consistent with aging-related changes known from human studies.

CONCLUSION: Our findings indicate that the APPswe/PS1dE9 mouse model does not exhibit evidence of major integrative brain clearance impairment, despite this being a hallmark of sporadic AD in humans. These results suggest limitations of this model for studying clearance-related mechanisms of late-onset AD, which should be acknowledged when planning future studies using this murine model.},
}

Animals
*Alzheimer Disease/metabolism/pathology/genetics
Mice, Transgenic
Disease Models, Animal
Mice
*Brain/metabolism/pathology
Amyloid beta-Protein Precursor/genetics
Presenilin-1/genetics
Male
Contrast Media/pharmacokinetics
Mice, Inbred C57BL
Plaque, Amyloid/pathology/metabolism
Microglia/metabolism/pathology

@article {pmid42706593,
year = {2026},
author = {Engelmann, GTO and de Alvarenga, JC and Moro, GCP and Bolaños Burgos, IC and Miranda, MF and Miranda, MF and de Souza, AS and Saldanha, MF and Hansen, EO and Dias, NS and da Cunha Cintra, FCM and Dias, BF and da Silva Souza, AL and Carvalho, AT and Martino-Adami, PV and Cintra, MTG and Labanca, L and Lanna, IN and de Ávila, RT and de Paula, JJ and Costa-Silva, L and Freitas Rosa, DV and de Miranda, DM and Romano-Silva, MA and de Marco, LAC and Ramírez, A and de Mattos Viana, B and Camargos Bicalho, MA},
title = {The Cog-Aging: a 15-year cohort study of cognition in Brazilian older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71780},
doi = {10.1002/alz.71780},
pmid = {42706593},
issn = {1552-5279},
support = {436735/2018-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/ ; 309953/2018-9//Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/ ; 315133/2021-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/ ; 406016/2025-9//Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/ ; 313895/2026-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/ ; 406935/2022-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) through the National Institute of Science and Technology in Responsible Neurotechnology (INCT NeuroTec-R)/ ; 88887.569376/2020-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)/ ; APQ-02662-14//Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)/ ; APQ-02465-23//Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)/ ; APQ-04706-10//Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)/ ; },
mesh = {Humans ; Brazil/epidemiology ; Male ; Female ; Aged ; *Cognitive Dysfunction/epidemiology ; Longitudinal Studies ; Disease Progression ; *Dementia/epidemiology ; Incidence ; *Aging ; Cohort Studies ; Aged, 80 and over ; *Cognition/physiology ; *Alzheimer Disease/epidemiology ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Prevalence of dementia is higher in low- and middle-income countries (LMICs). However, longitudinal studies characterizing cognitive decline and its clinical and epidemiological predictors remain scarce in Brazil.

METHODS: Participants were enrolled from 2011 to 2025 and followed through May 2026. A total of 887 participants were classified as cognitively unimpaired (CU) (n = 274), mild cognitive impairment (MCI) (n = 378), or dementia of the Alzheimer's type (DAT) (n = 235). CU and MCI participants were followed until dementia conversion, which was analyzed under competing risks using cumulative incidence functions and Fine-Gray models.

RESULTS: Overall, annualized dementia conversion rate in the MCI group was 10.72 per 100 person-years (95% confidence interval [CI]: 8.54% to 13.29%). In addition, 40.39% of participants progressed to dementia during a mean follow-up time of 3.75 years (standard deviation: 3.28), with an estimated cumulative incidence of 29.85% at 3 years (95% CI: 22.74% to 36.96%), accounting for death as a competing event.

DISCUSSION: This study adds valuable information for LMICs. However, estimates should be interpreted considering attrition and competing mortality.},
}

Humans
Brazil/epidemiology
Male
Female
Aged
*Cognitive Dysfunction/epidemiology
Longitudinal Studies
Disease Progression
*Dementia/epidemiology
Incidence
*Aging
Cohort Studies
Aged, 80 and over
*Cognition/physiology
*Alzheimer Disease/epidemiology
Neuropsychological Tests

@article {pmid42706797,
year = {2026},
author = {Ye, YF and Deng, C and Ge, XF and Zhang, R and Long, JL and Jia, JX and Ye, HY and Li, CJ and Cai, X and Witter, MP and Lu, L},
title = {Regional and laminar organization of the entorhinal cortex in tree shrews based on cytoarchitecture, chemoarchitecture, and connectivity.},
journal = {Zoological research},
volume = {47},
number = {5},
pages = {1714-1736},
doi = {10.24272/j.issn.2095-8137.2025.618},
pmid = {42706797},
issn = {2095-8137},
mesh = {Animals ; *Entorhinal Cortex/anatomy & histology/physiology/cytology ; *Tupaiidae/anatomy & histology/physiology ; *Tupaia/anatomy & histology ; },
abstract = {The entorhinal cortex (EC) is a pivotal interface that integrates multimodal cortical and subcortical information into the hippocampal formation and distributes hippocampal output to widespread telencephalic targets. It is also one of the earliest and most severely affected regions in Alzheimer's disease (AD). The tree shrew (Tupaia belangeri chinensis) has emerged as a promising model for AD research. However, the uncharted organization of tree shrew EC has limited its application in modeling early stages of AD. In this study, we provide a comprehensive anatomical reference for the tree shrew EC by delineating its boundaries, parcellating its medial and lateral subregions, and mapping its laminar connectivity based on cyto- and chemoarchitecture combined with tracing experiments. We found that the tree shrew EC exhibits an intermediate architecture between rodents and monkeys, mirroring its phylogenetic position and potentially links to the gradual evolution of place codes from rodents to primates. This study provides the first detailed entorhinal atlas of this species, establishing a critical foundation for future neural-tracing and electrophysiological investigations. It enhances the utility of the tree shrew in mechanistic studies of spatial coding and conscious memory, as well as a naturalistic model for incipient AD.},
}

Animals
*Entorhinal Cortex/anatomy & histology/physiology/cytology
*Tupaiidae/anatomy & histology/physiology
*Tupaia/anatomy & histology

@article {pmid42706972,
year = {2026},
author = {Yu, X and Yi, Y and Liu, X and Zhao, C and Li, C and Shang, Y and He, K and Zhai, Y},
title = {Scutellaria Barbata Flavonoids Mitigate Alzheimer's Disease-related Aβ25-35 Toxicity in N2a Cells through CREB Phosphorylation.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673438931260822121059},
pmid = {42706972},
issn = {1875-533X},
abstract = {BACKGROUND: Mouse neuroblastoma cells (N2a) are spontaneously derived from mice and possess the characteristics of neural stem cells. The proliferation, differentiation, and protrusion growth of N2a cells in vitro are consistent with those in vivo. Flavonoids isolated from the aerial parts of Scutellaria barbata (SBFs) can improve learning and memory deficits and protect against neuronal injury in many in vivo AD-- like models. N2a cells exposed to Aβ25-35 for Alzheimer's disease-related toxicity were subsequently used to observe the ameliorative effects of SBFs, and the effective mechanism through which SBFs promote the phosphorylation of CREB was further studied by using BI-D1870, an indirect inhibitor, and Rolipram, an activator of CREB phosphorylation.

METHODS: Immunofluorescence (IF) was used to detect the protein expression of the neuron-specific proteins NeuN, NeuroD1, and DCX. N2a cells were exposed to 100 μM Aβ25-35 and treated with SBFs at doses of 17.5, 35 and 75 mg·L-1 or 363 μM Rolipram. Cell morphology was observed under an inverted microscope, the cell survival rate was detected by the Cell Counting Kit-8 (CCK-8) method, and the release of lactate dehydrogenase (LDH) into the cell culture medium was determined by the pyruvate reduction method. The mRNA expression levels of ERK, RSK, CREB, and EGR-1 in cells were detected by real-time quantitative polymerase chain reaction (qPCR). IF and/or western blotting (WB) were used to measure the protein expression levels of BDNF, NGF, TrkB, Ras, ERK/p-ERK, Rsk/p90RSK, CREB/p-CREB-Ser133, and EGR-1 in N2a cells.

RESULTS: NeuN, NeuroD1, and DCX expression in N2a cells was positive, as indicated by green fluorescence. Both Aβ25-35 and BI-D1870 resulted in abnormal morphological changes in N2a cells, reduced the cell survival rate (P<0.01), increased the release of LDH (P<0.01) into the culture medium, and decreased the mRNA expression levels of ERK, RSK, and CREB and the protein expression levels of p-ERK, TrkB, p90RSK, pCreb-SER133, BDNF, NGF and EGR-1 (P<0.01) in cells. However, SBFs, to varying degrees, reversed the aforementioned abnormal changes in N2a cells caused by Aβ25-35 or BI-D1870, and the effects of SBFs were consistent with those of Rolipram.

CONCLUSION: SBFs protected against N2a cell damage induced by toxic Aβ25-35, and the effective mechanism by which SBFs promote the phosphorylation of CREB at the Ser133 site was confirmed through the application of the indirect CREB phosphorylation inhibitor BI-D1870 and the activator Rolipram. These findings suggest that SBFs may be helpful in the treatment of AD by intervening in CREB phosphorylation.},
}

@article {pmid42706977,
year = {2026},
author = {Saxena, B and Sisodiya, N and Khabiya, R and Pandit, A and Rajput, MS and Gupta, R},
title = {AI-Driven Precision Medicine in Alzheimer's Disease: Drug Repurposing, Digital Therapeutics and Clinical Decision Support.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128478269260818075055},
pmid = {42706977},
issn = {1873-4286},
abstract = {Alzheimer's Disease (AD) is a neurodegenerative disease that causes significant clinical, social, and economic burden worldwide. Despite improvements in understanding its multifaceted pathogenesis, current treatments are mostly symptomatic and ineffective across varied patient populations. To overcome these constraints, AI-driven precision medicine allows tailored risk assessment, treatment selection, and disease monitoring. This review covers AI's role in AD precision medicine, focusing on drug repurposing, digital therapies and clinical decision support systems. Machine and deep learning models are used to predict medication response, integrate heterogeneous data sources such as genomics, transcriptomics, neuroimaging and electronic health records, and uncover pharmacogenomic treatment success factors. The paper covers AIenabled precision pharmacology, including tailored dosing algorithms, adaptive therapeutic monitoring, and adverse drug reaction prediction. Bioinformatics-based target identification, network pharmacology, graphbased AI models, virtual screening, and real-world and clinical data validation are emphasized in AI-driven medication repurposing. AI-powered digital treatments like personalized cognitive training platforms, wearable- derived digital biomarkers, virtual and mixed reality interventions, adherence monitoring, and digital twins for therapy optimization have been discussed. AI-based clinical decision support systems are also thoroughly assessed for clinical value, accuracy, and explainability in disease subtyping, trajectory prediction, and risk stratification in preclinical and prodromal AD. Despite these promises, data heterogeneity, algorithmic bias, legal barriers, and privacy concerns exist. Federated learning enables safe multi-center collaboration and hybrid AI-human approaches, and it represents the future. AI's ability to alter AD care opens the door to precision medicine paradigms that use repurposed medications, digital tools and intelligent decision-making to improve patient outcomes.},
}

@article {pmid42706981,
year = {2026},
author = {Gou, KJ and Chen, Y and Sheng, Z and Yu, W and Wang, L and Lü, Y},
title = {Psychotropic Polypharmacy in Alzheimer's Disease: A Potentially Inappropriate Medication Perspective in Older Adults.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050502495260812063626},
pmid = {42706981},
issn = {1875-5828},
abstract = {Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD). Consequently, potentially inappropriate medication (PIM) use is particularly common among older adults with AD. Psychotropic polypharmacy may increase the risk of various adverse outcomes beyond cognitive decline. Although geriatric prescribing criteria and dementia-care guidelines offer important safety recommendations, a clinically integrated framework for potentially inappropriate psychotropic medication use in older adults with AD remains insufficiently developed. This article is a narrative review rather than a systematic review or meta-analysis. The authors searched the literature in PubMed, Embase, and the Cochrane Library, focusing on studies, guidelines, consensus statements, regulatory safety warnings, and medication-safety criteria published between January 2015 and June 2026. This review specifically examines anticholinergic drugs, antipsychotics, benzodiazepines and Z-drugs, tricyclic antidepressants, and select newer antidepressants-including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), mirtazapine, trazodone, and paroxetine-guided by the 2023 American Geriatrics Society (AGS) Beers Criteria®. Current evidence indicates that these medications may contribute to cognitive decline through anticholinergic burden, sedation, and pharmacodynamic interactions with cholinesterase inhibitors, such as donepezil and memantine. However, the strength of evidence varies considerably across drug classes and study designs, ranging from randomized controlled trials to observational studies and expert consensus. This study also summarizes current nonpharmacological strategies and proposes a structured clinical medication review framework. Overall, this review highlights the importance of minimizing inappropriate psychotropic use in AD, prioritizing non-pharmacological interventions, and conducting individualized risk-benefit assessments in clinical practice.},
}

@article {pmid42706996,
year = {2026},
author = {O'Shea, DM and Wang, L and Lukacsovich, D and Zhang, W and Galvin, JE},
title = {A blood DNA methylation marker of cognitive ability is associated with six-year cognitive performance independent of blood Alzheimer's disease biomarkers.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag222},
pmid = {42706996},
issn = {1758-535X},
abstract = {MethylCog is a 29-CpG blood DNA methylation (DNAm) score developed to index general cognitive ability (g). Whether it captures cognition-related information associated with later cognitive performance that is not fully represented by blood-based biomarkers of Alzheimer's disease and related dementias (ADRD) remains unclear. Using the held-out Health and Retirement Study Harmonized Cognitive Assessment Protocol (HRS-HCAP) test set from the original MethylCog study (N = 605), we examined associations with baseline g after adjustment for age, sex, education, apolipoprotein E (APOE) ε4 carrier status, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), phosphorylated tau 181 (p-tau181), and amyloid-β 42/40 ratio (Aβ42/40). Prospective associations with six-year follow-up g were examined after adjustment for baseline g, age, sex, education, and APOE ε4 carrier status, with additional adjustment for the ADRD biomarker panel. MethylCog remained associated with baseline g in the fully adjusted cross-sectional model (standardized β=.178, 95% CI: .111-.244, p<.001; ΔAdjR[2]=.025). MethylCog was also associated with six-year follow-up g after adjustment for baseline g and all covariates and biomarkers (standardized β=.101, 95% CI: .033-.170, p=.004; N = 331; ΔAdjR[2]=.007). Findings were similar among participants without baseline cognitive impairment. These findings provide preliminary evidence that a cognition-trained DNAm signature captures variation in later cognitive performance not fully represented by baseline cognition or available ADRD blood biomarkers.},
}

@article {pmid42707167,
year = {2026},
author = {Zhao, K and Dai, S and Zhang, Y and Liu, G and Gu, P and Lin, C and Thompson, PM and Leow, A and Huang, H and He, L and Zhan, L and Tang, H},
title = {Interpretable multimodal learning for integrating neuroimaging and genetic data in Alzheimer's disease.},
journal = {Frontiers in radiology},
volume = {6},
number = {},
pages = {1912277},
pmid = {42707167},
issn = {2673-8740},
abstract = {INTRODUCTION: Early detection of Alzheimer's disease (AD) requires models that combine brain structure changes with genetic risk, but existing methods struggle to align these different data types.

METHODS: We present R-GenIMA, an interpretable multimodal large language model that pairs a region-of-interest vision transformer with genetic prompting to jointly analyze structural MRI and single nucleotide polymorphisms (SNPs). Each brain region becomes a visual token and SNP profiles are encoded as structured text, letting the model link regional atrophy to genetic factors through cross-modal attention. Tested on the ADNI cohort, R-GenIMA performs well in classifying four groups: normal cognition, subjective memory concerns, mild cognitive impairment, and AD.

RESULTS: Beyond accuracy, it produces biologically meaningful explanations, identifying stage-specific brain regions and genes. The model consistently highlighted known AD risk genes (APOE, BIN1, CLU, RBFOX1) and revealed stage-specific patterns: striatal involvement in subjective decline, frontotemporal changes in early impairment, and broad network disruption in AD.

DISCUSSION: These results show that interpretable multimodal AI can integrate imaging and genetics to reveal disease mechanisms, providing a foundation for clinical tools that enable earlier risk assessment and inform precision treatment in Alzheimer's disease.},
}

@article {pmid42707241,
year = {2026},
author = {Mize, KD and Hage, D and Gonzalez, S and Hage, B},
title = {Complex atypical caregiving: navigating the margins of unique caregiver roles and burdens.},
journal = {Frontiers in psychology},
volume = {17},
number = {},
pages = {1819388},
pmid = {42707241},
issn = {1664-1078},
abstract = {The incidence and prevalence of Alzheimer's disease and related dementias (ADRDs) significantly impact care recipients, caregivers, and broader society. Most caregivers of ADRD care recipients are family members. These informal caregivers often experience health, emotional, and practical difficulties in their roles as informal caregivers of loved ones with ADRDs. Most family caregivers are adult children or spouses of ADRD care recipients. Complex atypical caregiver roles may include role reversal, unique caregiving dynamics, or multiple roles. For example, these roles may include a minor child taking care of their parent with a young onset condition, someone with an ADRD diagnosis also taking care of their loved one with a similar condition, or a parent taking care of their child with a neurodegenerative condition that would more typically involve the child taking care of the parent. This perspective format manuscript will discuss unique atypical caregiver roles with emphasis on common challenges experienced by this unique caregiver group and potential for resilience. Recommendations will include exploration of opportunities to increase attention to the topic of atypical caregiver roles, improve clinical practice strategies, and promote additional research focused on complex atypical caregivers and the individuals with ADRDs.},
}

@article {pmid42707243,
year = {2026},
author = {Pappafava, F and Gaetani, L and Ottaviani, MM and Fiorucci, G and Nardi, G and Salvadori, N and Megaro, A and Paolini Paoletti, F and Parnetti, L and Conti, C},
title = {Cerebrospinal fluid and plasma biomarkers in idiopathic normal pressure hydrocephalus: comparison with Alzheimer's and Parkinson's diseases.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1866009},
pmid = {42707243},
issn = {1663-4365},
abstract = {BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disorder whose diagnosis is complicated by clinical overlap with neurodegenerative diseases. Fluid biomarkers may provide insight into disease mechanisms and support differential diagnosis.

METHODS: We performed a small exploratory study at the Neurology and Neurosurgery Sections of the University Hospital of Perugia, between 2024 and 2025, comparing cerebrospinal fluid (CSF) and plasma biomarkers among patients with iNPH, Alzheimer's disease (AD), Parkinson's disease (PD), and non-neurodegenerative controls (CTRL). CSF concentrations of amyloid-β peptides (Aβ42, Aβ40, Aβ42/Aβ40 ratio), tau proteins (p-tau 181 and t-tau) and neurofilament light chain (NfL) were measured. In plasma, amyloid-β peptides (Aβ42, Aβ40, Aβ42/Aβ40 ratio), tau proteins (p-tau 217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were assessed. Both CSF and plasma biomarkers were measured using standardized immunoassays. Group differences and correlations between CSF and plasma biomarkers were analyzed.

