@article {pmid42535671,
year = {2026},
author = {Mortazavi, N and Vandewalle, G and Talwar, P},
title = {Response to "On the Directionality of Predictor-Outcome Assignment When Modeling Polygenic Risk for Alzheimer's Disease Alongside Sleep Arousal Phenotypes".},
journal = {Sleep},
volume = {},
number = {},
pages = {},
doi = {10.1093/sleep/zsag211},
pmid = {42535671},
issn = {1550-9109},
}

@article {pmid42535759,
year = {2026},
author = {Yang, D and Wu, X and Luo, X and Teng, Y and Duan, X and Kang, T and Wu, W},
title = {Stable Isotope-Resolved Metabolomics in Elucidating Mitochondrial Metabolic Reprogramming and Therapeutic Targets.},
journal = {Biomedical chromatography : BMC},
volume = {40},
number = {9},
pages = {e70560},
pmid = {42535759},
issn = {1099-0801},
support = {25ZC-36//the Natural Science Funding Program of Yibin Vocational and Technical College/ ; },
mesh = {Humans ; *Metabolomics/methods ; *Mitochondria/metabolism ; Metabolic Reprogramming ; Animals ; Isotope Labeling/methods ; Neoplasms/metabolism ; },
abstract = {Stable isotope-resolved metabolomics (SIRM) has emerged as a pivotal methodology for dissecting mitochondrial metabolic reprogramming and its connection to therapeutic targets. By combining isotopically labeled substrates with metabolic flux analysis (MFA), SIRM enables dynamic, quantitative tracking of carbon flux through mitochondrial pathways. This review focuses on three disease contexts where SIRM has provided transformative insights: cancer, neurodegenerative disorders (Alzheimer's and Parkinson's diseases), and metabolic syndrome (type 2 diabetes and non-alcoholic fatty liver disease). Recent applications have delineated reprogramming signatures, identified metabolic dependencies, and elucidated drug mechanisms. SIRM also facilitates therapeutic monitoring and resistance assessment, offering quantitative biomarkers for patient stratification. We summarize recent advances, technical challenges, AI-powered innovations, and future directions, providing a foundation for optimizing metabolism-targeted therapies.},
}

Humans
*Metabolomics/methods
*Mitochondria/metabolism
Metabolic Reprogramming
Animals
Isotope Labeling/methods
Neoplasms/metabolism

@article {pmid42535978,
year = {2026},
author = {Gholami, M and Ahmadi, AA and Niaki, MAA and Asouri, M and Saeedi, S and Amoli, MM and Larijani, B},
title = {New Genetic Associations Between Alzheimer's Disease and Its Key Risk Factors.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70198},
pmid = {42535978},
issn = {1479-8301},
support = {1403-2-221-73223//Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; Risk Factors ; Mitochondrial Precursor Protein Import Complex Proteins ; *Apolipoproteins E/genetics ; *Genetic Predisposition to Disease/genetics ; Membrane Transport Proteins/genetics ; ATP Binding Cassette Transporter 1/genetics ; Genome-Wide Association Study ; Female ; Polymorphism, Single Nucleotide ; Metabolic Syndrome/genetics ; Linkage Disequilibrium ; Male ; Haplotypes ; Aged ; Waist-Hip Ratio ; Diabetes Mellitus/genetics ; },
abstract = {INTRODUCTION: This study aimed to explore shared genetic architectures underlying Alzheimer's disease (AD) and its known risk factors.

METHODS: Significant common variants between AD and its risk factors were identified using GWAS data. The 1000 Genomes Project genotyping data enabled the detection of linkage disequilibrium (LD) blocks and haplotype structures. Functional impact assessments, protein-protein interaction analyses, pathway mapping and enrichment studies were performed.

RESULTS: Sixteen significant variants across nine genes were associated with AD and at least one risk factor (p ≤ 5 × 10[-8]). Genes APOE, ABCA1 and TOMM40 showed strong associations with AD (adjusted p = 9.75 × 10[-9]). High-confidence interactions were identified among these genes, as well as APP and LRP1, within the AD pathway. Variant rs429358 (p ≤ 3 × 10[-15]) on the APOE gene was linked to AD, metabolic syndrome (MetS), diabetes, waist-to-hip ratio (WHR) and ageing. Variant rs2075650 (p ≤ 6 × 10[-9]) on TOMM40 correlated AD risk with MetS, WHR and body mass index (BMI). Variants rs483082 (p ≤ 2 × 10[-32]) and rs71352238 (p ≤ 1 × 10[-11]) on APOC1 and TOMM40 were associated with AD and MetS. Variants rs4420638 (p ≤ 2 × 10[-34]) and rs1800978 (p ≤ 2 × 10[-9]) on APOC1 and ABCA genes were associated with AD and WHR. The rs13237518 (p ≤ 5 × 10[-11]) was associated with AD risk in diabetic patients. Furthermore, the rs4277405 (p ≤ 9 × 10[-20]) associated AD with cardiovascular disease (CVD). Haplotypic structures were also identified for all these variants (D' and r[2] ≥ 0.8).

DISCUSSION: This study identifies genetic variants and LD blocks on APOE, ABCA1, TOMM40 and APOC1 genes shared between AD and its risk factors, revealing common genetic links and potential shared susceptibility pathways.},
}

Humans
*Alzheimer Disease/genetics
Risk Factors
Mitochondrial Precursor Protein Import Complex Proteins
*Apolipoproteins E/genetics
*Genetic Predisposition to Disease/genetics
Membrane Transport Proteins/genetics
ATP Binding Cassette Transporter 1/genetics
Genome-Wide Association Study
Female
Polymorphism, Single Nucleotide
Metabolic Syndrome/genetics
Linkage Disequilibrium
Male
Haplotypes
Aged
Waist-Hip Ratio
Diabetes Mellitus/genetics

@article {pmid42536015,
year = {2026},
author = {Li, S and Jin, J and Liu, Y and Yuan, J and Dong, Y and Wang, Z and Li, L and Zhang, Y},
title = {Microglial immunometabolic reprogramming in Alzheimer's disease: From mitochondrial dysfunction and redox imbalance to NLRP3 inflammasome-driven neuroinflammation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469862},
doi = {10.1177/13872877261469862},
pmid = {42536015},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is increasingly recognized as a disorder in which amyloid-β deposition and tau pathology interact with neuroinflammation and metabolic dysregulation. Although mitochondrial dysfunction, redox imbalance, and NLRP3 inflammasome activation have each been implicated in AD pathogenesis, their mechanistic continuity within microglial immunometabolic reprogramming remains insufficiently defined. This narrative review integrates mechanistic, preclinical, and human-relevant evidence to propose a stage-dependent mitochondrial dysfunction-redox imbalance-NLRP3 inflammasome axis. We discuss how AD-related stimuli shift microglia toward a pro-inflammatory metabolic phenotype; how impaired mitochondrial quality control promotes reactive oxygen species generation and oxidized mitochondrial DNA release; and how these signals facilitate NLRP3 inflammasome activation and sustained inflammatory amplification. We further summarize therapeutic strategies targeting upstream mitochondrial homeostasis, intermediate metabolic-redox coupling, and downstream NLRP3 signaling, while emphasizing the translational limitations and biomarker needs. We conclude that this proposed axis provides a testable stage-dependent framework for interpreting chronic, self-amplifying neuroinflammation in AD and may inform biomarker-guided, combinatorial therapeutic strategies.},
}

@article {pmid42536022,
year = {2026},
author = {Rehman, MU and Masip, D},
title = {Artificial intelligence in retinal imaging for early Alzheimer's disease detection: A review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261473304},
doi = {10.1177/13872877261473304},
pmid = {42536022},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder that necessitates early, accessible, and non-invasive diagnostic methods.ObjectiveThis review examines the potential of artificial intelligence (AI)-based retinal imaging as a transformative and scalable tool for early AD detection across the full diagnostic continuum, including the preclinical stage.MethodsFollowing PRISMA guidelines, 63 primary studies were selected from an initial pool of 240 articles retrieved from PubMed, IEEE Xplore, Scopus, Web of Science, and Google Scholar (2017-mid-2025). Advancements in optical coherence tomography (OCT), retinal fundus imaging, and OCT angiography are examined for their capacity to capture structural and vascular biomarkers, including retinal nerve fiber layer thinning and microvascular alterations. AI architectures, including convolutional neural networks, vision transformers, and hybrid models, are evaluated for their accuracy in retinal biomarker analysis. Benchmark datasets, including public and private ones, are assessed for their role in supporting AI-based AD research.ResultsKey challenges are identified, including data heterogeneity arising from variability in acquisition protocols and demographic representation, as well as computational complexity and limited model interpretability. Emerging approaches-notably multimodal data integration and federated learning-offer promising avenues for enhancing diagnostic accuracy while preserving patient privacy.ConclusionsThe socioeconomic implications of integrating AI-based retinal imaging into clinical workflows are discussed. By synthesizing recent advancements, unresolved challenges, and future directions, this review underscores the transformative potential of AI-driven oculomics in facilitating early AD diagnosis and improving patient outcomes.},
}

@article {pmid42536222,
year = {2026},
author = {Serna, MF and Mosquera, M and García-Perdomo, HA},
title = {Motor performance and its association with Alzheimer's-related biomarkers: a systematic review.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42536222},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/physiopathology/diagnosis ; Biomarkers/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; *Cognitive Dysfunction/physiopathology/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Peptide Fragments/cerebrospinal fluid ; Neurofilament Proteins/cerebrospinal fluid ; },
abstract = {PURPOSE: To examine associations between neurodegenerative and inflammatory biomarkers and motor function in adults with Alzheimer's disease (AD), mild cognitive impairment (MCI), or at risk of AD.

METHODS: A systematic review was conducted using MEDLINE, Web of Science, Scopus, LILACS, and CENTRAL.

RESULTS: Seventeen studies (2018-2026) were included. CSF Aβ42 levels were associated with gait speed, balance, and mobility outcomes, while p-tau, p-tau181, p-tau217, and t-tau correlated with mobility impairments, dual-task performance, and reduced physical function. Higher neurofilament light chain (NfL) levels were linked to poorer Short Physical Performance Battery (SPPB) performance, slower gait speed, and lower grip strength. One study found serum IL-8 associated with mobility outcomes.

CONCLUSIONS: AD-related biomarkers, particularly Aβ42, p-tau, p-tau181, p-tau217, t-tau, and NfL, show consistent associations with gait disturbances, mobility decline, and reduced physical function. Motor changes may precede cognitive decline, supporting their potential as early indicators of neurodegeneration.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/physiopathology/diagnosis
Biomarkers/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
*Cognitive Dysfunction/physiopathology/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
Peptide Fragments/cerebrospinal fluid
Neurofilament Proteins/cerebrospinal fluid

@article {pmid42536296,
year = {2026},
author = {Li, YQ and Chen, DX and Zhu, XT and Li, W and Wu, JL and Fang, LM and Li, MQ},
title = {Therapeutic Potential of Jiedu Yizhi Formula for Alzheimer's Disease: A Randomized Controlled Trial.},
journal = {Chinese journal of integrative medicine},
volume = {},
number = {},
pages = {},
pmid = {42536296},
issn = {1993-0402},
abstract = {OBJECTIVE: To observe the clinical effect and safety of Jiedu Yizhi Formula (JYF) in Alzheimer's disease (AD) patients.

METHODS: Eligible patients with mild to moderate AD and Chinese medicine (CM) syndrome of Pi (Spleen)-Shen (Kidney) deficiency with phlegm-turbidity obscuring orifices were collected from the Third Affiliated Hospital of Changchun University of Chinese Medicine between December 2022 and December 2023. Patients were randomly assigned to JYF and donepezil groups at a 1:1 ratio by using a random number table and received a total of 24 weeks of continuous treatment. Both groups were given AD cognitive behavior training and health education at the same time. The Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), AD Assessment Scale-Cognitive (ADAS-cog), Activity of Daily Living (ADL), and Hamilton Depression (HAMD) scale scores were measured before treatment, 12 and 24 weeks after treatment. The cognitive domain scores and the total effective rates were also compared between groups. During the study period, any adverse reactions were recorded and compared between groups.

RESULTS: Totally 62 participants completed the study, with 31 in each group. The MMSE, MoCA, ADAS-cog, ADL, and HAMD scores significantly improved after 12 and 24 weeks of treatment in both groups (P<0.05 or P<0.01). Moreover, significant improvements in the ADL and HAMD scores were observed in the JYF group at 12 or 24 weeks than in the donepezil group (P<0.05 or P<0.01). Meanwhile, the cognitive domain scores of orientational and abstraction abilities and the total effective rate (64.52% vs. 45.16%) in the JYF group were significantly higher (P<0.05). No significant difference was found in the incidence of adverse reactions between groups (9.68% vs. 6.45%, P>0.05).

CONCLUSION: JYF can improve the cognitive dysfunction of mild to moderate AD patients with CM syndrome of Pi-Shen deficiency with phlegm-turbidity obscuring orifices, and its safety is good. (Trial registration No. NCT06393413).},
}

@article {pmid42536368,
year = {2026},
author = {Chiotis, S and Giannopoulos, G and Zagalioti, SC and Konstantinidou, SE and Mountourli, MI and Zgouridou, A and Anastasiou, A and Bakogiannis, K and Evaggeliou, A and Sapouridis, G and Toumpourleka, M and Triantafyllou, C and Poptsi, E and Symeonidis, A and Tsolaki, M and Vassilikos, V},
title = {Global and Domain-Specific Cognitive Outcomes After Catheter Ablation for Atrial Fibrillation.},
journal = {JAMA network open},
volume = {9},
number = {7},
pages = {e2626642},
doi = {10.1001/jamanetworkopen.2026.26642},
pmid = {42536368},
issn = {2574-3805},
mesh = {Humans ; *Atrial Fibrillation/surgery/complications ; *Catheter Ablation/adverse effects/methods ; Female ; Prospective Studies ; Male ; Middle Aged ; *Cognition ; *Cognitive Dysfunction/etiology ; Greece ; Magnetic Resonance Imaging ; Aged ; Treatment Outcome ; },
abstract = {IMPORTANCE: Atrial fibrillation (AF) is associated with cognitive impairment, but the cognitive effects of catheter ablation (CA) using contemporary techniques remain uncertain.

OBJECTIVE: To evaluate changes in global and domain-specific cognitive function after CA for AF.

This prospective cohort study included consecutive patients undergoing CA for AF and a nonablation AF control group at a tertiary university hospital in Greece between January 2022 and June 2024. Cognitive assessments were performed at baseline and at 6-month follow-up.

EXPOSURES: CA using cryoballoon or pulsed field ablation (PFA).

MAIN OUTCOMES AND MEASURES: Changes from baseline to 6 months in Montreal Cognitive Assessment (MoCA) scores and the novel REMEDES for Alzheimer (R4Alz) total and subdomain scores. Brain magnetic resonance imaging was performed before and within 48 hours after ablation to detect new cerebral infarcts.

RESULTS: Among 75 patients (40 [53.3%] female) undergoing ablation (mean [SD] age, 61.9 [10.4] years; 54 cryoballoon, 21 PFA) and 40 in a nonablation control group (26 [65.0%] female; mean [SD] age,61.4 [9.2] years), baseline cognitive scores were similar between groups. No new cerebral infarcts were detected after ablation. At 6 months, MoCA scores in the ablation group did not change significantly (mean change, 0.27; 95% CI, -0.08 to 0.62), whereas R4Alz total scores increased (mean change, 2.81; 95% CI, 1.55 to 4.07), mainly associated with gains in short-term working memory and perceptual inhibition. No significant changes were observed in the control group. Compared with the control group, the ablation cohort demonstrated significantly greater improvements in both MoCA (mean difference in change, 0.74; 95% CI, 0.17 to 1.31; P = .01) and R4Alz total score (mean difference in change score, 3.18; 95% CI, 0.87 to 5.49; P = .007). In adjusted analyses accounting for baseline cognitive score and clinical covariates, ablation was independently associated with higher follow-up MoCA (β = 0.88; 95% CI, 0.31 to 1.44) and R4Alz scores (β = 3.80; 95% CI, 1.70 to 5.90).

CONCLUSIONS AND RELEVANCE: In this prospective observational cohort study of 75 patients undergoing CA for AF, ablation was not associated with cognitive decline and was instead associated with modest short-term improvements in selected cognitive domains. Domain-specific assessment detected changes not captured by global cognitive screening, suggesting that modern ablation techniques may be associated with early subtle cognitive gains.},
}

Humans
*Atrial Fibrillation/surgery/complications
*Catheter Ablation/adverse effects/methods
Female
Prospective Studies
Male
Middle Aged
*Cognition
*Cognitive Dysfunction/etiology
Greece
Magnetic Resonance Imaging
Aged
Treatment Outcome

@article {pmid42536379,
year = {2026},
author = {Rubin, R},
title = {Soccer Players' Brains, P-Tau217 Blood Tests, Lifestyle and Dementia Risk, and More From AAIC 2026.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.14334},
pmid = {42536379},
issn = {1538-3598},
}

@article {pmid42536688,
year = {2026},
author = {Xie, Y and Lim, CT and Lam, XJ and Cheah, PS and Ling, KH and Huang, T},
title = {Integrative network pharmacology, transcriptomics, and molecular docking identify candidate Centella asiatica constituents and targets in neurodegenerative diseases.},
journal = {PloS one},
volume = {21},
number = {7},
pages = {e0354882},
pmid = {42536688},
issn = {1932-6203},
mesh = {*Molecular Docking Simulation ; *Neurodegenerative Diseases/drug therapy/genetics/metabolism ; *Centella/chemistry ; Humans ; *Network Pharmacology/methods ; *Triterpenes/chemistry/pharmacology ; *Transcriptome/drug effects ; Gene Expression Profiling ; },
abstract = {BACKGROUND: Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), are progressive disorders with limited therapeutic options. Centella asiatica (C. asiatica), a medicinal and edible plant, has been reported to exert neuroprotective and anti-neuroinflammatory properties. Yet, the mechanisms underlying its effects against neurodegenerative diseases remain largely unclear.

METHODS: We employed an integrative strategy combining network pharmacology, transcriptomic analyses, machine learning and molecular docking to prioritize disease-associated molecular networks and candidate compound-target relationships in AD, PD and HD.

RESULTS: Sixteen candidate constituents of C. asiatica met the predefined drug-likeness, gastrointestinal absorption and blood-brain barrier permeability criteria, yielding 370 unique predicted targets. Disease-gene mining identified 983 AD-associated genes, 1,103 PD-associated genes, and 3,316 HD-associated genes. Integration of compound targets, disease-associated genes, and transcriptomic profiles prioritized five hub genes in PD (CCKAR, MAPK8, PSEN2, SLC6A3, and TH), four in AD (APP, PGK1, PIK3CA, and TTR), and four in HD (CHRND, HSP90AA1, PRKCQ, and TH). Enrichment analyses highlighted disease-relevant processes involving neurotransmitter signalling, cAMP and calcium pathways, MAPK-related responses and inflammatory regulation. ROC analyses provided additional support for the discriminatory performance of the prioritized genes in independent datasets, whereas molecular docking identified favourable predicted Vina docking scores and structurally plausible interactions between selected compounds and hub targets.

CONCLUSION: This integrative computational analysis prioritizes candidate C. asiatica constituents, putative disease-associated targets, and molecular pathways in AD, PD, and HD. The findings provide a foundation for subsequent biochemical, cellular, and in vivo validation.},
}

*Molecular Docking Simulation
*Neurodegenerative Diseases/drug therapy/genetics/metabolism
*Centella/chemistry
Humans
*Network Pharmacology/methods
*Triterpenes/chemistry/pharmacology
*Transcriptome/drug effects
Gene Expression Profiling

@article {pmid42536712,
year = {2026},
author = {},
title = {Retraction: Detection of Peri-Synaptic Amyloid-β Pyroglutamate Aggregates in Early Stages of Alzheimer's Disease and in AβPP Transgenic Mice Using a Novel Monoclonal Antibody.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474572},
doi = {10.1177/13872877261474572},
pmid = {42536712},
issn = {1875-8908},
}

@article {pmid42537247,
year = {2026},
author = {Du, X and Bao, M and Li, Y and Ding, J and Zhang, Z and Chen, H and Liu, Y},
title = {Neuroprotective mechanism of Ribisin A on Aβ25-35-induced PC12 cell damage model.},
journal = {Tissue & cell},
volume = {104},
number = {Pt 1},
pages = {103825},
doi = {10.1016/j.tice.2026.103825},
pmid = {42537247},
issn = {1532-3072},
abstract = {Amyloid-β (Aβ) is a neurotoxic substance, and studies have found that its excessive deposition in the brain, forming senile plaques, is a major pathological feature of Alzheimer's disease (AD). In previous studies, Ribisin A, a benzofuran compound, was purified from Phellinus ribis and found to have neuroprotective effects. This study aims to elucidate the neuroprotective mechanism of Ribisin A in an Aβ25-35-damaged PC12 cell model. This study established an in vitro AD model using PC12 cells damaged by Aβ25-35. We applied methyl tetrazolium (MTT), enzyme-linked immunosorbent assay (ELISA) kits, flow cytometry, and western blotting techniques to study the effects of Ribisin A on the Aβ25-35 injury model and the relationship with the ERK pathway from the aspects of cell injury degree, cytokine content, Calcium ion (Ca[2 +]) concentration, mitochondrial membrane potential (MMP), and the ERK pathway-related protein expression. Results indicate that Ribisin A reduced lactate dehydrogenase (LDH), reactive oxygen species (ROS), tumour necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) levels in the Aβ25-35-induced cellular injury model while increasing superoxide dismutase (SOD) levels. Furthermore, it inhibited Aβ25-35-induced increases in Ca[2+] concentration and decreases in MMP, leading to upregulation of ERK pathway-related proteins TrkB, p-ERK1/2, and p-CREB, with significant elevations in p-ERK/ERK and p-CREB/CREB ratios (P < 0.01). Ribisin A can reduce oxidative damage, inhibit inflammation, restore mitochondrial function, and reduce apoptosis. The neuroprotective mechanism of Ribisin A may involve regulation of the TrkB-mediated ERK/CREB signaling cascade. Our study provides evidence for the neuroprotective mechanism of Ribisin A in an Aβ25-35-induced cellular injury model.},
}

@article {pmid42537334,
year = {2026},
author = {Larico-Ramirez, LP and Paco-Chipana, M and Herrera, MI and Goyzueta-Mamani, D and Chavez-Fumagalli, M and Barazorda-Ccahuana, HL},
title = {Integrative computational discovery of a lichen-derived acetylcholinesterase inhibitor candidate for Alzheimer's disease.},
journal = {Computational biology and chemistry},
volume = {125},
number = {},
pages = {109275},
doi = {10.1016/j.compbiolchem.2026.109275},
pmid = {42537334},
issn = {1476-928X},
abstract = {Alzheimer's disease (AD), the leading cause of dementia worldwide, is a progressive neurodegenerative disorder for which current pharmacological treatments provide only limited symptomatic relief. Human acetylcholinesterase (hAChE) remains one of the most extensively validated therapeutic targets because its inhibition enhances cholinergic neurotransmission and temporarily improves cognitive function. Motivated by the remarkable structural diversity of lichen secondary metabolites, we investigated their potential as novel hAChE inhibitors using an integrated multiscale computational strategy that combined structure-based virtual screening, ADME/Tox profiling, density functional theory (DFT) calculations, molecular dynamics (MD) simulations, and MM/GBSA binding free-energy analysis, with donepezil employed as the reference inhibitor. Among the screened compounds, calycin emerged as the most promising candidate. It displayed high predicted binding affinity together with favorable pharmacokinetic characteristics, including high gastrointestinal absorption and blood-brain barrier permeability. Electronic structure analysis revealed greater chemical reactivity and electronic adaptability than donepezil, indicating an enhanced ability to establish stabilizing interactions within the hAChE active site. Molecular electrostatic potential and local reactivity descriptors further identified chemically active regions responsible for favorable non-covalent interactions along the active-site gorge. Long-timescale MD simulations confirmed the structural stability of the hAChE-calycin complex, while MM/GBSA calculations demonstrated a thermodynamically favorable binding process predominantly driven by van der Waals and hydrophobic interactions with key aromatic residues. Collectively, these findings identify calycin as a promising lead scaffold for the development of next-generation hAChE inhibitors and demonstrate the potential of lichen-derived natural products as an underexplored source of chemically diverse candidates for Alzheimer's disease drug discovery.},
}

@article {pmid42537728,
year = {2026},
author = {Zhang, Y and Ge, P and Mao, J and Wang, T and Yuan, H},
title = {Role of auricular vagus nerve stimulation in alleviating neuronal apoptosis and cognitive dysfunction in male rats with vascular dementia.},
journal = {Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association},
volume = {},
number = {},
pages = {108716},
doi = {10.1016/j.jstrokecerebrovasdis.2026.108716},
pmid = {42537728},
issn = {1532-8511},
abstract = {BACKGROUND AND PURPOSE: Vascular dementia (VD) is characterized by cognitive impairment resulting from cerebrovascular damage. Prior studies have shown that vagus nerve stimulation improves learning and memory in patients with Alzheimer's disease. This study, therefore, investigated whether auricular vagus nerve stimulation (aVNS) ameliorates cognitive dysfunction in a rat model of VD through activation of the adenosine A2A receptor (A2AR) and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathways.