RESULTS: CSF Aβ40 levels were significantly lower in iNPH compared with all other groups (all p < 0.005), and showed preliminary apparent discrimination for iNPH, requiring external validation, with an AUC of 0.95, sensitivity of 95%, and specificity of 86% at a cut-off of 9,327.5 pg/mL. AD patients were clearly distinguished from iNPH and the other groups by AD-specific changes in fluid biomarkers. CSF Aβ42 levels were lower in iNPH than in CTRL (p = 0.001) and PD (p = 0.009), while CSF p-tau181 and t-tau were decreased compared with AD (p < 0.001) and CTRL (p ≤ 0.024). The CSF Aβ42/Aβ40 ratio remained preserved in iNPH, distinguishing it from AD (p < 0.001).Plasma NfL correlated strongly with CSF levels in each diagnostic group, including iNPH (r = 0.77, p = 0.0012), whereas plasma amyloid biomarkers poorly reflected CSF concentrations.

CONCLUSIONS: iNPH is associated with low CSF Aβ40 levels, possibly reflecting altered CSF dynamics rather than a primary pathophysiological mechanism. In iNPH, plasma NfL showed a preliminary correlation with CSF NfL; however, larger age-adjusted studies are required before peripheral markers can be considered clinically informative in this setting.},
}

@article {pmid42707257,
year = {2026},
author = {Mateen, N and Kaleem Ullah, RM and Baik, J and Hong, KS and Kang, MK and Kim, CS and Shin, YI},
title = {Target-level convergence of directional prefrontal connectivity across Alzheimer's disease stages: an fNIRS study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1834253},
pmid = {42707257},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly recognized as involving network-level dysfunction rather than isolated regional impairment. Although functional and effective connectivity have been studied in dementia, the reorganization of directional information flow within prefrontal networks remains incompletely characterized, particularly with functional near-infrared spectroscopy (fNIRS).

OBJECTIVE: This study investigated whether target-level convergence of directional effective connectivity within the prefrontal cortex differs across clinically defined cognitive groups, with emphasis on the mild cognitive impairment (MCI) vs. AD contrast.

METHODS: fNIRS signals were recorded from 60 participants (healthy controls (HC), MCI, and AD) during resting state and cognitive paradigms, including working memory (2-back), semantic verbal fluency (SVFT), and Stroop tasks. Signals from 48 prefrontal channels were aggregated into eight anatomically defined regions. Directional interactions were quantified using transfer entropy (TE) with adaptive hyperparameter tuning. Group differences were assessed using linear mixed-effects models with covariate adjustment and target-wise false discovery rate correction. Robustness was evaluated through parameter sensitivity, covariate, and surrogate-normalization analyses.

RESULTS: The analysis revealed structured target-level convergence patterns of directional connectivity across clinically defined cognitive groups, with the most prominent alterations observed in the MCI vs. AD comparison. Compared with MCI, AD showed reduced directed information flow to the right frontopolar cortex (FPC-R) during the 2-back and SVFT tasks (β = -0.71 to -1.18, q < 0.05), indicating diminished convergence of inputs from distributed prefrontal regions. Conversely, convergence toward the left dorsolateral prefrontal cortex (DLPFC-L) increased across multiple paradigms (β = 0.56-0.85, q < 0.05). Additional task-specific alterations were observed during the Stroop paradigm, although some effects demonstrated reduced stability in sensitivity analyses. Exploratory ROC analysis suggested contrast-specific discriminative utility of selected convergence features, with moderate performance in MCI vs. AD (AUC ≈ 0.77).

CONCLUSION: These findings suggest that MCI and AD are associated with distinct patterns of directional information flow within prefrontal networks, characterized by reduced convergence toward FPC-R and increased directional influence toward DLPFC-L. Collectively, the results indicate that TE applied to task-based fNIRS can capture directional alterations in network connectivity, highlighting the potential of directional connectivity metrics for studying network-level changes associated with cognitive decline.},
}

@article {pmid42707288,
year = {2026},
author = {Chen, L and Wang, B and Li, T and Li, N and Chen, X and Liu, F and Lv, T},
title = {Group mindfulness-based cognitive therapy associated with reduced professional caregiver burden and improved quality of care in dementia: a multi-method study.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1880966},
pmid = {42707288},
issn = {1664-2295},
mesh = {Humans ; *Mindfulness/methods ; *Dementia/therapy/psychology ; Female ; Male ; *Caregivers/psychology ; Retrospective Studies ; *Cognitive Behavioral Therapy/methods ; Middle Aged ; Aged ; Stress, Psychological/psychology/therapy ; *Psychotherapy, Group/methods ; *Caregiver Burden/psychology/therapy ; Cost of Illness ; *Quality of Health Care ; },
abstract = {PURPOSE: To evaluate the association between an 8-week group Mindfulness-Based Cognitive Therapy (MBCT) program and changes in professional dementia caregiver burden, perceived stress, and patient neuropsychiatric symptoms.

METHODS: This retrospective multi-method study included 94 professional dementia caregivers at a psychiatric hospital in China (intervention: n = 48; control: n = 46). The intervention group participated in an 8-week group MBCT program, while the control group received routine education. Caregiver burden (Neuropsychiatric Inventory Caregiver Distress Scale [NPI-D]), perceived stress (Perceived Stress Scale-10 [PSS-10]), and patient symptoms (Brief Psychiatric Rating Scale [BPRS], Behavioral Pathology in Alzheimer's Disease Rating Scale [BEHAVE-AD], Neuropsychiatric Inventory [NPI]) were assessed at baseline and five follow-up points over 20 weeks. Semi-structured interviews with 18 intervention participants explored perceived intervention mechanisms. Quantitative data were analyzed using repeated measures ANOVA; qualitative data were analyzed using reflexive thematic analysis.

RESULTS: The intervention group demonstrated significantly greater reductions in caregiver burden (NPI-D: from 32.15 ± 8.53 to 19.90 ± 5.71) and perceived stress (PSS-10: from 23.83 ± 4.23 to 16.82 ± 3.94) compared to the control group from week 8 through week 20 (all p < 0.001). Significant group × time interactions were observed for BPRS (F = 2.682, p = 0.021), BEHAVE-AD (F = 2.747, p = 0.018), and NPI severity (F = 2.353, p = 0.040), with patient improvements emerging at week 12, independent of antipsychotic medication adjustments. Correlation analysis revealed positive associations between caregiver burden reduction and patient symptom improvement (r = 0.36-0.44, all p < 0.001). Qualitative findings identified five themes: development of mindful awareness, cognitive reappraisal of patient behaviors, cultivation of self-compassion, value of group support, and barriers and facilitators to sustained practice.

CONCLUSION: The 8-week group MBCT program was associated with sustained reductions in caregiver burden and perceived stress, accompanied by improvements in patient neuropsychiatric symptoms among professional dementia caregivers. The group format provided additional perceived benefits through peer support and experience normalization. These findings support further investigation of group-based mindfulness interventions within professional dementia care settings using randomized controlled designs.},
}

Humans
*Mindfulness/methods
*Dementia/therapy/psychology
Female
Male
*Caregivers/psychology
Retrospective Studies
*Cognitive Behavioral Therapy/methods
Middle Aged
Aged
Stress, Psychological/psychology/therapy
*Psychotherapy, Group/methods
*Caregiver Burden/psychology/therapy
Cost of Illness
*Quality of Health Care

@article {pmid42707409,
year = {2026},
author = {Niño-Rivero, S and Blanco, E and Rodríguez-Canclini, V and Morelli, L and Lagos, P and Galeano, P},
title = {Tracing melanin-concentrating hormone function: decades of memory research and emerging links to Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1918594},
pmid = {42707409},
issn = {1662-4548},
abstract = {Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide classically implicated in the regulation of energy homeostasis, sleep-wake cycle and motivated behaviors. Over the last 30 years, an increasing amount of evidence has revealed a complex, non-linear role in memory processing. In this mini-review, we summarize experimental findings on the multifaceted influence of MCH on memory, highlighting how this neuropeptide can promote consolidation by improving synaptic efficacy, induce the forgetting of hippocampus-dependent memories during REM sleep or negatively regulate memory formation. We also discuss emerging evidence linking MCH dysregulation to the pathophysiology of Alzheimer's disease (AD). Early interest in MCH as a cerebrospinal fluid biomarker has been superseded by non-invasive blood assays. Recent data, however, suggest therapeutic potential and a unique pathological vulnerability. While emerging evidence suggests MCH somata may show early resilience, their axonal projections are severely compromised by amyloid pathology. Ultimately, tau pathology appears to drive late-stage somatic degeneration and reduced activation during REM sleep. Importantly, activating surviving MCH neurons has been shown to restore sleep architecture in preclinical models, offering a potential therapeutic target for sleep disturbances. In conclusion, decades of basic memory research together with human and preclinical studies identify the MCH system as an important neuromodulatory network for understanding the memory and sleep alterations characteristic of AD.},
}

@article {pmid42707439,
year = {2026},
author = {Liang, J and Yu, P and You, Q and Yang, K},
title = {The association between hearing loss in adults and cognitive outcomes: an umbrella review and meta-analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1852163},
pmid = {42707439},
issn = {1663-4365},
abstract = {PURPOSE: Hearing loss (HL) has been increasingly recognized as a potential risk factor for cognitive decline and dementia. However, findings from existing meta-analyses remain heterogeneous. This umbrella review aimed to comprehensively synthesize current meta-analytic evidence on the association between adult hearing loss and cognitive outcomes.

METHODS: PubMed, Embase, Web of Science, and the Cochrane Library were systematically searched from inception to 9 January 2026. Systematic reviews with meta-analyses examining the relationship between hearing loss and cognitive outcomes in adults were included. Methodological quality was assessed using AMSTAR-2. Evidence credibility was evaluated using the Ioannidis classification framework, and certainty of evidence was assessed using the GRADE approach. Overlap among primary studies across meta-analyses was quantified using the corrected covered area (CCA).

RESULTS: Nine meta-analyses were included. Hearing loss was significantly associated with increased risk of cognitive impairment (OR = 1.34, 95% CI: 1.17-1.53) and dementia (OR = 1.43, 95% CI: 1.21-1.68). In older adults, the associations were slightly stronger. Hearing loss was also associated with higher risk of Alzheimer's disease (OR = 1.66, 95% CI: 1.33-2.07). Evidence credibility was classified as highly suggestive for cognitive impairment and dementia.

CONCLUSION: Adult hearing loss is significantly associated with increased risks of cognitive impairment and dementia. These findings highlight the importance of hearing health in cognitive aging and support further prospective and interventional studies.},
}

@article {pmid42707600,
year = {2026},
author = {Zhang, Z and Lu, Y and Yang, J and Li, M and Yang, M and Xu, Y and Ullah, MS and Wan, Q and Bao, B and Yu, W and Liu, X},
title = {Neurotoxic mechanisms of cadmium in neurodegenerative diseases.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1899381},
pmid = {42707600},
issn = {2296-634X},
abstract = {Cadmium (Cd) is a highly toxic, bioaccumulative heavy metal increasingly implicated in the pathogenesis of neurodegenerative disorders. This review systemically characterizes the molecular mechanisms underlying Cd-induced neurotoxicity, with particular emphasis on oxidative stress-mediated pathways that initiate interconnected processes including ferroptosis, mitochondrial impairment, disruption of calcium homeostasis, and chronic neuroinflammation. Evidence indicates that Cd exerts both convergent and disease-specific effects in neurodegenerative conditions. In Alzheimer's disease (AD), Cd exposure has been associated with enhanced amyloid-β (Aβ) deposition and increased tau hyperphosphorylation. In Parkinson's disease (PD), Cd disrupts metabolic homeostasis via the gut-liver-brain axis and promotes aberrant conformational changes and aggregation of α-synuclein (α-Syn). Within the amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) spectrum, Cd contributes to TDP-43 proteinopathy and impairs nucleocytoplasmic transport mechanisms. Therapeutic strategies targeting Cd-induced neurotoxicity are also explored, including upstream approaches like metal chelation and downstream interventions aimed at restoring autophagic flux, modulating the neuroimmune microenvironment, and enhancing neuronal repair. Although emerging platforms such as brain organoids provide valuable mechanistic insights, translating findings from in vitro models to real-world chronic exposure scenarios remains a significant challenge. This review provides a comprehensive framework for the development of early-warning systems and precision-based interventions for Cd-related neurodegeneration.},
}

@article {pmid42707818,
year = {2026},
author = {Roux, CM and Krantic, S},
title = {Update on sex-specific microglia contribution to early synaptic dysfunction in Alzheimer's disease.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1905780},
pmid = {42707818},
issn = {1662-5099},
abstract = {Women are twice as likely to develop Alzheimer's disease (AD) as men. Despite substantial progress in understanding the pathogenesis of sporadic AD, sex-specific mechanisms remain insufficiently explored, and preclinical research has historically been biased toward male subjects. Furthermore, there is often a delay of more than 10 years between the onset of neuropathological changes and clinical diagnosis. This latent pre-symptomatic period, during which pathological alterations may still be reversible, represents a promising window for therapeutic intervention. In this context, synaptic dysfunction and neuroinflammatory alterations are among the earliest detectable AD-associated impairments and have recently emerged as promising therapeutic targets. This mini-review summarizes the currently limited knowledge on sex-related differences in synaptic functions during pre-symptomatic stage of AD pathology in both pre-clinical and clinical studies. We further position sex as a critical biological variable impacting neuronal activity, either directly or indirectly through microglia-neuron crosstalk. Finally, we emphasize the importance and rationale for integrating sex-specific neuroimmune mechanisms into early-stage research to guide design of targeted, sex-tailored therapeutic strategies that modulate neuron-microglia interactions before clinical onset.},
}

@article {pmid42708265,
year = {2026},
author = {Verma, R and Agarwal, U and Chauhan, B and Singh, H and Mishra, AK and Kumar, N and Kumar, A},
title = {Vanillin and its Derivatives: Therapeutic Strategies in Modern Medicine.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575461522260820050915},
pmid = {42708265},
issn = {1875-5607},
abstract = {INTRODUCTION: Vanillin, a phenolic aldehyde, is the primary component of the vanilla bean's ethanolic extract. Synthetic vanillin is now more commonly used as a flavoring in foods, beverages, and pharmaceuticals. Natural vanilla extract consists of several hundred derivatives, while artificial vanilla flavoring is often a synthetic ethanol solution of pure vanillin. The first commercial synthesis of vanillin began with eugenol, and today, it is made from guaiacol or lignin.

METHODS: This narrative review aggregates and critically assesses available literature on vanillin and its synthetic derivatives. A thorough literature review was conducted using prominent scientific databases, including PubMed, Scopus, Web of Science, and Google Scholar, covering papers from 2000 to 2024, with a specific focus on recent research. Experimental and review studies concerning the synthesis, structural changes, pharmacological activities, toxicological features, and structure- activity connections of vanillin and its derivatives were systematically examined and analyzed. The review emphasizes the biological evaluations, modes of action, and therapeutic potential of vanillinderived drugs in various illness types.

RESULTS: Comprehensive evaluation of vanillin and its derivatives revealed their broad pharmacological spectrum, including significant neuroprotective effects against neurodegenerative disorders such as Alzheimer's disease and potent anti-diabetic properties. In addition, Several vanillin derivatives demonstrated promising antimicrobial and anticancer activities, emphasizing their therapeutic potential. The review highlights that diverse synthetic strategies such as Schiff base formation, Azo-Schiff base reactions, Williamson ether synthesis, Steglich esterification, Claisen-Schmidt condensation, and Mannich or reductive amination reactions are effectively employed to design and modify vanillin structures. These synthetic methods target functional groups like hydroxyl, methoxy, and aldehyde moieties, enabling the generation of novel bioactive derivatives with improved pharmacological profiles. Aldehyde (CHO) groups in vanillin are more susceptible to substitution than other functional groups.

DISCUSSION: Vanillin is a structurally versatile phenolic aldehyde with broad pharmacological potential. Structural modifications of its hydroxyl, methoxy, and aldehyde groups significantly enhance biological activities, including neuroprotective effects against Alzheimer's disease, anti-diabetic, antimicrobial, and anticancer properties. The aldehyde moiety plays a key role in synthetic diversification through reactions such as Schiff base formation, Mannich reaction, and Claisen-Schmidt condensation, enabling the development of potent bioactive derivatives. Although promising preclinical results highlight the therapeutic potential of vanillin-based compounds, further pharmacokinetic and clinical investigations are required to advance them toward drug development.

CONCLUSION: Vanillin and its derivatives represent a versatile class of compounds with multifaceted biological activities and vast potential in drug discovery. Their structural modifiability through various synthetic approaches allows the development of new therapeutic agents with enhanced efficacy and specificity. Continued exploration of their chemistry and pharmacology could pave the way for innovative treatments in neurodegenerative, metabolic, microbial, and cancer-related diseases.},
}

@article {pmid42708270,
year = {2026},
author = {Rajput, R and Sharma, A and Mittal, V and Sharma, D},
title = {Circadian Rhythm Disruption in Alzheimer's Disease: Molecular Mechanisms, Clinical Implications, and Therapeutic Approaches.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026473002260820065219},
pmid = {42708270},
issn = {1875-5739},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a progressive neurological disorder characterized by unusual behavior, memory deterioration, and a decline in cognitive abilities. A growing body of research indicates that circadian rhythm disturbances play a crucial role in the pathophysiology of AD, impacting both molecular processes and clinical outcomes. This review critically evaluates the molecular interplay between circadian rhythm disruption and AD pathology, explores its impact on clinical manifestations and disease progression, and assesses emerging diagnostic and therapeutic strategies to restore circadian regulation and improve patient outcomes.

METHODS: A thorough analysis of recent research on molecular clock genes (CLOCK, BMAL1, PER, and CRY) and their roles in regulating hormone rhythms, metabolism, and sleep-wake cycles was conducted. Research on technology-based methods, therapeutic treatments, and circadian biomarkers was assessed to determine their applicability in AD.

RESULTS: Circadian gene dysregulation was found to exacerbate tau hyperphosphorylation, amyloid- β accumulation, oxidative stress, and neuroinflammation. Clinically, circadian disruption manifests itself as mood disorders, sleep-wake abnormalities, and accelerated cognitive deterioration.

DISCUSSION: Light therapy, melatonin supplements, chrono-pharmacology, and behavioural techniques are among the interventions that have shown promise in restoring rhythm stability. Wearables, smart lighting, neuromodulation, and multi-omics modelling are examples of technological advancements that increase the range of diagnostic and treatment possibilities.

CONCLUSION: Patient heterogeneity, translational gaps, and a lack of mechanistic knowledge continue to pose difficulties despite progress. To enhance AD outcomes, future research should focus on integrated, customized therapies that target the circadian rhythm.},
}

@article {pmid42708298,
year = {2026},
author = {Akgündoğdu, A and Çeli̇kbaş, Ş},
title = {Nested Continual Learning with Elastic Weight Consolidation for Progressive Alzheimer's Disease Classification from MRI.},
journal = {Current medical imaging},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115734056512153260820074645},
pmid = {42708298},
issn = {1573-4056},
abstract = {UNLABELLED: Introduction/ Objective: MRI-based Alzheimer's staging is often modeled as separate tasks, although clinical assessment progresses from screening to more refined staging. This study developed a continual-learning framework for retaining earlier diagnostic knowledge.

METHODS: A nested multi-head framework was implemented for sequential learning of related binary classification tasks from structural MRI slices. Because verified subject identifiers were unavailable in the Mendeley dataset, the primary experiments were kept at the level of slice-based methodological analysis. Subject-level external validation was additionally carried out on OASIS-VBM with subject-wise three-fold cross-validation.

RESULTS: In the Mendeley slice-level evaluation, the proposed EWC + replay model retained high post-sequence discrimination, with AUC values of 0.976, 0.985, and 1.000 for T1, T2, and T3. The ECE values were 0.034, 0.057, and 0.187. When the model was tested at the subject level on OASIS, AUC values decreased to 0.753, 0.748, and 0.749. This difference shows that the slice-level results should be interpreted cautiously.

DISCUSSION: The findings support the use of the proposed framework for studying sequential retention and forgetting in hierarchical AD staging. However, Mendeley results are methodological findings at the slice level and should not be interpreted as patient-level clinical performance.

CONCLUSION: This study presents a nested continual-learning framework for hierarchical Alzheimer's disease staging. The framework was tested with ablation, calibration, baseline, and subject-level validation analyses. The results show that it can be used to study retention across related AD staging tasks. Future studies using subject-wise longitudinal cohorts, 3D models, and multimodal data may further improve its clinical relevance.},
}

@article {pmid42708376,
year = {2026},
author = {Hosoki, S and Sachdev, PS and Ihara, M},
title = {Arterial spin labeling-derived cerebral blood flow as a translational biomarker and candidate surrogate endpoint for cognitive impairment.},
journal = {Current opinion in psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1097/YCO.0000000000001112},
pmid = {42708376},
issn = {1473-6578},
abstract = {PURPOSE OF REVIEW: Arterial spin labeling (ASL) MRI noninvasively quantifies cerebral blood flow (CBF), but its role as a mechanistic biomarker and surrogate endpoint in trials of cognitive impairment remains undefined. This review evaluates evidence linking regional CBF to cognition across Alzheimer's disease, mild cognitive impairment (MCI), and cerebral small vessel disease (SVD), with particular emphasis on CADASIL as a mechanistically informative model.

RECENT FINDINGS: Multipostlabeling-delay ASL, spatial coefficient of variation metrics, and harmonized processing pipelines have improved reproducibility. Cross-sectional and longitudinal studies consistently link reduced CBF to cognitive impairment, with baseline CBF predicting cognitive decline, MCI-to-Alzheimer's disease conversion, white matter hyperintensity progression, and vascular events. In CADASIL, CBF is independently associated with cognitive performance and predicts subcortical hyperintensity progression over 2 years. Interventional data from SPRINT MIND, PRESERVE, and pilot lecanemab studies indicate that ASL-CBF is responsive to therapy.

SUMMARY: Within the FDA-NIH BEST framework, ASL-CBF appears to meet several criteria consistent with a reasonably likely surrogate endpoint, capturing upstream, potentially reversible hemodynamic dysfunction beyond established structural markers. CADASIL provides an optimal context for qualifications. Larger clinical trials linking treatment-induced CBF changes to clinical benefit, further protocol harmonization, and regulatory engagement are needed to translate ASL-CBF into a validated trial endpoint.},
}

@article {pmid42708464,
year = {2026},
author = {Bhattarai, S and Foster, EG and Kadry, R and Lu, Y and Kumar, M and Qasim, S and Mitra, A and Pathak, H and Poluektova, LY and Gorantla, S and Mosley, RL and Yeapuri, P and Gendelman, HE},
title = {Increased Amyloidogenic Neuronal Injury in HIV-1-infected APP-KI Alzheimer's disease mice.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71807},
doi = {10.1002/alz.71807},
pmid = {42708464},
issn = {1552-5279},
support = {P01 DA028555/NH/NIH HHS/United States ; R01 NS36126/NH/NIH HHS/United States ; P01 NS31492/NH/NIH HHS/United States ; P01 MH64570/NH/NIH HHS/United States ; P01 NS43985/NH/NIH HHS/United States ; P30 MH062261/NH/NIH HHS/United States ; R01 AG043540/NH/NIH HHS/United States ; 2R01 NS034239/NH/NIH HHS/United States ; //Frances and Louie Blumkin and Harriet Singer Research Foundations/ ; //Carol Swarts, MD Emerging Neuroscience Research Laboratory/ ; //the Margaret R. Larson Professorship/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/genetics/virology/metabolism ; *Amyloid beta-Protein Precursor/genetics ; Disease Models, Animal ; *HIV-1 ; Mice ; *Neurons/pathology/metabolism ; Mice, Transgenic ; *HIV Infections/pathology/complications ; Brain/pathology/metabolism/virology ; Amyloid beta-Peptides/metabolism ; Humans ; Microglia ; },
abstract = {INTRODUCTION: A higher incidence of dementia, including Alzheimer's-like pathology, is observed in aged people living with human immunodeficiency virus-1 (HIV-1). However, mechanisms linking HIV-1 to Alzheimer's disease (AD) pathology remain unclear, due to the lack of animal models that allow for concurrent studies of HIV-1 and AD.

METHODS: We created a novel amyloid precursor protein (APP) (Swedish mutation) knock-in (KI) AD mouse on an immunocompromised NOG background, NOG/APP[KM670,671NL]/IL-34 (NAIL). Following CD34+ hematopoietic stem cell (HSC) reconstitution, humanized hNAIL mice develop human microglia-like cells in the brain and human immune system in the periphery. This allows, for the first time, studies of progressive brain HIV-1 replication in an AD brain. Four-month-old HSC reconstituted mice were infected with the HIV-1ADA strain, and evaluated at 8 weeks post infection to study the role of brain HIV-1 replication on AD-like pathologies.

RESULTS: HIV-1 replication increased amyloid-beta (Aβ) load in the brain and reduced synaptic and neuronal integrity. Cell type-specific spatial transcriptomic analysis demonstrated that Aβ and HIV-1 drive distinct transcriptional patterns, whereas dual pathology amplified AD-like pathology. Neurons showed the highest transcriptional change, with genes linked to neuroinflammation, protein trafficking, and synaptic dysfunction.

DISCUSSION: The hNAIL mice enable interrogation of HIV-AD comorbidities, with a future potential for the development of novel therapeutic interventions.},
}

Animals
*Alzheimer Disease/pathology/genetics/virology/metabolism
*Amyloid beta-Protein Precursor/genetics
Disease Models, Animal
*HIV-1
Mice
*Neurons/pathology/metabolism
Mice, Transgenic
*HIV Infections/pathology/complications
Brain/pathology/metabolism/virology
Amyloid beta-Peptides/metabolism
Humans
Microglia

@article {pmid42708477,
year = {2026},
author = {Grollero, D and Gabb, V and Blackman, J and Heslegrave, A and de Vivo, L and Coulthard, E and Bellesi, M},
title = {Are infraslow oscillations the missing link between sleep and Alzheimer's?.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71525},
doi = {10.1002/alz.71525},
pmid = {42708477},
issn = {1552-5279},
support = {//Alzheimer's Research United Kingdom/ ; //Giovanni Armenise-Harvard Foundation/ ; //NIHR Bristol Biomedical Research Centre/ ; //Above and Beyond/ ; //David Telling Charitable Trust/ ; //Bristol and Weston Hospitals Charity/ ; //BRACE/ ; //Philanthropic donations from S Scobie and A Graham/ ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/blood ; Male ; Electroencephalography ; Female ; Amyloid beta-Peptides/blood ; *Sleep/physiology ; Aged ; Biomarkers/blood ; Aged, 80 and over ; Glial Fibrillary Acidic Protein/blood ; tau Proteins/blood ; Locus Coeruleus/physiopathology ; },
abstract = {INTRODUCTION: Locus coeruleus (LC) and glymphatic dysfunction have been linked both to Alzheimer's disease (AD) and, recently, to infraslow oscillation (ISO) in sleep spindle (sigma) activity (ISO). Here we hypothesize ISO integrity is a critical link between sleep and AD.

METHODS: We analyzed non-rapid eye movement sleep electroencephalogram (EEG) data from AD participants and controls, extracting ISO peak amplitude, intrinsic frequency, and bandwidth from the sigma-power time-course. We assessed group differences and correlations with plasma biomarkers (Aβ42/40, pTau181, pTau217, neurofilament light chain [NfL], glial fibrillary acidic protein [GFAP]).

RESULTS: ISO peak amplitude was significantly reduced in AD, while intrinsic frequency and bandwidth were preserved. ISO peak amplitude showed a trend-level association with Aβ42/40, whereas ISO bandwidth was positively associated with NfL, and showed trends with GFAP and lower verbal memory retention.

DISCUSSION: Selective weakening of ISO in AD is consistent with LC dysfunction and impaired glymphatic cycling. ISO may be a novel mechanism and electrophysiological marker linking sleep microarchitecture to AD pathology.},
}

Humans
*Alzheimer Disease/physiopathology/blood
Male
Electroencephalography
Female
Amyloid beta-Peptides/blood
*Sleep/physiology
Aged
Biomarkers/blood
Aged, 80 and over
Glial Fibrillary Acidic Protein/blood
tau Proteins/blood
Locus Coeruleus/physiopathology

@article {pmid42708492,
year = {2026},
author = {Moczygemba, W and Stratton, L and Zimmerman, S and Fazio, S},
title = {Lived Perspectives on "Reconstructing Person-Centeredness".},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {45},
number = {1_suppl},
pages = {97S-101S},
doi = {10.1177/07334648261473666},
pmid = {42708492},
issn = {1552-4523},
mesh = {Humans ; *Patient-Centered Care ; *Dementia/therapy ; *Quality of Health Care ; Alzheimer Disease/therapy ; },
abstract = {Numerous papers in the "Reconstructing Person-Centeredness" supplement of the Journal of Applied Gerontology reference the perceived relationship between person-centeredness and quality dementia care, from fostering meaningful relationships and individualizing care, to practical applications of shared decision making and co-design of technologies and research measures. This article draws upon reflections from members of the Alzheimer's Association Early Stage Advisory Group regarding person-centeredness and quality dementia care. Their experiences, beliefs, and perspectives provide lived examples and context to three cross-cutting topics discussed throughout the supplement: relationships as underlying person-centeredness, the role of person-centered care in long-term and other healthcare settings, and person-centeredness and technology. By bridging first-hand narratives with academic inquiry, this article adds context to other papers in this supplement, and addresses the importance of person-centered dementia care from the perspective of those living with dementia.},
}

Humans
*Patient-Centered Care
*Dementia/therapy
*Quality of Health Care
Alzheimer Disease/therapy

@article {pmid42708494,
year = {2026},
author = {Zimmerman, S and Port, C and Mast, B and Van Haitsma, K and Fazio, S},
title = {A New Tool to Assess the Person-Centeredness of Research Measures: The Person-Centered Measure Evaluation Tool (PC-MET).},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {45},
number = {1_suppl},
pages = {54S-62S},
doi = {10.1177/07334648261478663},
pmid = {42708494},
issn = {1552-4523},
mesh = {Humans ; *Dementia/therapy ; *Patient-Centered Care ; Reproducibility of Results ; Caregivers ; Research Design ; },
abstract = {BackgroundNo tool exists to assess whether research measures themselves are consistent with principles of person-centeredness.ObjectiveThis project developed a tool to assess the extent of person-centeredness employed in the development, content, and application of research measure development in the context of measures relevant to persons living with dementia and/or their caregivers.MethodsLiterature review and expert input informed the development of the tool; pilot testing assessed interrater reliability and rater acceptability.ResultsThe tool includes six criteria (each with three subcategories): Co-Creation, Accommodation, Incorporation, Biopsychosocial-Cultural Components, Pragmatism, and Systemic Focus. Kappa agreement was substantial or better (0.61-1.00) for most (16/18) subcategories and for all six criteria (0.74-1.00). Raters found the tool easy to understand and score and the criteria to be relevant and complete.ConclusionsThe resulting tool-named the Person-Centered Measure Evaluation Tool (PC-MET)-can reliably critique existing measures and guide the development of new measures.},
}

Humans
*Dementia/therapy
*Patient-Centered Care
Reproducibility of Results
Caregivers
Research Design

@article {pmid42708495,
year = {2026},
author = {Efird-Green, L and Jones, LB and Fazio, S and Zimmerman, S},
title = {Definitions of Person-Centeredness for Persons With Dementia in the United States: A Scoping Review.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {45},
number = {1_suppl},
pages = {17S-29S},
doi = {10.1177/07334648261463391},
pmid = {42708495},
issn = {1552-4523},
mesh = {Humans ; *Dementia/therapy/psychology ; *Patient-Centered Care ; United States ; Personhood ; },
abstract = {Person-centeredness first emerged as a concept in dementia care in the 1980s. Nearly 40 years later, it has no universal definition, which limits operationalization and implementation of care and supportive services, measures, interventions, policy, and regulation for people with dementia. Thus, a scoping review of the current definitions of person-centeredness in US dementia care was conducted. Of the 71 included studies, there was considerable variability in elements/themes, complexity, and cited theories; the most common themes were needs and preferences, relationships, and personhood, all of which were present in at least half of the studies' definitions. Importantly, more than 150 articles that were reviewed did not contain a definition, despite including the term in their titles or abstracts. Further investigation in pursuit of a more nuanced conceptualization of person-centeredness that includes these key themes, while also addressing concerns about applicability to diverse cultures and contexts (e.g., organizations and systems), is recommended.},
}

Humans
*Dementia/therapy/psychology
*Patient-Centered Care
United States
Personhood

@article {pmid42708793,
year = {2026},
author = {Sahhar, L and Albrecht, M and Pahl, J and Häger, A and Reetz, K and Costa, AS},
title = {Cross-sectional relationships between memory scores and neurodegeneration biomarkers in patients with suspected cognitive impairment.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/13803395.2026.2729728},
pmid = {42708793},
issn = {1744-411X},
abstract = {INTRODUCTION: We aimed to examine whether additional metrics derived from the CERAD Word List Memory Test (WLMT) such as acquisition patterns, error frequencies, and consolidation efficiency, are associated with cerebrospinal fluid (CSF) biomarkers of amyloid and tau pathology, as well as magnetic resonance imaging (MRI) ratings of brain atrophy and small vessel disease, in individuals with suspected cognitive impairment who nonetheless perform within normative ranges on the traditional WLMT measures.

METHODS: We included 109 patients from a memory clinic setting (46% female, median age 69.5 years, 55.1% with normal AD biomarkers, 25.7% in the AD continuum) that underwent comprehensive neuropsychological assessment, CSF biomarker analysis, and visual MRI rating. Associations between traditional and additional memory scores and the biomarkers were examined using regression analyses, controlling for demographic variables and adjusting for multiple comparisons.

RESULTS: Correlations were modest and partly mediated by demographics. Traditional scores showed the strongest links, but additional scores "lost access" and "learning ratio" were also associated with lower Aβ CSF levels (ρ = -.23, p = .034) and medial‑temporal lobe atrophy (e.g. learning ratio, ρ = -.30, p = .036), suggesting sensitivity to subtle learning‑consolidation inefficiencies. High burden of white matter hyperintensities was associated with intrusion errors (U = 807.5, p < .05, d' = 0.23) and less stable learning (U = 613.0, p < .01, d' = 0.41).

CONCLUSIONS: Both traditional and additional memory scores can assist early detection and risk stratification of neurodegenerative disease in patients with normative performance, but these findings require replication in larger, more heterogeneous cohorts.},
}

@article {pmid42708923,
year = {2026},
author = {Sun, L and Duke, L and Vied, C and Hammel, G and Pate, B and Wang, J and Zhang, Y and Tian, DS and Fan, J and Ren, Y},
title = {A Rapid Poly(ethylene glycol)-Assisted Magnetic Isolation Approach for High-Throughput Extracellular Vesicle Isolation and Subsequent Biomarker Analysis.},
journal = {ACS nano},
volume = {20},
number = {35},
pages = {24492-24511},
doi = {10.1021/acsnano.6c09351},
pmid = {42708923},
issn = {1936-086X},
support = {P30AG072958/AG/NIA NIH HHS/United States ; DMS-2053832//Division of Mathematical Sciences/ ; DMS-2054014//Division of Mathematical Sciences/ ; R21NS123595//National Institutes of Health (NIH)/ ; },
mesh = {*Polyethylene Glycols/chemistry ; Biomarkers/analysis ; *Extracellular Vesicles/chemistry/metabolism ; Humans ; Animals ; *High-Throughput Screening Assays ; Proteomics ; },
abstract = {Extracellular vesicles (EVs) are crucial mediators of intercellular communication and have the potential to serve as biomarkers for disease diagnosis and therapeutic monitoring. However, most EV isolation methods often require large sample volumes and specialized instruments or involve trade-offs between purity, yield, cost, and scalability. We developed MagPEG, a workflow that combines poly(ethylene glycol) (PEG)-mediated EV aggregation with magnetic beads to provide a simple, reproducible alternative to ultracentrifugation, size-exclusion chromatography, and commercial precipitation kits. Our optimization experiments clarified the PEG concentration, ionic strength, and bead surface chemistry that collectively influence EV aggregation, capture efficiency, and contaminant coprecipitation, allowing us to define conditions that improve purity while maintaining high recovery. Compared with commonly used methods, MagPEG produced EVs with comparable size distribution, EV markers, and proteomic profiles while relying only on standard laboratory supplies. A key feature of the platform is that EVs and EV-associated DNA, RNA, and proteins can be sequentially extracted from the same bead-bound material, reducing sample loss and hands-on time and enabling multiomic analysis for limited clinical or small animal samples. MagPEG is compatible with downstream applications including proteomics, bead-based assays, and miRNA quantification. When applied to human serum, the method supported high-throughput EV proteomic profiling and enabled the identification of Alzheimer's disease-associated protein signatures, illustrating its utility for biomarker discovery. Overall, our results establish MagPEG as a powerful, rapid, scalable, and high-throughput solution for translational applications in biomarker discovery.},
}

*Polyethylene Glycols/chemistry
Biomarkers/analysis
*Extracellular Vesicles/chemistry/metabolism
Humans
Animals
*High-Throughput Screening Assays
Proteomics

@article {pmid42700489,
year = {2026},
author = {Nayok, SB and Sreeraj, VS and Nichenmetla, S and Chhabra, H and Jayasankar, P and Balachander, S and Holla, B and Viswanath, B and Benegal, V and Reddy, YJ and Varghese, M and Jain, S and , and John, JP and Venkatasubramanian, G},
title = {Gaze fixation stability is a transdiagnostic marker of major psychiatric disorders: A high-density family-based study.},
journal = {Psychiatry research},
volume = {366},
number = {},
pages = {117418},
doi = {10.1016/j.psychres.2026.117418},
pmid = {42700489},
issn = {1872-7123},
abstract = {BACKGROUND: Eye movement tracking non-invasively captures subtle cognitive and neural differences. Fixation stability (FS), the ability to maintain steady visual fixation, has been proposed as a transdiagnostic marker in major psychiatric disorders. This study evaluates fixation stability as a canidate transdiagnostic endophenotype in individuals from multiplex families with major psychiatric disorders.