METHODS: Fifty male rats were randomly assigned to five groups by a computer-generated sequence: control (A), sham-operated (B), VD model (C), aVNS-treated (D), and aVNS combined with the A2AR antagonist SCH 58261 (E). Rats in the aVNS group received stimulation (0.6 mA, 40 Hz, 0.5 ms square pulses) for 4 weeks. Spatial learning and memory were evaluated using the Morris water maze test. Rat brain microvascular endothelial cells were cultured and treated with an A2AR agonist and/or a protein kinase A (PKA) inhibitor to verify the involvement of the A2AR-Nrf2/HO-1 pathway. Expression levels of inflammatory cytokines (IL-1β and IL-6), key signaling proteins (A2AR, p-PKA, p-Nrf2, and HO-1), and phosphorylated tau (p-tau) were measured using western blot or enzyme-linked immunosorbent assays.

RESULTS: Compared with Groups C and E, Group D exhibited improved spatial learning and memory. aVNS markedly increased the p-PKA and p-Nrf2/HO-1 levels while reducing p-tau and proinflammatory cytokine levels. In vitro experiments showed that A2AR agonist treatment upregulated p-PKA and p-Nrf2/HO-1 expression; however, this effect was abolished by PKA inhibition.

CONCLUSION: aVNS ameliorates cognitive impairments in VD rats and attenuates neuronal apoptosis, p-tau accumulation, and neuroinflammation, and these effects are associated with activation of the A₂AR/PKA/Nrf2/HO-1 signaling pathway. These findings suggest that aVNS may represent a promising therapeutic strategy for cognitive impairment associated with VD.},
}

@article {pmid42537760,
year = {2026},
author = {Misrani, A and Wang, J and Xu, Y and Liu, F},
title = {IL-17A levels in Alzheimer's Disease brains are mediated by X chromosome dosage.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112065},
doi = {10.1016/j.brainresbull.2026.112065},
pmid = {42537760},
issn = {1873-2747},
abstract = {Among inflammatory mediators, interleukin-17A (IL-17A) has emerged as a potential contributor to AD pathogenesis, although its role remains incompletely defined. Notably, sex differences are evident in AD, with males exhibiting earlier mortality and greater cognitive deficits during aging and preclinical stages compared to females. While hormonal influences have been widely studied, the contribution of sex chromosome complement was suggested critical and remains poorly understood. Here, we investigated the impact of sex chromosome on cognitive function and neuroinflammation using amyloid and tau mouse models. Female Tg2576 and PS19 mice were crossed with XY* males to generate XX, XO, XY, and XXY genotypes, enabling separation of X from Y chromosomal effect. Behavioral assessments, including fear conditioning, novel object recognition, and Barnes maze, revealed that XY mice exhibited significantly greater cognitive impairment compared to XX and XXY counterparts. The same pattern was seen in IL-17A levels, indicating an effect of X chromosome instead of Y. Amyloid-β and phosphorylated tau pathology by immunohistochemistry and Elisa confirmed robust disease-associated accumulation in Tg2576 and PS19 mice, but showed no differences across sex chromosome complements. Collectively, our study identifies X chromosome dosage as a key modulator of cognitive resilience and IL-17A-linked neuroinflammation in AD models. Future studies focused on understanding how X-linked factors regulate IL17 mediated neuroinflammatory pathways could reveal novel therapeutic targets for AD.},
}

@article {pmid42537824,
year = {2026},
author = {Abouali, O and Mokabber, A and Naderpour, S and Vojoudi, E and Sefat, F and Saeinasab, M and Rahimzadegan, M and Nosrati, R},
title = {Chitosan-based hydrogel for intranasal drug delivery; current advances in the brain diseases treatment.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {127259},
doi = {10.1016/j.ijpharm.2026.127259},
pmid = {42537824},
issn = {1873-3476},
abstract = {Neurodegenerative diseases represent a growing health concern that is projected to become more prevalent and affect more people in the upcoming decades. One of the most complicated components of recent neurodegenerative disease therapies is the penetration and delivery of therapeutics to the central nervous system (CNS), which are hindered via the blood-brain barrier (BBB). In response, innovative treatment approaches leveraging noninvasive techniques including nanosized drug delivery systems and intranasal (IN) administration with higher treatment efficacy and patient satisfaction are developing as potential options. IN administration delivers medications directly to the brain through both the olfactory and trigeminal pathways, with the olfactory pathway representing the primary route for nose-to-brain transport. Among various IN platforms, chitosan (CS)-based hydrogels have attracted considerable attention because of their excellent biocompatibility, biodegradability, mucoadhesive properties, and ability to enhance drug permeation by prolonging nasal residence time and transiently modulating epithelial tight junctions. This review critically summarizes recent advances in CS-based hydrogels for IN drug delivery for the treatment of brain diseases including Alzheimer's disease (AD), Parkinson's disease (PD), depressive manifestations, ischemia,brain tumors,epilepsy, seizures, and schizophrenia. In addition, the review discusses the relationships between hydrogel design and therapeutic performance, highlights current translational challenges, and outlines future perspectives for the clinical development of CS-based IN hydrogel systems.},
}

@article {pmid42537957,
year = {2026},
author = {Chen, K and Xuan, ZY and Sun, BY and Zhong, GN and Sun, XL and Yan, J},
title = {The critical role of microglia in the stress response.},
journal = {Neuroscience and biobehavioral reviews},
volume = {189},
number = {},
pages = {106894},
doi = {10.1016/j.neubiorev.2026.106894},
pmid = {42537957},
issn = {1873-7528},
abstract = {Microglia are the principal resident innate immune cells of the central nervous system (CNS). Beyond maintaining brain homeostasis via cytokine secretion and phagocytic clearance, they fulfill essential roles in synaptic pruning, oligodendrocyte maturation, and higher-order functions including learning and memory. In response to stress exposure, microglia undergo robust activation, characterized by morphological remodeling, altered phagocytic activity, and dysregulated inflammatory signaling, positioning them as active mediators of the integrated systemic stress response. This review systematically synthesizes preclinical and clinical evidence regarding the multifaceted contributions of microglia to stress processing, their mechanistic involvement in the pathogenesis of major stress-related disorders-including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), Alzheimer's disease (AD), and Parkinson's disease (PD)-and summarizes emerging microglia-targeted therapeutic strategies. We underscore the substantial mechanistic and translational value of microglial research for advancing our understanding of stress adaptation and associated brain pathologies.},
}

@article {pmid42538506,
year = {2026},
author = {Zhang, M and Ho, FK and Pell, JP and Celis-Morales, C and Bailey, MES and Strawbridge, RJ and Lyall, DM},
title = {Heterogeneity in the association between APOE ε4 carrier status and dementia risk by modifiable and non-modifiable risk factors.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42538506},
issn = {2509-2723},
abstract = {Dementia is a major public health challenge, and Apolipoprotein E (APOE) ε4 is strongly associated with all-cause dementia, particularly Alzheimer's disease (AD). We aim to quantify the overall contribution of modifiable lifestyle, adiposity, socioeconomic status (SES), and health conditions occurring before dementia, to the association between ε4 genotype and the development of all-cause dementia, with AD examined as a major subtype. A population cohort study of 181,006 white UK Biobank participants aged ≥ 55 years at baseline was conducted, to examine the associations between APOE ε4 and all-cause dementia, and specifically AD, including modification and mediation role of lifestyle factors, adiposity, SES, and health conditions occurring before dementia. All risk factors, except for high alcohol intake, low diet quality, and phenotypic obesity, were associated with higher risk of all-cause dementia. The interaction contributions of lifestyle, adiposity, SES, and health conditions occurring before dementia varied by sex and dementia type. Low educational attainment had the strongest interaction effects with the association of APOE ε4 carriers and AD/all-cause dementia (up to 32.1%). In women, high deprivation level, abnormal sleep duration, anxiety, and depression showed interaction effects with APOE genotype (5-11.6%) as well. Phenotypic adiposity was associated with an increased risk of dementia among APOE ε4 non-carriers, but with a reduced risk among APOE ε4 carriers. Educational attainment explained a meaningful proportion of the APOE ε4 association with dementia. The strength of the association between APOE ε4 and dementia differed by risk factors and sex.},
}

@article {pmid42538752,
year = {2026},
author = {Van Langenhove, T and Van Mossevelde, S and Miatton, M and De Lepeleire, J and Bruffaerts, R and Bier, JC and Segers, K and Verschraegen, J and Petrovic, M and Ventura, M and Jedidi, H and Beyer, I and Mormont, E and Vandenberghe, R and Delva, A and Gilles, C and Van Weehaeghe, D and Picard, G and De Deyn, P and Strauss, M and Thiery, E and Salmon, E and Cypers, G and Vlaemynck, J and Gillis, K and Versijpt, J and Bjerke, M and Sieben, A and Hanseeuw, B and Engelborghs, S and Deryck, O and , },
title = {Biomarker-Based Diagnosis and Care Pathways for Alzheimer's Disease in the Era of Disease-Modifying Treatments: A Consensus Statement by Belgian Experts.},
journal = {European journal of neurology},
volume = {33},
number = {8},
pages = {e70668},
doi = {10.1111/ene.70668},
pmid = {42538752},
issn = {1468-1331},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; *Biomarkers/cerebrospinal fluid/blood ; Belgium ; },
abstract = {BACKGROUND: The recent approval of disease-modifying therapies (DMTs) for early Alzheimer's disease (AD) marks a major shift in clinical practice. Biomarker confirmation of amyloid pathology is now required alongside clinical assessment, and blood-based tests are improving accessibility. This creates increased demand for timely and accurate diagnosis while avoiding overdiagnosis in low-probability cases. This Belgian consensus aims to guide biomarker-based diagnosis of AD in the era of DMTs and to highlight the system adaptations required for safe and equitable implementation. Belgium, with universal healthcare but regionally organised dementia care, provides a relevant case to illustrate both opportunities and challenges.

METHODS: This consensus was developed by 31 experts in cognitive neurology, geriatrics, neuropsychology, neuroimaging, neurochemistry, and primary care, coordinated by the Belgian Dementia Council (BeDeCo). Recommendations were based on multidisciplinary discussion, current evidence, and the organisation of dementia care in Belgium.

RESULTS: The consensus outlines a stepwise diagnostic approach that integrates clinical assessment with biomarker confirmation using cerebrospinal fluid, amyloid-PET, and emerging blood-based tests. We review the strengths and limitations of each modality and provide guidance for use across clinical scenarios. Using Belgium as a case example, we illustrate challenges that are shared across European healthcare systems, such as limited reimbursement, unequal access to expertise, and insufficient diagnostic capacity, and formulate pragmatic recommendations to address these issues.

CONCLUSIONS: This consensus offers practical guidance for embedding biomarker-based diagnostic strategies into clinical care. By outlining structured pathways and system-level priorities, it facilitates safe, feasible, and equitable implementation of DMTs for AD.},
}

Humans
*Alzheimer Disease/diagnosis/therapy
*Biomarkers/cerebrospinal fluid/blood
Belgium

@article {pmid42538765,
year = {2026},
author = {Sun, H and Huang, D and Yang, F and Zhang, P and Yang, D and Zeng, C},
title = {Metabolomic Discoveries for Traditional Chinese Medicine Efficacy in Alzheimer's Disease.},
journal = {BioMed research international},
volume = {2026},
number = {1},
pages = {e2455800},
pmid = {42538765},
issn = {2314-6141},
support = {2023008//Scientific Research Projects of Medical and Health Institutions of Longhua District, Shenzhen/ ; 82270940//The National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Medicine, Chinese Traditional/methods ; *Metabolomics/methods ; *Drugs, Chinese Herbal/therapeutic use ; Animals ; Brain/metabolism ; Metabolic Networks and Pathways/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and behavioral alterations. However, the complex etiology and pathogenesis of AD have thus far precluded the development of satisfactory therapeutic agents. Traditional Chinese medicine (TCM) has garnered increasing recognition for its potential in AD management due to its multicomponent, multitarget therapeutic strategy. Metabolomics, an advanced analytical methodology for investigating metabolic alterations in biological systems, has yielded significant insights into both the therapeutic efficacy and mechanistic underpinnings of TCM interventions for AD. This review synthesizes recent metabolomic findings associated with TCM approaches to AD treatment, identifying key metabolic pathways across diverse biological specimens, including brain tissue, blood, urine, and feces. Through systematic elucidation of these metabolic networks, metabolomics offers substantial potential to facilitate the advancement of TCM-derived therapeutics for AD, potentially enhancing global patient outcomes.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy
*Medicine, Chinese Traditional/methods
*Metabolomics/methods
*Drugs, Chinese Herbal/therapeutic use
Animals
Brain/metabolism
Metabolic Networks and Pathways/drug effects

@article {pmid42538866,
year = {2026},
author = {Jiang, Y and Yang, T},
title = {In APP/PS-1 Transgenic Mice and Aβ-Induced P12 Cell Models, ADCYAP1 Inhibits Neuronal Apoptosis and Autophagy, Thereby Alleviating The Pathology of Alzheimer's Disease.},
journal = {Cell journal},
volume = {28},
number = {1},
pages = {1-13},
doi = {10.22074/cellj.2026.2045830.1718},
pmid = {42538866},
issn = {2228-5814},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly. ADCYAP1 encodes pituitary adenylate cyclase activating polypeptide (PACAP), which can exert neuroprotective effects in neurodegenerative diseases. This study aims to probe the specific function of ADCYAP1 in AD.

MATERIALS AND METHODS: In this experimental study, brain tissue samples from AD patients and healthy controls were collected to assess ADCYAP1 expression. APP/PS-1 transgenic mice were utilised as an AD mouse model along with amyloid beta (Aβ)-induced PC12 cells as an AD cell model. ADCYAP1 expression in the AD mice was determined by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. An IF assay was employed to test Aβ deposition and microtubule-associated protein 2 (MAP2) expression (a neuron marker). Behavioural tests, including the Morris water maze (MWM) and footprint tests, were performed to evaluate cognitive impairment and motor ability. Cell apoptosis was determined using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-nick end labelling (TUNEL) assay. Western blot was utilised to test the expression of autophagy-related genes, including LC3 and beclin1. The expressions of transcription factors involved in neuronal differentiation was assessed by RTqPCR.

RESULTS: ADCYAP1 expression was significantly downregulated in the brain tissues of AD patients and mice. ADCYAP1 overexpression reduced Aβ deposition and enhanced MAP2 expression in the AD mice. ADCYAP1 overexpression effectively improved cognitive impairment and mobility decline in the AD mice. ADCYAP1 upregulation inhibited neuronal apoptosis and autophagy both in vivo and in vitro. ADCYAP1 upregulated the expression of neuronal differentiationrelated factors [transforming growth factor β (TGFβ), early growth response 1 (Egr1), brain-derived neurotrophic factor (BDNF), fibroblast growth factor 21 (FGF21), and insulin-like growth factor 1 (Igf1)] in the AD models.

CONCLUSION: ADCYAP1 inhibits neuronal apoptosis and autophagy to improve AD progression in APP/PS-1 mice and Aβ-induced P12 cells.},
}

@article {pmid42538916,
year = {2026},
author = {Villalba-Moreno, JL and El-Amri, Y and Kim, KY and Villalba-Moreno, ND and Shafiq, M and Ortiz-Cordero, C and Wang, S and Ossa, JA and Suarez-Uribe, I and Cardona-Madrigal, D and Villegas, A and Glatzel, M and Krasemann, S and Posada-Duque, R and Kiessling, LL and Lopera, F and Arboleda-Velasquez, J and Kalaria, R and Ellisman, M and Sepulveda-Falla, D},
title = {Astrocyte-driven small vessel disease is an early, amyloid-independent feature of PSEN1 E280A familial Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.17.739026},
pmid = {42538916},
issn = {2692-8205},
abstract = {Cerebral Small vessel disease (cSVD) is a prevalent feature of Alzheimer's disease (AD) pathology. Whether this pathology is a late consequence of amyloid and tau accumulation or an early, direct effect of PSEN1 dysfunction has remained unresolved. We found that it is more severe in familial AD (FAD) caused by E280A mutation in presenilin 1 (PSEN1). These cases present with a distinctive proteomic signature, associated with pathological features, more dysregulated in the occipital cortex (OC) compared to the frontal cortex (FC), and characterized by multiple dysregulated proteins involved in extracellular matrix (ECM) and RNA-associated processes. This proteomic fingerprint was associated with abnormal collagen build up, ECM disorganization, and signatures of aberrant angiogenesis. Six months old transgenic knock-in mice homozygous for Psen1 E280A mutation (PSEN1Ki) also showed a similar phenotype with microvascular tortuosity and proteomic changes. Critically, these mice develop neither Aβ plaques nor tau tangles, indicating that the shared microvascular and RNA-associated changes are direct consequences of PSEN1 dysfunction rather than downstream effects of amyloid pathology. Remarkably, dysregulated RNA-associated protein networks overlapped between FAD and PSEN1Ki mice. Cerebral microvessels microstructure in PSEN1Ki mice at two months and six months showed abnormal astrocytic end-feet with lamellar deposits implicating blood-brain barrier damage. Finally, single nuclei transcriptomic analysis of AD patients and controls showed similar abnormal astrocytes in both sporadic and familial variants, but FAD astrocytes expressed dysregulated genes identified in the proteomic analyses, such as GLUL, APOE, and CLU. Our findings suggest that cSVD is an early pathological event in PSEN1 FAD and that is driven by abnormal RNA-associated processes and astrocytic dysfunction.},
}

@article {pmid42538997,
year = {2026},
author = {Krunic, A and Umesh Ganesh, N and Coskun, U and Brennan, W and Patel, C and Joshi, O and Lee, J and Gu, TS and Caruso, J and O'Connell, A and Lisboa, C and Crossland, N and Kurkela, M and Julia, T and Fowler, A and Tay, TL and Fischer, A and Delalle, I and Blusztajn, JK and Mellott, TJ},
title = {MicroRNA-223 Enhances Microglia-Dependent Clearance of Amyloid Beta Plaques and Ameliorates Behavioral Deficits in a Mouse Model of Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.20.738977},
pmid = {42538997},
issn = {2692-8205},
abstract = {The Alzheimer's disease (AD) brain is characterized by dysregulated expression of multiple microRNAs (miRNA), positioning them as promising diagnostic and therapeutic targets. The levels of glia-enriched miR-223 are abnormal in the brains and plasma of AD patients and miR-223 is neuroprotective in models of stroke. However, whether miR-223 can be beneficial in AD is not known. Here, we report that intracerebroventricular (ICV) injection of miR-223 oligonucleotide mimic alleviated cognitive impairment, reduced amyloid beta (Aβ) pathology, and ameliorated the defects in synaptic marker expression in App [NL-G-F] AD model mice. Mechanistically, miR-223 induced microglial clustering around Aβ plaques with a concomitant upregulation of microglial phagocytic receptors AXL, TREM2 and CD11c, while pharmacological microglial depletion abolished the plaque-clearance phenotype. Moreover, in human iPSC-derived microglia miR-223 directly targeted multiple genes in the endo-lysosomal pathway, including AD risk gene SPPL2A , indicating that it acts as a major regulator of microglial phenotype. Lastly, long-term AAV-mediated overexpression of miR-223 recapitulates its beneficial effects on cognition, pathology, and synaptic marker expression. Our study demonstrates a novel approach for the treatment of AD using miR-223 and highlights the potential of RNAi-based therapeutics in neurodegenerative disease.},
}

@article {pmid42539005,
year = {2026},
author = {DeLong, LN and Salimi, Y and Balabin, H and Galdi, P and Fleuriot, JD and Brennan, P and , },
title = {Encoding Discordance in the Alzheimer's Disease A/T/N Framework.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.19.26358425},
pmid = {42539005},
abstract = {INTRODUCTION: The biomarker-based amyloid/ tau/ neurodegeneration (A/T/N) framework has become a popular staging method for Alzheimer's disease (AD) research. Previous studies use the framework either as a rule-based or data-driven approach but typically sacrifice either adaptivity or interpretability.

METHODS: We present an interpretable, hybrid method, called Neurosymodal Data Fusion, for predicting incident AD in the ADNI dataset. Specifically, we encode the A/T/N framework as a logic program, where the input biomarker features are extracted by one or more neural networks.

RESULTS: Our pipeline predicted four-year incident AD with a sensitivity of up to 0.84. Additionally, our models learned scores for each A/T/N profile, denoting relative importances to model predictions. These scores also indicated that empirically-derived cut-off values for the A and T criteria might be uninformative for the ADNI data.

DISCUSSION: Our pipeline provides a novel way to use the A/T/N framework that could potentially improve early AD screening years before clinical manifestations.},
}

@article {pmid42539013,
year = {2026},
author = {Stark, D and Shin, H and Münster, N and Federmann, L and Ritter, K and , },
title = {What Do Persistent Misclassifications Tell Us About Alzheimer's Disease Detection using Structural MRI?.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.17.26358326},
pmid = {42539013},
abstract = {Deep learning classifiers applied to structural MRI (sMRI) have achieved high performance in detecting Alzheimer's Disease (AD), yet systematic investigation of their failure modes remains limited. In this study, we trained two deep learning architectures to classify AD from cognitively normal (CN) participants using sMRI data from the ADNI dataset, and examined whether misclassifications persist across models and training configurations. We identified a subgroup of subjects who were persistently misclassified across 100 model instances, and found that these subjects exhibited a markedly different atrophy subtype distribution compared to correctly classified AD cases, with substantial enrichment of hippocampal-sparing and minimal atrophy subtypes. To disentangle whether persistent false negatives (FN) reflect earlier disease stage or atypically presenting disease, we analyzed longitudinal follow-up scans and tested whether model predictions changed as neurodegeneration progressed. A change in prediction (from FN to true positive (TP)) was observed in only a subgroup of subjects and required intervals of up to five years, suggesting that persistent misclassification may not always be explained by disease staging alone. Although the sample size is small, these findings underscore the importance of accounting for disease heterogeneity in the development and evaluation of clinical AI models for AD detection.},
}

@article {pmid42539024,
year = {2026},
author = {Yang, C and Cook, N and Zeng, Y and Fu, T and Budde, J and Cruchaga, C and Belloy, ME},
title = {LocusBlend: Flexible multi-index regional visualization of genomic association signals.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42539024},
abstract = {SUMMARY: It has become standard practice to visualize regional signals from genome-wide association studies (GWAS) using LocusZoom plots. Similarly, GWAS signals are compared to regionally matched quantitative trait loci (QTLs), i.e. variant-to-gene regulation data, using LocusCompare plots to aid assessment of candidate trait-related genes. Despite broad usage, these tools annotate variants by linkage disequilibrium (LD) to a single lead or index variant. This single-index representation has limitations for visualizing complex loci that contain multiple independent signals. We present LocusBlend, an interactive web application for multi-index LD-blended visualization of genomic loci. LocusBlend supports one or two genomic association summary-statistic datasets and one to three index variants, multi-index LocusZoom color-blended plots, and matching LocusCompare visualizations. Applications to Alzheimer's disease GWAS and QTL signals illustrate LocusBlend enables visualization and separation of independent signals despite shared LD and high genomic complexity. Overall, LocusBlend is aimed at supporting researchers handle the continuously expanding complexity of human genomics findings.

LocusBlend is freely available at https://locusblend.wustl.edu . Publication ready plots are generated in <1min. Source code, documentation, example datasets, input templates, and reproducibility instructions are available at https://github.com/Belloy-Lab/LocusBlend . LocusBlend is implemented in Python using Streamlit, Plotly, and PLINK.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}

@article {pmid42539043,
year = {2026},
author = {Krogsaeter, EK and McKetney, J and Li, L and Liu, I and Richards, AL and Subramanyam, V and Yin, K and Gordon, M and Belio Mairal, P and Stevenson, EJ and Qian, H and Huang, Y and Goodarzi, H and Krogan, NJ and Swaney, DL},
title = {APOE4 disrupts the central dogma by arresting neuronal proteome dynamics.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.15.738801},
pmid = {42539043},
issn = {2692-8205},
abstract = {Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease and promotes neuronal dysfunction through incompletely understood mechanisms. Here, we integrated transcriptomic, translatomic, and proteomic profiling of isogenic APOE3 and APOE4 human iPSC-derived neurons and found that APOE4 fundamentally impairs neuronal proteome renewal. Although transcriptional changes were modest, APOE4 disrupted ribosome occupancy, altered translational dynamics, and uncoupled protein abundance from transcript levels. Proteome-wide turnover measurements revealed a global extension of protein half-lives and widespread accumulation of long-lived proteins. Functional proteomic analyses demonstrated concurrent lysosomal and proteasomal impairments associated with reduced proteasome activity and increased association of APOE with neuronal proteasomes. Longitudinal proteomics further showed that protein accumulation emerges during neuronal maturation and precedes a senescence-like cellular stress state. Together, these findings identify impaired proteome renewal as a central mechanism underlying neuronal vulnerability to APOE4 and establish defective proteostasis as an early pathogenic event in Alzheimer's disease.},
}

@article {pmid42539046,
year = {2026},
author = {Wang, H and Matei, E and Dou, J and Morgan, RK and Colacino, J and Bakulski, KM},
title = {Cell composition, transcriptomic, and functional pathway changes in the hippocampus in Alzheimer's disease and overlap with lead (Pb) exposure signatures.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.21.26358590},
pmid = {42539046},
abstract = {BACKGROUND: Lead (Pb) is associated with Alzheimer's disease (AD); however, the relationships between Pb and AD hippocampal transcription remains unclear. We evaluated overlap between Pb-response signatures and cell-type-independent AD transcriptomic signatures.

METHOD: Three toxicology studies (two neuronal cell lines, one mouse hippocampus) provided Pb-response genes. Five human postmortem hippocampal AD case-control transcriptional datasets (n=90 AD, n=106 normal cognition) were cell type deconvoluted and tested with beta regression. Differential gene expression, adjusted for age, sex, and estimated cell-types, were meta-analyzed. Overlapping Pb and AD genes and biological pathways were identified (p adj <0.05).

RESULTS: Consistent Pb response was observed at 25 genes (INPP5F , KIF20B , KIFC1) and 47 pathways (ensheathment of neurons, glial cell differentiation, regulation of nervous system processes). Relative to controls, AD samples had fewer neurons (-2.46%), greater microglia (0.42%), astrocytes (0.31%), oligodendrocytes (0.46%), and endothelial cells (0.95%), and 1,455 differentially expressed genes, which were enriched for cellular energy production and metabolism pathways. Six genes (EHD3 , LAP3 , NRXN3 , PPP1R16B , RPL29 , THRA) and four pathways (synaptic vesicle maturation, vesicle docking) overlapped between Pb and AD.

CONCLUSION: We identified overlapping Pb and AD transcriptomic signatures and pathways, providing molecular context for epidemiologic associations.},
}

@article {pmid42539058,
year = {2026},
author = {Bos, L and van Nederpelt, DR and Cole, JH and Jasperse, B and Meije Wink, A and Tranfa, M and Strijbis, E and Killestein, J and Uitdehaag, BMJ and Barkhof, F and Vrenken, H and Schoonheim, MM and Pontillo, G},
title = {The value of brain age as a transdiagnostic biomarker of neurodegeneration.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.21.26358569},
pmid = {42539058},
abstract = {Progressive structural brain changes are a hallmark of neurodegenerative conditions like Alzheimer's disease (AD), frontotemporal dementia (FTD), multiple sclerosis (MS), and Parkinson's disease (PD). The brain-predicted age difference (brain-PAD) has emerged as a promising biomarker to quantify these alterations, yet its unique clinical contribution relative to conventional measures of global brain atrophy such as the brain parenchymal fraction (BPF) remains underexplored. In this transdiagnostic study across AD, FTD, MS, and PD, we systematically evaluated brain-PAD's capacity to distinguish patients from controls, its cross-sectional and longitudinal associations with cognition, and its voxel-wise structural correlates. We benchmarked brain-PAD against BPF to determine its added explanatory value. Brain-PAD successfully distinguished patients from controls, adding to BPF alone, in AD, FTD, and MS, but not PD. Across disorders, higher brain-PAD correlated with worse cognition, showing clear added value beyond BPF particularly in AD and MS. Baseline brain-PAD also independently predicted subsequent cognitive changes in AD, FTD, and MS, over and above BPF. Voxel-wise analyses revealed spatial features underlying brain-PAD including, beyond global tissue loss, specific regional atrophy matching each disease's characteristic pattern. Collectively, these findings demonstrate that brain-PAD is a clinically meaningful, transdiagnostic biomarker of neurodegeneration that complements conventional volumetric measures like the BPF.},
}

@article {pmid42539062,
year = {2026},
author = {Ambaw, Y and Nana, A and Li, Z and Singh, S and Monetti, M and Miller, B and Spina, S and Grinberg, L and Seeley, W and Walther, T and Farese, R},
title = {Shared lipidome and proteome signatures of frontotemporal lobar degeneration and Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10305293/v1},
pmid = {42539062},
issn = {2693-5015},
abstract = {Frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) differ in their clinical features and genetic etiologies but share progressive cognitive decline. Emerging evidence implicates lipid dysregulation in neurodegeneration, but its extent across FTLD subtypes and how it compares to AD are unclear. Here, we performed integrated lipidomic and proteomic analyses of matched frontal (disease-vulnerable) and occipital (relatively spared) post-mortem cortices from individuals with genetic and sporadic FTLD-TDP, FTLD-tau (Pick's disease, PiD), AD, and controls. FTLD and AD exhibited convergent lipid alterations, including reduced levels of cardiolipins and phosphatidylethanolamines, alongside increased gangliosides, diacylglycerols, cholesterol esters, acylcarnitines, and coenzyme Q, with generally greater changes in FTLD frontal cortex. FTLD displayed additional alterations, including reductions in bis(monoacylglycerol)phosphate, ceramides, phosphatidylserines, phosphatidylinositols, and sulfatides. These lipid changes were accompanied by proteomic alterations involving lysosomal proteins, phospholipases, phospholipid remodeling enzymes, and fatty acid oxidation pathways. Although lipidomic and proteomic signatures were broadly shared across FTLD subtypes, GRN associated FTLD-TDP and PiD showed the most extensive alterations. Triglycerides were selectively reduced in PiD in association with decreased DGAT1 expression, whereas cholesterol esters were elevated across all subtypes except C9orf72 associated FTLD-TDP. These findings identify shared disruptions in lipid homeostasis and lysosomal lipid metabolism across FTLD and AD, highlighting convergent metabolic pathways underlying neurodegeneration.},
}

@article {pmid42539070,
year = {2026},
author = {Doherty, LK and Dechiario, I and Sherif, H and Bowers, A and Martinez, D and Sanchez, DL and Febres, GJ and Carmichael, O and Shah, V and Nadkarni, NK and Goldberg, TE and Noble, J and Luchsinger, JA and Temprosa, M and , },
title = {Implementing the National Alzheimer's Coordinating Center Uniform Data Set (v3) within the Diabetes Prevention Program Outcomes Study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.17.26357765},
pmid = {42539070},
abstract = {INTRODUCTION: The Diabetes Prevention Program (DPP) was a randomized clinical trial designed to prevent type 2 diabetes (T2D) in adults with prediabetes. The DPP Outcomes Study (DPPOS) is the 30-year follow-up of this cohort, focusing on T2D, prediabetes, and related complications. Cognitive assessments began in 2009 and expanded in 2022 to examine cognitive impairment, including Alzheimer's disease (AD) and AD related dementias (ADRD), in the surviving cohort. To support these aims, the National Alzheimer's Coordinating Center Uniform Data Set version 3 (NACC-UDSv3), the standardized framework used by Alzheimer's Disease Research Centers, was implemented in DPPOS in 2022 to enable data sharing with NACC. These forms were complemented by cognitive tests administered in DPPOS. We aimed to integrate the NACC-UDSv3 into the existing longitudinal DPPOS framework while maintaining fidelity to its structure and developing automated reports to streamline cognitive outcomes adjudication.

METHODS: Items from the 16 NACC-UDSv3 data forms were compared with those already collected within DPPOS to integrate overlapping similar items, add missing NACC-UDSv3 items, and create a dataset harmonized with NACC-UDSv3. Forms were adapted for electronic data capture (EDC) using the MIDAS (Multimodal Integrated Data Acquisition System, George Washington University). Automated reports integrated current and prior neuropsychological scores to support adjudications. In the first wave of the DPPOS-AD/ADRD study, 1561 cognitive adjudications were successfully completed using the harmonized DPPOS and NACC-UDSv3 data implemented into MIDAS.

DISCUSSION: The DPPOS-AD/ADRD project demonstrated that NACC-UDSv3 can be successfully integrated into a long-standing longitudinal cohort not originally designed for AD/ADRD research. The harmonization, electronic capture, and automated adjudication processes may provide a practical framework for other cohorts seeking to incorporate NACC-UDSv3 to align with national AD/ADRD research standards.},
}

@article {pmid42539099,
year = {2026},
author = {Rabin, J and Alexander, MW and Nyman, A and Casaletto, K and Saloner, R and Vandeloo, K and Splinter, T and Swardfager, W and Ottoy, J and Masellis, M and Galea, L and Black, S and Einstein, G and Denkinger, M and Ashton, N and Caldwell, J and Johnson, S and Arvanitakis, Z},
title = {Age at menopause, APOE-ε4, and Alzheimer's disease risk.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10121551/v1},
pmid = {42539099},
issn = {2693-5015},
abstract = {Importance: APOE-ε4 is an established risk factor for Alzheimer's disease (AD) and confers greater risk in women than in men. Earlier age at menopause also increases AD risk in women. Yet whether menopause timing influences APOE-ε4 -related AD risk remains unclear. Objective: To examine whether age at menopause modifies the association of APOE-ε4 with AD risk. Design, setting and participants: Data were analyzed from postmenopausal women free from known dementia at study entry in two longitudinal datasets: (1) the harmonized data from the Religious Orders Study, Rush Memory and Aging Project, and Minority Aging Research Study (ROS/MAP/MARS), and (2) the Wisconsin Registry for Alzheimer's Prevention (WRAP). Data were collected between 1994-2025. Main outcomes and measures: In both datasets, neuropsychological tests assessed longitudinal memory performance, and MRI quantified cortical thickness and brain volume in AD vulnerable regions. In WRAP, which included in vivo AD biomarkers, AD pathology was assessed using longitudinal plasma p-tau217 and cross-sectional beta-amyloid (Aβ) PET. Menopause history was self-reported, and APOE status was classified as ε4 carrier vs. non-carrier. Linear mixed-effects or linear regression models were used, as appropriate, to test interactions between APOE-ε4 carrier status and age at menopause on memory decline, brain atrophy, p-tau217 accumulation, and Aβ-PET burden, adjusting for relevant covariates. Results: The study included 2,625 women in ROS/MAP/MARS (mean [ SD ] age=77.4 [7.77], mean [SD] age at menopause=47.9 [7.10]) and 512 women in WRAP (mean [SD] age=60.2 [5.57], mean [SD] age at menopause=50.1 [6.29]). In both datasets, earlier age at menopause strengthened associations of APOE-ε4 with memory decline (ROS/MAP/MARS: β=0.068, p =.02; WRAP: β=0.092, p =.03) and MRI measures of brain atrophy (ROS/MAP/MARS: β=0.071, p =.05; WRAP: β=0.256, p =.03). In WRAP, earlier menopause also amplified associations of APOE-ε4 with p-tau217 accumulation (β=-0.029, p =.05) and global Aβ-PET burden (β=-0.146, p =.01). Conclusions and relevance: Earlier menopause strengthened the associations between APOE -ε4 and key AD outcomes. These findings suggest that menopause timing may influence APOE -ε4-related susceptibility to AD, highlighting midlife endocrine processes as potential targets for prevention in women.},
}

@article {pmid42539115,
year = {2026},
author = {Tewolde, S and Rosellini, AJ and Michals, A and Skotko, BG and Fortea, J and Khor, B and Handelman, S and Rubenstein, E},
title = {Death in People with Down syndrome: Mortality statistics and novel predictors in US Medicaid and Medicare enrolled adults.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.17.26358090},
pmid = {42539115},
abstract = {People with Down syndrome have higher age-specific mortality rates compared to the general population as well as peers with other intellectual and developmental disabilities. While a large proportion of mortality is attributable to Alzheimer's disease, many die prior to Alzheimer's diagnosis and some live to old ages, dying without Alzheimer's. Our objectives were to use 11 years of Medicaid and Medicare data to describe characteristics and factors related to death in adults with Down syndrome and use machine learning to identify which conditions most strongly predict death in the full population and stratified by age. We identified death using Center for Medicare and Medicaid Systems reported date of death health conditions using ICD 9 and 10 codes. We used a case-control design with risk set sampling to have that controls to mimic the distribution of times of incident Alzheimer's disease. We trained gradient boosted trees to identify strongest predictors. Our cohort included 137,293 adults with Down syndrome. Among those, 30,894 (22.5%) died during the study period. Mean age at death among those who died was 55 years (SD=10). Mean age of death in those with Alzheimer's disease was 59 (SD=7) and those without was 52 (SD=12). The most influential predictors of mortality were any claim for dementia, any claim for pneumonia, re-occurring claim for cardiovascular disease three years before index death, and any claim for heart failure and epilepsy. Our results align with previous clinical work and highlight intervenable areas to reduce mortality in the Down syndrome population.},
}

@article {pmid42539145,
year = {2026},
author = {Brown, K and Storey, B and Williams, J and Simet, D and Umar, MB and Madsen, E and Shan, Z and Bi, L},
title = {Spatial MALDI-MSI Reveals a Coordinated Vicious Cycle of Oxidative Membrane Damage and Ceramide-Driven Sphingolipid Dysregulation in the Chronically Neuroinflamed Brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.14.738110},
pmid = {42539145},
issn = {2692-8205},
abstract = {BACKGROUND: Chronic neuroinflammation is a major driver of cognitive decline, vascular cognitive impairment, and Alzheimer's disease. However, the spatial lipidomic alterations underlying neuroinflammatory brain injury remain poorly defined. Oxidative stress and sphingolipid dysregulation have been implicated, but their regional distribution and interplay in the brain are not well characterized.

METHODS: We performed positive-ion mode matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) on coronal brain sections from middle-aged spontaneously hypertensive rats (SHR), a model of chronic neuroinflammation, and normotensive Wistar-Kyoto (WKY) controls. Spatial distributions and relative abundances of multiple lipid classes, including phosphatidylcholines (PCs), sphingomyelins (SMs), hexosylceramides (HexCers), ceramides, phosphatidylserines (PSs), phosphatidylinositols (PIs), phosphatidylethanolamines (PEs), phosphatidic acids (PAs), and sulfatides, were mapped and compared between genotypes. Region-of-interest analysis was used to quantify changes across cortex, hippocampus, and white-matter tracts.

RESULTS: SHR brains exhibited a coordinated lipidomic signature characterized by pronounced oxidative stress and membrane remodeling. Oxidized and short-chain PCs were markedly upregulated (up to 11.6-fold), while major structural diacyl PCs were broadly downregulated. Concurrently, sphingolipids were significantly altered, with robust upregulation of SM(d36:1) (7.5-fold) and multiple HexCer species (1.5-1.9-fold), accompanied by accumulation of ceramides. These changes were accompanied by heterogeneous redistribution of PS, PI, and PE species, particularly within the hippocampus. Sulfatide patterns in white-matter tracts were also altered, suggesting myelin remodeling. Region-of-interest analysis confirmed that the most pronounced lipid alterations were concentrated in the hippocampus and white-matter regions.

CONCLUSIONS: Chronic neuroinflammation induces a spatially organized, multi-class lipid remodeling response in the brain, driven by advanced oxidative membrane damage and a shift toward a pro-apoptotic sphingolipid profile. The convergence of these pathways creates a vicious cycle of membrane injury, mitochondrial dysfunction, and sustained neuroinflammation that is especially prominent in the hippocampus and white matter. These spatially resolved findings provide direct evidence that oxidative stress and sphingolipid dysregulation are central, interrelated mechanisms contributing to neurovascular injury and increased risk of cognitive impairment. The study highlights the power of MALDI-MSI to uncover region-specific lipid pathology and identifies potential lipid-based targets for therapeutic intervention in neuroinflammatory brain disease.},
}

@article {pmid42539244,
year = {2026},
author = {Wagle, MM and Wang, Y and Samanta, S and Liu, Z and Patrick, E and Yang, P and Kellis, M},
title = {Deep interpretable learning of sample representations for characterizing disease states in single-cell transcriptomics.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.21.738207},
pmid = {42539244},
issn = {2692-8205},
abstract = {Single-cell transcriptomics technology offers unprecedented insights into molecular heterogeneity. However, capturing sample-level representations that reflect both systemic and cellular states remains challenging, especially when disease annotations are mostly available as coarse sample-level labels. Here, we introduce Phenoverse, an interpretable deep learning framework that learns sample-level disease state representations through cell type-aware residual encoding, prototype learning, and Perceiver-based aggregation. Applied to independent single-cell transcriptomic cohorts of COVID-19, Alzheimer's disease, and systemic lupus erythematosus, totaling over 5 million cells, we demonstrate that learned sample representations enable disease state prediction and encode a continuous spectrum of disease severity on unseen data that correlate with multiple clinical and pathological measures, despite being trained solely on binary phenotype labels. Further, we demonstrate that trajectory-derived genes reveal cross-cohort molecular programs and show consistently higher reproducibility than traditional case-control comparisons. Finally, prototype learning provides intrinsic model interpretability and enables the characterization of cell type-specific disease states. Taken together, Phenoverse offers an interpretable disease-phenotyping approach to dissecting sample heterogeneity, and our results highlight its utility in translating complex single-cell transcriptomic data into patient-level biological insights.},
}

@article {pmid42539274,
year = {2026},
author = {Javid, S and Nir, TM and Zhu, AH and Bhatt, RR and Aksman, LM and Jahanshad, N and , },
title = {FastEBM: Fast, Scalable, and Uncertainty-Aware Event-Based Disease Progression Modeling.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.18.739221},
pmid = {42539274},
issn = {2692-8205},
abstract = {Event-based models (EBMs) are used to infer ordering of biomarker alteration patterns with respect to disease progression. However, EBM approaches rely on computationally expensive permutation-based inference, assumptions of feature independence, and likelihood optimization that can limit scalability and stability in high-dimensional settings. Here, we introduce Fast Event-Based Model (FastEBM), a scalable, uncertainty aware, Markov- chain-based framework that reformulates disease progression inference as a subject-ordering problem on a data-driven diffusion manifold. The progression uncertainty, used to derive positional variance diagrams, is quantified using first-passage-time variability derived directly from the inferred Markov process. Using synthetic experiments varying feature dimensionality, cohort size, noise level, and feature-correlation structure, we compared FastEBM with established methods, including Gaussian mixture model EBM (GMM-EBM), kernel density estimation EBM (KDE-EBM), and discriminative EBM (DEBM). FastEBM achieved the best accuracy and runtime. In low-subject/high-dimensional stress tests, FastEBM retained event-order recovery. FastEBM remained robust in simulations containing correlated and redundant features after decorrelation and feature-group handling. We applied FastEBM to real-world data to characterize biomarker progression in Alzheimer's disease. First, we evaluated a low-dimensional multi- modal dataset from The Alzheimer's Disease Prediction Of Longitudinal Evolution (TAD- POLE) challenge. Second, to demonstrate high-dimensional disease progression mapping, we applied FastEBM to regional cortical tau-PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). In both cases, FastEBM recovered progression patterns broadly consistent with the literature, also revealing lateralized progression trends. These results show that diffusion-based Markov geometry provides a scalable and robust alternative to conventional event-based modeling. FastEBM is available at: https://github.com/sjusc07/FastEBM .},
}

@article {pmid42539283,
year = {2026},
author = {Chattopadhyay, T and Shelar, K and Thomopoulos, S and Thompson, PM},
title = {When does more data help? Spectral Geometry and Scaling Laws in MRI Transformers.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.14.738571},
pmid = {42539283},
issn = {2692-8205},
abstract = {Scaling laws describe how model performance improves as the amount of training data increases, and recent theories such as the zeta law suggest that scaling behavior is influenced by the eigenspectrum of the model's latent representation. Here, we evaluated whether the distribution of discriminative signals across spectral modes predicts the future scaling behavior, for MRI transformers trained for disease classification. We trained three supervised 3D vision transformers (ViT3D, MINiT, and NIT) for Alzheimer's disease classification using 2,822 training scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI); we compared their encoder spectra with that of a frozen self-supervised DINO ViT-B/16 encoder adapted to 3D MRI. The supervised models learned highly concentrated representations, with 90-96% of CLS-token variance captured by a single principal component, whereas DINO distributed signal across many latent directions. Via spectral expansion of the Mahalanobis signal, we found that supervised training concentrated disease information into a single dominant mode, while self-supervised training produced a richer spectral geometry with higher effective rank and discoverability. This led to different scaling behavior: supervised models exhibited flatter AUC(N) curves, yet DINO continued to improve as sample size increased, gaining 11.0 percentage points from N=50 to N=2,822. Overall, the spectral distribution of the discriminative signal, for these different encoder types, influenced how much performance remained discoverable as sample size increased. Distributed representations may retain signal across many latent modes and continue to improve with additional data, whereas concentrated representations tend to exhaust most of the discoverable signal at much lower sample sizes.},
}

@article {pmid42539361,
year = {2026},
author = {Srikanth, M and Jiang, S and Wellman, SM and Sarkar, S and Lorman, DE and Lantin, T and Runyan, AM and Kumar, M and Sydney, E and Figueroa, HY and Yang, M and Wang, Q and Myeku, N},
title = {Immunoproteasome Deficiency Impairs Microglial Clearance and Worsens Tau and Amyloid Pathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.14.738427},
pmid = {42539361},
issn = {2692-8205},
abstract = {Immunoproteasome induction is prominent in Alzheimer's disease (AD), but whether it protects proteostasis or amplifies neuroinflammation remains unresolved. Here, we generated immunoproteasome-deficient PS19 tauopathy and APP/human tau double-knock-in mice by crossing each disease model with L7M1 mice lacking two immunoproteasome catalytic subunits. Immunoproteasome deficiency increased phospho-tau burden, exacerbated amyloid-β pathology and heightened microglial reactivity without suppressing constitutive 26S proteasome activity. In primary microglia and longitudinal two-photon imaging, immunoproteasome-deficient microglia engaged and engulfed tau aggregate-bearing material but failed to resolve internalized cargo, revealing a post-engulfment degradative checkpoint. Single-nucleus transcriptomics identified a remodeled P2ry12 [low] /Trem2 [high] microglial state with impaired phagolysosomal and mitochondrial programs. Reanalysis of human single-nucleus transcriptomic datasets showed that reduced microglial immunoproteasome expression was associated with cargo-processing gene-program changes similar to those observed in immunoproteasome-deficient mouse microglia. Together, these findings identify immunoproteasome biogenesis as a protective glial stress response that supports microglial aggregate clearance in AD.},
}

@article {pmid42539398,
year = {2026},
author = {Liu, L and Chen, X and Zeng, Q and Zhou, S and Zhang, X},
title = {An edge-aware salient context fusion and refinement network for hippocampal segmentation in MR images and its diagnostic value for mild cognitive impairment.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1899123},
doi = {10.3389/fneur.2026.1899123},
pmid = {42539398},
issn = {1664-2295},
abstract = {BACKGROUND: Accurate assessment of hippocampal volume is of significant clinical value for the early diagnosis and disease monitoring of Alzheimer's disease (AD). However, automatic segmentation of the hippocampus in MR images remains challenging due to its elongated and irregular morphology, blurred boundaries, low contrast with surrounding tissues, and substantial inter-individual anatomical variability.