METHODS: Monocular eye tracking data were recorded using infrared cameras while participants fixed their gaze on a stimulus in trials with and without distractors. FS measures were compared across affected 449 individuals (26 Alzheimer's Dementia (AD), 89 schizophrenia (SCZ), 116 bipolar disorder (BD), 98 obsessive-compulsive disorder (OCD), and 120 substance-use disorder (SUD)), 442 unaffected first degree relatives (FDRs) and 145 healthy controls (HC). FS performance was compared across groups using a linear mixed effects model controlling for familiality, age and sex.

RESULT: Affected individuals performed significantly poorly (fixation frequency(F=6.37, pcor=0.003), median fixation duration(F=4.79, pcor=0.009), saccade frequency(F=7.74, pcor<0.001), mean saccade amplitude(F=4.92, pcor=0.009), mean scanpath length(F=6.83, pcor=0.003)) in the trials with distractors when compared to FDRs and HC. The performance of FDRs and HC did not differ significantly from that of the other. Furthermore, in a cross-diagnostic comparison, impaired performance was observed only in SCZ and BD, with both performing significantly worse than SUD, OCD, and HC.

CONCLUSIONS: FS was impaired in major psychiatric disorders, especially SCZ and BD. No difference noted between FDRs and HC suggesting it as an illness-related, but not a endophenotypic marker. Further studies accounting for disorder-specific familial risk are needed to clarify its endophenotypic potential.},
}

@article {pmid42700507,
year = {2026},
author = {Cuervo-Lombard, C and El Haj, M and Hallit, S and Chapelet, G and Bulteau, S and Voltzenlogel, V},
title = {Envisioning the self: self-defining future projections in Alzheimer's disease.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {74},
number = {Pt A},
pages = {104344},
doi = {10.1016/j.gerinurse.2026.104344},
pmid = {42700507},
issn = {1528-3984},
abstract = {Self-defining future projections (SDFPs) are vivid, emotionally salient projections of personally meaningful events that anchor identity and guide motivation. While past self-defining memories ground the self in remembered experiences, SDFPs extend this function into the future, offering a forward-looking perspective on identity and well-being. In Alzheimer's disease (AD), cognitive decline threatens autonomy, memory, and self-continuity, yet little is known about how SDFPs are affected. The present study examined SDFPs in 37 individuals with mild AD and 40 cognitively healthy older adults. Participants generated SDFPs, which were evaluated for specificity, integrative meaning, importance, and emotional valence. Compared to controls, patients with AD produced less specific, less integrated, and less important future events, while emotional intensity remained comparable across groups. In AD patients, better cognitive functioning predicted greater specificity, whereas higher depression and anxiety were associated with reduced specificity, integration, and importance, as well as higher negative emotions. These findings highlight that AD compromises the structural and identity-related features of future self-projections, but preserves emotional engagement, suggesting a potential pathway for interventions to support motivation, self-continuity, and well-being.},
}

@article {pmid42700644,
year = {2026},
author = {Cote, I and Valfort, AC and Sanders, RK and Burris, SL and Hayes, ME and Arya, R and Maram, L and Elgendy, B and Yue, F and Burris, TP},
title = {BE2012 a novel, REV-ERB antagonist that promotes regenerative myogenesis in vivo with substantially improved pharmacokinetics relative to SR8278.},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {393},
number = {9},
pages = {105011},
doi = {10.1016/j.jpet.2026.105011},
pmid = {42700644},
issn = {1521-0103},
abstract = {Pharmacological inhibition of REV-ERBs has emerged as a potential therapeutic strategy for several diseases with unmet medical needs. Indeed, chronic treatment with SR8278, a synthetic REV-ERB antagonist, has mitigated pathology in various preclinical models of human musculoskeletal and neurological diseases, including Duchenne muscular dystrophy, epilepsy, Alzheimer disease, Parkinson disease, and frontotemporal dementia. However, SR8278, the first and most widely used REV-ERB antagonist, has poor pharmacokinetic properties, which limits its utility. The REV-ERBs (α and β) are widely expressed nuclear receptors that function as ligand-dependent transcriptional repressors, and the therapeutic potential for inhibition of these receptors remains unclear because of the lack of adequate pharmacological tools. Here, we report BE2012, a significantly improved REV-ERB antagonist with >22-fold longer half-life than SR8278. In a cell-based reporter assay, BE2012 exhibited greater potency toward REV-ERBα (EC50 = 0.38 μM) and REV-ERBβ (EC50 = 0.57 μM) compared with SR8278. Notably, in primary myoblast differentiation assays, BE2012 outperformed SR8278 in increasing the proportion of MyoG[+] cells as well as differentiation and fusion indices. In a cardiotoxin-induced muscle injury model, both BE2012 and SR8278 led to increased myofiber cross-sectional area (22%-34% higher than controls). Lastly, transcriptomic profiling revealed remarkable overlap of differentially expressed genes between the 2 compounds, with oxidative phosphorylation and mitochondrial protein complex emerging as the most significantly enriched pathways for both ligands, which have been shown to accelerate regenerative myogenesis. These results establish BE2012 as a refined REV-ERB antagonist for in vivo applications and a valuable tool for deeper exploration of the therapeutic potential of inhibiting REV-ERB activity. SIGNIFICANCE STATEMENT: This study establishes BE2012 as a novel REV-ERBα/β antagonist with a 22-fold longer half-life and improved potency compared with SR8278, the only available REV-ERB antagonist whose poor bioavailability has limited its utility for in vivo use. In an acute muscle injury model in mice, BE2012 promoted regenerative myogenesis and induced a broad transcriptomic reprogramming that was highly concordant with that of SR8278, suggesting it could serve as a new gold-standard REV-ERB antagonist tool compound in the field.},
}

@article {pmid42700732,
year = {2026},
author = {Avendaño-Godoy, J and Álamos, C and Araya, E and Olea-Azar, C and Ortega-Campos, J and Cattoën, X and Valenzuela, JM and Kogan, MJ},
title = {Mesoporous silica-coated gold nanorods functionalized with the D3 peptide and loaded with epigallocatechin-3-gallate reduce β-amyloid toxicity in the presence of Zn(II) ions.},
journal = {Biomaterials advances},
volume = {190},
number = {},
pages = {215149},
doi = {10.1016/j.bioadv.2026.215149},
pmid = {42700732},
issn = {2772-9508},
abstract = {Alzheimer's disease (AD) is characterized, among other factors, by the accumulation of the β-amyloid peptide (Aβ), redox imbalance, and disruption of metal homeostasis-processes that act synergistically, promoting neurotoxicity. In this work, a core-shell nanosystem based on mesoporous silica-coated gold nanorods (GNR@mSiO2) was developed, functionalized with the anti-Aβ aggregation D3 peptide and loaded with epigallocatechin-3-gallate (EGCG), an antioxidant and modulator of Aβ aggregation and toxicity, to reduce Aβ-induced toxicity in vitro in presence of Zn(II) ions. Nanosystem formation and the incorporation of each component were confirmed by transmission electron microscopy (TEM), UV-Vis-NIR spectroscopy, dynamic light scattering (DLS), ζ-potential, and fourier transform infrared (FT-IR) spectroscopy. The GNR@mSiO2-PEG-D3/EGCG nanosystem exhibited high antioxidant activity, evidenced by its ability to sequester metal ions and deactivate DPPH• and •OH radicals. Furthermore, it effectively inhibited Aβ aggregation and promoted its disaggregation, particularly under Zn(II) ions overload conditions. In differentiated SH-SY5Y neuronal cells, the nanosystem converted Aβ aggregates formed in the presence of Zn(II) ions into non-toxic species, resulting in a marked reduction of cytotoxicity and intracellular ROS production. Taken together, these findings highlight the potential of GNR@mSiO2-PEG-D3/EGCG as a promising multifunctional platform against AD.},
}

@article {pmid42700769,
year = {2026},
author = {Evered, AH and Shippy, DC and Lash, JN and Oliai, SF and Ulland, TK},
title = {The anti-leukemia drug ponatinib attenuates NLRP3 inflammasome activation in macrophages.},
journal = {Immunobiology},
volume = {231},
number = {5},
pages = {153241},
doi = {10.1016/j.imbio.2026.153241},
pmid = {42700769},
issn = {1878-3279},
abstract = {The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is an established driver of inflammation in diseases such as diabetes, Alzheimer's disease, and gout. Previously, we screened 875 FDA-approved drugs for NLRP3 inhibitors and identified ponatinib as one of the five candidates that reduced NLRP3 inflammasome activation without causing cytotoxic effects in bone marrow-derived macrophages (BMDMs). Therefore, we hypothesize that ponatinib may be an effective NLRP3 inflammasome inhibitor. We performed dose curves and cytotoxicity assays to determine an effective in vitro concentration of ponatinib in BMDMs (1 μM) and primary microglia (0.5 μM) that reduced IL-1β secretion without inducing cytotoxicity. In BMDMs, ponatinib inhibited Nlrp3- and Caspase-1-dependent IL-1β and IL-18 secretion and significantly reduced caspase-1 processing. Ponatinib also reduced IL-1β secretion by microglia, indicating possible NLRP3 inflammasome inhibition in this cell type, but further testing is required. Although ponatinib has previously been demonstrated to drive cardiotoxicity-mediated inflammation, these data suggest that at specific doses, in vitro ponatinib can be non-cytotoxic and effective in attenuating NLRP3 inflammasome activation in macrophages and microglia.},
}

@article {pmid42700779,
year = {2026},
author = {Li, Z and Xu, Z and Li, X and Ren, H and Zhang, Y and Sun, Z and Xu, H and Zeng, F and Liu, Z and Chen, J and Shi, J and Wei, W and Li, X},
title = {Activity-dependent DNA methylation and demethylation: epigenetic regulators of learning and memory.},
journal = {Neurobiology of disease},
volume = {229},
number = {},
pages = {107596},
doi = {10.1016/j.nbd.2026.107596},
pmid = {42700779},
issn = {1095-953X},
abstract = {Learning and memory are fundamental cognitive processes that rely on activity-dependent epigenetic mechanisms to shape synaptic and neuronal plasticity. Among these, DNA methylation and demethylation have emerged as pivotal regulators that convert transient neural activity into enduring transcriptional programs. In mammals, DNA methylation marks include 5-methylcytosine (5mC) as well as the less well-established N6-methyladenine (6mA) and the more enigmatic N4-methylcytosine (4mC). Compared with 5mC, the abundance, genomic distribution, and regulatory role of 6mA and 4mC remain incompletely defined, partly due to low abundance and technical challenges, yet these non-canonical marks may provide an additional regulatory layer in specific biological contexts. Accordingly, this review focuses on the best-characterized pathway in the nervous system, 5mC and its activity-regulated oxidative turnover. This system comprises a dynamic spectrum of cytosine modifications, including 5mC, 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), orchestrated by distinct enzyme families such as DNMTs, TETs, and TDG. We review current insights about how these regulators shape activity-induced gene expression programs underlying learning and memory, and we discuss how dysregulated DNA (de) methylation contributes to impaired transcriptional control and cognitive decline in neurodegenerative diseases, particularly Alzheimer's disease. Finally, we highlight recent advances in high-resolution mapping technologies for DNA modifications, which are expanding our ability to resolve cell type- and locus-specific epigenetic dynamics in the brain. A deeper understanding of these pathways may inform targeted strategies to preserve or restore cognitive function in neurological disorders.},
}

@article {pmid42700810,
year = {2026},
author = {Han, Z and Liu, W and Fu, W and Wang, K and Tan, Z and Zhang, D and Yang, F and Dong, W and Sang, Z},
title = {Imidazo[1,2-a]pyridine-based HDAC6 inhibitor a17 for the treatment of Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {1034},
number = {},
pages = {179320},
doi = {10.1016/j.ejphar.2026.179320},
pmid = {42700810},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a prevalent, chronic, and progressive neurodegenerative disorder that predominantly affects the elderly population, and no effective pharmacological treatments are currently available. Histone deacetylase 6 (HDAC6) is overexpressed in the hippocampus of AD patients, and its inhibition has been shown to clear amyloid-β (Aβ) deposits, promote tau protein degradation, ameliorate mitochondrial transport deficits, and restore α-tubulin acetylation. Thus, selective HDAC6 inhibition represents a promising therapeutic strategy for AD, yet the underlying mechanisms by which HDAC6 inhibitors ameliorate cognitive impairment in AD remain elusive. In our previous study, a series of novel imidazo [1,2-a]pyridine-based HDAC6 inhibitors were developed, among which compound a17 exhibited potent HDAC6 inhibitory activity with an IC50 value of 7.51 nM, warranting further investigation into its anti-AD effects. Herein, we demonstrated that a17 exerted robust neuroprotective effects against L-Glutamate (L-Glu-)/Aβ25-35-induced HT22 cell injury. Additionally, a17 displayed favorable blood-brain barrier (BBB) permeability in vitro and drug-likeness properties. In vivo studies revealed that a17 significantly attenuated AD-like phenotypes in an Aluminium chloride (AlCl3)-induced zebrafish AD model, a mechanism potentially associated with the differential regulation of ODC1, Serpine1, and PAG-1. Furthermore, a17 markedly improved scopolamine-induced memory deficits in mice. Collectively, these findings indicate that an HDAC6 inhibitor, a17, was found to attenuate AD-associated pathological and behavioral markers by regulating the expression of ODC1, Serpine1, or PAG-1. Accordingly, a17 merit consideration for a pharmacological treatment of choice for AD.},
}

@article {pmid42700866,
year = {2026},
author = {Liu, A and Xing, L and Li, J and Gao, W and Yao, M and Song, J and Li, H},
title = {Mitochondria-Endoplasmic Reticulum Contact Sites (MERCS/MAM): Multi-Layered Upstream Regulators of Microglial Senescence in Alzheimer's Disease.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103352},
doi = {10.1016/j.arr.2026.103352},
pmid = {42700866},
issn = {1872-9649},
abstract = {BACKGROUND: Alzheimer's disease (AD) is an age-dependent neurodegenerative syndrome in which microglial senescence bridges biological ageing and Aβ-tau pathology. Senescent microglia undergo permanent cell-cycle arrest, upregulate p16[INK4a] and SA-β-gal, and secrete a pro-inflammatory senescence-associated secretory phenotype (SASP) that sustains chronic neuroinflammation. Mitochondria-endoplasmic reticulum contact sites (MERCS) are dynamic physical junctions between the endoplasmic reticulum (ER) and mitochondria, whereas mitochondria-associated membranes (MAM) are biochemically enriched ER subdomains located at MERCS. MERCS coordinate calcium shuttling, mitochondrial dynamics, lipid trafficking and the unfolded protein response (UPR); however, whether their dysfunction drives microglial senescence in vivo remains largely untested.

MAIN TEXT: This review critically integrates five MERCS-linked signalling axes that are hypothesised to drive microglial senescence, namely calcium overload, mitochondrial fission-fusion imbalance, inflammatory amplification, lipid dysregulation and unresolved ER stress. We apply a standardized four-tier evidence-grading framework to stratify causal evidence, systematically distinguish dystrophic, disease-associated (DAM) and bona-fide senescent microglia on the basis of transcriptomic and proteomic data from AD models and human tissues, and address underexplored dimensions including APOE/TREM2 crosstalk, mitophagy, epigenetic regulation, peripheral inflammation and senolytic combinations. We stress that inflammatory activation, oxidative stress and mitochondrial dysfunction represent common cellular stress responses that cannot independently define bona-fide microglial senescence. Because more than 90% of current mechanistic evidence is derived from non-microglial models, MERCS dysfunction in microglia remains a compelling hypothesis that requires rigorous in-vivo validation. Notably, MERCS dysfunction and AD-relevant APOE/TREM2 signalling engage in mutually modulatory crosstalk rather than a simple linear upstream-downstream hierarchy.

CONCLUSION: Translational development faces several barriers, including poor blood-brain barrier (BBB) penetration, off-target neurotoxicity, uncharacterised long-term safety and limited generalisability from APP/PS1 models lacking tauopathy. All MERCS-targeted and senolytic combinatorial strategies discussed herein represent prospective pre-clinical research directions rather than mature clinical therapeutic approaches. We propose an experimental roadmap based on conditional knockouts, intravital imaging and bidirectional interventions. Overall, MERCS dysfunction is proposed as a candidate multimodal upstream hub for calcium, mitochondrial, inflammatory, lipid and ER-stress signalling, and rigorous in-vivo validation together with microglia-selective delivery platforms is essential for therapeutic translation.},
}

@article {pmid42700879,
year = {2026},
author = {Premchandani, T and Qutub, M and Thave, T and Taksande, J and Tatode, A and Umekar, M},
title = {The redox paradox in neurological disorders: balancing cytoprotection, ferroptosis, and therapeutic targeting.},
journal = {Brain research},
volume = {},
number = {},
pages = {150528},
doi = {10.1016/j.brainres.2026.150528},
pmid = {42700879},
issn = {1872-6240},
abstract = {Neurological disorders, including ischaemic and haemorrhagic stroke, traumatic brain injury, and chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, represent a major global health burden. Despite diverse etiologies, these conditions share common pathological mechanisms driven by oxidative stress, neuroinflammation, mitochondrial dysfunction, iron dysregulation, and secondary neuronal injury. The nuclear factor erythroid 2-related factor 2 (Nrf2) signalling cascade and its downstream target heme oxygenase-1 (HO-1) are master regulators of cellular redox homeostasis. HO-1 plays a pivotal yet dichotomous role: its products biliverdin/bilirubin and carbon monoxide exert antioxidant, anti-inflammatory, and anti-apoptotic effects, whereas excessive HO-1 induction can exacerbate iron-mediated oxidative injury and ferroptosis through the release of redox-active ferrous iron. Rather than cataloguing protective studies, this review builds a contextual framework that specifies when HO-1 activation is protective versus detrimental, organised around three converging determinants: cell-type specificity, iron-handling capacity, and disease stage. We extend this framework to the often-overlooked dimensions of sex, age, and model heterogeneity, and use it to interrogate conflicting findings across the literature. We further dissect how Nrf2/HO-1 regulates ferroptosis through the GPX4-ACSL4-SLC7A11 axis, critically appraise the largely unexamined relationship between Nrf2 and the parallel FSP1/CoQ10, GCH1/BH4, and DHODH defence systems, and distil lessons from clinical trials of Nrf2 activators. The goal is an analytical account that identifies where the evidence is robust, where it is contradictory, and where the principal research gaps lie.},
}

@article {pmid42701059,
year = {2026},
author = {Laczó, M and Lerch, O and Nedelska, Z and Laczó, J},
title = {Spatial navigation and the basal forebrain in Alzheimer's disease and other neurodegenerative diseases.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2026.08.005},
pmid = {42701059},
issn = {1878-108X},
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD) and Lewy body disease (LBD) are frequently associated with spatial navigation impairments. However, these impairments are less pronounced in frontotemporal dementia and limbic-predominant age-related TDP-43 encephalopathy. While basal forebrain degeneration occurs in all of these diseases, disruption of cholinergic pathways and related cholinergic deficits has been primarily observed in AD and LBD, and in both of these conditions, basal forebrain degeneration appears to be associated with spatial navigation deficits. In this review, we discuss current understanding of spatial navigation impairments in neurodegenerative diseases, with a particular focus on disease-related changes in the basal forebrain and their associations with impaired spatial navigation abilities in humans.},
}

@article {pmid42701177,
year = {2026},
author = {Riedlinger, D and Karamercan, MA and Dündar, ZD and Janssens, K and Adam, VN and Bjørnsen, LP and Fabbri, A and Laribi, S and Möckel, M and Polyzogopoulou, E and Somodi, S and Koc, M and Colak, T and Slagman, A and , },
title = {Non-traumatic chief complaints in older patients in European emergency departments and associated outcomes during the Covid-19 pandemic - a secondary analysis of the cross sectional EGERS study.},
journal = {BMC geriatrics},
volume = {26},
number = {1},
pages = {},
pmid = {42701177},
issn = {1471-2318},
mesh = {Humans ; Cross-Sectional Studies ; Female ; Europe/epidemiology ; *Emergency Service, Hospital/statistics & numerical data ; Male ; Aged, 80 and over ; *COVID-19/epidemiology ; Aged ; Prospective Studies ; Hospital Mortality ; Emergency Room Visits ; Hospitalization/statistics & numerical data ; Pandemics ; },
abstract = {BACKGROUND: The scope of medical conditions addressed in Emergency Departments (ED) increases with growing numbers of older patients among the ED patient population. More information on their chief complaints and related treatment outcomes is essential to ensure high-quality ED care. The objective of this study was to describe the pattern of chief complaints of older ED patients and evaluate the associations between these complaints and outcomes such as mortality and hospital admission.