METHODS: We propose an Edge-aware Salient Context Fusion Refinement Network (ESCFR-Net). Built upon a classic U-shaped encoder-decoder architecture, the proposed network employs a Salient Feature Enhancer to suppress background interference and enhance weak feature responses of the hippocampus. A Global Channel Context Attention (GCCA) module is introduced to model long-range spatial dependencies, while a Multi-scale Context Fusion Refinement Module (MCFRM) improves the utilization of multi-scale features. Furthermore, an Edge-Guided Refinement Attention (EGRA) module synergistically enhances edge and semantic features to precisely delineate weak boundaries.

RESULTS: Experimental results on a self-constructed dataset comprising 225 3D-T1 MRI scans demonstrate that ESCFR-Net achieves a Dice coefficient of 0.9004, outperforming state-of-the-art methods such as SwinUNETR and PMFS-Net. Clinical association analysis, conducted on 91 healthy controls (HCs) and 91 patients with mild cognitive impairment (MCI), reveals that bilateral hippocampal volumes in MCI group are significantly smaller than those in HCs (p < 0.001). Additionally, the total hippocampal volume achieves an area under the curve (AUC) of 0.927 in distinguishing HCs from patients with MCI, with sensitivity and specificity reaching 90.11 and 83.52%, respectively.

CONCLUSION: This study provides a highly accurate and robust automated hippocampal segmentation tool for early diagnosis, disease monitoring, and clinical decision-making in Alzheimer's disease.},
}

@article {pmid42539584,
year = {2026},
author = {Lo, H and Li, S and Chen, J and Zhou, Q and Qiu, Y and Ma, S and Yu, B and Gu, T and Nie, L},
title = {Multispectral photoacoustic microscopy and NIR-II fluorescence imaging of TREM2-positive microglia in Aβ-driven Alzheimer's pathogenesis.},
journal = {Fundamental research},
volume = {6},
number = {4},
pages = {2235-2249},
doi = {10.1016/j.fmre.2026.04.016},
pmid = {42539584},
issn = {2667-3258},
abstract = {Monitoring microglial activation mediators remains challenging in neurodegeneration. Few imaging studies track amyloid-β (Aβ)-linked microglial dynamics across a wide field of view with high spatiotemporal resolution. Leveraging the triggering receptor expressed on myeloid cells 2 (TREM2), a pivotal Alzheimer's disease (AD) biomarker that enhances Aβ clearance while suppressing neuroinflammation, we developed a dual-modal probe, TREM2-ICG, by conjugating a TREM2-specific antibody with indocyanine green (ICG), an FDA-approved dye, for robust in vivo photoacoustic and near-infrared-II (NIR-II) fluorescence imaging. Multi-wavelength photoacoustic microscopy imaged AD pathology at 532 nm (hemoglobin, vasculature), 559 nm (Aβ probe AOI987), and 780 nm (TREM2-ICG for peri‑plaque microglia). Time-resolved NIR-II imaging (30 frames/sec) tracked Aβ-oligomer-induced microglial displacement at ∼50 µm resolution, showing a rapid chemotaxis phenomenon. Immunofluorescence-verified TREM2-microglia plaque engagement demonstrates AD pathogenesis. Overall, our multiscale photoacoustic-fluorescence imaging resolved cortex-wide Aβ-microglial interactions, combining wide-field, high-speed, and deep-penetration to overcome confocal depth and two-photon field of view limits. This enabled in vivo tracking of microglial responses to Aβ, revealing potential for investigating AD-specific mechanisms.},
}

@article {pmid42539597,
year = {2026},
author = {Varrasi, S and Pulvirenti, A and Catania, V and Palesi, M and Spampinato, C and Patti, D and Tomarchio, O and Micale, G and Simone, A and Passarello, L and Proietto Salanitri, F and Patanè, G and Ravidà, S and Chisari, CG and Zappalà, G and D'Amico, E and Avolio, C and Felicetti, F and Gasperini, C and Rossi, S and Manganotti, P and Busan, P and Rodolico, C and Laudani, R and Marino, R and Villari, M and Patti, F and , and , },
title = {AI-based predictive biomarkers for chronic neurological diseases: the rAIdD prospective, multicenter, observational study protocol.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1885919},
doi = {10.3389/fneur.2026.1885919},
pmid = {42539597},
issn = {1664-2295},
abstract = {BACKGROUND: Chronic neurological disorders such as Multiple Sclerosis (MS), Parkinson's disease (PD), and Alzheimer's Disease (AD) represent a major global health burden characterized by progressive neurodegeneration, functional disability, and cognitive decline. Despite differences in etiology and clinical presentation, these conditions share multifactorial pathophysiological mechanisms influenced by genetic, environmental, and lifestyle-related factors. Advances in artificial intelligence (AI), wearable technologies, and multimodal clinical data integration offer new opportunities for identifying predictive digital biomarkers and improving personalized disease management. The rAIdD project ("eHealth Network: AI and new ICT technology equipment for digital diagnosis") aims to develop an interoperable digital infrastructure to support early diagnosis, monitoring, and risk stratification in chronic neurological diseases. This study protocol describes the neurological component of the rAIdD network focusing on MS, PD, and AD.

METHODS AND ANALYSIS: This prospective, multicenter, observational study involves six Italian academic and clinical centers and will enroll 780 participants: 300 MS, 150 PD, 150 AD, and 180 healthy controls. Participants will be followed for 18 months within a 48-month study period. Standardized clinical, neuropsychological, neuroimaging, and digital assessments will be performed at baseline and at 6-, 12-, and 18-month follow-ups. Clinical evaluation includes disease-specific disability and functional scales, mood and quality-of-life assessments, and lifestyle and environmental risk factor profiling. Continuous digital monitoring will be conducted using wearable sensors to collect biometric and behavioral data, including physical activity, sleep patterns, and cardiovascular parameters. Structural neuroimaging will be acquired longitudinally and integrated with clinical and digital data through a centralized web-based electronic data capture platform. Machine learning approaches will be applied to identify multimodal predictive biomarkers and model disease progression patterns across disorders.

ETHICS AND DISSEMINATION: The study has been approved by the Ethics Committee of the coordinating center and by local ethics committees of all participating institutions. Written informed consent is obtained from all participants in accordance with the Declaration of Helsinki and the General Data Protection Regulation (GDPR 2016/679). Results will be disseminated through peer-reviewed publications, scientific conferences, and digital communication platforms to support knowledge translation and implementation of precision neurology approaches.},
}

@article {pmid42539626,
year = {2026},
author = {Han, J and Zhao, W and Deng, R and Wang, Y and Gong, W and Wang, Z and Sun, G and Liu, H and Geng, M and Zhang, Y},
title = {Sodium oligomannate reduces cerebral infarction and improves neurological function through microbiota remodeling in MCAO/R rats.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1880590},
doi = {10.3389/fphar.2026.1880590},
pmid = {42539626},
issn = {1663-9812},
abstract = {BACKGROUND: Ischemic stroke is the second leading cause of death worldwide, characterized by high mortality and a narrow therapeutic window for thrombolysis. Gut microbiota dysbiosis and gliosis following ischemic stroke are key drivers of post-stroke neurological impairment. Sodium oligomannate (GV-971) is a low-molecular-weight acidic oligosaccharide that targets the gut-brain axis. It alleviates gliosis and improves cognitive dysfunction by remodeling gut microbiota in Alzheimer's disease. However, it is still unknown whether GV-971 has pharmacological activity against ischemic stroke.

METHODS: Here, we explore the efficacy of GV-971 on infarct volume, gliosis, blood-brain barrier integrity, gut microbiota composition, and post-stroke cognitive impairment (PSCI) using a middle cerebral artery occlusion/reperfusion (MCAO/R) model in male Sprague-Dawley rats.

RESULTS: Administer medication before surgery for 4 consecutive days and once after surgery, after stroke 24-hour triphenyltetrazolium chloride (TTC) staining revealed that 0.3 mg/kg GV-971 significantly reduced infarct volume in ischemic brain tissue from 37.81±2.391% to 13.30±4.801% and neurological impairment score of GV-971 treatment significantly decreased from 11.50±0.54 to 7.29±1.47. After stroke 24-hour immunofluorescence analysis of glial activation confirmed that GV-971 significantly reduced central inflammatory responses. Western blot combined with Evans blue staining collectively demonstrated that after stroke 24-hour, GV-971 exerts a significant protective effect on the blood-brain barrier. In the gut, GV-971 reversed microbial dysbiosis, as revealed by shotgun metagenomics, enhanced intestinal barrier integrity, and suppressed colonic inflammation. Antibiotic depletion abolished GV-971's neuroprotective effect, while fecal microbiota transplantation from GV-971-treated donors restored protection, supporting a microbiota-dependent contribution. Furthermore, GV-971-treated rats subjected to MCAO/R exhibited significant improvements in motor and cognitive function. For example, on day 35, Y-maze test results indicated that GV-971 administered either before MCAO/R (pre-treatment) or during the perioperative period (co-treatment) increased spontaneous alternation rate from 60.95±4.91% to 85.60±6.32% and 85.64±5.027%. On day 32, novel object recognition assay results indicated that GV-971 treatment increased new-object exploration from 0.2039±0.03752 to 0.3991±0.1122 (pre-treatment) and 0.5066±0.06982 (co-treatment). On day 42, Barnes maze test results indicated that GV-971 treatment reduced the time required to locate the target hole from 76.45±17.41s to 31.03±20.75 s and 33.37±19.30 s for pre- and co-treatment, respectively.

CONCLUSION: Taken together, GV-971 demonstrated neuroprotective potential in experimental ischemic stroke.},
}

@article {pmid42539875,
year = {2026},
author = {Luo, Y and Yu, H and Ye, K},
title = {Distinct factors drive the progression of tau pathology in Alzheimer's disease.},
journal = {Fundamental research},
volume = {6},
number = {4},
pages = {2289-2298},
doi = {10.1016/j.fmre.2025.04.001},
pmid = {42539875},
issn = {2667-3258},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia worldwide. The primary histopathological markers for AD diagnosis are extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs), featured by aggregation of hyperphosphorylated and truncated tau proteins. Emerging evidence shows that tau pathology, rather than amyloid-β deposition, exhibits a stronger correlation with brain atrophy and cognitive decline in AD, emphasizing its pivotal role in disease progression. However, the molecular mechanisms of tau propagation in the brain are incompletely understood, and there is no effective therapy to halt tau pathology propagation in AD. In this review, we summarize current knowledge on the multifactorial triggers of tau pathology in AD in the aspects of (1) physiological or pathological driving factors, (2) different types of brain cells and (3) key regulatory proteins that steer tau aggregation and spread. Based on these findings, we also critically evaluate the current and potential therapeutic strategies against tau pathology in AD. Together, this review provides a comprehensive understanding of tau pathology regulation and highlights promising strategies for therapeutic intervention.},
}

@article {pmid42539876,
year = {2026},
author = {Singh, R and Asthana, S and Arya, A and Kaushik, M and Khan, M},
title = {The Oral-Brain Axis: Mechanistic Insights Linking Periodontitis With Alzheimer's and Parkinson's Diseases.},
journal = {Cureus},
volume = {18},
number = {6},
pages = {e111856},
doi = {10.7759/cureus.111856},
pmid = {42539876},
issn = {2168-8184},
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are major causes of disability and mortality worldwide. Emerging evidence suggests that chronic peripheral inflammation and microbial dysbiosis may contribute to neurodegenerative processes. The oral-brain axis has recently gained attention as a biological framework linking oral microbial communities, systemic inflammatory responses, immune regulation, and central nervous system function. Within this context, periodontitis, a prevalent chronic inflammatory disease driven by oral dysbiosis, has been proposed as a potential modifiable risk factor for neurodegeneration. This narrative review examines current evidence supporting the oral-brain axis and its role in the relationship between periodontitis and neurodegenerative disorders. Key mechanisms include systemic dissemination of periodontal pathogens and their virulence factors, persistent inflammatory signaling, blood-brain barrier dysfunction, neuroimmune activation, oxidative stress, and protein aggregation. Particular attention is given to the contribution of Porphyromonas gingivalis and associated virulence factors to neuroinflammation, amyloidogenesis, and neuronal injury. Epidemiological, clinical, and experimental studies linking periodontal disease with cognitive decline, Alzheimer's disease, and Parkinson's disease are also discussed. Current evidence supports a biologically plausible association between periodontal disease and neurodegeneration through interconnected microbial, inflammatory, and vascular pathways. Although causality remains to be established, the oral-brain axis provides valuable insight into potential mechanisms underlying this relationship. Improved understanding of these interactions may facilitate the development of preventive and therapeutic strategies that integrate oral healthcare with approaches aimed at preserving neurological health and reducing the burden of neurodegenerative diseases.},
}

@article {pmid42540036,
year = {2026},
author = {Chan, AM and Ng, R and Inderjeeth, C and Nossent, J},
title = {Temporal incidence and impact of dementia in rheumatoid arthritis: a cohort study.},
journal = {EULAR rheumatology open},
volume = {2},
number = {2},
pages = {100159},
doi = {10.1016/j.ero.2026.03.007},
pmid = {42540036},
issn = {3050-7081},
abstract = {OBJECTIVES: The objective of this study is to address conflicting evidence that chronic inflammation may increase the risk of dementia in patients with rheumatoid arthritis (RA).

METHODS: Retrospective population-based study using longitudinally linked administrative health data over a 30-year period for ever hospitalised patients with RA (n = 14,041, age 64 years, 67.2% female) and controls (n = 33,785, age 65 years, 65.6% female). Dementia was defined by the International Classification of Diseases codes for Alzheimer's disease (AD), vascular dementia, and nonspecific dementia subtypes. Dementia incidence rate (IR) and mortality rate (MR) per 1000 person-years and comorbidities are reported.

RESULTS: During 9.6 years of follow-up, 1463 (10.4%) of patients with RA and 3701 (11%) of controls were diagnosed with dementia at respective age of 83 vs 84 years (P = .01). The IR was 12.07 (95% CI: 11.15-12.71) in patients with RA and 11.59 (95% CI: 11.22-11.97) in controls corresponding to an IR ratio of 1.04 (95% CI: 0.98-1.11, P = .21), which did not change significantly over 3 decades. Traditional risk factors for dementia were equal in both groups, but patients with RA with dementia were less likely to be classified as AD (odds ratio = 0.59, 95% CI: 0.48-0.73, P < .001). Hospitalisation rates after dementia diagnosis were higher for patients with RA, and the crude MR (overall 91.8 vs 90.4, P = .64) remained similar before or after 2000 for both groups.

CONCLUSIONS: There was no difference in temporal incidence and MRs for dementia between patients with RA and matched controls. These data suggest that there is minimal impact of RA on the frequency and outcome of dementia.},
}

@article {pmid42540093,
year = {2026},
author = {Floden, AM and Manocha, GD and Frolov, NI and Lerick, AE and Combs, CK},
title = {Comparison of amyloid and tau pathology in the small and large intestines of individuals with Alzheimer's disease, Parkinson's disease, and Dementia with Lewy bodies.},
journal = {microPublication biology},
volume = {2026},
number = {},
pages = {},
doi = {10.17912/micropub.biology.002056},
pmid = {42540093},
issn = {2578-9430},
abstract = {Alzheimer's disease (AD) brains are characterized by accumulations of neurofibrillary tangles and amyloid β (Aβ) plaques. Since enteric neurons express tau and the amyloid precursor protein (APP), we asked whether neurofibrillary tangles and Aβ aggregates were present in AD intestines compared to healthy controls and individuals with Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Neuron-like APP and Aβ immunoreactivities were observed in all groups with no observable plaques. No tangle-like structures were observed in any group although p-Ser 396/404 tau immunoreactivity was seen. The enteric nervous system appears to be protected from developing tangle and plaque pathology in AD.},
}

@article {pmid42540265,
year = {2026},
author = {Taşci, H and Avcı, A and Özenver, N and Sağlık Özkan, BN and Tozkoparan, B and Kelekçi, NG},
title = {Benzoxazolinone-Based Propionyl Thiosemicarbazides as Multi-Target-Directed Ligands for Alzheimer's Disease: Cholinesterase and MAO Inhibition, Docking, and Molecular Dynamics.},
journal = {ACS omega},
volume = {11},
number = {29},
pages = {43129-43156},
doi = {10.1021/acsomega.5c12925},
pmid = {42540265},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) benefits from multitarget-directed ligands (MTDLs) that can enhance cholinergic transmission while attenuating monoamine-oxidase-linked oxidative stress. Here, we report a benzoxazolinone-based propionyl thiosemicarbazide series, synthesized and fully characterized by infrared (IR) spectroscopy, [1]H nuclear magnetic resonance (NMR), and high-resolution mass spectra (HRMS). The compounds showed consistent submicromolar inhibitory activity across AChE, BChE, MAO-A, and MAO-B in vitro. Several AChE potencies approached the reference donepezil, and selected BChE activities were within an order of magnitude of tacrine. Notably, 4bk' (5-Me/benzyl) inhibited three targets (IC50: 0.029 ± 0.001 μM for AChE, IC50: 0.071 ± 0.003 μM for BChE, IC50: 0.048 ± 0.002 μM for MAO-B), and 4af' (5-Cl/phenyl) showed a balanced profile (IC50: 0.025 ± 0.001 μM for AChE, IC50: 0.056 ± 0.002 μM for BChE, IC50: 0.095 ± 0.003 μM for MAO-A), 4ac' (5-Cl/propyl) combined potent AChE and MAO-B inhibition (IC50: 0.035 ± 0.001 μM for AChE, IC50: 0.045 ± 0.002 μM for MAO-B), whereas 4ag' (5-Cl/4'-Cl-phenyl) was strongly MAO-B-selective (IC50: 0.041 ± 0.001 μM for MAO-B). Antioxidant capacity was pronounced for para-substituted analogues. The efficient compounds 4bk', 4af', 4ac', and 4ag' presented quite low toxicity on healthy cells (cell survival % was above %70 for 4bk', 4af', and 4ac', while it was around 64% for 4ag') even when they were applied at 100 times higher concentrations than their IC50 values, which indicates that they are safe at effective doses. Moreover, assessment of the compounds at a concentration of 10 μM demonstrated no cytotoxic effects on either healthy BV-2 microglial cells or H9c2 rat myoblastoma cells. Docking and 100 ns molecular dynamics (MD) simulations (AChE: 4EY7; MAO-B: 2V5Z) supported stable binding for dual-active representatives (RMSD ∼1.5-2.8 Å). In silico ADME (QikProp) indicated compliance with Lipinski's Rule of Five and Jorgensen's Rule of Three. Collectively, this scaffold is tunable from MAO-B-selective to balanced MTDL profiles suitable for further AD-relevant optimization.},
}

@article {pmid42540280,
year = {2026},
author = {Chu, AL and Chu, BSL and Qiang, W},
title = {Molecular Dynamics Simulations of Aβ42 Dimers with Solid-State NMR Restraints Capture the Key Structural Motifs in Aβ42 Fibrillation Pathways.},
journal = {ACS omega},
volume = {11},
number = {29},
pages = {44425-44433},
doi = {10.1021/acsomega.6c05189},
pmid = {42540280},
issn = {2470-1343},
abstract = {Formation of the β-amyloid (Aβ) plaques is a pathological hallmark of Alzheimer's disease (AD) and is believed to be a primary cause of dementia in elderly individuals. In the present work, we performed molecular dynamics (MD) simulations on the conformational evolution of Aβ42 dimers in solution and in a membrane-like environment to explore the folding of Aβ42 during fibrillation. Particularly, the MD simulation was steered by experimental internuclear distance restraints obtained using solid-state nuclear magnetic resonance (ssNMR) spectroscopy. Our results revealed that several hydrophobic and polar motifs within the Aβ42 sequence played key roles in the early-stage nucleation process of fibrillation, and these motifs are also the stabilizing agents in the mature fibrils, as judged by the energy contribution. Our results also indicated that the membrane-binding of small Aβ oligomers could modulate their structural evolution pathways toward fibrillation. These findings contributed to a better understanding of the molecular-level structural polymorphisms inherent to Aβ42 fibrils. Further, the current work demonstrated that the combination of MD simulations with ssNMR-based experimental restraints provided a reliable method for studying structural changes of Aβ.},
}

@article {pmid42540298,
year = {2026},
author = {McFall-Boegeman, H and Talbot, C and Montalbano, M and Puangmalai, N and Wang, KW and Kannan, M and Shi, J and Linning-Duffy, K and Nick, S and Yan, L and Kuo, MH and Kayed, R and Huang, X},
title = {A Virus-Like-Particle-Based Conjugate Vaccine Targeting the Microtubule Binding Region of Tau Protein.},
journal = {ACS omega},
volume = {11},
number = {29},
pages = {43242-43254},
doi = {10.1021/acsomega.6c00852},
pmid = {42540298},
issn = {2470-1343},
abstract = {There is a pressing need to develop novel strategies to ameliorate symptoms and slow the progression of Alzheimer's disease. One of the hallmarks of Alzheimer's disease is the high levels of tau protein, which can form toxic oligomers and characteristic neurofibrillary tangles in the brain. Antitau antibodies can potentially bind tau protein and reduce tau pathology. In order to elicit a powerful antitau antibody response, virus-like-particle bacteriophage Qβ-based conjugate vaccines were developed targeting the microtubule binding region of tau protein. The Qβ-tau vaccines were able to produce a strong antitau antibody response in not only wild-type mice but also in human tau transgenic mice and a llama. The levels of antibody induced were superior to those generated by a corresponding keyhole limpet hemocyanin-based tau conjugate mimicking the one vaccine that successfully completed phase 1/2 human clinical trials. The Qβ-tau vaccine significantly improved the cognitive functions of the immunized mice and reduced the levels of inflammatory cytokines and tau in the brains, suggesting its translational potential.},
}

@article {pmid42540333,
year = {2026},
author = {Gabb, VG and Neary, C and Mair, D and Kendrick, A and Russell, G and Clayton, J and Begum, S and Huckstepp, RTR and Turner, N and Coulthard, E},
title = {Sleep Apnoea and Memory (SAM): protocol for a prospective study of prevalence and symptoms of sleep apnoea in memory clinics.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1862599},
doi = {10.3389/fnagi.2026.1862599},
pmid = {42540333},
issn = {1663-4365},
abstract = {INTRODUCTION: Sleep apnoea is common in older adults and a risk factor for cognitive decline and dementia but is rarely assessed in memory clinics. The Sleep Apnoea and Memory (SAM) study will assess the prevalence of sleep apnoea and identify optimal screening for sleep apnoea in memory clinics.

METHODS: SAM is a prospective observational multi-site study recruiting adults attending NHS memory clinics. Participants will undergo a single night of polygraphy using a home sleep apnoea test (WatchPAT[®] 300) and complete questionnaires based on NICE guidance for sleep apnoea assessment. The primary outcome will be the prevalence of sleep apnoea. Secondary outcomes include determining sleep apnoea prevalence across different cognitive diagnoses, identifying which symptoms and risk factors which best predict sleep apnoea, and assessing feasibility of remote sleep apnoea screening.

DISCUSSION: The SAM study will improve understanding of the extent of sleep apnoea in people attending memory clinics and inform design of an interventional trial for treating sleep apnoea in patients with cognitive impairment. Treating sleep apnoea in memory clinics may help to improve symptoms and/or prognosis for people experiencing memory problems.},
}

@article {pmid42540517,
year = {2026},
author = {Otenaike, TA and Farodoye, OM and Olaniyan, H and Teibo, JO and Faleke, HO and Akinola, IA and Molik, ZA and Aschner, M and Abolaji, AO},
title = {Neurotoxicity of heavy metals across the lifespan: The beneficial role of nutrition from fetus to the elderly.},
journal = {Advances in neurotoxicology},
volume = {16},
number = {1},
pages = {307-349},
doi = {10.1016/bs.ant.2026.03.003},
pmid = {42540517},
issn = {2468-7480},
abstract = {Heavy metals pose a profound threat to neurological health across all stages of human life, from prenatal development to old age. Heavy metals such as lead, mercury, cadmium, and arsenic are pervasive environmental pollutants that disrupt neural function through mechanisms including oxidative stress, inflammation, mitochondrial dysfunction, and neurotransmitter system imbalances. During critical developmental windows such as fetal growth and early childhood, exposure can impair neurogenesis, synaptic plasticity, and myelination, leading to lifelong cognitive deficits, behavioral disorders, and increased vulnerability to neurodegenerative diseases in later life. Even in adulthood and aging, chronic exposure exacerbates neurodegeneration, accelerating conditions like Alzheimer's and Parkinson's diseases through persistent oxidative damage and inflammatory cascades. This chapter underscores the dual role of nutrition as both a shield and a therapeutic tool against heavy metal neurotoxicity. Key nutrients, such as polyphenols, vitamins, and essential minerals, counteract heavy metal-induced damage by scavenging free radicals, enhancing antioxidant defenses, modulating inflammation, and promoting neuronal repair. By integrating evidence from epidemiological, preclinical, and clinical studies, this chapter emphasizes actionable strategies, such as fortified infant formulas, plant-based proteins, and micronutrient supplementation to reduce heavy metal bioavailability and bolster neurological resilience. Public health initiatives targeting vulnerable populations, alongside policies regulating environmental pollutants, are critical to curbing this silent epidemic. This chapter advocates for a proactive, nutrition-centered approach to safeguarding brain health, demonstrating that dietary interventions are not merely complementary but foundational in combating the pervasive threat of heavy metal neurotoxicity across generations.},
}

@article {pmid42540519,
year = {2026},
author = {Rajabpour-Sanati, A and Nasiri, H and Khosravi, F and Ghahrieh, F and Asemanrafat, A and Bahaqiqat, AK and Saberian, P and Bakhshi, R and Rastegari, F and Ahangar-Sirous, R and Shahidzadehasadi, A and Seif, H and Ghahremani, M and Gandomi-Nasrabadi, F and Azizan, Z and Mayeli, M and , },
title = {Diagnostic Performance of the AlzoSure Predict Assay and Its Association With Alzheimer's Disease Biomarkers and Imaging Findings.},
journal = {Health science reports},
volume = {9},
number = {8},
pages = {e72914},
doi = {10.1002/hsr2.72914},
pmid = {42540519},
issn = {2398-8835},
abstract = {BACKGROUND: Early diagnosis of Alzheimer's disease (AD) is critical for improving patient outcomes. The laboratory-developed blood test of AlzoSure measures the unfolded conformational variant of p53 (U-p53AZ) in plasma and has shown promise as a screening tool for AD risk. We aimed to evaluate the association between U-p53AZ with established cerebrospinal fluid (CSF) and neuroimaging measures, and to determine its diagnostic performance in distinguishing cognitively normal (CN) individuals from those with mild cognitive impairment (MCI).

METHODS: Participants included CN and MCI individuals aged 55-90 years with complete baseline and 24-month follow-up assessments. Associations between U-p53AZ, CSF biomarkers, standardized uptake value ratio (SUVR) of glucose measured by fluorodeoxyglucose positron emission tomography (FDG-PET), and cognition were examined with multivariable regression models adjusted for age, sex, and APOE ε4 status. Diagnostic performance was assessed with receiver operating characteristic (ROC) analysis.

RESULTS: At baseline, no significant group differences were observed in plasma U-p53AZ, FDG SUVR, or CSF biomarkers between CN and MCI. Longitudinally, FDG SUVR significantly declined in MCI (p = 0.040), while CSF t-tau and p-tau181 increased in both groups (all p < 0.05). Higher U-p53AZ levels were independently associated with elevated CSF t-tau (β = 0.38; p = 0.033) and p-tau181 (β = 0.37; p = 0.033) at baseline, and these associations persisted at follow-up (β range 0.43-0.48; all p < 0.02). No significant associations were found with FDG SUVR or cognitive scores. The discriminative ability of U-p53AZ to distinguish CN from MCI was modest (AUC = 0.617, 95% CI 0.518-0.716).

CONCLUSION: AlzoSure measurements are significantly associated with CSF tau values but demonstrate limited utility in differentiating CN from MCI. Although promising as a marker of tau-related neurodegeneration, AlzoSure has a modest diagnostic performance as a stand-alone assessment.},
}

@article {pmid42540536,
year = {2026},
author = {Wang, S and Lin, Y and Che, Y and Zhao, J and Xu, L and He, W and Zhang, W},
title = {Genetically inferred effects of brain structure and gene expression on neurodegenerative diseases: a Mendelian randomization study.},
journal = {Archives of medical science : AMS},
volume = {22},
number = {3},
pages = {1663-1677},
doi = {10.5114/aoms/219499},
pmid = {42540536},
issn = {1734-1922},
abstract = {INTRODUCTION: Against the backdrop of accelerating population aging, the risk of neurodegenerative diseases (NDDs) has risen significantly. While brain structure plays a critical role in NDDs, the interplay between them remains unclear. This study employed Mendelian randomization (MR) to investigate potential causal relationships between brain structure, region-specific gene expression, and four NDDs - Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) - providing new directions and genetically informed hypotheses for disease research.

MATERIAL AND METHODS: MR analyses were conducted using inverse-variance weighted (IVW), MR-Egger, weighted median, weighted mode, and Wald ratio methods. Summary-data-based MR (SMR) was applied to identify brain genes influencing NDDs. We calculated F-statistics, 95% confidence intervals (CIs), odds ratios, and p-values. Sensitivity analyses included the heterogeneity I[2] statistic, Cochran's Q test, Egger intercept test, MR-PRESSO, and leave-one-out validation.

RESULTS: Data from 512 unsupervised deep-learning imaging phenotypes (UDIPs) were analyzed. Thirty-four UDIPs showed associations consistent with a potential causal role in AD, 56 in PD, 22 in ALS, and 92 in MS. After false discovery rate (FDR) correction, 4 remained significant for AD and PD, 3 for ALS, and 28 for MS (p < 0.05). Brain regions (excluding the cervical spinal cord C-1) exhibited shared causal genetic features across all four NDDs, primarily involving HLA-class genes.

CONCLUSIONS: This study provides genetic evidence suggestive of potential causal associations between UDIPs, brain gene expression, and NDDs. These findings offer genetically predicted evidence that may generate hypotheses and inform future mechanistic research into NDD pathogenesis.},
}

@article {pmid42540688,
year = {2026},
author = {Paonessa, F and Bizzini, BD and Campbell, T and Coode, E and Lam, J and Solanki, R and Butler, R and Smith, J and Davidson, CM and Larrieu, D and Brand, AH and Livesey, FJ},
title = {NAT10 inhibition corrects nuclear defects in tau mutant human neurons and extends lifespan in a Drosophila tauopathy model.},
journal = {iScience},
volume = {29},
number = {8},
pages = {116861},
doi = {10.1016/j.isci.2026.116861},
pmid = {42540688},
issn = {2589-0042},
abstract = {Mutations in the gene encoding the microtubule-associated protein tau (MAPT) that are causal for frontotemporal dementia result in nuclear envelope deformation and disrupted nucleocytoplasmic transport when expressed in human neurons. A small-molecule inhibitor of the acetyltransferase NAT10 has been shown to correct similar nuclear membrane defects in Hutchinson-Gilford progeria syndrome, primarily by modulating microtubule dynamics. We report here that NAT10 inhibition and loss of function correct nuclear membrane abnormalities in human MAPT-mutant neurons. Similarly, NAT10 inhibition and haploinsufficiency correct neuronal nuclear shape defects and extend lifespan in vivo in a Drosophila model of tauopathy. NAT10 inhibition changes microtubule dynamics and corrects aberrant nucleocytoplasmic transport, and NAT10 directly interacts with regulators of microtubule dynamics in human MAPT-mutant neurons. We conclude that NAT10 mediates neuronal pathologies in tauopathies and is a potential therapeutic target in these diseases.},
}

@article {pmid42540732,
year = {2026},
author = {Saloner, R and Paolillo, EW and VandeBunte, AM and Cadwallader, CJ and Chen, C and Steffen, BT and Bennett, DA and Boeve, BF and Rosen, HJ and Boxer, AL and Kramer, JH and Casaletto, KB},
title = {Plasma proteomics reveals molecular overlap between physical activity and dementia risk.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag287},
doi = {10.1093/braincomms/fcag287},
pmid = {42540732},
issn = {2632-1297},
abstract = {Physical activity (PA) is a modifiable lifestyle behaviour associated with lower dementia risk; however, molecular pathways bridging PA-related dementia prevention are poorly understood. We leveraged large-scale plasma proteomics to identify biological signatures of objectively monitored PA and cognitive ageing in functionally intact older adults, cross-validated these signatures in independent exercise cohorts and tested associations with both symptomatic and presymptomatic stages of neurodegeneration across multiple Alzheimer's disease and related dementias (ADRD) cohorts. We analysed large-scale plasma proteomics data (SomaScan 7k) across three cohorts including naturalistic, objective PA monitoring (University of California, San Francisco Brain Aging Network for Cognitive Health cohort, n = 65), self-reported PA (Atherosclerosis Risk In Communities study, n = 10 644) and PA intervention (Health Risk Factors, Exercise Training and Genetics study, n = 654). Differential regression models examined individual protein correlates of PA, adjusting for age and sex. Weighted gene co-expression network analysis assembled proteins into unbiased modules of protein co-expression, which were annotated for gene ontology and cell-type enrichment. To test clinical relevance to ADRD, we examined PA-related protein levels across-cohorts of symptomatic Alzheimer's disease and Parkinson's disease (Stanford Alzheimer's Disease Research Center), as well as frontotemporal dementia-spectrum disorders (ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium). PA-related plasma proteins were also tested as predictors of antemortem cognitive change and post-mortem brain tissue mass spectrometry proteomic signatures in brain donors from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) cohort. Differential regression and network analyses identified PA plasma proteomic signatures linked to cell adhesion/extracellular matrix (ECM), immune response and lipid metabolism. Protein co-expression module M12 ECM/neurodevelopment harboured growth factor, cell adhesion and vascular remodelling proteins that (i) were positively associated with PA across exercise cohorts, (ii) positively associated with cognitive function and (iii) negatively associated with Alzheimer's disease, Parkinson's disease and frontotemporal dementia. Furthermore, M12 was enriched for proteins from Alzheimer's disease risk genes and antemortem plasma abundance of anthrax toxin receptor cell adhesion molecule 2 (ANTXR2), an M12 'hub' protein and top PA hit across-cohorts, forecasted longitudinal global cognitive decline and post-mortem brain tissue signatures of synaptic function and proteolysis in ROSMAP. Collectively, our integrated systems biology analysis of six independent plasma proteomic datasets facilitated discovery and validation of blood-detectable molecular signatures of PA and neurodegenerative disease, including PA-related proteins with clinical and biological relevance to early stages of disease. Circulating levels of PA-related proteins reflecting ECM biology (e.g. ANTXR2) may represent key molecular targets for dementia prevention.},
}

@article {pmid42541080,
year = {2026},
author = {Espinosa, PS and Li, S and Preisler, J and Hennekens, CH},
title = {Donanemab Infusion and Recurrent Seizures in a Patient With Alzheimer's Disease and Epilepsy in the Absence of Amyloid-Related Imaging Abnormalities (ARIA).},
journal = {Cureus},
volume = {18},
number = {7},
pages = {e111911},
doi = {10.7759/cureus.111911},
pmid = {42541080},
issn = {2168-8184},
abstract = {Donanemab is an immunoglobulin G1 (IgG1) monoclonal antibody that was recently approved by the United States Food and Drug Administration for the treatment of early symptomatic Alzheimer's disease (AD). The drug was approved with boxed warnings for amyloid-related imaging abnormalities (ARIA). While seizures are recognized adverse events, they are predominantly characterized in the context of ARIA and accompanied by edema (ARIA-E) or hemosiderin deposition (ARIA-H). The precise epileptogenic mechanisms of anti-amyloid immunotherapies independent of macroscopic ARIA remain poorly understood. We report the case of a 90-year-old man with mild cognitive impairment due to AD and a history of well-controlled focal epilepsy on levetiracetam, who experienced two generalized tonic-clonic seizures. Each paroxysmal event occurred within two hours of completing his fifth and sixth monthly donanemab (1,400 mg intravenous) infusions. Inter-ictal magnetic resonance imaging (MRI), including fluid-attenuated inversion recovery (FLAIR) and susceptibility-weighted imaging (SWI) sequences, demonstrated no evidence of ARIA-E or ARIA-H. Routine electroencephalography (EEG) revealed no interictal epileptiform discharges. Seizure recurrence necessitated an escalation of his levetiracetam dosage to 750 mg twice daily and the immediate discontinuation of donanemab therapy, after which he remained seizure-free. The temporal proximity of the seizures to the infusions, the positive rechallenge, and the absence of identifiable structural, metabolic, or infectious precipitants raise the possibility of an association with donanemab. However, causality cannot be established from a single case report. Several biologically plausible mechanisms may explain this temporal association, including rapid amyloid-beta (Aβ) clearance, microglial activation, neuroinflammatory responses, and transient blood-brain barrier dysfunction, which may lower the seizure threshold in a patient with pre-existing epileptogenic networks. However, these mechanisms remain hypothetical and were not directly demonstrated in this patient. Clinicians should maintain a high index of suspicion for acute post-infusion seizures in patients receiving donanemab, particularly those with a history of epilepsy, even in the absence of radiographically detectable ARIA. Clinicians should be aware of this potential safety signal in patients with pre-existing epilepsy. Additional studies are needed before specific monitoring or treatment recommendations can be established.},
}

@article {pmid42541117,
year = {2026},
author = {McNamara, E and Smith, C and Postlethwaite, N and Wozencraft, A},
title = {Privacy-Enhancing Technologies: Unlocking Responsible Cross-Border Data Research.},
journal = {International journal of population data science},
volume = {11},
number = {5},
pages = {3615},
doi = {10.23889/ijpds.v11i5.3615},
pmid = {42541117},
issn = {2399-4908},
mesh = {Humans ; *Information Dissemination/legislation & jurisprudence ; *Privacy/legislation & jurisprudence ; *Confidentiality/legislation & jurisprudence ; *International Cooperation ; *Computer Security/legislation & jurisprudence ; },
abstract = {International data transfer rules, designed to protect individuals, often create barriers to collaborative research by imposing constraints misaligned with modern data ecosystems. Frameworks like GDPR and UK GDPR can unintentionally hinder scientific progress by failing to recognise the safeguards provided by emerging technologies. More nuanced legal approaches are needed to preserve privacy while enabling responsible international research. We will examine how privacy-enhancing technologies (PETs) can help address these challenges. Informed by insights from pilot projects under the Alzheimer's Disease Data Initiative which seek to address critical dementia questions, while expanding dataset access. With dementia cases projected to rise globally from 57 million to 153 million by 2050, this work demonstrates the urgent need for cross-border data sharing in brain health research. Specifically, we will explore how PETs offer pathways through regulatory barriers, and how Trusted Research Environments (TREs), aligned with the Five Safes Framework, provide strong safeguards to prevent identifiable data disclosure. We will demonstrate how remote querying techniques enable international analysis without data transfers, as researchers receive only aggregate results. The presentation will address persistent challenges: under European Data Protection Board guidance, even viewing data across borders constitutes a transfer, meaning TRE access may trigger complex compliance requirements despite technical safeguards. We will explore the rapidly evolving landscape through new UK legislation, the European Health Data Space, and emerging case law. Finally, we will discuss whether PETs can bridge the gap between privacy protection and scientific progress, and what regulatory adaptations are required to recognise the protections they provide.},
}

Humans
*Information Dissemination/legislation & jurisprudence
*Privacy/legislation & jurisprudence
*Confidentiality/legislation & jurisprudence
*International Cooperation
*Computer Security/legislation & jurisprudence

@article {pmid42541418,
year = {2026},
author = {Zhang, J and Wang, C and Liang, C and Peng, T and Chang, K and Bu, J and Wang, Z and Wang, X and Hua, Q and Tan, Y},
title = {Neurolymphatic formula restores meningeal and peripheral lymphatic function via VEGFR3 activation: Mechanistic validation of coptisine as a key anti-Alzheimer's compound.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470114},
doi = {10.1177/13872877261470114},
pmid = {42541418},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation with impaired lymphatic clearance, yet therapies targeting lymphatic dysfunction remain underexplored. The Neurolymphatic Formula (NLF), a traditional Chinese medicine, demonstrates lymphatic modulation potential, but its mechanistic role in AD remains unknown.ObjectiveThis study aimed to elucidate NLF's therapeutic efficacy in AD and investigate whether it enhances central and peripheral lymphangiogenesis via VEGF receptor 3 (VEGFR3) activation.MethodsWe evaluated NLF's pharmacological effects on behavior and AD pathology in APP/PS1 mice, including sunitinib-induced lymphatic impairment models. Underlying mechanisms were explored using network pharmacology, molecular docking, and in vitro assays on human lymphatic endothelial cells (HLECs).ResultsIn APP/PS1 mice, 4-week NLF treatment reduced Aβ plaque burden by 43% (p < 0.01) and improved spatial memory latency by 35% (p < 0.05). NLF restored meningeal and mesenteric lymphatic density in sunitinib-treated mice to 82% and 133% of baseline, respectively (p < 0.01), while upregulating serum VEGFR3 2.3-fold (p < 0.01). To validate NLF's molecular basis, coptisine was identified as a representative VEGFR3 ligand (-7.1 Kcal/mol). In vitro, coptisine (25 μM) enhanced HLEC viability by 60%, accelerated wound closure 2.5-fold, and increased tube junctions by 75% (all p < 0.01) alongside VEGFR3 upregulation.ConclusionsNLF alleviates AD pathology by promoting Aβ clearance through VEGFR3-mediated dual modulation of central and peripheral lymphatic systems. The in vitro efficacy of its constituent, coptisine, mechanistically validates this pro-lymphangiogenic pathway, highlighting NLF's therapeutic potential as a holistic lymphatic-targeted AD treatment.},
}

@article {pmid42531136,
year = {2026},
author = {Shen, D and Jin, H and Feng, H and Gao, R and Sun, R and Xiao, Y and Wan, W and Ma, C and Liu, Y},
title = {Neutral Borate Buffer Activates Diazo for Rapid Protein Labeling.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {e1990347},
doi = {10.1002/anie.1990347},
pmid = {42531136},
issn = {1521-3773},
support = {22374148//National Natural Science Foundation of China/ ; 2024JH3/50100009//Liaoning Province Science Foundation for Distinguished Young Scholars/ ; 2022RJ04//Dalian Science Foundation for Distinguished Young Scholars/ ; 028GJHZ2023079FN//International Partnership Program of Chinese Academy of Sciences for Future Network/ ; 2023JJ12WZ037//Dalian Science and Technology Innovation Foundation/ ; 2024-MSBA-59//Natural Science Foundation of Liaoning Province/ ; DICP I202458//Innovation Program of Science and Research from the DICP, CAS/ ; DICP I202310//Innovation Program of Science and Research from the DICP, CAS/ ; DICP I202529//Innovation Program of Science and Research from the DICP, CAS/ ; },
abstract = {Diazo, a carbene precursor, offers an effective chemistry for bioorthogonal labeling upon activation by acids, metals, and/or photo-illumination. Here, we report neutral borate buffer can trigger diazo compounds into carbene for protein labeling without the need for acid, metal, or light. We show that such boron-diazo-mediated covalent modification rapidly occurs within seconds under physiological conditions and preferentially targets carboxylate-containing amino acid residues. Towards applications of such boron-diazo protein chemistry, we exemplify the design of an affinity-based covalent inhibitor for dihydrofolate reductase by installing diazo on the non-covalent trimethoprim drug. When extended to stressed cells, we also capture cellular aggresomes using a diazo-Thioflavin T probe that selectively labels aggregated proteins. Finally, in Alzheimer's disease brain tissue, we employ this boron-diazo chemistry to label, enrich, and profile amyloid plaques, identifying proteins related to pathological deposition. Together, the boron-diazo chemistry reported herein provides a rapid and facile protein modification strategy under mild conditions.},
}

@article {pmid42531512,
year = {2026},
author = {Khawar, M and Nasir, MF and Qadeer, A and Khawar, MMH and Malik, MA and Mubarika, M and Iftikhar, Q and Shahid, A and Zahid, A and Awais, M and Dalil, L and Khaliq, M and Ali, SZ},
title = {Diagnosed oral cavity and salivary gland disorders and the risk of incident Parkinson disease, Alzheimer disease, dementia and all-cause mortality: a retrospective cohort study.},
journal = {Internal medicine journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/imj.70577},
pmid = {42531512},
issn = {1445-5994},
abstract = {BACKGROUND: Oral diseases encompass a heterogeneous group of conditions affecting the oral cavity and associated structures. Certain chronic inflammatory oral diseases, particularly periodontitis, have been linked to systemic inflammation and may contribute to neurodegenerative processes. However, long-term evidence on their association with Parkinson's disease (PD), Alzheimer's disease (AD), dementia and mortality remains inconsistent. This study aims to investigate whether diagnosed oral cavity and salivary gland disorders are associated with long‑term risk of PD, AD, dementia and all-cause mortality in older adults.

AIMS: To investigate whether diagnosed oral cavity and salivary gland disorders are associated with long-term risk of Parkinson disease, Alzheimer disease, dementia, and all-cause mortality in older adults.

METHODS: This retrospective propensity score-matched cohort study utilised the TriNetX US Collaborative Network. Patients aged ≥60 years with a documented diagnosis of diseases of the oral cavity and salivary glands (ICD-10-CM K00-K14) were 1:1 matched with patients without oral diseases on demographics, comorbidities and medication use (n = 232 809 per group after matching). The index date was the first documented oral disease diagnosis (exposure cohort) or equivalent healthcare encounter (control cohort). New-onset PD, AD, any-type dementia and all-cause mortality were assessed at 5- and 13-year follow-up using risk ratios (RRs), hazard ratios (HRs) and Kaplan-Meier survival analysis.

RESULTS: At 5 years, diagnosis of oral cavity and salivary gland diseases was associated with significantly increased risk of new-onset PD (HR 1.212, 95% confidence interval (CI) 1.133-1.296), any dementia (HR 1.132, 95% CI 1.098-1.167) and all-cause mortality (HR 1.117, 95% CI 1.101-1.134). AD risk was modestly elevated (HR 1.100, 95% CI 1.033-1.171). At 13 years, the increased risk persisted for PD (HR 1.146), dementia (HR 1.060) and mortality (HR 1.113), but the association with AD was no longer significant (HR 0.998, 95% CI 0.959-1.038).