METHODS: This secondary analysis is based on the observational 'Epidemiology of Geriatric patients in Europe' (EGERS) study. This prospective, routine data cross-sectional study was conducted in 36 EDs across 9 European countries. Data collection from routine clinical records of all patients aged 65 and older over a 7-day period from October 19 to November 30, 2020 during the Covid-19 pandemic. Patients with one documented non-traumatic chief complaint were analyzed. Descriptive statistics, logistic regression, and general linear mixed models were used to assess factors associated with hospital admission and in-hospital mortality. Odds ratios (OR) and 95% confidence intervals (CI) were reported.

RESULTS: The study population consisted of 2,794 patients with one specified chief complaint. The mean age was 77.4 (± 8.2) years. The most frequent chief complaints were shortness of breath, abdominal pain, chest pain, weakness and fatigue, and extremity pain and numbness, representing 59% of the cohort. Highest age (≥ 85), geriatric risks (i.e. presence of dementia/Alzheimer's disease (AD), home help service or previous falls), polypharmacy, and shortness of breath increased the odds of being admitted to hospital (OR 1.4 [1.2-1.9]; OR 1.6 [1.3-1.9]; OR 1.3 [1.1-1.6]; OR 3.0 [2.4-3.8]), while female sex was negatively associated with admission (OR 0.7 [0.6-0.8]). Shortness of breath was positively associated with in-hospital mortality (OR 2.2 [1.4-4.3]).

CONCLUSION: Older patients frequently require hospital admission. As chief complaints do not reflect underlying condition or severity, structured evaluation, staff training and geriatric specific care pathways may improve care and reduce adverse clinical outcomes.},
}

Humans
Cross-Sectional Studies
Female
Europe/epidemiology
*Emergency Service, Hospital/statistics & numerical data
Male
Aged, 80 and over
*COVID-19/epidemiology
Aged
Prospective Studies
Hospital Mortality
Emergency Room Visits
Hospitalization/statistics & numerical data
Pandemics

@article {pmid42701205,
year = {2026},
author = {Gabb, VG and Harding, S and Lemke, T and Alderman, S and Woodward, N and Clayton, J and McNair, A and Barrett-Muir, W and Richardson, A and Dooley, J and Rudd, S and Coulthard, E and Turner, N},
title = {Outcomes reported in interventional studies for mild cognitive impairment: a scoping umbrella review to inform core outcome set development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71800},
pmid = {42701205},
issn = {1552-5279},
support = {NIHR204135//National Institute for Health Research (NIHR)/ ; },
mesh = {Humans ; *Cognitive Dysfunction/therapy ; *Outcome Assessment, Health Care ; Treatment Outcome ; },
abstract = {There is currently no consensus on the most important treatment outcomes in patients with mild cognitive impairment (MCI). As part of developing a core outcome set for MCI, we conducted a pragmatic scoping umbrella review to summarize outcomes reported in previous studies. Six electronic databases were searched from inception to August 2023. Systematic and scoping reviews in English with ≥70% of studies describing at least one quantitative outcome of interventions involving adults with MCI were eligible. Verbatim outcomes were extracted from eligible papers within selected reviews. From 170 papers covering 153 studies from 42 reviews, 143 unique outcomes were identified. Global cognition was the only outcome reported by more than 50% of studies. Two-thirds of outcomes were reported by no more than three studies. Heterogeneous outcome reporting limits evidence synthesis and treatment evaluation. A core outcome set for MCI is warranted to standardize outcome reporting and offer stronger evidence for decision-making.},
}

Humans
*Cognitive Dysfunction/therapy
*Outcome Assessment, Health Care
Treatment Outcome

@article {pmid42701209,
year = {2026},
author = {Mathai, G and Chemuru, S and Moyle, AB and Song, JH and Rempel, D and Giblin, D and Gross, ML},
title = {Mass Spectrometric Footprinting and DFT Calculations Explain the Effect of Curcumin on the Aggregation of Amyloid β 42 (Aβ42).},
journal = {Journal of the American Chemical Society},
volume = {148},
number = {34},
pages = {36365-36378},
doi = {10.1021/jacs.5c22337},
pmid = {42701209},
issn = {1520-5126},
support = {NA//NIH/ ; },
mesh = {*Curcumin/pharmacology/chemistry ; *Amyloid beta-Peptides/chemistry/metabolism ; *Peptide Fragments/chemistry/metabolism ; *Density Functional Theory ; Mass Spectrometry ; Models, Molecular ; *Protein Aggregates/drug effects ; Humans ; },
abstract = {Curcumin, a polyphenolic natural product, binds to Aβ42, a protein involved in Alzheimer's Disease, to inhibit self-aggregation in vitro. Molecular understanding of the binding is important in designing new molecules to inhibit Aβ42 aggregation. We performed OH radical footprinting of Aβ42 in the presence and absence of curcumin by using fast photochemical oxidation of proteins (FPOP), followed by mass spectral analysis, to monitor changes in Aβ42 protein dynamics in the presence of curcumin. The results reveal that curcumin binding reduces oxidative footprinting at the N-terminus and middle region, indicating binding at these sites. Kinetic modeling of the percentage modification shows a significant change in the aggregation of Aβ42 in the presence of curcumin, whereby one aggregate population nearly disappears. The [Aβ42:curcumin] binding complexes were also explored using density functional theory (DFT), optimizating the starting structures at the B3LYP/6-31G(d) level for both the N-terminal/middle and C-terminal/middle regions. The structure of the lowest-energy complex has curcumin binding at the N-terminal plus middle regions, and this was validated by reoptimization using 6-311G(d,p) and applying Grimme's dispersion function (GD3). This structure was further confirmed by reoptimization in aqueous media using the Conductor-like Polarizable Continuum Model (CPCM). The new structure not only accounts for the observed changes in •OH footprinting of the N-terminal, middle, and C-terminal regions but also forecasts how this approach can provide insight into protein aggregation. A molecular-level understanding of the binding site of curcumin with Aβ42 should be helpful in the design of new aggregation modulators.},
}

*Curcumin/pharmacology/chemistry
*Amyloid beta-Peptides/chemistry/metabolism
*Peptide Fragments/chemistry/metabolism
*Density Functional Theory
Mass Spectrometry
Models, Molecular
*Protein Aggregates/drug effects
Humans

@article {pmid42701403,
year = {2026},
author = {Zhang, G and Kong, L and Guo, RB and Ding, SW and Liu, Y and Zang, J and Zheng, Y and Wei, B and Chen, ZC and Yang, Y and Li, XT and Yu, Y},
title = {Microglia-targeted Panax notoginseng polysaccharide nanoparticles alleviate Alzheimer's disease via AMPK-mTOR/HIF-1α-mediated immunometabolic reprogramming.},
journal = {Materials today. Bio},
volume = {40},
number = {},
pages = {103620},
pmid = {42701403},
issn = {2590-0064},
abstract = {Alzheimer's disease (AD) is increasingly recognized as an immunometabolic disorder characterized by a self-reinforcing cycle of neuroinflammation and glycolytic reprogramming in microglia. Herein, we developed KPBIT@NPs, a microglia-targeted polysaccharide-based nanomedicine. Unlike many conventional nanocarriers that mainly serve as passive delivery vehicles, KPBIT@NPs employ the natural macromolecule Panax notoginseng polysaccharide (PNP) to construct a dual-functional, responsive nanoparticle platform. Through rational engineering via phenylboronic ester grafting, the polysaccharide backbone enables amphiphilic self-assembly and efficient co-loading of icaritin and tanshinone IIA, while allowing pathological reactive oxygen species (ROS)-triggered disassembly. In addition, surface decoration with the KLVFFAED peptide facilitates blood-brain barrier transport and targeted accumulation in activated microglia. Mechanistically, KPBIT@NPs activate AMP-activated protein kinase and suppress the mechanistic target of rapamycin/hypoxia-inducible factor 1α signaling axis, thereby reversing pathological glycolytic skewing and restoring mitochondrial oxidative metabolism. This coordinated regulation disrupts the inflammation-metabolism feed-forward loop and successfully reprograms microglia from a pro-inflammatory, metabolically stressed state toward a reparative phenotype. In AD animal models, KPBIT@NPs effectively restore cerebral energy metabolism, markedly reduce amyloid-β deposition, alleviate neuroinflammation, preserve neuronal integrity, and ultimately rescue cognitive deficits. This study establishes an innovative nanotherapeutic paradigm based on bioactive polysaccharides and offers a promising materials strategy for neurodegenerative diseases driven by coupled metabolic and inflammatory dysregulation.},
}

@article {pmid42701538,
year = {2026},
author = {Knapton, AE and Verma, N and Kotiya, D and Sowton, AP and Thackray, BD and Holzner, LMW and Darwin, PM and Despa, S and Despa, F and Murray, AJ},
title = {Amyloid-Forming Amylin Secreted by the Pancreas Promotes Hypoxia-Inducible Factor Activation and Mitochondrial Alterations in Liver and Heart During Type 2 Diabetes Pathogenesis.},
journal = {Comprehensive physiology},
volume = {16},
number = {5},
pages = {e70252},
pmid = {42701538},
issn = {2040-4603},
abstract = {In humans, hypersecretion of amyloidogenic amylin (islet amyloid polypeptide, IAPP) in the setting of insulin resistance and type 2 diabetes (T2D) promotes systemic oligomerization and tissue deposition, with deposits identified in failing human hearts and the cerebrovasculature of patients with Alzheimer's Disease. In the renal vasculature, amylin aggregation disrupts microvascular integrity, activating hypoxia signaling pathways and contributing to maladaptive erythropoietic responses, including excess erythrocytosis. We hypothesized that amyloid-forming amylin would activate hypoxia-inducible factor (HIF) signaling, leading to metabolic alterations in liver and heart during T2D pathogenesis. To investigate this, we used the HIP rat, which expresses human amylin specifically in pancreatic β-cells, comparing tissues from 14 to 16-month-old rats with those from age-matched wild-type, hyperglycemic UCD and amylin-knockout (AKO) rats. We found greater accumulation of HIF-1α and HIF-2α in HIP rat livers compared with those in other groups, alongside increased expression of HIF-1 target genes. Mitochondrial ETS capacity was elevated in HIP rat livers, in conjunction with the formation of mitochondrial supercomplexes. Amylin aggregates formed in the hearts of HIP rats, alongside HIF-1α and HIF-2α accumulation. This was associated with suppression of ETS capacity, and increased p-AMPK/AMPK, indicating possible cardiac energetic impairment. Pancreatic secretion of amyloidogenic amylin is thus associated with HIF activation in key metabolic organs beyond the renal vasculature, and occurs alongside mitochondrial alterations in liver and heart that are consistent with sustained hypoxic stress. Our results, alongside previous work, suggest that amylin dysregulation is an overlooked, human-relevant aspect of diabetes pathogenesis, and as such, a potential therapeutic target.},
}

@article {pmid42701867,
year = {2026},
author = {Fernandez-Gamez, B and Solis-Urra, P and Sanchez-Martinez, J and Sclafani, A and Olvera-Rojas, M and Rodríguez-Palacios, MT and Mellow, ML and Dumuid, D and Smith, AE and Ortega, FB and Esteban-Cornejo, I},
title = {Microstructural Brain Reserve Moderates the Associations Between 24-h Movement Behaviors and Cognition in Older Adults: Cross-Sectional Findings From the AGUEDA Trial.},
journal = {Scandinavian journal of medicine & science in sports},
volume = {36},
number = {9},
pages = {e70360},
pmid = {42701867},
issn = {1600-0838},
support = {RTI2018-095284-J-100//MCIN/AEI/ ; RYC2019-027287-I//MCIN/AEI/ ; PID2022-137399OB-I00//MCIN/AEI/ ; //Horizon Europe Framework Programme/ ; 101095426//European Union/ ; HOR_2025_03, FIBAO//Consejería de Salud y Consumo - Junta de Andalucía/ ; 22/02476//Spanish Ministry of Science, Innovation and Universities/ ; 72220164//National Agency for Research and Development/ ; GNT2042383//National Health & Medical Research Council Investigator/ ; //Biomedicine Doctoral Studies of the University of Granada/ ; },
mesh = {Humans ; Female ; Cross-Sectional Studies ; Aged ; *Cognition/physiology ; Sedentary Behavior ; *Exercise ; Male ; Sleep ; Accelerometry ; Alzheimer Disease/physiopathology/diagnostic imaging ; *Brain/diagnostic imaging/physiology ; Gray Matter/diagnostic imaging ; Memory, Short-Term ; Processing Speed ; Memory, Episodic ; Attention ; },
abstract = {This study examined the associations between 24-h movement behaviors and cognitive function in cognitively unimpaired older adults, and whether Alzheimer's disease brain signatures, including gray matter mean diffusivity (GMMD) and thickness/volume signatures, moderated these associations. A total of 91 participants were enrolled in the AGUEDA trial (NCT05186090), with 89 included in this cross-sectional analysis (mean age = 71.61 ± 3.85 years; 56.2% females). Moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), sedentary behavior (SB), and sleep were objectively assessed using 9-day wrist-worn accelerometry. Cognitive function was assessed across attention/inhibitory control, episodic memory, processing speed, visuospatial processing, and working memory. Thickness/volume and GMMD signatures were derived from cortical and hippocampal regions. Compositional linear regression models (CoDA) examined associations, adjusting for age, sex, and education, and tested interactions between movement behaviors and Alzheimer's disease brain signatures. No direct associations were observed between 24-h movement behaviors and cognitive domains (all p > 0.05). However, GMMD signature, but not thickness/volume signature, moderated several movement behavior-cognition associations. Moderation was most evident for episodic memory, with significant interactions for MVPA, LPA, and sleep, while LPA exhibited the broadest pattern of moderation across cognitive domains, interacting with attention/inhibitory control, episodic memory, processing speed, and working memory (all p for interaction ≤ 0.04). In conclusion, the associations between 24-h movement behaviors and cognitive function may depend on microstructural brain integrity (i.e., GMMD). These findings highlight the importance of considering Alzheimer's disease-related brain signatures when investigating lifestyle-cognition associations and support a more personalized approach to promoting cognitive health in older adults. Future prospective longitudinal studies and CoDA interventional trials are needed to establish temporal precedence and evaluate whether targeted time reallocations can actively attenuate cognitive trajectories across distinct microstructural vulnerability profiles. Trial Registration: NCT05186090.},
}

Humans
Female
Cross-Sectional Studies
Aged
*Cognition/physiology
Sedentary Behavior
*Exercise
Male
Sleep
Accelerometry
Alzheimer Disease/physiopathology/diagnostic imaging
*Brain/diagnostic imaging/physiology
Gray Matter/diagnostic imaging
Memory, Short-Term
Processing Speed
Memory, Episodic
Attention

@article {pmid42701962,
year = {2026},
author = {Abd El-Salam, RA and El-Hadidy, AR and Omar, NM and Sarhan, NR},
title = {The neuroprotective potential of thymoquinone and intermittent fasting on aluminum chloride-induced Alzheimer's disease like model in rat hippocampus: insights into neurogenesis and autophagy.},
journal = {Journal of molecular histology},
volume = {57},
number = {5},
pages = {},
pmid = {42701962},
issn = {1567-2387},
mesh = {Animals ; *Alzheimer Disease/chemically induced/pathology/drug therapy/metabolism ; *Neurogenesis/drug effects ; Aluminum Chloride ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Autophagy/drug effects ; *Benzoquinones/pharmacology ; *Intermittent Fasting ; Male ; *Hippocampus/drug effects/pathology/metabolism ; Disease Models, Animal ; Rats ; Oxidative Stress/drug effects ; Apoptosis/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Thymoquinone (TQ) is the active component of black seeds with many health benefits. Intermittent fasting (IF) is a dietary pattern with antioxidant and neuro-regenerative effects. This study explored the neuroprotective potential of TQ, IF or their combination on hippocampus of AD-like rat model with emphasis on the underlying mechanisms as neurogenesis and autophagy. Eighty adult male rats were divided into 7 groups: control, TQ given TQ (50 mg/kg/day orally), IF underwent IF for 14 h/day, AL given Aluminum chloride (AlCl3) (300 mg/kg/day orally) to induce AD-like pathology, AL + TQ, AL + IF and AL + TQ+ IF for 4 weeks. AD-like pathology was evaluated by behavioral tests, histopathology, immunostaining for apoptosis (Bax), microglia (CD68) and neurogenesis (nestin). Expressions of p-Tau, oxidative stress & autophagy markers (P62 and LC3B II) were assessed by western blot. AL group showed histological and ultrastructural AD-like features as apoptotic neurons, amyloid β deposition, significant elevation in MDA, p-Tau and P62, reduction in SOD and LC3B II, upregulation of Bax immune-expression and number of CD68 + activated microglia and diminished nestin positive cell number. TQ and IF mitigated these changes particularly when used in combination. In conclusion, TQ and IF protect against AlCl3-induced hippocampal AD-like pathology through reduction of oxidative stress, apoptosis, amyloid deposits, p-Tau expression and their modulatroy effects on microglia activation, neurogenesis and autophagy. The neuroprotective potential of IF is superior to TQ, while the optimal neuroprotection is achieved by the combination of both.},
}