CONCLUSIONS: Diagnosed oral cavity and salivary gland diseases are independently associated with sustained long-term risk of PD, dementia and all-cause mortality, but the association with AD appears time-limited. These findings highlight oral health as a potentially modifiable factor in neurodegenerative disease prevention and support multidisciplinary approaches to oral care in older adults.},
}

@article {pmid42531527,
year = {2026},
author = {Kuran, İ and Eşme, M},
title = {Comments on "Persistent Functional Impairment as an Early Indicator of Alzheimer Disease Pathology and Progression".},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70614},
pmid = {42531527},
issn = {1532-5415},
}

@article {pmid42531533,
year = {2026},
author = {Mohamed, MI and Sameh, R and Farghaly, D and Ashraf, B and Kamel, B and Mahmoud, NH and Abdelall, NA and Nada, MAF},
title = {Autoimmune Neurologic Disorders and the Risk of Alzheimer, Vascular, and Other Dementias: A Comprehensive Systematic Review and Meta-Analysis (P2-13.006).},
journal = {Neurology},
volume = {107},
number = {5},
pages = {e218536},
doi = {10.1212/WNL.0000000000218536},
pmid = {42531533},
issn = {1526-632X},
}

@article {pmid42531538,
year = {2026},
author = {Lin, YR and Lee, WJ and Lee, PL and Lin, CP and Wang, PN and Chen, LK and Chung, CP},
title = {Validation of the VasCog-2-WSO VCID Criteria in a Dementia-Free and Stroke-Free Community Cohort: Cardiovascular Risk and Mortality.},
journal = {Neurology},
volume = {107},
number = {4},
pages = {e218311},
doi = {10.1212/WNL.0000000000218311},
pmid = {42531538},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; Aged ; *Dementia, Vascular/mortality/diagnosis/diagnostic imaging ; *Cardiovascular Diseases/mortality/epidemiology ; Middle Aged ; Longitudinal Studies ; *Cognitive Dysfunction/diagnosis/mortality ; Magnetic Resonance Imaging ; Neuropsychological Tests ; Cohort Studies ; },
abstract = {BACKGROUND AND OBJECTIVES: Vascular cognitive impairment and dementia (VCID), a major contributor of dementia, remains underrecognized, owing to the absence of universally accepted diagnostic criteria. The VasCog Society and WSO recently released updated criteria (VasCog-2-WSO); however, their applicability is unknown yet. We aimed to evaluate these criteria in a dementia-free and stroke-free community cohort and determine their associations with vascular burden and long-term mortality.

METHODS: We conducted a community-based cohort study using data from the I-Lan Longitudinal Aging Study. Adults aged 50 years or older without prior stroke or dementia underwent standardized brain MRI and comprehensive neuropsychological assessment. VCID was classified according to the VasCog-2-WSO criteria using a neuroimaging-first approach. Participants were categorized as non-VCID, preclinical VCID (with or without objective cognitive impairment), or vascular mild cognitive impairment (vaMCI). Baseline 10-year Framingham cardiovascular disease risk was assessed. The primary outcome was all-cause mortality over a mean follow-up of 9.4 years, analyzed using multivariable Cox proportional hazards and Poisson regression models.

RESULTS: A total of 1,236 participants (62.7 ± 8.8 years; 52.9% female) were included. Neuroimaging evidence of cerebrovascular disease was present in 19.6% of participants; 19.2% met criteria for preclinical VCID and 0.4% for vaMCI. Compared with non-VCID participants, neuroimaging-positive groups had worse cognitive performance and higher 10-year cardiovascular risk. Mortality increased across the VCID spectrum (7.4 [95% CI 5.7-9.4], 24.9 [16.0-37.1], 27.4 [18.2-39.6], and 137.9 [37.6-353.2] per 1,000 person-years). In adjusted Cox models, preclinical VCID was associated with a 1.5-1.7-fold higher mortality risk, and vaMCI with a hazard ratio of 7.2 (95% CI 2.4-21.1), with a significant graded association across the spectrum (p for trend <0.001).

DISCUSSION: The VasCog-2-WSO criteria identify a spectrum of MRI-defined vascular cognitive vulnerability associated with increased cardiovascular risk and mortality, with excess mortality risk detectable at a neuroimaging-defined preclinical stage before overt cognitive impairment. These findings support their utility for early detection and risk stratification in community settings. A key limitation is the inability to assess mixed etiologies due to the absence of genetic data and Alzheimer disease biomarkers, which limits the ability to thoroughly evaluate the VasCog-2-WSO VCID diagnostic framework.},
}

Humans
Female
Male
Aged
*Dementia, Vascular/mortality/diagnosis/diagnostic imaging
*Cardiovascular Diseases/mortality/epidemiology
Middle Aged
Longitudinal Studies
*Cognitive Dysfunction/diagnosis/mortality
Magnetic Resonance Imaging
Neuropsychological Tests
Cohort Studies

@article {pmid42531673,
year = {2026},
author = {Leuci, R and Paparella, M and Cerini, M and Simic, S and Chaves, S and Carrieri, A and Tortorella, P and Loiodice, F and Laghezza, A and Santos, MA and Wackerlig-Damle, J and Piemontese, L},
title = {Lead optimization of rivastigmine-like hybrids: Impact of nitro group and halogen substitution on multi-target anti-Alzheimer's activity.},
journal = {Bioorganic & medicinal chemistry},
volume = {141},
number = {},
pages = {118760},
doi = {10.1016/j.bmc.2026.118760},
pmid = {42531673},
issn = {1464-3391},
abstract = {The multifactorial profile of Alzheimer's disease has led researchers to adopt a multi-target strategy for the design of new small molecules. In this context, starting from the structure of ROS151, a novel series of seventeen rivastigmine-like hybrids was developed. Structural modification involved the aryloxy-methylene portion, with the substitution of the nitro group with other groups and the variation of type and position of the halogen atom. The nitro group was confirmed to be essential for high anti-ChE activity, with compound 3 showing the most balanced profile, superior to that of the lead compound (IC50 = 0.827 ± 0.012 μM and 4.58 ± 0.01 μM against hAChE and eqBChE, respectively). Hybrid 2 showed inhibitory activity against hAChE close to that of donepezil (IC50 = 0.029 ± 0.005 μM), while 7 had better activity against eqBChE than the parent drug rivastigmine (IC50 = 0.45 ± 0.02 μM). In silico experiments were performed to corroborate these results. When the nitro group was reduced to amine, as for compound 10, relevant antioxidant activity (ABTS, IC50 = 25.2 ± 1.2 μM) and remarkable chelating properties toward Fe[3+] (pM = 15.6) and Cu[2+] (pM = 11.4), with a good selectivity over Zn[2+] (pM = 6.0) were observed. Inhibition of fatty acid amide hydrolase (hFAAH) resulted less relevant but still appreciable. Cyano-derivative 8 appears to be the only compound with preserved multi-enzymatic inhibitory potential, even without nitro-group in its structure and can be used as starting point for further series. Finally, many hybrids demonstrated interesting experimental pharmacokinetic properties, evaluated using bioanalytical methods.},
}

@article {pmid42531948,
year = {2026},
author = {Chang, CH and Chien, SC and Wang, CC and Chuang, CC and Chen, JC},
title = {Alzheimer's disease-related β-amyloid deposition prediction based on plasma biomarkers, ApoE4, and CDR with a machine learning approach.},
journal = {Computer methods and programs in biomedicine},
volume = {286},
number = {},
pages = {109567},
doi = {10.1016/j.cmpb.2026.109567},
pmid = {42531948},
issn = {1872-7565},
abstract = {BACKGROUND: Alzheimer's disease (AD) is an irreversible, incurable neurodegenerative disorder that imposes a substantial economic and social burden. As current therapies can only slow disease progression, early detection is of critical importance. Among existing diagnostic tools, amyloid positron emission tomography (PET) remains the most accurate non-invasive method for detecting β-amyloid deposition; however, its high cost significantly limits its applicability for early screening. To address this challenge, this study investigates the use of plasma biomarkers as a low-cost alternative for predicting cerebral β-amyloid burden.

METHODS: The predictive performance of three machine learning models-Classification and Regression Trees (CART), Support Vector Machines (SVM), and Logistic Regression (LR)-was systematically compared under varying feature subsets and thresholding strategies. Data were obtained from 276 participants in the ADNI database. The qualitative status of cerebral amyloid deposition, defined using threshold-based classification of Centiloid values, was set as the prediction target. Plasma biomarkers and other AD-related risk factors were employed as model features.

RESULTS: Cross-domain data integration enabled effective prediction of amyloid deposition status. The SVM model, combined with feature subset selection (FSS) and a threshold value of 25, achieved the best performance, yielding an area under the curve (AUC) of 0.80.

CONCLUSION: By applying the Centiloid quantification framework for amyloid-PET and employing plasma biomarkers along with established AD-related risk factors, this study demonstrates the feasibility of machine learning models as a low-risk, cost-effective approach for predicting amyloid-PET imaging outcomes. These findings highlight the potential to support clinical decision-making and reduce reliance on costly imaging techniques for early AD detection.},
}

@article {pmid42532103,
year = {2026},
author = {Pfuhlmann, K and Koch, AK and Langhorst, J},
title = {Ginkgo biloba Leaf Extracts in Global Dementia and Mild Cognitive Impairment Guidelines. A Review.},
journal = {Planta medica},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2895-5345},
pmid = {42532103},
issn = {1439-0221},
abstract = {Age-related diseases like dementia are increasing globally, with limited treatments. Extracts of Ginkgo biloba are often used alongside synthetic drugs. The aim of this article was to identify clinical guidelines from countries around the world to assess recommendations on the use of Ginkgo biloba in dementia, mild cognitive impairment, and prevention. PubMed was systematically searched for guidelines on dementia and mild cognitive impairment on the 25th of April 2023. A search update was conducted on the 3rd of March 2026. Additional guidelines were identified via citation searching and organisations. Seventy-seven guideline documents were included: 47 on dementia (subtype not further defined), 25 on Alzheimer's disease, 19 on vascular dementia, 18 on mild cognitive impairment, and seven on prevention, with some guidelines including multiple mentions. The guidelines come from four continents and 28 countries, plus seven international guidelines. Regarding Ginkgo biloba, 52 give positive, 18 negative, and 26 neutral recommendations (double mentions possible); 27 do not mention it. Ginkgo biloba is referred to in guidelines worldwide, usually without reference to specific preparations. Preparation standardisation would be beneficial.},
}

@article {pmid42532278,
year = {2026},
author = {Haut, MW and Vieira Ligo Teixeira, C and Ranjan, M and Carpenter, J and Mehta, RI and Worhunsky, P and D'Haese, PF and Arsiwala, T and Everson, K and Suffridge, J and Keith, C and Phelps, HE and Ebbert, M and Finomore, V and Rezai, A},
title = {Neuromodulation in Alzheimer's disease: a review with illustrative pilot data using focused ultrasound.},
journal = {Biological psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biopsych.2026.07.019},
pmid = {42532278},
issn = {1873-2402},
abstract = {Alzheimer's disease (AD) is increasingly characterized as a disorder of large-scale brain networks driven by synaptic dysfunction, excitation-inhibition imbalance, and progressive breakdown of hippocampal-cortical communication. While recently developed disease-modifying therapies target molecular pathology, their clinical benefits remain modest, underscoring the need for interventions that target dysfunctional circuits. Neuromodulatory techniques such as transcranial magnetic stimulation, transcranial electrical stimulation, and deep brain stimulation demonstrate safety and act at network/system levels to engage target sites yet are limited by their ability to modulate deep anatomic structures and/or their invasiveness. Focused ultrasound (FUS) offers the distinct capability of modulating cortical and deep subcortical networks noninvasively and with anatomic precision. Preclinical studies demonstrate that FUS neuromodulation can influence mechanosensitive ion channels, synaptic plasticity, neurotrophic signaling, and oscillatory dynamics, with downstream effects on distributed memory networks. Early human investigations similarly suggest FUS neuromodulation can alter functional connectivity within default mode, frontoparietal, and limbic networks. Together, these findings support a framework in which FUS may help reshape pathological network states that emerge prior to irreversible neurodegeneration. Here, we present a narrative review of evidence across neuromodulation approaches to define principles of circuit engagement in AD and discuss a network-based rationale for ultrasound interventions. As an illustration of this framework, we also report preliminary findings from a Phase I pilot study of FUS neuromodulation in amyloid-positive mild cognitive impairment demonstrating safety, tolerability, and measurable modulation of hippocampal connectivity. We conclude mechanistic biomarkers of network response may accelerate translational development and guide future controlled trials.},
}

@article {pmid42532327,
year = {2026},
author = {Tan, C},
title = {Depression and amyloid-β across CSF, PET, and plasma biomarkers: a systematic review and meta-analysis.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.07.065},
pmid = {42532327},
issn = {1873-7544},
abstract = {Alzheimer's disease is increasingly defined by biomarker evidence of amyloid-β and tau pathology, sharpening questions about whether late-life depression contributes to, or instead reflects, this pathology. We conducted a systematic review and meta-analysis of studies published between 2000 and 2025 that compared amyloid-β biomarkers in adults with and without depression, with depression defined by validated clinical diagnoses or symptom rating scales. Twenty-four studies were included, spanning three biomarker sources: cerebrospinal fluid, positron emission tomography imaging, and plasma. Across all sources, the pooled difference in amyloid-β burden between depressed and non-depressed individuals was small and clustered near zero, indicating only a weak, statistically non-significant tendency toward higher amyloid in depression. When the three sources were examined separately, each yielded a similar near-null result, although between-study heterogeneity was considerable for cerebrospinal fluid and plasma and moderate for imaging. Importantly, a prespecified subgroup analysis showed that imaging results diverged by quantification method: studies using the simpler standardized uptake value ratio clustered around zero, whereas the smaller group of studies using kinetic distribution volume ratio modelling showed a significant positive association, suggesting that methodological choices critically influence the observed relationship. Taken together, these findings indicate that depression is not consistently accompanied by greater amyloid-β burden across widely used biomarker platforms. The distribution volume ratio signal nonetheless raises the possibility of subtle associations that cruder methods may obscure, and suggests that depression may shape Alzheimer's disease trajectories more by modifying the clinical impact of amyloid than by altering its amount.},
}

@article {pmid42532345,
year = {2026},
author = {Di Domenico, F and Barone, E and Perluigi, M},
title = {BACH1/HO-1 axis dysregulation links Down syndrome to Alzheimer-like neurodegeneration.},
journal = {Neurochemistry international},
volume = {199},
number = {},
pages = {106232},
doi = {10.1016/j.neuint.2026.106232},
pmid = {42532345},
issn = {1872-9754},
abstract = {Down syndrome (DS), caused by trisomy of chromosome 21, is characterized by early-onset oxidative stress, impaired neuronal development, and an increased risk of Alzheimer's disease (AD)-like neuropathology. Among chromosome 21 genes, the transcription factor BTB and CNC homology 1 (BACH1) has emerged as a critical regulator of redox homeostasis. Under physiological conditions, the balance between BACH1 and nuclear factor erythroid 2-related factor 2 (NRF2) warrants tight control of antioxidant defenses and heme metabolism. However, in DS, BACH1 overexpression disrupts this balance, impairing the induction of heme oxygenase-1 (HO-1) and of other cytoprotective pathways, thereby contributing to chronic oxidative stress, neuronal vulnerability, and pathological processes. The present review summarizes the molecular mechanisms that regulate the BACH1/HO-1 axis in the central nervous system. We recapitulate data from studies showing how dysregulation of this axis affects antioxidant defenses, iron homeostasis, ferroptosis, neuroinflammation, and mitochondrial function. We further provide evidence from the aging and AD literature, highlighting BACH1 as a convergent molecular node linking genetic and age-related neurodegeneration. Remarkably, we explore BACH1's contribution to the transition of DS to AD-like pathology. Finally, we evaluate emerging therapeutic strategies employing BACH1 inhibitors, NRF2 activators, and upstream signaling pathway modulators, and assess their applicability to the AD-like dementia context, concluding that targeting BACH1-dependent regulation of HO-1 represents a promising and unifying strategy to mitigate neurodegeneration in both DS and AD.},
}

@article {pmid42532353,
year = {2026},
author = {Li, T and Chang, Y and Tang, S and Chen, Y and Li, X and Wang, Y},
title = {The Microbiota-Gut-Brain Axis in Neuropsychiatric Disorders: Mechanisms, Advances, and Clinical Applications.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112062},
doi = {10.1016/j.brainresbull.2026.112062},
pmid = {42532353},
issn = {1873-2747},
abstract = {Neuropsychiatric disorders are increasingly recognized as systemic conditions arising from dynamic interactions within the gut-brain-immune network. The Microbiota-Gut-Brain Axis (MGBA) serves as a central regulatory system orchestrating neurodevelopment, neural homeostasis, and immune-metabolic balance. This review summarizes evidence across seven major neuropsychiatric disorders, Depression, Autism Spectrum Disorder, Attention-Deficit/Hyperactivity Disorder, Alzheimer's disease, Schizophrenia, Anxiety and Obsessive Compulsive Disorder, demonstrating that dysregulation of the MGBA constitutes a shared pathological mechanism. On this common basis, we delineate disorder specific neurochemical and immunological features and highlight the clinical potential of microbiota-targeted interventions. Moreover, psychotropic medications profoundly alter microbial physiology, influencing bacterial growth and metabolism, thereby complicating interpretation of MGBA-disease relationships. Future research should define strain-specific therapeutic actions and integrate multi-omics approaches to unravel causal pathways, ultimately enabling precision microbiome modulation in neuropsychiatric medicine.},
}

@article {pmid42532399,
year = {2026},
author = {Yildirim, C and Bekerecioglu, S and Akyıldız, S and Bingol, B and Ulusal, H and Yilmaz, SG and Bal, R},
title = {Naringin preserved cognitive function through modulation of cholinergic dysfunction, oxidative stress, and synaptic proteins in scopolamine-induced cognitive impairment.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111868},
doi = {10.1016/j.pnpbp.2026.111868},
pmid = {42532399},
issn = {1878-4216},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline. The cholinergic hypothesis remains central to its framework, suggesting that the degeneration of cholinergic neurons and resulting neurotransmission disruption play a major role in cognitive impairment. Naringin, a potent polyphenolic compound abundant in citrus fruits, has gained attention for its antioxidant, anti-inflammatory, and neuroprotective properties. This study aims to investigate naringin's neuroprotective potential in a scopolamine-induced amnesia model, focusing on the BDNF/GAP-43 signaling pathway and markers of synaptic plasticity.

MATERIALS AND METHODS: A total of 42 male Wistar albino rats were divided into six groups: Saline, Scopolamine (Sco; 1 mg/kg/day), Sco + Naringin (50, 100, and 200 mg/kg), and Sco + Donepezil (3 mg/kg). Following a 21-day treatment period, cognitive and emotional behaviors were assessed using the Morris Water Maze (MWM) and Elevated Plus Maze (EPM) tests. Hippocampal tissues were analyzed for acetylcholinesterase (AChE) activity and oxidative/nitrosative stress markers (MDA, Peroxynitrite, NO, NOS). BDNF and GDNF mRNA expression was quantified by RT-qPCR, and the protein levels of BDNF, GAP-43, PSD-95, SYP, GFAP, SIRT1, KEAP1, Nrf2, and HO-1 were evaluated by Western blot. PSD-95, SYP, GFAP, and NeuN were further examined by confocal imaging.

RESULTS: Scopolamine administration induced significant impairments in spatial learning and memory, alongside anxiogenic-like behaviors. Biochemical analyses revealed a marked increase in AChE activity and oxidative/nitrosative stress in the Sco group. Additionally, scopolamine caused a profound reduction in BDNF, GDNF, GAP-43, PSD-95, and SYP levels, while increasing GFAP expression. Naringin treatment effectively attenuated these deficits by lowering AChE activity, reducing oxidative damage, and suppressing neuroinflammation. Notably, naringin preserved the expression of synaptic proteins, in association with upregulation of the BDNF/GAP-43 pathway and maintaining pre- and post-synaptic protein levels (SYP and PSD-95).

CONCLUSION: These findings demonstrate that naringin exerts significant neuroprotective effects against scopolamine-induced cholinergic amnesia. These findings are consistent with the possibility that naringin preserves synaptic plasticity, enhances neurotrophic support, and mitigates inflammatory responses, suggesting that it may represent a promising natural therapeutic candidate for Alzheimer-like neurodegeneration.},
}

@article {pmid42532494,
year = {2026},
author = {Alfaqih, MA and Haessner, P and LeLaurin, JH and Guo, J and Hammer, NC and Ike-Okpe, O and Pappa, MJ and He, X and Salloum, RG and Bian, J and Gregory, ME},
title = {Co-designing an Outpatient Clinical Decision Support Prototype for Managing Social Risks in Patients Living with Dementia.},
journal = {Applied clinical informatics},
volume = {17},
number = {3},
pages = {659-667},
doi = {10.1055/a-2917-6503},
pmid = {42532494},
issn = {1869-0327},
support = {R01AG089445/NH/NIH HHS/United States ; },
mesh = {Humans ; *Dementia ; *Decision Support Systems, Clinical ; *Outpatients ; Female ; *Risk Management ; },
abstract = {BACKGROUND: Patients living with dementia (PLWD) require attention to social determinants of health (SDoH), but social information is often unavailable or incomplete during care encounters, and clinicians report uncertainty about how to act on this information.

OBJECTIVE: This study aimed to co-design the Intelligent Social Risk Management in Alzheimer's Disease and Alzheimer's Disease-Related Dementias Patients (iSMART) clinical decision support (CDS) prototype, which integrates an AI-driven individualized polysocial risk score (iPsRS) to identify PLWD at high social risk for hospitalization.

METHODS: We conducted a qualitative user-centered design study with nine outpatient providers and clinical staff who care for PLWD at a large academic health system. Participants completed semi-structured interviews to explore perceived social risks in dementia care, gather feedback on the iSMART prototype and its features, and identify implementation considerations. Interview transcripts were coded and analyzed via rapid qualitative and thematic analysis.

RESULTS: Nine participants (six providers, two nurses, and one social worker) were interviewed. Lack of caregiver or family support was identified as the most important social factor to consider for PLWD, followed by financial strain and transportation issues. Participants described the iSMART prototype as helpful for identifying social risks among PLWD, summarizing and prioritizing factors contributing to hospitalization risk, and connecting patients to relevant social resources. Participants suggested primary care providers and social workers should be the primary users. Recommended improvements included auto-populated (as opposed to manual entry) but editable SDoH fields for model input, incorporating caregiver presence as a model input, and providing clearer visual representations of risk.

CONCLUSION: Outpatient providers and staff viewed the iSMART prototype as a promising approach to support social risk screening, resource connection, and referral support in dementia care. These findings inform practical strategies for integrating iPsRS-informed CDS tools into routine workflows in dementia clinics.},
}

Humans
*Dementia
*Decision Support Systems, Clinical
*Outpatients
Female
*Risk Management

@article {pmid42532804,
year = {2026},
author = {Ptomey, LT and Aschenbrenner, AJ and Helsel, B and Bodde, A and Clina, JG and Danon, JC and Lepping, R and Martin, LE and Brucks, M and Sherman, JR and Forsha, DE and Washburn, RA and Donnelly, JE},
title = {The impact of a 12-month randomized exercise intervention on cognitive function and brain volume in adults with down syndrome.},
journal = {Disability and health journal},
volume = {},
number = {},
pages = {102134},
doi = {10.1016/j.dhjo.2026.102134},
pmid = {42532804},
issn = {1876-7583},
abstract = {BACKGROUND: Adults with Down syndrome (DS) have a high risk for Alzheimer's disease (AD). While exercise improves cognition and brain health in the general population, few long-term studies have evaluated its effects in DS.

OBJECTIVE: We examined the impact of a 12-month remotely delivered exercise program on cognitive function and brain volume in adults with DS.

METHODS: 81 adults with DS (mean age = 27 years) were randomized to high-frequency remote exercise (3 sessions/week, RH), low-frequency remote exercise (1 session/week, RL), or a support and education control (SE). Cognitive function was assessed using the DS-adapted Cambridge Neuropsychological Test Automated Battery (CANTAB), and brain volumes were measured via MRI at baseline and 12 months.