Animals
*Alzheimer Disease/chemically induced/pathology/drug therapy/metabolism
*Neurogenesis/drug effects
Aluminum Chloride
*Neuroprotective Agents/pharmacology/therapeutic use
*Autophagy/drug effects
*Benzoquinones/pharmacology
*Intermittent Fasting
Male
*Hippocampus/drug effects/pathology/metabolism
Disease Models, Animal
Rats
Oxidative Stress/drug effects
Apoptosis/drug effects

@article {pmid42702172,
year = {2026},
author = {Castellanos-Perilla, N and Borda, MG and Chong, JR and Tovar-Rios, DA and Jaramillo-Jimenez, A and Berge, RK and Barreto, GE and Aarsland, D and Vik-Mo, AO},
title = {Corrigendum to "Distinct associations between body mass index and polyunsaturated fatty acids in dementia with Lewy Bodies and Alzheimer's disease" [J Nutr Health Aging, 30 (2026) 100810].},
journal = {The journal of nutrition, health & aging},
volume = {30},
number = {10},
pages = {100974},
doi = {10.1016/j.jnha.2026.100974},
pmid = {42702172},
issn = {1760-4788},
}

@article {pmid42702232,
year = {2026},
author = {Xie, H and Li, Y and Gan, R and Zhao, Z and , and Chen, Q and Jia, Z},
title = {Associations of peripheral inflammation with hippocampal atrophy in Alzheimer's disease.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111917},
doi = {10.1016/j.pnpbp.2026.111917},
pmid = {42702232},
issn = {1878-4216},
abstract = {Peripheral inflammation has been implicated in Alzheimer's disease (AD), yet its links to hippocampal neurodegeneration and clinical progression remain incompletely defined. This study investigated associations of peripheral inflammatory markers with hippocampal volume fraction (HVF) and cognitive outcomes, alongside potential intermediary pathways. We included 320 participants (mean age 74.9 ± 6.9 years; 58.8% male) spanning cognitively unimpaired, mild cognitive impairment and AD individuals from the Alzheimer's Disease Neuroimaging Initiative. Peripheral inflammation was quantified using the neutrophils to lymphocytes ratio (NLR), platelet to lymphocytes ratio (PLR), and systemic immune-inflammation index (SII). We evaluated their cross-sectional associations with HVF, Aβ, tau and cerebrospinal fluid central inflammatory markers. Linear mixed-effects models characterized longitudinal HVF and cognitive trajectories, and Cox regression modelled clinical progression. Consequently, higher peripheral inflammatory markers correlated with reduced HVF (β = -0.12 to -0.17, q < 0.05). Mediation analyses indicated peripheral inflammatory burden may serve as an intermediary pathway linking APOE ε4-related genetic susceptibility to HVF. Longitudinally, higher baseline PLR and SII were associated with faster HVF decline, whereas no significant associations were observed with longitudinal cognitive trajectories. In an exploratory subgroup restricted to cognitively normal participants, the median SII tertile was tentatively associated with subsequent progression to MCI or AD (HR = 3.09, p = 0.02). Peripheral inflammatory markers showed no associations with Aβ, tau, or central inflammatory markers. These results support a link between systemic inflammatory burden and hippocampal vulnerability, while relationships with AD pathology and clinical progression warrant further investigation.},
}

@article {pmid42702294,
year = {2026},
author = {Xi, YT and Jia, CX and Wang, HD and Liu, PY and Li, P and Niu, Q and Yin, YL},
title = {Convergent Vulnerability and Divergent Outcomes of the Dopaminergic System in Parkinson's and Alzheimer's Diseases.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103358},
doi = {10.1016/j.arr.2026.103358},
pmid = {42702294},
issn = {1872-9649},
abstract = {Dopaminergic neurons constitute a heterogeneous neuronal system that regulates diverse brain functions, whereas distinct dopaminergic neuronal subpopulations exhibit unique intrinsic biological properties, selective vulnerability, and disease-specific pathological trajectories across neurodegenerative disorders. Parkinson's disease (PD) is characterized by the progressive degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons, whereas Alzheimer's disease (AD) predominantly involves progressive dysfunction of ventral tegmental area (VTA)-associated dopaminergic circuits rather than widespread dopaminergic neuronal loss. This review provides a comprehensive overview of the regional heterogeneity of SNc and VTA dopaminergic neurons across multiple dimensions, including anatomical organization, electrophysiological properties, Ca[2+] homeostasis, bioenergetics, dopamine metabolism, and proteostasis, and discusses how these cell-autonomous characteristics collectively shape the intrinsic vulnerability of distinct dopaminergic neuronal subpopulations. Furthermore, it discusses how intrinsic vulnerability interacts with disease-associated pathological processes to drive the divergent pathological trajectories of the dopaminergic system, culminating in selective neuronal degeneration in PD and progressive dysfunction of VTA-associated neural circuits in AD. Building on this evidence, this review proposes a conceptual framework in which the pathological fate of the dopaminergic system is shaped by the interplay between intrinsic vulnerability and circuit dependency. Building upon this framework, the review further discusses disease-modifying strategies and their translational implications for PD and AD. This conceptual framework provides an integrated perspective for understanding the divergent pathological trajectories of the dopaminergic system in PD and AD and establishes a foundation for future hypothesis-driven studies on neuronal subtype-specific vulnerability.},
}

@article {pmid42702341,
year = {2026},
author = {Wang, S and Luo, L and Jiang, X and Hai, J and Liu, W and Zhou, X and Li, Y and Yang, L},
title = {HIF-1 exerts a double-edged sword regulatory role in hippocampal neuronal PANoptosis of Alzheimer's disease through HK2/VDAC1/NLRP3 axis and RIPK3 signal.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108440},
doi = {10.1016/j.phrs.2026.108440},
pmid = {42702341},
issn = {1096-1186},
abstract = {Extensive neuronal loss in brain regions critical for learning and memory is a hallmark of Alzheimer's disease (AD). PANoptosis, a newly characterized form of programmed cell death, integrates the key features of pyroptosis, apoptosis and necroptosis, and explains the molecular crosstalk among these pathways. However, whether PANoptosis is a new manner for hippocampal neuron death in AD, and the involved regulatory mechanisms remains largely unknown. Here, we demonstrate that PANoptosis is a crucial mechanism driving hippocampal neuronal loss in an AD mouse model. Moreover, we uncovered that the HIF-1 signaling pathway exerts a double-edged sword effect on hippocampal neuronal PANoptosis by activating the HK2/VDAC1/NLRP3 axis while concurrently suppressing RIPK3 signal. This observation may offer a partial explanation for the double-edged sword role of HIF-1 as both a neuroprotective and neurotoxic factor in AD. Finally, we uncovered that semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), mitigates hippocampal neuronal PANoptosis by reprograming the double-eged sword effect of HIF-1 mediated by GLP-1R-AMPK signaling pathway, highlighting its potential as a therapeutic avenue for AD. These findings uncover a previously unrecognized role of PANoptosis in AD and provide new insights into the HIF-1-mediated regulatory mechanisms, offering a promising target for therapeutic intervention.},
}

@article {pmid42702342,
year = {2026},
author = {Yin, L and Ren, R and Leo, C and Lu, Y},
title = {From Target Engagement to Translational Disconnect: A Systematic Review and Narrative Synthesis of Direct Tau-Targeted Clinical Trials in Alzheimer's Disease and Primary Tauopathies.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108439},
doi = {10.1016/j.phrs.2026.108439},
pmid = {42702342},
issn = {1096-1186},
abstract = {BACKGROUND: Tau pathology is strongly associated with neurodegeneration and clinical progression in Alzheimer's disease (AD), positioning it as an important therapeutic target. However, tau-targeted therapies have thus far demonstrated limited and inconsistent translation into meaningful clinical benefit.

OBJECTIVE: To examine clinical trials of tau-targeted therapies and explore potential mechanisms underlying their translational disconnect between biological target engagement and clinical outcomes.

METHODS: A structured search of PubMed, MEDLINE, Embase, Cochrane CENTRAL, and related databases was conducted to identify interventional clinical trials targeting tau pathology. Eligible studies included randomized and early-phase trials evaluating monoclonal antibodies, vaccines, antisense oligonucleotides, and small-molecule aggregation inhibitors. Findings were synthesized using a structured narrative approach due to heterogeneity in study design, disease populations, therapeutic mechanisms and clinical end points. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool.

RESULTS: Eleven clinical trials were included, comprising seven monoclonal antibody studies, two vaccine trials, one antisense oligonucleotide study, and one small-molecule aggregation inhibitor study. Across monoclonal antibody and vaccine programs, biomarker modulation and target engagement were observed in some studies, yet these findings did not consistently translate into meaningful reductions in cognitive or functional decline. The antisense oligonucleotide BIIB080 demonstrated substantial reductions in cerebrospinal fluid tau biomarkers, supporting biological activity and target engagement; however, clinical efficacy remains to be established. Similarly, the small-molecule aggregation inhibitor LMTM did not demonstrate consistent clinical benefit in phase 3 trials. Most studies exhibited low risk of bias or some concerns, suggesting that methodological limitations alone may not fully explain the observed translational challenges.

CONCLUSION: Tau-targeted therapies highlight a translational gap between biological activity and clinically meaningful benefit across multiple therapeutic mechanisms. Emerging evidence suggests that disease-stage timing, biomarker interpretation, tau heterogeneity, and aging-related factors may contribute to this disconnect. Future strategies will likely require earlier, and more biologically stratified intervention approaches, improved biomarker validation, and combination paradigms addressing the multifactorial complexity of neurodegenerative disease.},
}

@article {pmid42687883,
year = {2026},
author = {Rodriguez-Espinosa, N and , },
title = {CSF α-synuclein seed amplification assay positivity identifies a distinct soluble amyloid-β profile linked to fibrillar amyloid burden and structural neurodegeneration.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42687883},
issn = {2693-5015},
abstract = {PURPOSE: To determine whether cerebrospinal fluid (CSF) α-synuclein seed amplification assay (SAA) positivity identifies a reproducible soluble amyloid-β (Aβ) configuration and whether its dimensions carry distinct information about downstream pathology and neurodegeneration.

METHODS: In ADNI, 72 participants (13 SAA-positive [SAA+]) had same-day BACE1 activity, sAPPβ, and mass-spectrometry Aβ38/Aβ40/Aβ42. T captured common Aβ38/Aβ40 variation and D42 Aβ42 depletion relative to Aβ38/Aβ40. A one-factor measurement-error model tested common-factor compatibility. The pattern was then tested in 560 participant-disjoint individuals (131 SAA+), with T and D42 reconstructed de novo, and related to amyloid PET, clinical change, whole-brain MRI, and tau PET.

RESULTS: In the proximal cohort, SAA + was associated with lower T (β=-0.549 SD, 95% CI -1.005 to -0.093), but this effect was compatible with the one-factor model (directional compatibility probability = 0.288). In the participant-disjoint cohort, SAA + was associated with lower T (β=-0.267 SD) and higher D42 (β = 0.206 SD); their direct contrast was - 0.473 SD. Higher D42 was associated with subsequent amyloid burden, faster 0-2.5-year clinical worsening, greater whole-brain loss, and subsequent tau burden; lower T independently predicted faster whole-brain loss.

CONCLUSIONS: SAA positivity identifies a reproducible T-low/D42-high soluble-Aβ configuration. The preferential association of D42 with fibrillar amyloid, tau burden, and clinical worsening links the Aβ42-selective component to the AD pathological cascade, while the overall pattern points to altered post-β-cleavage APP/Aβ handling.},
}

@article {pmid42699207,
year = {2026},
author = {Tan, NIYZ and Welton, T and Tan, YJ and Saffari, SE and Morgenroth, E and Foo, SJY and Kwok, ZR and Lim, YC and Chiew, HJ and Ng, KP and Ting, SKS and Kumar, S and Keong, N and Ng, ASL},
title = {Correction: Choroid plexus enlargement is negatively associated with cognitive performance in a DTI-ALPS-dependent manner.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1951916},
doi = {10.3389/fnagi.2026.1951916},
pmid = {42699207},
issn = {1663-4365},
abstract = {[This corrects the article DOI: 10.3389/fnagi.2026.1883244.].},
}

@article {pmid42699398,
year = {2026},
author = {Yasuno, F and Kimura, Y and Yamauchi, Y and Minami, H and Kasuga, K and Ikeuchi, T and Takeda, A and Sakurai, T},
title = {Longitudinal associations of serum MCP-1 with cognitive decline and psychological stress in biomarker-confirmed Alzheimer's disease: A pilot study.},
journal = {Brain, behavior, & immunity - health},
volume = {56},
number = {},
pages = {101333},
pmid = {42699398},
issn = {2666-3546},
abstract = {INTRODUCTION: Monocyte chemoattractant protein-1 (MCP-1; also known as CCL2) is a chemokine implicated in neuroinflammatory pathways that may contribute to cognitive decline in Alzheimer's disease (AD). Elevated MCP-1 is associated with glial activation, blood-brain barrier dysfunction, and immune-cell recruitment. This study assessed the longitudinal association between peripheral MCP-1 and cognitive decline in biomarker-confirmed participants across the AD continuum and explored whether psychological stress was associated with longitudinal MCP-1 changes.

METHODS: This pilot longitudinal study included 21 amyloid-/p-tau-positive participants across the AD continuum, including six with mild cognitive impairment and 15 with AD. Participants underwent baseline and a single 1-year follow-up assessment. Global cognition was assessed using the Alzheimer's Disease Assessment Scale cognitive subscale Japanese version, and serum MCP-1 concentrations were measured using enzyme-linked immunosorbent assay. Stress response, depression, anxiety, apathy, and neuropsychiatric symptoms were assessed using validated behavioral and psychological scales. Stepwise multiple regression and partial correlation analyses were performed.

RESULTS: Annual changes in peripheral MCP-1 were significantly associated with cognitive decline (β = 0.54, P = 0.005). Psychological stress, measured by the Stress Response Scale-18, was positively correlated with MCP-1 changes (r = 0.75, P = 0.003). These findings suggest that longitudinal serum MCP-1 changes may be associated with cognitive decline in the AD continuum and that psychological stress may be related to MCP-1 dynamics.

DISCUSSION: MCP-1 may contribute to AD-related neuroinflammatory activity. The association between psychological stress and MCP-1 changes should be interpreted as exploratory and requires validation in larger longitudinal cohorts.},
}

@article {pmid42699553,
year = {2026},
author = {Laginha, I and Schmitz, M and da Silva Correia, Â and Saleem, T and da Silva Correia, S and Zafar, S and Younas, N and Canaslan, S and Göbel, S and Root, E and Breitbarth, M and Fischer, AL and Dittmar, K and Žakova, D and Hermann, P and Zerr, I},
title = {Prion protein (PrP) profiles in blood and CSF: insights into pre-symptomatic and symptomatic prion disease.},
journal = {Brain communications},
volume = {8},
number = {5},
pages = {fcag321},
pmid = {42699553},
issn = {2632-1297},
abstract = {The conversion of native prion protein (PrP) into its misfolded isoform, scrapie (PrP[Sc]) and its intracellular accumulation represent central events in the pathogenesis of prion diseases. Reduction of native PrP in the central nervous system (CNS) has emerged as a promising strategy for treatment and prevention of prion diseases in humans. To facilitate translation into clinical practice, it is essential to identify at-risk individuals through biomarker development and to elucidate PrP behaviour across prion disease subtypes and biological fluids. Measurements of PrP in accessible biofluids, such as plasma and cerebrospinal fluid (CSF), may provide a pharmacodynamic readout and enable monitoring for PrP-targeted therapies. This study systematically quantifies PrP in plasma and CSF of individuals with sporadic and genetic prion diseases, healthy controls (HC), patients with non-neurodegenerative neurological conditions (ND) and Alzheimer's disease (AD). We analysed 136 plasma and 84 CSF samples, including HC, AD, sporadic Creutzfeldt-Jakob disease (sCJD), as well as symptomatic patients and asymptomatic carriers of the mutations D178N, E200K and P102L. Quantification of PrP was performed using a BetaPrion Human ELISA. Statistical analyses assessed differences between diagnostic groups, associations with demographic factors and PRNP codon 129 polymorphism, and diagnostic accuracy via ROC curves. Plasma PrP was significantly reduced in patients with sCJD (P = 0.043), in symptomatic patients with the E200K (P = 0.0078) and in both symptomatic and asymptomatic D178N carriers (P = 0.0002) compared to HC. Furthermore, symptomatic and asymptomatic D178N carriers had significantly lower plasma PrP levels than patients with AD (P = 0.0025 and P = 0.0041, respectively). In CSF, PrP concentrations were notably lower in D178N symptomatic patients (P = 0.0026) versus non-neurodegenerative (ND) controls. Plasma PrP levels showed no association with age, sex or disease onset and were lower in genetic prion disease patients with the methionine/valine (MV) genotype at PRNP codon 129. The diagnostic accuracy for PrP quantification in plasma as a biomarker discriminated D178N asymptomatic carriers [area under the curve (AUC) = 0.96] and D178N symptomatic patients (AUC = 0.90) from HC with excellent accuracy. In CSF, PrP quantification discriminated D178N symptomatic patients from ND with good accuracy (AUC = 0.64). Taken together, this study defines a characteristic profile of persistently low plasma and CSF PrP in D178N symptomatic and asymptomatic mutation carriers. Low plasma levels in sCJD and E200K, in contrast to P102L, are puzzling. Mutation-specific patterns of PrP need to be considered for monitoring purposes in clinical trials.},
}

@article {pmid42699651,
year = {2026},
author = {Trivedi, MR and Shah, J and Su, Y and Reiman, EM and Wu, T and Wang, Q},
title = {Single cell transcriptomic analysis by deep learning identifies novel microglial transcription regulations in Alzheimer's Disease.},
journal = {AI in neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42699651},
issn = {2997-979X},
abstract = {Artificial Intelligence (AI) has been increasingly applied to investigate genetic irregularities associated with Alzheimer's Disease (AD). However, its potential to uncover deeper, more detailed molecular and cellular mechanisms remains underexplored, primarily due to limitations in integrating large-scale data and capturing the complex, cell-type-specific dynamics involved in AD pathology. Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool in transcriptomics, offering high-resolution, cell-specific insights into complex biological systems. Despite this advancement, a significant gap remains in identifying both common and cell-type-specific transcriptomic signatures that define AD-related cellular and molecular processes. To address this, we propose a deep learning framework leveraging a Multi-Layer Perceptron (MLP) to classify AD versus control nuclei using scRNA-seq data from the Religious Orders Study/Memory and Aging Project (ROSMAP). We focus on microglial subclusters, particularly those representing homeostatic and activated states, to train the MLP model for optimal classification performance. We utilize the predicted embeddings from the MLP to model a disease progression trajectory for each of the datasets. Our model demonstrates strong performance in both classification and disease trajectory inference. To enhance interpretability, SHapley Additive exPlanations (SHAP) are applied to identify key AD-associated genes. Based on the most salient genes implicated in AD, we built transcription gene regulatory networks, revealing novel transcription factors and regulons for AD pathogenesis. These regulons highlight profound impacts of dysregulations of proteostasis, endoplasmic reticulum (ER) stress responses, and circadian rhythm on synaptic plasticity and neuronal survival in AD, offering a more holistic approach to drug target discovery compared to conventional single-target strategies, potentially leading to greater efficacy in slowing or reversing disease progression. This work demonstrates the transformative potential of AI in elucidating the molecular mechanisms of AD, offering improvements over traditional methods and uncovering novel insights into disease pathogenesis and potential therapeutic targets.},
}