RESULTS: There were no significant changes in any group in executive function or episodic memory (all p > 0.05), but the RH arm significantly improved processing speed across the 12-month intervention (EMM change: 0.17; p = 0.04). No between-group differences were observed for changes in overall cognitive scores. The RL group showed a decrease in total grey matter volume (EMM change -0.82; p = 0.02) and the RH group had no change (EMM change: 0.08; p = 0.72), yielding a significant group effect across time (EMM: 0.90; p = 0.04). Additionally, the RH arm had an increase in right hippocampal volume over 12 months (EMM change: 0.004; p = 0.04).

CONCLUSION: The improvements in reaction time, right hippocampal volume, and grey matter preservation suggest that structured exercise may influence cognition and brain health in adults with DS.

CLINICAL TRIALS REGISTRATION: NCT04048759.},
}

@article {pmid42533036,
year = {2026},
author = {Yu, R and Suraev, A and Vidal, V and Kong, S and Zachariae, R and Piccio, L and Heneka, MT and Naismith, SL and Michaelian, JC},
title = {Neuroinflammatory markers sTREM2 and YKL-40 in association with Alzheimer's disease pathology: a systematic review and meta-analysis.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42533036},
issn = {1476-5578},
abstract = {BACKGROUND/OBJECTIVES: Neuroinflammation is increasingly recognised as a key feature of Alzheimer's Disease (AD) pathophysiology. Markers of glial reactivity, sTREM2 and YKL-40, are elevated in mild cognitive impairment (MCI) and AD, but their associations with core pathology across these stages have not yet been systematically investigated. This systematic review and meta-analysis examined their cross-sectional and longitudinal associations with core pathological biomarkers of AD, and examine how these relationships may evolve dynamically across the disease continuum.

METHODS: A systematic literature search conducted across Medline, Embase, PsycINFO, PubMed and Scopus (PROSPERO: CRD420250653864) identified 42 studies for sTREM2 and 44 for YKL-40 that were included in this study.

RESULTS: Meta-analyses revealed that both markers showed robust positive associations with pTau181, tTau and NfL (pooled r = 0.31-0.55), including in covariate-adjusted correlations. In contrast, associations with Aβ pathology (CSF Aβ42/40, Aβ-PET) were weaker and not significant in covariate-adjusted estimates. Meta-regression analyses revealed that glial-tau associations were strongest in cognitively unimpaired (CU) individuals, and progressively weakened in MCI and AD, independent of age effects. Longitudinal data were limited and summarised descriptively; glial reactivity predicts increases in soluble CSF hyperphosphorylated tau pathology, yet is concurrently associated with slower accumulation of insoluble PET-detectable amyloid and tau aggregates.

CONCLUSIONS: Our findings indicate that sTREM2 and YKL-40 preferentially associate with tauopathy and neurodegeneration over pathological Aβ accumulation. The progressive attenuation of glial-pathology coupling may reflect glial saturation or "exhaustion" with disease progression, offering new insights into how impaired glial responses may be involved in AD pathophysiology.},
}

@article {pmid42533108,
year = {2026},
author = {Breithaupt, AG and Weiner, M and Tang, A and Possin, KL and Sirota, M and Lah, J and Levey, AI and Van Hentenryck, P and Zandehshahvar, R and Gorno-Tempini, ML and Giorgio, J and Wang, J and Rauschecker, AM and Rosen, HJ and Nosheny, RL and Miller, BL and Pinheiro-Chagas, P},
title = {Agentic AI for scaling diagnosis and care in neurodegenerative disease.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {42533108},
issn = {2662-8465},
support = {NA/ALZ/Alzheimer's Association/United States ; NA//Eisai/ ; NA//American Brain Foundation (ABF)/ ; 2112533//National Science Foundation (NSF)/ ; 2112533//National Science Foundation (NSF)/ ; },
abstract = {US healthcare systems are struggling to meet the growing demand for neurological care, particularly in Alzheimer's disease and related dementias. Generative artificial intelligence (AI) built on large language models now enables agentic AI systems that can streamline clinical workflows, integrate multimodal data and learn from practicing specialists. We envision an agentic AI system that scales specialist-level care to nonspecialist clinical settings through a continuously learning healthcare system. We describe this destination and outline a phased roadmap for responsible design and integration into care of Alzheimer's disease and related dementias: (1) high-quality standardized data collection across modalities; (2) decision support; (3) clinical integration enhancing workflows; (4) rigorous validation and monitoring protocols; (5) continuous learning through clinical feedback; and (6) robust ethics and risk management frameworks. This human-centered approach optimizes clinicians' capabilities in comprehensive data collection, interpretation of complex clinical information and timely application of relevant medical knowledge while prioritizing patient safety, healthcare equity and transparency.},
}

@article {pmid42533130,
year = {2026},
author = {Cao, T and Pang, JC and Gajwani, M and Segal, A and Holmes, A and Wiley, JF and Chopra, S and Zhou, JH and Chen, CLH and Ji, F and Harrison, BJ and Davey, CG and Constable, T and Tiego, J and Hartshorn, B and Kwee, J and Bellgrove, MA and Fornito, A},
title = {The cross-site reproducibility of MRI morphometric phenotypes in psychiatric disorders.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42533130},
issn = {1546-1726},
support = {2034000//Department of Health | National Health and Medical Research Council (NHMRC)/ ; 2033976//Department of Health | National Health and Medical Research Council (NHMRC)/ ; 1146292, 1197431//Department of Health | National Health and Medical Research Council (NHMRC)/ ; DP200103509, FL220100184//Department of Education and Training | Australian Research Council (ARC)/ ; },
abstract = {Decades of structural magnetic resonance imaging (MRI) studies have documented alterations of gray matter morphometry in psychiatric disorders, but the field has failed to identify any consensus disease phenotypes. Here we examine whether current approaches will ever converge on such phenotypes by evaluating the consistency of brain-wide maps of gray matter volume and cortical thickness differences obtained for each of 59 study sites of five psychiatric disorders (schizophrenia, schizoaffective disorder, autism spectrum disorder, major depressive disorder and bipolar disorder), totaling 2,437 patients and 2,065 controls. We find that cross-site consistency is low (median r ≤ 0.16); markedly reduced compared to Alzheimer's disease (r = 0.54); unexplained by demographic, clinical or scanner differences; and robust to analytic choices. Using bootstrapping, we observe that consistency may improve for sample sizes ≥200 per group for schizophrenia but that other disorders may require much larger samples. Our findings indicate that current widespread practices in structural MRI are unlikely to identify robust morphometric phenotypes for psychiatric disorders.},
}

@article {pmid42533301,
year = {2026},
author = {Singh, AK and Dunde, V and Maurya, MH and Vora, N and Maheta, D and Frishman, WH and Aronow, WS},
title = {Protecting the Aging Brain in Diabetes: Mechanism, Biomarkers, and Emerging Therapeutic Frontiers in Cognitive Impairment-A Comprehensive Review.},
journal = {Cardiology in review},
volume = {},
number = {},
pages = {},
doi = {10.1097/CRD.0000000000001405},
pmid = {42533301},
issn = {1538-4683},
abstract = {Diabetes, which impacts over 500 million individuals globally, has been identified as a significant risk factor for accelerated cognitive aging, mild cognitive impairment, and various forms of dementia, including Alzheimer's disease and vascular dementia. Despite its clinical relevance, cognitive decline remains an underrecognized complication within diabetes management. This comprehensive review aims to synthesize evidence across the mechanisms, biomarkers, and therapeutic approaches pertinent to diabetes-associated cognitive impairment, with a particular emphasis on the aging brain. The primary literature search was conducted across the decade 2015-2025; however, earlier landmark studies and foundational scientific contributions have been selectively included where necessary to contextualize contemporary findings within the broader historical trajectory of the field. A systematic literature search was executed across PubMed, MEDLINE, Embase, and PsycINFO utilizing MeSH terms such as "type 2 diabetes mellitus," "cognitive decline," "dementia," "insulin resistance," "neuroinflammation," and "neuroprotection." Diabetes contributes to accelerated brain aging via several convergent pathways, including insulin resistance, chronic neuroinflammation, oxidative stress, blood-brain barrier dysfunction, and cerebrovascular damage. These mechanisms facilitate amyloid-beta accumulation and tau hyperphosphorylation, thereby linking diabetes to the Alzheimer's disease spectrum. Promising biomarkers for early detection include plasma p-tau 217, neurofilament light chain, and various neuroimaging markers.},
}

@article {pmid42533535,
year = {2026},
author = {Qiya, Z and Mandic, M and Waterboer, T and Ruijie, X and Brenner, H and Schöttker, B},
title = {Associations of Inherited Chromosomally-Integrated Human Herpesvirus 6 With Dementia Incidence, Inflammation, and Other Dementia Risk Factors in the UK Biobank.},
journal = {Journal of medical virology},
volume = {98},
number = {8},
pages = {e71085},
doi = {10.1002/jmv.71085},
pmid = {42533535},
issn = {1096-9071},
support = {//China Scholarship Council/ ; /WT_/Wellcome Trust/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; //Department of Health, Scottish government/ ; //Northwest Regional Development Agency/ ; //Welsh Assembly Government/ ; //British Heart Foundation./ ; },
mesh = {Humans ; *Herpesvirus 6, Human/genetics/immunology ; Female ; Male ; Risk Factors ; United Kingdom/epidemiology ; Aged ; *Inflammation/epidemiology/virology ; *Dementia/epidemiology/virology ; Incidence ; Middle Aged ; *Roseolovirus Infections/epidemiology/virology/complications ; Antibodies, Viral/blood ; Biological Specimen Banks ; Aged, 80 and over ; UK Biobank ; Alzheimer Disease/epidemiology/virology ; Biomarkers/blood ; },
abstract = {The infection theory of dementia states that viral infections and chronic inflammation play a role in its pathogenesis. We aimed to test whether testing positive for inherited chromosomally-integrated human herpesvirus 6 (iciHHV-6) is associated with an increased dementia incidence, inflammation, and other dementia risk factors. We included n = 247,731 participants of the UK Biobank in the analysis, of whom n = 3388 (1.4%) tested positive for iciHHV-6. Linear and logistic regression models were performed to assess the associations between iciHHV-6 with HHV-6 antigens, blood-based biomarkers of inflammation, and other dementia risk factors. Cox proportional hazards regression models were applied to assess the associations of iciHHV-6 with all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD). Subjects with iciHHV-6 exhibited statistically significantly higher antibody responses to the HHV-6 antigens IE1A (p = 0.002) and IE1B (p < 0.001). IciHHV-6 positivity was significantly more frequent among subjects with European or Chinese ethnicity, with lower education, higher alcohol consumption, current smoking, and longer telomere length. Interestingly, iciHHV-6 positive subjects had lower C-reactive protein (CRP) levels (p = 0.029). All other inflammatory biomarkers did not differ according to iciHHV-6 status. Overall, 6615 participants were diagnosed with all-cause dementia during a median of 13.6 years, including 3340 with AD and 1708 with VD. There was no significant association between iciHHV-6 positivity and the risk of any dementia outcome. IciHHV-6 positivity was not a risk factor for dementia outcomes or increased inflammation in this large study, but was associated with higher antibody responses against HHV-6 antigens, ethnicity, telomere length, and lifestyle factors.},
}

Humans
*Herpesvirus 6, Human/genetics/immunology
Female
Male
Risk Factors
United Kingdom/epidemiology
Aged
*Inflammation/epidemiology/virology
*Dementia/epidemiology/virology
Incidence
Middle Aged
*Roseolovirus Infections/epidemiology/virology/complications
Antibodies, Viral/blood
Biological Specimen Banks
Aged, 80 and over
UK Biobank
Alzheimer Disease/epidemiology/virology
Biomarkers/blood

@article {pmid42533583,
year = {2026},
author = {Chen, X and Qian, FY and Zhao, N and Liu, XT and Wang, YJ and Geng, F and Zhu, MM and Zhang, ZJ and Ren, QG},
title = {DNAJB6a deficiency induces tau pathology through IRE1α-Xbp1-induced mitochondria dysfunction.},
journal = {Zoological research},
volume = {47},
number = {4},
pages = {1319-1331},
doi = {10.24272/j.issn.2095-8137.2025.348},
pmid = {42533583},
issn = {2095-8137},
mesh = {Animals ; *HSP40 Heat-Shock Proteins/genetics/metabolism/deficiency ; *Protein Serine-Threonine Kinases/metabolism/genetics ; *Mitochondria/metabolism ; Humans ; *tau Proteins/metabolism/genetics ; *X-Box Binding Protein 1/metabolism/genetics ; *Alzheimer Disease/genetics/metabolism/pathology ; *Molecular Chaperones/genetics/metabolism ; *Endoribonucleases/metabolism/genetics ; Mice ; *Nerve Tissue Proteins/genetics/metabolism ; Gene Expression Regulation ; Brain/metabolism ; Mice, Knockout ; },
abstract = {Endoplasmic reticulum (ER) stress and mitophagy have been indicated in the early stage of Alzheimer's disease (AD), in which tau hyperphosphorylation is one major pathological alteration. However, the precise mechanism remains unclear. Herein, the study identifies a crucial protein, the DnaJ (Hsp40) homolog, subfamily B, member 6a (DNAJB6a), and elucidates its potential pathogenic role in AD. The DNAJB6 gene is systematically screened using bioinformatics methods, confirming its decreased expression in AD patients' brains. And decreased DNAJB6a was found in the brains of the APP/PS1 mice compared to the control mice. DNAJB6a [-/-] mice exhibited cognitive impairment, synaptic loss and the pathological phenotypes of AD. Depletion of DNAJB6a led to activated ER stress depending on the downregulation of heat shock 70kDa protein 5 (HSPA5). Furthermore, DNAJB6a deficiency induced and accelerated AD-like phenotypes through activating IRE1α-XBP1 induced mitochondria dysfunction. These findings highlight DNAJB6a as a potential key target for preventing AD pathology.},
}

Animals
*HSP40 Heat-Shock Proteins/genetics/metabolism/deficiency
*Protein Serine-Threonine Kinases/metabolism/genetics
*Mitochondria/metabolism
Humans
*tau Proteins/metabolism/genetics
*X-Box Binding Protein 1/metabolism/genetics
*Alzheimer Disease/genetics/metabolism/pathology
*Molecular Chaperones/genetics/metabolism
*Endoribonucleases/metabolism/genetics
Mice
*Nerve Tissue Proteins/genetics/metabolism
Gene Expression Regulation
Brain/metabolism
Mice, Knockout

@article {pmid42533677,
year = {2026},
author = {Lin, YC and Chiu, SC and Massey, R and Fang, YD and , },
title = {Classification of tau status with machine learning models in amyloid-positive cohorts.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71683},
doi = {10.1002/alz.71683},
pmid = {42533677},
issn = {1552-5279},
support = {P30AG086401/NH/NIH HHS/United States ; },
mesh = {Humans ; *Machine Learning ; *tau Proteins/metabolism ; Positron-Emission Tomography ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; Magnetic Resonance Imaging ; Female ; Aged ; Cognitive Dysfunction/diagnostic imaging/pathology ; Predictive Learning Models ; Classification Algorithms ; Brain/diagnostic imaging/pathology ; Aged, 80 and over ; Neuroimaging ; },
abstract = {INTRODUCTION: Although tau positron emission tomography (PET) imaging is effective for staging tau pathology, it is limited clinically by cost and availability. Machine learning models based on magnetic resonance imaging (MRI)- and amyloid PET-derived features may serve as useful screening tools for tau pathology.

METHODS: Multiple machine learning models were developed to classify tau positivity in the Braak III/IV region using structural MRI, amyloid PET, and demographic features. Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 410) data were used for model training. Open Access Series of Imaging Studies (OASIS-3; n = 143) and the Standardized Centralized Alzheimer's Disease Neuroimaging (SCAN; n = 154) data were used for external validation.

RESULTS: Logistic regression achieved the best performance with areas under the curve (AUCs) of 0.92 for both internal and external validation. Combined external validation yielded accuracy/sensitivity/specificity of 85%/83%/85%. Subjects with mild cognitive impairment and predicted tau positivity progressed to AD at a significantly faster pace (p < 10[-6]).

DISCUSSION: Our model demonstrates the feasibility of classifying tau burden in amyloid-positive cohorts with MRI- and amyloid PET-derived features and may serve as a surrogate biomarker.},
}

Humans
*Machine Learning
*tau Proteins/metabolism
Positron-Emission Tomography
*Alzheimer Disease/diagnostic imaging/pathology/metabolism
Magnetic Resonance Imaging
Female
Aged
Cognitive Dysfunction/diagnostic imaging/pathology
Predictive Learning Models
Classification Algorithms
Brain/diagnostic imaging/pathology
Aged, 80 and over
Neuroimaging

@article {pmid42533763,
year = {2026},
author = {Nakashima, S and Sato, K and Niimi, Y and Ihara, R and Suzuki, K and Iwata, A and Satake, W and Iwatsubo, T and , },
title = {Therapeutic Time Window of Disease-Modifying Therapy for Early Alzheimer's Disease in Japanese Individuals: Analysis Based on J-ADNI Study.},
journal = {Geriatrics & gerontology international},
volume = {26},
number = {8},
pages = {e70698},
doi = {10.1111/ggi.70698},
pmid = {42533763},
issn = {1447-0594},
support = {24dk0207068//Japan Agency for Medical Research and Development/ ; 25dk0207075//Japan Agency for Medical Research and Development/ ; JP24K10653//Japan Society for the Promotion of Science/ ; JP25K19014//Japan Society for the Promotion of Science/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis ; Female ; Japan/epidemiology ; Retrospective Studies ; Male ; Aged ; Time Factors ; Aged, 80 and over ; Mental Status and Dementia Tests ; *Antibodies, Monoclonal, Humanized/therapeutic use ; East Asian People ; },
abstract = {BACKGROUND: Lecanemab and donanemab are recently approved disease-modifying therapies (DMTs) for early Alzheimer's disease (AD), indicating amyloid positivity, with Mini-Mental State Examination (MMSE) requirements. Prior analyses using North American population data suggested that baseline Clinical Dementia Rating-Global Score (CDR-GS) and MMSE may define the "therapeutic time window," but generalizability to Asian populations remains uncertain.

OBJECTIVE: To investigate the duration and predictors of the therapeutic time window, defined as the period until patients with early AD no longer meet eligibility criteria in Japanese patients.

METHODS: We retrospectively analyzed amyloid-positive participants from Japanese Alzheimer's Disease Neuroimaging Initiative, classified as lecanemab-eligible (MMSE 22-30, n = 129) or donanemab-eligible (MMSE 20-28, n = 143). Kaplan-Meier survival was estimated over 24 months, and Cox proportional-hazards models included age, sex, MMSE, CDR-GS, and baseline diagnosis. Education years, apolipoprotein-E ε4 (APOE-ε4), and CDR-Sum of Boxes (CDR-SB) were tested individually.

RESULTS: At 12 and 24 months, survival probabilities for remaining eligible were 82% and 69% (MCI) versus 51% and 38% (AD) in the lecanemab group, and 92% and 81% (MCI) versus 69% and 52% (AD) in the donanemab group. Baseline CDR-GS of 1 versus 0.5 predicted shorter eligibility for donanemab (HR = 2.50, 95% CI: 1.20-5.21), but not for lecanemab (HR = 0.48, 95% CI: 0.18-1.29). Each one-point increase in MMSE above threshold was protective (HR = 0.67-0.68).

CONCLUSIONS: Baseline CDR-GS and MMSE strongly predict the therapeutic time window in Japanese patients, supporting cross-population generalizability and contributing to the management of AD DMTs under resource constraints.},
}

Humans
*Alzheimer Disease/drug therapy/diagnosis
Female
Japan/epidemiology
Retrospective Studies
Male
Aged
Time Factors
Aged, 80 and over
Mental Status and Dementia Tests
*Antibodies, Monoclonal, Humanized/therapeutic use
East Asian People

@article {pmid42534606,
year = {2026},
author = {Wen, J and Zhao, M and Xiao, Y and Li, S and Hu, W},
title = {Correction: OATP1A2 mediates Aβ1-42 transport and may be a novel target for the treatment of Alzheimer's disease.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1903977},
doi = {10.3389/fphar.2026.1903977},
pmid = {42534606},
issn = {1663-9812},
abstract = {[This corrects the article DOI: 10.3389/fphar.2024.1443789.].},
}

@article {pmid42534730,
year = {2026},
author = {Liu, L and Xiao, H and Zhou, J and Zhang, M and Duan, J},
title = {Polyphenols and microglial dynamics in neurodegenerative diseases: mechanistic advances and therapeutic perspectives.},
journal = {PeerJ},
volume = {14},
number = {},
pages = {e21359},
pmid = {42534730},
issn = {2167-8359},
mesh = {*Polyphenols/pharmacology/therapeutic use ; *Microglia/drug effects/metabolism ; Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; Blood-Brain Barrier/metabolism ; Neuroinflammatory Diseases/drug therapy ; },
abstract = {Neuroinflammation plays a central role in multiple neurological and neurodegenerative disorders, including ischemic brain injury, Alzheimer's disease (AD), and Parkinson's disease (PD). Microglia, the principal immune cells with in the central nervous system (CNS) are pivotal mediators of neuroinflammatory responses via their dynamic transition across a spectrum of polarization states, broadly delineated by pro-inflammatory M1-like and anti-inflammatory M2-like phenotypic profiles. A pathological skew towards pro-inflammatory microglial activation drives and exacerbates disease progression, thereby rendering the modulation of microglial polarization states a promising therapeutic target for neuroprotective intervention. Natural polyphenols have garnered increasing interest owing to their capacity to traverse the blood-brain barrier (BBB), confer neuroprotective effects, and mitigate neuroinflammation. Despite challenges in clinical translation stemming from poor bioavailability and rapid in vivo metabolism, innovative delivery systems are being developed to address these limitations. This review consolidates current evidence regarding the mechanisms by which polyphenols modulate microglial phenotypic balance and polarization states and examines advanced delivery strategies designed to enhance their therapeutic efficacy in neuroinflammatory disorders. By synthesizing these perspectives, we offer novel insights into the potential application of polyphenols in neuroprotective therapies targeting pathological neuroinflammation.},
}

*Polyphenols/pharmacology/therapeutic use
*Microglia/drug effects/metabolism
Humans
*Neurodegenerative Diseases/drug therapy
Animals
*Neuroprotective Agents/pharmacology/therapeutic use
Blood-Brain Barrier/metabolism
Neuroinflammatory Diseases/drug therapy

@article {pmid42534796,
year = {2026},
author = {Manchester, M and Boughrum, A and Helmly, V and Olupitan, O and Arias, J},
title = {A 10-state investigation of AD/ADRD-capable assisted living regulations using a comprehensive dementia care model.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1789887},
pmid = {42534796},
issn = {2813-3919},
abstract = {INTRODUCTION: State regulation is central in shaping dementia care practices in assisted living facilities. Yet, there is limited systematic evidence examining how regulatory requirements vary and affect residents across states. Additionally, regulatory frameworks governing the training requirements and staff presence of ALFs play a vital role in shaping ALFs' dementia care capacity.

METHODS: This article reports the results of a legal mapping study that evaluated the variation of assisted living facility (ALF) memory care regulations across 10 states. We compared the regulations of these 10 selected states to the "gold standard" Dementia Care Practice Recommendations, a comprehensive memory care model compiled by the Alzheimer's Association (Fazio et al., 2018).

RESULTS: Of the care model's nine recommendations, regulations aligned most to the following: 1. Supportive and Therapeutic Environment (84% average alignment across 10 states), 2. Information Education and Support (74% average), and 3. Ongoing Care (70% average). States with regulation in highest alignment to the care model included California, Missouri, and Minnesota. Regulations were least aligned with the following recommendations: 7. Person-Centered Care (55% average), 8. Detection and Diagnosis (51% average), and 9. Medical Management (50%). States with regulation in lowest alignment to the care model included Texas, Georgia, and Connecticut.