@article {pmid42700087,
year = {2026},
author = {Huang, W and Xiao, L},
title = {Alzheimer disease and lichen planus: A Mendelian randomization analysis.},
journal = {Medicine},
volume = {105},
number = {36},
pages = {e50313},
doi = {10.1097/MD.0000000000050313},
pmid = {42700087},
issn = {1536-5964},
mesh = {*Alzheimer Disease/genetics/epidemiology ; Humans ; *Mendelian Randomization Analysis ; *Lichen Planus/genetics/epidemiology ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; },
abstract = {Observational studies suggest an association between lichen planus (LP) and Alzheimer disease (AD), but causality remains unclear due to confounding and reverse causation. In this study, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis using Integrative Epidemiology Unit OpenGWAS database for LP (ID: finn-b-L12_LICHENPLANUS) and AD (ID: ebi-a-GCST90012877). The inverse-variance weighted (IVW) method was used as the primary analysis, complemented by MR-Egger, weighted median, simple mode, weighted mode, and sensitivity analyses to assess the robustness of the findings. Our analysis revealed a significant correlation between genetically predicted AD and an increased susceptibility to LP (P = .0001, odds ratio = 1.4326, 95% confidence interval = 1.1934-1.7196, IVW), providing genetic evidence supporting the oral-brain axis hypothesis. However, we did not detect any causal effect of genetic liability for LP on AD (P = .3749, odds ratio = 1.0147, 95% confidence interval = 0.9825-1.0476, IVW). This bidirectional MR study provides genetic evidence supporting a potential association between AD liability and increased susceptibility to LP, while no evidence was observed for an effect of LP on AD. These findings highlight the importance of further investigating immune-mediated mechanisms, including neuroinflammation and systemic immune dysregulation, that may connect neurodegenerative disorders with oral inflammatory diseases. Future studies are warranted to validate these findings and explore potential therapeutic implications.},
}

*Alzheimer Disease/genetics/epidemiology
Humans
*Mendelian Randomization Analysis
*Lichen Planus/genetics/epidemiology
Genetic Predisposition to Disease
Polymorphism, Single Nucleotide

@article {pmid42700121,
year = {2026},
author = {Andrade, GS and Salomão, CC and Lucena, JT and de Araujo-Souza, P and Hamdan, AC},
title = {Associations of CR1 polymorphism, education and occupation with high cognitive functioning in older adults: A Brazilian sample.},
journal = {Journal of neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jnp.70078},
pmid = {42700121},
issn = {1748-6653},
support = {//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; },
abstract = {Although ageing is naturally associated with cognitive decline, some lifestyle factors, such as formal education and occupational complexity, were shown to promote the preservation of cognitive functions such as memory. Genetic factors, such as the Complement Receptor 1 (CR1) gene, were also identified to have an impact on cognition. This cross-sectional study aimed to assess the associations of education, occupational complexity, and CR1 polymorphisms (rs6656401) with cognitive functions in a sample of autonomous, healthy older adults. A final sample of 102 participants was tested for executive functions, episodic memory, non-verbal memory, and reaction speed, while the final sample for the genetic assessment was 48. The mPACC scores were calculated in order to classify the participants into standard or High-Performing Older Adults. The lifelong occupations were classified according to the International Standard Classification of Occupations-08 criteria. The results revealed that education was more strongly associated with cognitive performance than occupational complexity. However, occupational complexity was independently associated with mental state among the highest education group. Furthermore, normative scores for older adults over 75 are provided. The CR1 AG/AA genotypes were associated with poorer memory performance among older participants, although these exploratory findings should be interpreted with caution due to the limited genetic sample size. The findings are consistent with the hypothesis that both education and occupation are associated with higher cognitive performance in older adults. The findings also suggest distinct cognitive effects of CR1 polymorphisms regarding ageing, although these results should be considered hypothesis-generating rather than confirmatory.},
}

@article {pmid42700142,
year = {2026},
author = {El-Ghazawi, K and Veeramasu, Y and Largoza, GE and Mills, WA and Skalak, SH and Peachey, CH and Eluvathingal Muttikkal, TT and Tang, BA and Wythe, JD and Eyo, UB and Peirce-Cottler, SM},
title = {EXPRESS: Brain pericytes bridge and constrict capillaries in a streptozotocin diabetes mouse model.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261488530},
doi = {10.1177/0271678X261488530},
pmid = {42700142},
issn = {1559-7016},
abstract = {Diabetes is an established driver of microvascular disease, causing complications such as retinopathy, nephropathy, and neuropathy. However, the mechanisms whereby diabetes disrupts brain microvascular function remain poorly understood. Diabetes is strongly associated with cognitive impairments, including Alzheimer's Disease (AD), in which pericyte pathology is implicated in cerebrovascular dysfunction. Pericytes are critical regulators of blood-brain barrier integrity and capillary blood flow, yet their behavior during early diabetes remains uncharacterized. Using a 14-day streptozotocin (STZ) mouse model of early hyperglycemia, we demonstrate two distinct phenotypic changes in the brain prior to pericyte loss. First, tissue clearing and 3D imaging reveal significantly increased pericyte-vessel bridging across multiple brain regions, including the entorhinal cortex and hippocampus, regions among the earliest and most affected in AD. Second, longitudinal two-photon microscopy demonstrates that brain pericytes constrict capillaries in a manner correlated with blood-glucose levels. Capillary constriction occurs at pericyte soma and is associated with significantly reduced red blood cell velocity. Pericytes exhibiting early constriction predominantly maintain this phenotype rather than transitioning to a bridging state, suggesting these represent distinct disease-associated behaviors. These findings indicate that early pericyte pathology may contribute to cerebrovascular dysfunction in diabetes, with implications for understanding microvascular mechanisms linking diabetes and AD.},
}

@article {pmid42700283,
year = {2026},
author = {Atiq, A and Choe, K and Kang, MH and Park, HY and Atiq, U and Ahmad, W and Ali, W and Park, TJ and Kim, MO},
title = {Neuroprotective Effect of Isorhapontigenin (ISO) Against LPS-Induced Neurodegenerative Condition via TLR4/RAGE-Mediated p-NF-kB Activation.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42700283},
issn = {1559-1182},
mesh = {Animals ; *Toll-Like Receptor 4/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Lipopolysaccharides ; *NF-kappa B/metabolism ; *Stilbenes/pharmacology/therapeutic use ; Signal Transduction/drug effects ; *Receptor for Advanced Glycation End Products/metabolism ; Oxidative Stress/drug effects ; Male ; Mice ; *Neurodegenerative Diseases/metabolism/drug therapy/chemically induced/pathology ; Microglia/metabolism/drug effects ; Glycogen Synthase Kinase 3 beta/metabolism ; Mice, Inbred C57BL ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by persistent neuroinflammation, oxidative imbalance, cognitive decline, Aβ buildup, tau phosphorylation, and synaptic dysfunction. Despite progress in understanding AD's development, effective treatments are still limited. Isorhapontigenin (ISO), a methoxylated stilbenoid similar to resveratrol, shows neuroprotective, anti-inflammatory, and antioxidative effects. In this study, we explored ISO's therapeutic potential in a mouse model of AD-like pathology induced by LPS, focusing on TLR4/RAGE-triggered NF-κB signaling pathway and related neuroinflammatory responses, oxidative stress, GSK3β signaling, tau pathology, Aβ accumulation, glial activation, and synaptic health. Western blot and immunofluorescence techniques were used to measure the levels of TLR4/RAGE signaling components, glial markers (GFAP and Iba-1), p-NF-κB signaling pathway activation, proinflammatory cytokines (TNF-α, COX-2, and IL-1β), oxidative stress indicators (Nrf2 and HO-1), neurodegeneration markers (p-GSK3β, p-tau, and Aβ), and synaptic proteins (PSD-95, SNAP-23, and SYP). Nissl staining helped assess neuronal density and structure. BV2 microglial cells were treated similarly in vitro, followed by viability tests and Apotox-Glo™ triplex assays, along with protein expression analysis. The levels of TLR4, RAGE, GFAP, and Iba-1 increased in the LPS-treated group, along with proinflammatory mediators, ROS, LPO, and neurodegenerative markers. Yet, ISO treatment significantly reduced their expression. Moreover, LPS lowered Nrf2 and HO-1 levels, reduced p-GSK3β, and decreased synaptic proteins, indicating oxidative damage and synaptic failure. ISO reversed these changes by restoring p-GSK3β, activating Nrf2/HO-1, and boosting synaptic protein levels, followed by behavioral improvement as evidenced by reduced escape latency and increased spontaneous alternations in the Morris water maze (MWM) and Y-maze tests. Additionally, ISO preserved neuronal and synaptic integrity and provided consistent neuroprotection in BV2 cells. Overall, these results demonstrate that ISO reduces LPS-induced AD-like pathology by activating TLR4/RAGE-driven p-NF-κB, decreasing neuroinflammation, enhancing Nrf2/HO-1 activity, inhibiting GSK3β, lowering Aβ and p-Tau accumulation, preserving synaptic health, and prominent improvement in spatial memory, emphasizing its potential as an AD treatment.},
}

Animals
*Toll-Like Receptor 4/metabolism
*Neuroprotective Agents/pharmacology/therapeutic use
Lipopolysaccharides
*NF-kappa B/metabolism
*Stilbenes/pharmacology/therapeutic use
Signal Transduction/drug effects
*Receptor for Advanced Glycation End Products/metabolism
Oxidative Stress/drug effects
Male
Mice
*Neurodegenerative Diseases/metabolism/drug therapy/chemically induced/pathology
Microglia/metabolism/drug effects
Glycogen Synthase Kinase 3 beta/metabolism
Mice, Inbred C57BL

@article {pmid42700326,
year = {2026},
author = {Aldiqs, M and Aliev, M and Gajjar, TB and Senapati, JN and Alhasso, B and Urazbaeva, D and Aminqulov, S and Mishra, MK},
title = {Therapeutic potential of apigenin in neurodegenerative diseases and brain health.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42700326},
issn = {1573-4978},
mesh = {Humans ; *Apigenin/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Oxidative Stress/drug effects ; *Brain/drug effects/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Antioxidants/pharmacology ; Mitochondria/drug effects/metabolism ; },
abstract = {Neurodegenerative disorders are characterized by progressive neuronal loss and remain a major global health concern, largely due to their complex and multifactorial nature. These conditions, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, involve overlapping mechanisms such as oxidative stress, chronic inflammation, mitochondrial dysfunction, and impaired neurotransmission. In recent years, natural bioactive compounds have gained attention as potential therapeutic candidates. Among them, apigenin, a dietary flavonoid widely found in fruits and vegetables, exerts neuroprotective effects through multiple cellular pathways. This review highlights the potential role of apigenin in modulating key pathological processes in the central nervous system. Apigenin reduces oxidative stress by scavenging reactive oxygen species and activating endogenous antioxidant systems, particularly through Nrf2 signaling. It also exhibits anti-inflammatory effects by inhibiting pathways such as NF-κB and MAPK, thereby lowering pro-inflammatory cytokine production and regulating microglial activation. In addition, apigenin supports mitochondrial function and inhibits apoptosis by modulating Bcl-2 family proteins and caspase activity. Its role extends beyond maintaining blood-brain barrier integrity to regulating autophagy and mitophagy and enhancing neurotrophin signaling, especially through the BDNF/TrkB pathways. Moreover, apigenin influences neurotransmission by balancing excitatory and inhibitory signaling and modulating cholinergic and monoaminergic systems. Despite promising preclinical findings, its clinical application remains limited due to bioavailability challenges and insufficient human studies.},
}

Humans
*Apigenin/pharmacology/therapeutic use
*Neurodegenerative Diseases/drug therapy/metabolism
Animals
Oxidative Stress/drug effects
*Brain/drug effects/metabolism
*Neuroprotective Agents/pharmacology/therapeutic use
Signal Transduction/drug effects
Antioxidants/pharmacology
Mitochondria/drug effects/metabolism

@article {pmid42700370,
year = {2026},
author = {Wu, F and Wang, M},
title = {Entorhinal cortex astrocytes in early Alzheimer disease: Human evidence, cross-species circuit rationale, and translational boundaries.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag098},
pmid = {42700370},
issn = {1554-6578},
support = {//Gansu Province International Cooperation/ ; 25JRRA1271//Gansu Province Science and Technology Project Joint Research Fund/ ; },
abstract = {Alzheimer disease (AD) pathology affects the transentorhinal/entorhinal region early but whether entorhinal cortex (EC) astrocytes are causal drivers or therapeutic targets remains unresolved. This narrative review evaluates EC astrocytes through an explicit evidence hierarchy. We distinguish: (1) human EC-specific neuropathology, imaging, and transcriptomic findings, (2) human AD astrocyte data lacking EC-cell resolution, (3) mechanistic evidence from animal and cellular models, and (4) translational hypotheses. Human data support early EC vulnerability and region- and stage-dependent astrocyte remodeling, whereas the most direct functional evidence comes from rodent medial EC layer II and should be interpreted as circuit plausibility rather than anatomical equivalence to the human EC. We therefore prioritize candidate astrocyte modules according to astrocyte specificity, relevance to EC or medial temporal pathology, mechanistic links to circuit dysfunction, and the availability of measurable target-engagement readouts. These modules include inflammatory-complement signaling, EAAT2/GLT-1-mediated glutamate clearance, MAO-B/GABA metabolism, AQP4-related gliovascular regulation, astrocytic calcium signaling, and APOE-related lipid handling. Cell transplantation, glial reprogramming, and engineered extracellular vesicles remain experimental platforms. EC astrocytes should therefore be viewed as candidate circuit-glial vulnerability nodes requiring human validation, not as established clinical targets.},
}

@article {pmid42700426,
year = {2026},
author = {Bian, K and Zhao, X and Yuan, X and Feng, X and Yang, Z and Sun, W and Xu, G and Jin, H},
title = {Prevalent Stroke, Fatigue, and Incident Dementia Risk in the UK Biobank.},
journal = {Cerebrovascular diseases (Basel, Switzerland)},
volume = {},
number = {},
pages = {1},
doi = {10.1159/ced/accag021},
pmid = {42700426},
issn = {1421-9786},
abstract = {BACKGROUND: Stroke is a major risk factor for dementia, and fatigue is common among stroke survivors. Whether self-reported fatigue is associated with dementia risk among individuals with prevalent stroke remains unclear.

METHODS: We conducted a prospective cohort study of 484,749 UK Biobank participants without dementia at baseline. Participants were classified into four groups according to prevalent stroke and self-reported fatigue: neither exposure, fatigue only, prevalent stroke only, and prevalent stroke with fatigue. The primary outcome was incident all-cause dementia. Secondary outcomes were Alzheimer disease and vascular dementia. Cox proportional hazards models used age as the time scale and adjusted for demographic, socioeconomic, lifestyle, and cardiometabolic factors. Sensitivity analyses included landmark, competing-risk, extended-adjustment, stroke-subtype, and time-updated stroke analyses.

RESULTS: Of 484,749 participants, 60,379 had fatigue only, 5,706 had prevalent stroke only, and 1,697 had both prevalent stroke and fatigue. Compared with participants with neither exposure, adjusted hazard ratios for all-cause dementia were 1.51 (95% CI, 1.42-1.60) for fatigue only, 1.94 (95% CI, 1.74-2.17) for prevalent stroke only, and 2.79 (95% CI, 2.32-3.35) for prevalent stroke with fatigue. For participants with both prevalent stroke and fatigue, hazard ratios were 1.86 (95% CI, 1.32-2.62) for Alzheimer disease and 4.33 (95% CI, 3.24-5.80) for vascular dementia. Among participants with prevalent stroke, fatigue was associated with all-cause dementia after adjustment for time from recorded stroke occurrence to baseline assessment (HR, 1.36; 95% CI, 1.10-1.70), whereas the associations with Alzheimer disease and vascular dementia were not statistically significant.

CONCLUSIONS: Prevalent stroke with self-reported fatigue was associated with the highest risk of incident dementia compared with neither exposure. Among participants with prevalent stroke, fatigue was associated with all-cause dementia but not clearly with Alzheimer disease or vascular dementia.},
}

@article {pmid42700451,
year = {2026},
author = {Sprenger, RJ and Ewald, AC and Romero, PZ and Marino, KM and Gumnit, MG and McCann, EC and Radcliff, AB and Ulland, TK and Watters, JJ and Baker, TL},
title = {Amyloid beta plaque pathology induces chemosensory deficits and increases apnoeas in the 5XFAD mouse model of Alzheimer's disease.},
journal = {The Journal of physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/JP290936},
pmid = {42700451},
issn = {1469-7793},
support = {T32AG000213/NH/NIH HHS/United States ; R01HL142752-03S1/NH/NIH HHS/United States ; R01HL142752/NH/NIH HHS/United States ; R01AG070973/NH/NIH HHS/United States ; R01AG083883/NH/NIH HHS/United States ; P30AG062715/NH/NIH HHS/United States ; RF1AG082215/NH/NIH HHS/United States ; DGE-1747503//NSF/ ; },
abstract = {Sleep disordered breathing (SDB) commonly co-presents with other ventilatory impairments in patients with Alzheimer's disease (AD). Typically reported as either obstructive (OSA) or complex sleep apnoea in AD patients, SDB results in repeated bouts of hypoxia and hypercapnia from insufficient ventilation. It is thought not only that these repeated hypoxic events result in an exacerbation of AD but also that SDB and other ventilatory impairments may be a precursor to neurodegenerative diseases. Although the cause of SDB in AD patients is unclear, chemosensory drive malfunction, a response critical to maintaining homeostatic oxygen and carbon dioxide balance, may play a role. We examined basal ventilation, SDB and chemosensory function in 5XFAD mice, a beta amyloidosis model of AD which displays progressive amyloid beta (Aβ) plaque deposition by 8 months of age. We found that both male and female 5XFAD mice had nearly twice as many spontaneous apnoeas per hour compared to WT mice. Basal ventilation (V̇E) and air convection requirement (ACR) while awake were unchanged, but both hypoxic and hypercapnic ventilatory responses were impaired in 5XFAD mice. While WT mice responded to acute hypoxia with the expected increase in V̇E of ∼150%, 5XFAD mice showed a blunted increase of ∼70% with a similarly blunted hypercapnic response (∼100% increase in 5XFAD mice/∼200% increase in WT mice). Further, we found substantial Aβ deposition in the ventral lateral medulla, an important site for rhythm generation and chemosensing. Taken together, these data suggest a correlation between SDB, Aβ deposition and chemosensory deficits in 5XFAD mice. KEY POINTS: Respiratory dysfunction is common among Alzheimer's disease (AD) patients, but the nature of this dysfunction is not well understood Sleep disordered breathing (SDB) is prevalent in AD patients and is thought to contribute to disease progression 5XFAD mice, a model of beta amyloidosis, display similar respiratory deficits to humans with AD, including SDB and chemosensory changes We show that amyloid beta plaque deposition in the brainstem of 5XFAD mice localizes to regions of respiratory control Our data suggest that amyloid beta plaque deposition in brainstem respiratory control regions contributes to chemosensory dysfunction in 5XFAD mice, a pathology that could worsen SDB occurrence and potentially Aβ-dependent neuropathologies such as AD.},
}

@article {pmid42695408,
year = {2026},
author = {Li, Y and Fan, H and Han, X and Ni, M and Hou, X and Xia, H and Shi, Y and Zhang, L and Sun, J},
title = {Effect of MALT1 inhibition by MI‑2 on the microglial phenotype switch, inflammatory cytokine secretion, neuronal loss and oxidative stress in Alzheimer's disease.},
journal = {International journal of molecular medicine},
volume = {58},
number = {5},
pages = {},
doi = {10.3892/ijmm.2026.5973},
pmid = {42695408},
issn = {1791-244X},
mesh = {*Microglia/metabolism/drug effects/pathology ; *Oxidative Stress/drug effects ; *Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/antagonists & inhibitors/metabolism ; *Alzheimer Disease/metabolism/pathology/drug therapy ; Humans ; *Neurons/metabolism/pathology/drug effects ; Animals ; *Cytokines/metabolism ; Mice ; Phenotype ; Reactive Oxygen Species/metabolism ; NF-kappa B/metabolism ; Cell Line ; Amyloid beta-Peptides ; Cell Survival/drug effects ; },
abstract = {Mucosa‑associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key paracaspase enzyme regulating immune responses, inflammation and oxidative stress. The present study aimed to investigate the effect of MALT1 inhibition on neuroinflammation, neuronal loss and oxidative stress in Alzheimer's disease (AD). A co‑culture system involving microglia and neuron cells under β‑amyloid (Aβ) intervention was used to establish AD cellular models using human microglia HMC3 cells and neuroblastoma SH‑SY5Y cells and mouse microglia BV‑2 and hippocampal neuron HT‑22 cells. The inhibition of MALT1 proteolytic activity was achieved by MALT1 inhibitor 2 (MI‑2) treatment, and the NF‑κB pathway was activated by phorbol 12‑myristate 13‑acetate (PMA) treatment in HMC3 and BV‑2 cells. Western blotting, ELISA, Cell Counting Kit‑8, EdU staining, reactive oxygen species (ROS) detection and reduced glutathione (GSH) assays were performed to evaluate molecular changes, inflammatory responses, neuronal viability and oxidative stress. MALT1 expression was upregulated following Aβ treatment in HMC3 and BV‑2 cells. MALT1 inhibition by MI‑2 suppressed the microglial M1 phenotype but enhanced the M2 phenotype, reduced the levels of the proinflammatory cytokines TNF‑α and IL‑1β and inactivated the NF‑κB pathway in HMC3 and BV‑2 cells. Moreover, microglial MALT1 inhibition elevated cell viability (verified by Cell Counting Kit‑8 and EdU assays), increased the level of reduced glutathione and decreased the levels of reactive oxygen species in SH‑SY5Y and HT‑22 cells. NF‑κB activation by PMA attenuated the effects of MALT1 inhibition on the microglial phenotype switch and proinflammatory cytokine secretion in HMC3 and BV‑2 cells, as well as cell viability and oxidative stress in SH‑SY5Y and HT‑22 cells. The present study reveals that MALT1 inhibition may suppress microglial M1 phenotype, neuroinflammation, neuronal loss and oxidative stress by inactivating the NF‑κB pathway in AD.},
}

*Microglia/metabolism/drug effects/pathology
*Oxidative Stress/drug effects
*Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/antagonists & inhibitors/metabolism
*Alzheimer Disease/metabolism/pathology/drug therapy
Humans
*Neurons/metabolism/pathology/drug effects
Animals
*Cytokines/metabolism
Mice
Phenotype
Reactive Oxygen Species/metabolism
NF-kappa B/metabolism
Cell Line
Amyloid beta-Peptides
Cell Survival/drug effects

@article {pmid42695591,
year = {2026},
author = {Lu, M and Zheng, Y and Chen, T and Wu, Y and Li, Z and Zheng, T and Chen, Q and Peng, X and Shi, L and Pan, Y and Xu, Y and Wei, D},
title = {Quantitative Assessment of Cerebrospinal Fluid-Vascular Association in Alzheimer's Disease Using Phase-Contrast and 4D-Flow Magnetic Resonance Imaging.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {235},
pages = {},
doi = {10.3791/71768},
pmid = {42695591},
issn = {1940-087X},
mesh = {*Alzheimer Disease/cerebrospinal fluid/physiopathology/pathology ; Humans ; *Magnetic Resonance Imaging/methods ; Glymphatic System/pathology ; *Cerebrospinal Fluid/physiology ; },
abstract = {From a neuropathological perspective, the most well-known pathological change in Alzheimer's disease (AD) to date is primarily tau protein hyperphosphorylation, which leads to the formation of intracellular neurofibrillary tangles (NFTs) and amyloid protein deposition-namely, the accumulation of amyloid protein (Aβ) and other protein aggregates outside cells, resulting in neurofibrillary tangles. The glymphatic system, driven by arterial pulsation, clears waste, including amyloid-β, via perivascular spaces (PVS). In AD, vascular dysfunction and slow-wave sleep speculation have been separately observed, and both are hypothesized to impair glymphatic clearance. However, causal links among these factors remain unproven, and the proposed self‑reinforcing cycle-where vascular failure may aggravate protein deposition and further vascular damage-is speculative. This study utilized two-dimensional cine phase-contrast MRI (PC-MRI) and four-dimensional flow MRI (4D-Flow) to quantify hydrodynamic parameters, including cerebrospinal fluid (CSF) flow in the cerebral aqueduct (CA) and blood flow in the internal carotid artery (ICA). Altered CSF-vascular association was observed in AD, suggesting possible glymphatic involvement. The integration of CSF and vascular flow metrics provides a promising biomarker framework for early AD detection and monitoring. PC-MRI and 4D-Flow reveal altered CSF-vascular association in Alzheimer's disease, reflecting potential glymphatic alteration and offering a non-invasive, quantitative method for potential adjunctive biomarker and disease monitoring.},
}

*Alzheimer Disease/cerebrospinal fluid/physiopathology/pathology
Humans
*Magnetic Resonance Imaging/methods
Glymphatic System/pathology
*Cerebrospinal Fluid/physiology

@article {pmid42696024,
year = {2026},
author = {Sultana, SM and Kong, CY and Badhulika, S},
title = {Simultaneous Detection of Dopamine and Xanthine in Human Sweat by Ultrasensitive MoB-MBene/PVA Sponge-like Hydrogel Grown on a Porous Nickel Substrate.},
journal = {ACS applied bio materials},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsabm.6c01330},
pmid = {42696024},
issn = {2576-6422},
abstract = {Dopamine and xanthine are essential biomolecules for neurological disorders and oxidative stress, respectively, and their abnormal concentrations are associated with Parkinson's disease, schizophrenia, Alzheimer's disease, and renal dysfunction. To overcome the limitations of invasive conventional diagnostics, a flexible MoB/PVA hydrogel on nickel foam is fabricated for the simultaneous, non-invasive electrochemical detection of dopamine and xanthine in human sweat. It is prepared through selective alkali etching and solvothermal synthesis. Characterization of the optimized MoB-MBene hydrogel (7 wt %), such as FTIR, confirms characteristic Mo-B vibrational bands, while SEM analysis reveals a sponge-like porous morphology favorable for rapid ion transport and enhanced electroactive sites. Using the DPV technique, the MoB/PVA hydrogel/NF sensor, which has a higher active surface area, demonstrates the simultaneous detection of dopamine, with a linear range from 50 nM to 500 μM, detection limit of 0.35 nM, and sensitivity of 158 μA nM-1 cm-2, and xanthine, with a linear range of 100 nM to 1 mM, detection limit of 0.098 nM, and sensitivity of 95.2 μA nM-1 cm-2, with a peak separation (ΔEp) of 285 mV. The superior electrochemical performance is attributed to the synergistic effect arising from abundant active sites in the ion-rich MoB/PVA hydrogel, facilitating higher charge-transfer kinetics and resulting in enhanced peak currents and well-resolved peaks for simultaneous sensing with 99.6-101.3% recovery for dopamine and 99.3-101.4% recovery for xanthine. Repeatability tests (N = 4) yielded dopamine with a 0.6% RSD and xanthine with a 1.93% RSD. The flexible sensor exhibits excellent selectivity and stability for up to 4 weeks and holds potential for point-of-care and flexible wearable devices.},
}

@article {pmid42696146,
year = {2026},
author = {Zhou, Y and Del Toro, S and Zeng, MY},
title = {Nutritional regulation of gut-brain immune crosstalk across the lifespan.},
journal = {Gut microbes},
volume = {18},
number = {1},
pages = {2725371},
doi = {10.1080/19490976.2026.2725371},
pmid = {42696146},
issn = {1949-0984},
mesh = {Humans ; *Brain/immunology ; Animals ; *Gastrointestinal Microbiome ; Aging/immunology ; *Gastrointestinal Tract/immunology ; *Brain-Gut Axis ; },
abstract = {The gut-brain immune axis integrates microbial, immune, and neural signals to regulate neurodevelopment, homeostasis, and disease susceptibility. Early-life nutrition, particularly human milk oligosaccharides, shapes beneficial microbiota composition, enhances hippocampal plasticity, promotes anti-inflammatory microglia polarization, and fosters immune tolerance. Gut microbiota-derived metabolites, including short-chain fatty acids, tryptophan derivatives and secondary bile acids, regulate microglia maturation, astrocyte function, T cell differentiation, neurotransmitter production, and vagus nerve signaling. These processes influence synaptic pruning, neurogenesis, and neuroinflammation. Adaptive immune cells in the central nervous system, notably meningeal and infiltrating CD4 T cells, further connect peripheral immunity to neuronal responses through cytokines, such as IL-4, IFNγ, and IL-17A. Nutritional imbalances may exacerbate disease-associated microglia and pathogenic T cell activity in Multiple Sclerosis, Alzheimer's disease, and autism spectrum disorders. In aging, diet helps mitigate "inflammaging" by countering metabolic shifts in microglia and lymphocytes. This review examines how nutrition modulates bidirectional gut-brain immune crosstalk across the lifespan.},
}

Humans
*Brain/immunology
Animals
*Gastrointestinal Microbiome
Aging/immunology
*Gastrointestinal Tract/immunology
*Brain-Gut Axis

@article {pmid42696208,
year = {2026},
author = {Chauhdary, Z and Masood, MS and Irfan, M and Shafi, A and Rafique, D and Arif, A and Akmal, M},
title = {Molecular target for neuroinflammation and pain management: transient receptor potential vanilloid 1.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42696208},
issn = {1568-5608},
abstract = {Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel and polymodal sensor of noxious heat, protons, capsaicin and endogenous lipids. The wide variety of functions of TRPV1 in pain transmission, inflammatory pathways and neurological disorders has triggered efforts to understand the molecular mechanisms underlying these functions, particularly pain and neuroinflammation. The molecular structure and its tetrameric structure, temperature and ligand dependent activation and post-translational modification are discussed. It also covers the Ca[2][+]-dependent signalling pathways such as CaMKII/Nrf2, MAPK, NF-κB and PI3K/ERK, and the localization of TRPV1 in sensory neurons, microglia, astrocytes, T lymphocytes and brain tissues. Other notable mentions are the involvement of TRPV1 in acute inflammatory, neuropathic, and visceral pain as well as in neuroinflammatory and neurodegenerative diseases like multiple sclerosis, Alzheimer's disease and Parkinson's disease. Evidence that comes from the various studies suggests that TRPV1 may cause a number of different responses depending on the cell and disease context, whether pro-inflammatory or neuroprotective. Therapeutic strategies directed to TRPV1 such as desensitizing agents, allosteric and state-selective modulators, peptide-based and natural-product based ligands, and gene-directed strategies, are also taken into account. To conclude, the context-dependent activity of TRPV1 signalling holds promise for therapeutic applications, and highlights the importance for context-specific, local and precise targeting of TRPV1 in clinical practice.},
}

@article {pmid42696209,
year = {2026},
author = {Wasim, R},
title = {Targeting cytokine-driven neuroinflammation in Alzheimer's disease: mechanistic insights and pharmacological strategies.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42696209},
issn = {1568-5608},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia worldwide. Although the classical pathological hallmarks of AD include extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, increasing evidence indicates that neuroinflammation plays a central role in disease initiation and progression. Among the key mediators of neuroinflammatory responses, cytokines have emerged as critical regulators of immune communication within the central nervous system. Activated microglia and reactive astrocytes release a wide range of pro-inflammatory cytokines, including IL-1β, IL-6, TNF-α, and interferon-γ, which contribute to synaptic dysfunction, neuronal injury, and amplification of inflammatory signaling pathways. Conversely, anti-inflammatory cytokines such as interleukin-10, interleukin-4, and transforming growth factor-β participate in regulating immune homeostasis and may exert neuroprotective effects by suppressing excessive inflammatory responses. This review provides a comprehensive overview of cytokine-mediated neuroinflammation in Alzheimer's disease, focusing on the cellular sources of cytokine production within the brain, including microglia, astrocytes, neurons, and endothelial cells. Key intracellular signaling pathways involved in cytokine activity, such as nuclear factor-κB (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK-STAT), and mitogen-activated protein kinase (MAPK) pathways, are also discussed in relation to their roles in inflammatory amplification and neurodegeneration. Furthermore, the complex interactions between cytokine signaling, amyloid-β accumulation, and tau pathology are examined to highlight the interconnected mechanisms underlying disease progression. Finally, emerging therapeutic strategies targeting cytokine-driven neuroinflammatory pathways are explored, emphasizing their potential in the development of novel anti-inflammatory and disease-modifying treatments for Alzheimer's disease.},
}

@article {pmid42696253,
year = {2026},
author = {Bianchessi, C and Serpente, M and Ferri, E and Giudici, G and Arcaro, M and Borracci, V and Visconte, C and Buccellato, F and Sacchi, L and Pintus, M and Arosio, B and Arighi, A and Fenoglio, C and Galimberti, D},
title = {Microglia-derived extracellular vesicles uncover early alterations of inflammatory signaling in Alzheimer's disease.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42696253},
issn = {2509-2723},
abstract = {Alzheimer's disease (AD) is increasingly recognized as a neurodegenerative disorder associated with chronic low-grade inflammation and age-related immune dysregulation. Microglial-derived extracellular vesicles (MDEVs) are emerging as important mediators of neuroimmune communication and potential biomarkers reflecting pathological processes occurring within the central nervous system (CNS). However, how EV-associated inflammatory signalling changes across different stages of AD remains poorly understood. In this study, we characterized the inflammatory molecular profile of serum-derived MDEVs in 22 AD patients, 19 prodromal AD subjects, and 23 healthy controls (HC). Cytokine concentrations were also evaluated in paired serum and cerebrospinal fluid (CSF) samples to compare vesicle-associated and soluble inflammatory signals across biological compartments. MDEVs were isolated by size exclusion chromatography followed by TMEM119-based immunoenrichment. Cytokine quantification was performed using the Ella Simple Plex automated immunoassay platform. MDEVs from AD patients showed a generalized reduction in both pro- and anti-inflammatory cytokines compared to HC, including IL-1β, TNF-α, IL-2, IFN-γ, IL-6, IL-12p70, IL-10, and IL-4. Notably, several alterations were already detectable at the prodromal stage. In contrast, soluble cytokines in serum and CSF displayed a predominantly pro-inflammatory profile in AD patients, with increased levels of IL-1β, TNF-α, and IL-12p70. No significant correlations were observed between cytokine levels measured in MDEVs and those detected in serum or CSF. Overall, these findings support the presence of a compartment-specific reorganization of inflammatory signalling during AD progression. Early alterations in MDEV inflammatory cargo may reflect disrupted EV-mediated neuroimmune communication and highlight the potential of MDEVs as accessible peripheral biomarkers of neuroinflammatory processes in AD.},
}

@article {pmid42696260,
year = {2026},
author = {Nakaoka, Y and Sohara, K and Matsuda, H and Mizumura, S and Suda, M and Imai, S and Sekine, T and Ando, T and Tanaka, A and Ishiwata, A and Tateno, A and Koeda, M and Saito, T and Suda, S and Yamazaki, A and Hayashi, H and Kumita, S},
title = {Association of global gray matter volume and cortical thickness with cognitive function stratified by amyloid PET status.},
journal = {Annals of nuclear medicine},
volume = {},
number = {},
pages = {},
pmid = {42696260},
issn = {1864-6433},
support = {Nihon Medi-Physics//Nihon Medi-Physics/ ; },
abstract = {OBJECTIVE: Structural magnetic resonance imaging (MRI) measures may relate to cognition differently depending on the underlying biological context. We examined the associations of global gray matter volume and cortical thickness with cognitive performance after stratification by amyloid positron emission tomography (PET) status.

METHODS: This cross-sectional study included 113 participants (mean age 76.3 ± 7.8 years; 68.1% female) who underwent amyloid PET, structural MRI, and Mini-Mental State Examination (MMSE). Amyloid burden was quantified on the Centiloid scale, with positivity defined as > 25 (44 amyloid-negative, 69 amyloid-positive). Global gray matter volume normalized by total intracranial volume (GM/TIV) and global cortical thickness were derived with CAT12/SPM12. Multivariable linear regression was used to assess associations with the MMSE score after adjustment for age, sex, and amyloid burden, with prespecified stratification by amyloid status. Formal interaction analyses tested effect modification.

RESULTS: In the overall cohort, GM/TIV was independently associated with the MMSE score (β = 0.35, p = 0.007), whereas cortical thickness was not (β = 0.02, p = 0.844). In exploratory stratified analyses, GM/TIV was associated with the MMSE score in amyloid-positive participants (β = 0.48, p = 0.003) but not in amyloid-negative participants (β = 0.05, p = 0.835). Age was associated with the MMSE score in amyloid-negative participants (β = -0.33, p = 0.041) but not in amyloid-positive participants (β = 0.11, p = 0.377). Formal interaction analyses were not significant.

CONCLUSIONS: In this cohort, global GM/TIV was associated with cognitive performance more consistently than global cortical thickness. Exploratory stratified analyses suggested different association patterns according to amyloid PET status; however, formal interaction analyses were not significant. These findings should therefore be interpreted cautiously and validated in larger longitudinal studies.},
}

@article {pmid42696296,
year = {2026},
author = {Rubin, R},
title = {Nearly Half of Dementia Cases May Be Preventable-Here's What the Research Says So Far.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.9439},
pmid = {42696296},
issn = {1538-3598},
}