DISCUSSION: Overall, inconsistencies in state alignment to the Care Model also underscore the absence of a standardized enforcement mechanism across assisted living systems. Additional evidence is needed to link regulatory standards to actual measured changes in state-level care coordination practice in the ALF setting. Target areas for regulation change may also exist outside of mechanisms that govern the staff and services directly provided by ALFs. Methods of this study are building blocks from which researchers may systematically collect and analyze regulations data for future across-state LTSS studies.},
}

@article {pmid42534839,
year = {2026},
author = {Li, Z and Ming, Q and Fu, L and Yang, J and Lv, Y and Chen, B and Qiu, X and Lu, Z},
title = {Anemia, iron deficiency, and blood biomarkers for Alzheimer disease: clinical interpretation and dementia risk stratification.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1897378},
pmid = {42534839},
issn = {2296-861X},
abstract = {Anemia and iron deficiency are common in older adults, yet their relevance to blood biomarkers for Alzheimer disease (AD) remains underappreciated. As these biomarkers move into clinical pathways, their interpretation depends not only on assay performance but also on comorbidity, kidney function, inflammation, and nutritional status. Against this backdrop, anemia, absolute iron deficiency, and functional iron deficiency are better viewed as distinct hematopoietic nutritional phenotypes than as background covariates, with important implications for interpreting the amyloid-β42/40 ratio, phosphorylated tau 217 (p-tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Current human data link anemia and iron-restricted states to higher dementia risk and to variation in plasma p-tau217, GFAP, and NfL; kidney function, body mass index (BMI), inflammation, and multimorbidity further shift biomarker distributions and cutoff interpretation. Among available analytes, p-tau217 is closest to routine clinical use within validated intended-use diagnostic pathways; however, its interpretation remains assay- and cutoff-specific and depends on pretest probability, gray-zone handling, kidney function, BMI, hemoglobin, ferritin, and transferrin saturation. Mechanistic work supports plausible links involving impaired oxygen delivery, disrupted iron-mitochondrial bioenergetics, hepcidin-mediated functional iron restriction, and glial, myelin, and blood-brain barrier vulnerability, although a complete human causal chain has not been established. Current evidence therefore favors phenotype-aware interpretation over hemoglobin-only screening or biomarker-only reading. In memory clinics and geriatric practice, complete blood count and iron studies may provide useful interpretive context in selected patients, particularly when multimorbidity, chronic kidney disease (CKD), inflammation, nutritional vulnerability, fatigue, or low or low-normal hemoglobin could affect biomarker interpretation or downstream decisions. Future studies should test whether, and in whom, correcting iron-related phenotypes changes biomarker-guided risk stratification, biomarker trajectories, or clinical decisions.},
}

@article {pmid42534861,
year = {2026},
author = {Wu, X and Yu, T and Hu, S and Zhang, T},
title = {Global research trends and hotspots of short-chain fatty acids in cognitive impairment: a bibliometric analysis based on two databases.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1857769},
pmid = {42534861},
issn = {2296-858X},
abstract = {OBJECTIVE: Short-chain fatty acids (SCFAs) have been widely investigated in research related to cognitive impairment, yet systematic bibliometric analyses focusing on their correlation remain relatively scarce. This study employed bibliometric analysis to objectively review relevant literature, identify key research contributors, and uncover emerging frontiers in the field.

METHODS: Relevant literature published from 2009 to 2025 was retrieved from the Web of Science Core Collection (WoSCC) and Scopus databases. Bibliometric analyses were performed using the Bibliometrix R package, VOSviewer, and CiteSpace software to evaluate research outputs and generate visualizations.

RESULTS: A total of 425 eligible articles from WoSCC and 514 from Scopus were included. Annual publications on SCFAs and cognitive impairment showed a continuous upward trend from 2009 to 2025. China contributed the largest number of publications in this field, and an international collaboration network has been established, with Wenzhou Medical University (China) serving as the core collaboration hub. International Journal of Molecular Sciences was identified as a major publication platform, and Zhang, Xin was recognized as a core author in SCFA-cognitive impairment research. High-frequency keywords included "gut microbiota," "Alzheimer's disease," "neuroinflammation," and "gut-brain axis." In addition, recent research frontiers encompassed "drug therapy," "microbiology," and "chemistry," revealing the core themes and trends of SCFA and cognitive impairment studies.

CONCLUSION: This study conducted a comprehensive bibliometric analysis of the association between SCFAs and cognitive impairment, clarified the evolutionary trajectory of research themes, and identified potential future research directions. It revealed a developmental pattern whereby research in this field has gradually advanced from exploring basic correlations between diet and gut microbiota to in-depth investigations of pathological mechanisms, precise targeted interventions, and clinical translational applications. By systematically depicting the current research landscape, this study aims to provide guidance for subsequent investigations and fill critical knowledge gaps.},
}

@article {pmid42534986,
year = {2026},
author = {Xavier, C and Correia, AP and Lopes, J and Fernandes, J and Laranjinha, I and Pinto, N},
title = {Mapping Alzheimer's disease heterogeneity through exploratory unsupervised learning.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1869804},
pmid = {42534986},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is becoming one of the most pressing health challenges of the century, affecting circa 55 million people worldwide and expected to triple this number by 2050. Besides the growing prevalence, AD remains difficult to diagnose due to its long preclinical phase and substantial symptomatic heterogeneity. Despite the existence of international guidelines for AD diagnosis emphasizing the use of biomarkers (such as neuroimaging and cerebrospinal molecular biomarkers), most research studies are still using data disregarding their diagnostic quality, blurring the overall statistical outcomes. Aiming to circumvent this effect, biomarker confirmed samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used, which integrate genetic and neuroimaging data for all participants.

METHODS: Unsupervised machine learning clustering methods were tested to explore whether curated genetic markers can reveal underlying substructure within sporadic AD (sAD). Here two specific sets of single nucleotide polymorphisms (SNPs) were selected: (i) candidate SNPs highlighted in previous studies that identified the existence of different subtypes in sAD and (ii) SNPs found associated with sAD in genome wide association studies (GWAS) that used at least 50% of samples with biomarker-confirmed diagnosis.

RESULTS: This strategy minimized background noise and enabled the construction of high quality SNP sets for analysis. Different clustering algorithms were evaluated with agglomerative hierarchical clustering consistently yielding the most robust performance. Across SNP sets, most trials revealed a reproducible binary structure within sAD samples, suggesting the presence of genetically distinguishable subgroups.

DISCUSSION: These findings align with emerging multimodal evidence supporting biological heterogeneity in AD. Overall, this work demonstrates that curated SNP panels combined with unsupervised learning can uncover meaningful substructure in sAD, reinforcing the value of integrating high quality genetic data into subtype research.},
}

@article {pmid42535261,
year = {2026},
author = {Saef, B and Petersen, KK and Volluz, K and Li, Y and Tosun, D and Mila-Aloma, M and Shaw, LM and Zetterberg, H and Dage, JL and Rubel, CE and Ferber, K and Du-Cuny, L and Coomaraswamy, J and Baratta, M and Mordashova, Y and Saad, ZS and Triana-Baltzer, G and Ashton, NJ and Meyers, EA and Rosenbaugh, EG and Sabandal, JM and Bannon, AW and Potter, WZ and , and , and Schindler, SE},
title = {Exploring longitudinal relationships among Alzheimer's disease biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71711},
doi = {10.1002/alz.71711},
pmid = {42535261},
issn = {1552-5279},
support = {//the Foundation for the National Institutes of Health (FNIH)/ ; R01AG070941 (S.E.S.)/AG/NIA NIH HHS/United States ; //AbbVie Inc., Alzheimer's Association, Diagnostics Accelerator at the Alzheimer's Drug Discovery Foundation, Biogen, Janssen Research & Development, LLC, and Takeda Pharmaceutical Company Limited/ ; //Foundation for the National Institutes of Health/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/blood/pathology ; *Biomarkers/blood ; Positron-Emission Tomography ; *tau Proteins/blood ; *Amyloid beta-Peptides/blood ; Longitudinal Studies ; Female ; Male ; Aged ; Peptide Fragments/blood ; Brain/diagnostic imaging/pathology ; },
abstract = {INTRODUCTION: While most studies of Alzheimer's disease (AD) examine cross-sectional relationships among biomarkers, longitudinal relationships are also highly relevant.

METHODS: This study in the Alzheimer's Disease Neuroimaging Initiative cohort (n = 373) used non-parametric Spearman correlations to explore the relationships of baseline values and rates of change in plasma biomarkers and rates of change in key AD outcomes.

RESULTS: Compared to rates of change of plasma biomarkers, baseline values of plasma biomarkers were more strongly associated with rates of change in key AD outcomes. Change in amyloid positron emission tomography (PET) was most strongly associated with baseline values of amyloid beta (Aβ)42/Aβ40 and phosphorylated tau (p-tau)217, especially in amyloid PET--negative individuals. Changes in cortical thickness and measures of cognition were most strongly associated with baseline p-tau217, especially in amyloid PET-positive individuals.

DISCUSSION: Baseline p-tau217 is associated with rates of change of amyloid pathology and cognition. Visualization tools were developed to enable researchers to explore AD biomarker relationships.},
}

Humans
*Alzheimer Disease/diagnostic imaging/blood/pathology
*Biomarkers/blood
Positron-Emission Tomography
*tau Proteins/blood
*Amyloid beta-Peptides/blood
Longitudinal Studies
Female
Male
Aged
Peptide Fragments/blood
Brain/diagnostic imaging/pathology

@article {pmid42535268,
year = {2026},
author = {Hampel, H and Nakamura, Y and Bell, J and Hendrix, S and Derchansky, M and Montezano, BB and Stoeckel, LE and Teipel, S and Willis, DR and Cummings, JL and Cobb, BR},
title = {Evaluating digital cognitive tests for clinical use in Alzheimer's disease: A novel framework and scoping review.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71559},
doi = {10.1002/alz.71559},
pmid = {42535268},
issn = {1552-5279},
support = {//Eisai Incorporated/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Cognitive Dysfunction/diagnosis ; Digital Health ; *Neuropsychological Tests ; Early Diagnosis ; Prodromal Symptoms ; Digital Media ; },
abstract = {Mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease (AD), remains undiagnosed in > 90% of individuals, delaying access to timely evaluation and interventions. Self-administered digital cognitive assessments (SA-DCAs) offer scalable approaches for early detection, yet their real-world validation and clinical readiness remain uncertain. We developed a use-case-specific framework to evaluate SA-DCAs intended for community and primary-care MCI screening and applied it to a comprehensive scoping review of published evidence (2012-2025). Among 79 identified SA-DCAs, only four tools met predefined framework criteria across nine eligible studies. Common limitations included restricted population representativeness, inconsistent diagnostic performance reporting, limited biomarker anchoring, and reliance on prefiltered cohorts. Overall, the current evidence base is methodologically heterogeneous and incomplete for clinical deployment. The proposed framework characterizes requirements including anchoring strength, prevalence-adjusted performance reporting, and representative sampling establishing a foundation for advancing robust real-world evidence needed to translate SA-DCAs from research to clinical practice.},
}

Humans
*Alzheimer Disease/diagnosis
*Cognitive Dysfunction/diagnosis
Digital Health
*Neuropsychological Tests
Early Diagnosis
Prodromal Symptoms
Digital Media

@article {pmid42535277,
year = {2026},
author = {Kang, SH and Park, YJ and Lee, S and Kang, J and Lee, S and Lee, ES and Jung, HN and Ryoo, I and Hwang, H and Choi, K and Eo, JS and Suh, SI and Oh, K and Koh, SB},
title = {Heterogeneity in plasma p-tau217 response and its association with cognitive trajectories under lecanemab treatment.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71705},
doi = {10.1002/alz.71705},
pmid = {42535277},
issn = {1552-5279},
support = {RS-2025-16066879//National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT)/ ; K2615351//Korea University Guro Hospital (Korea Research-Driven Hospital) and grant funded by Korea University Medicine/ ; RS-2023-00273685//Starting Growth Technological R&D Program (TIPS Program) funded by the Ministry of SMEs and Startups, Korea/ ; BT240027//Seoul R&BD Program through the Seoul Business Agency funded by the Seoul Metropolitan Government/ ; },
mesh = {Humans ; *tau Proteins/blood ; *Alzheimer Disease/drug therapy/blood ; Female ; Biomarkers/blood ; Male ; Aged ; Disease Progression ; Phosphorylation ; Prospective Studies ; Longitudinal Studies ; Treatment Effect Heterogeneity ; Aged, 80 and over ; *Cognition/drug effects ; },
abstract = {INTRODUCTION: Plasma phosphorylated tau 217 (p-tau217) is a promising biomarker for monitoring treatment response in Alzheimer's disease (AD), but its longitudinal dynamics and clinical relevance remain unclear.

METHODS: In this prospective real-world study, 153 patients with early AD receiving lecanemab were analyzed. Longitudinal changes in plasma p-tau217 were assessed, and trajectory patterns were identified using clustering and slope-based approaches. Associations with baseline factors and cognitive outcomes were evaluated.

RESULTS: Plasma p-tau217 levels decreased significantly from 3 months, with the greatest decline between 3 and 6 months, followed by a plateau. Two distinct trajectory groups were identified. Patients in the greater reduction group showed more favorable cognitive trajectories, particularly slower progression in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. Hypertension was associated with a diminished biomarker response.

DISCUSSION: These findings support plasma p-tau217 as an early pharmacodynamic biomarker and highlight its potential role in guiding individualized treatment strategies in routine clinical practice.},
}

Humans
*tau Proteins/blood
*Alzheimer Disease/drug therapy/blood
Female
Biomarkers/blood
Male
Aged
Disease Progression
Phosphorylation
Prospective Studies
Longitudinal Studies
Treatment Effect Heterogeneity
Aged, 80 and over
*Cognition/drug effects

@article {pmid42535660,
year = {2026},
author = {Duncan-Cross, I and Miles, E and Hicks, B},
title = {Coping Styles Predict Timing of Dementia Diagnosis: Evidence From DETERMIND.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {8},
pages = {e70246},
doi = {10.1002/gps.70246},
pmid = {42535660},
issn = {1099-1166},
support = {ES/S010351/1//Economic and Social Research Council/ ; },
mesh = {Humans ; *Adaptation, Psychological ; *Dementia/diagnosis/psychology ; Female ; *Coping Skills ; Male ; Aged ; Caregivers/psychology ; Aged, 80 and over ; *Delayed Diagnosis/psychology ; Early Diagnosis ; Middle Aged ; Treatment Delay ; },
abstract = {OBJECTIVES: Early diagnosis underpins global policy directives aimed at supporting people to live well with dementia. While people encounter numerous barriers when seeking early dementia diagnosis, previous research has primarily focussed on non-modifiable, socio-demographic determinants of diagnostic timing. This study examined whether individuals' coping style could provide further insight into diagnostic delay.

METHODS: Coping was assessed via the dispositional Brief COPE in 935 individuals recently diagnosed with dementia and 697 carers from the DETERMIND cohort. Through principal component analysis, we identified three distinct coping styles. Hierarchical regression assessed the association of participant demographics and coping factors with diagnostic timing, operationalised via symptom severity and time between first symptoms and diagnosis.

RESULTS: Coping predicted diagnostic timing in terms of both symptom severity and temporal delay. Increased symptom severity at diagnosis was predicted by individuals with dementia using more avoidant coping and less approach coping. Longer temporal delays were associated with individuals with dementia using less support seeking coping and carers using less avoidant coping.

CONCLUSIONS: Our findings suggest diagnostic timing is related to the coping strategies employed by individuals with dementia and their carers, over and above demographic influences. These results identify coping as a modifiable factor that could help understand who is most at risk and inform interventions to promote early diagnosis, aligning with global policy directives.},
}

Humans
*Adaptation, Psychological
*Dementia/diagnosis/psychology
Female
*Coping Skills
Male
Aged
Caregivers/psychology
Aged, 80 and over
*Delayed Diagnosis/psychology
Early Diagnosis
Middle Aged
Treatment Delay

@article {pmid42525357,
year = {2026},
author = {Sklinda, K and Bocianski, J and Budlewski, T and Kobylecka, M and Dorobek, M and Gorecki, A and Mruk, B and Błaszczak, M and Walecki, J},
title = {Perfusion as a biomarker of brain dysfunction in dementia (AD, DLB, FTD/PPA, PDD): comparison of CT, MRI (ASL/DSC/DCE), SPECT, and PET with interpretive pitfalls - a narrative review.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {42525357},
issn = {2240-2993},
abstract = {The term 'brain perfusion' is applied in clinical practice to a family of neuroimaging techniques that measure, in reality, quite different physiological quantities in the brain circulation. CT perfusion (CTP) and DSC-MRI track a contrast bolus to derive semi-quantitative haemodynamic parameters. ASL-MRI estimates cerebral blood flow (CBF) without contrast, but the result is sensitive to arterial transit time, haematocrit, and the patient's haemodynamic state on the day of the scan. DCE-MRI quantifies blood-brain barrier (BBB) permeability, a property of the neurovascular unit rather than a flow measurement. Perfusion SPECT provides a relative, normalisation-dependent CBF map that is distorted by cortical atrophy. [[18]F]FDG-PET reflects synaptic glucose metabolism, but not blood flow. Because these techniques answer different physiological questions, their results are not interchangeable, and applying a threshold or pattern derived from one modality to interpret another is methodologically unsound - yet this conflation occurs with regularity in clinical practice. This narrative review synthesises the clinical applications, diagnostic performance, and interpretive pitfalls of each technique in Alzheimer's disease (AD)/mild cognitive impairment (MCI-AD), dementia with Lewy bodies (DLB)/Parkinson's disease dementia (PDD), frontotemporal dementia (FTD)/primary progressive aphasia (PPA), and mixed dementia with vascular pathology. Recognised limitations include the narrative study design and the small number of head-to-head multi-modal studies in pathologically confirmed cohorts. A comparative table and practical minimum reporting elements are provided.},
}

@article {pmid42525901,
year = {2026},
author = {Zheng, J and Lip, GYH and Zhang, Z and Lee, SWR},
title = {Association of Sugar Restriction in Utero Through Age 2 Years on Dementia Risk Later in Life.},
journal = {Neurology},
volume = {107},
number = {4},
pages = {e218313},
doi = {10.1212/WNL.0000000000218313},
pmid = {42525901},
issn = {1526-632X},
mesh = {Humans ; Female ; *Dementia/epidemiology/etiology/diagnostic imaging ; *Prenatal Exposure Delayed Effects/epidemiology ; Pregnancy ; Male ; Middle Aged ; United Kingdom/epidemiology ; Developmental Origins of Health and Disease ; Risk Factors ; Dementia, Vascular/epidemiology ; Magnetic Resonance Imaging ; Alzheimer Disease/epidemiology ; Brain/diagnostic imaging ; Aged ; Adult ; Infant ; },
abstract = {BACKGROUND AND OBJECTIVES: Excess sugar intake in early life may affect long-term brain health, but evidence for dementia is limited. We used the abrupt end of UK sugar rationing in September 1953 as a natural experiment to test whether exposure to sugar rationing during different windows within the first 1,000 days from conception was associated with adult risk of all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD).

METHODS: We analyzed UK Biobank participants born around the end of UK sugar rationing. Exposure was classified as rationing in utero only, in utero plus the first year of life, in utero plus 1-2 years of life, or no exposure. Incident dementia was identified from linked ICD-10 records. MRI of the brain and cognitive function were assessed in the imaging subcohort. Adjusted Cox and Gompertz models estimated HRs and 95% CIs, Fine-Gray models accounted for competing risk, and mediation analyses evaluated type 2 diabetes and hypertension.

RESULTS: Among 64,737 participants included in the analysis, the mean age at recruitment was 54.6 years, and 56.4% were women; 40,963 were exposed to sugar rationing during fetal and/or early-childhood life, and 23,774 were unexposed. Compared with unexposed individuals, sugar rationing in utero plus the first year of life was associated with lower hazards of all-cause dementia (HR, 0.79; 95% CI 0.66-0.94) and AD (HR, 0.77; 95% CI 0.59-1.00). Similar or slightly stronger associations were observed for exposure in utero plus 1-2 years (all-cause dementia: HR, 0.77; 95% CI 0.63-0.95; AD: HR, 0.72; 95% CI 0.53-0.98). Exposure in utero plus 1-2 years was associated with delayed onset of all-cause dementia by 2.55 years, AD by 2.87 years, and VaD by 2.49 years. Early-life sugar rationing was also associated with higher total gray matter volume (β, 3.27; 95% CI 0.46-6.07), lower white matter hyperintensity volume (β, -0.64; 95% CI -0.97 to -0.31), and better performance in processing speed and reasoning. Incident type 2 diabetes and hypertension jointly mediated 25.5% of the association.

DISCUSSION: Sugar restriction in the first 1,000 days was associated with lower dementia hazards, delayed onset, and more favorable brain-health profiles. These results support early-life sugar reduction as a potential strategy for dementia prevention.},
}

Humans
Female
*Dementia/epidemiology/etiology/diagnostic imaging
*Prenatal Exposure Delayed Effects/epidemiology
Pregnancy
Male
Middle Aged
United Kingdom/epidemiology
Developmental Origins of Health and Disease
Risk Factors
Dementia, Vascular/epidemiology
Magnetic Resonance Imaging
Alzheimer Disease/epidemiology
Brain/diagnostic imaging
Aged
Adult
Infant

@article {pmid42526376,
year = {2026},
author = {Hu, H},
title = {Interpreting plasma p-tau217 discordance in real-world memory clinics.},
journal = {Journal of the neurological sciences},
volume = {489},
number = {},
pages = {126117},
doi = {10.1016/j.jns.2026.126117},
pmid = {42526376},
issn = {1878-5883},
}

@article {pmid42526554,
year = {2026},
author = {Peng, B and Zou, S and Shi, Y and Zhu, X and Liu, M and Li, H and Zhang, Y},
title = {Fluorescence imaging-based investigation of tau-mediated promotion of U1 small nuclear ribonucleoprotein 70 kDa co-phase separation.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153818},
doi = {10.1016/j.ijbiomac.2026.153818},
pmid = {42526554},
issn = {1879-0003},
abstract = {Neurofibrillary tangles formed by Tau protein are a core pathological hallmark of Alzheimer's disease (AD). Although liquid-liquid phase separation (LLPS) of Tau is thought to induce its aggregation, and the basic-acidic dipeptide (BAD) domain-containing protein U1 small nuclear ribonucleoprotein 70 kDa (U1-70K) abnormally co-localizes with Tau tangles in AD brains, the molecular mechanism underlying their co-aggregation remains unclear. In this study, we found that Tau co-phase separates with two low-complexity domains (LC1/LC2). Both LC1 and LC2 promote the gelation of Tau droplets and the formation of pathological Tau aggregates under the conditions tested. Furthermore, under cellular stress, Tau and U1-70K exhibit aberrant cytoplasmic co-localization, suggesting a functional link between them under pathological conditions and providing new insights into the molecular basis of Tau pathology in AD.},
}

@article {pmid42526715,
year = {2026},
author = {Bang, KY and Walenga, R and Chopski, S and Luke, MC and Blinova, K and Zhao, L and Guo, S},
title = {Intranasal drug delivery to the brain for neurodegenerative diseases: Current efforts and challenges in delivery platforms and modeling.},
journal = {Advanced drug delivery reviews},
volume = {},
number = {},
pages = {115938},
doi = {10.1016/j.addr.2026.115938},
pmid = {42526715},
issn = {1872-8294},
abstract = {Neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD), globally pose a significant challenge with an aging population. Despite the presence of various therapeutic agents, AD and PD treatments with small molecules currently only address the symptoms; certain biologic agents for AD have been approved for their disease-modifying effects, but the risk of intracerebral hemorrhage severely limits their use. Moreover, the bioavailability of orally administered agents in the brain is challenged by the blood-brain barrier, complicating brain-targeted drug development. Extensive efforts are currently underway to develop intranasal platforms with nanoparticles for direct nose-to-brain drug delivery. Additionally, various in vitro designs involving brain organoids, and in vivo models, such as rodents and zebrafish, have been explored to improve the efficiency and accuracy of preclinical models. Efforts to develop sophisticated computational modeling of intranasal drug delivery, including computational fluid dynamics (CFD) deposition and physiologically based pharmacokinetics (PBPK) modeling, also continue to advance the intranasal drug delivery research and potentially improve the feasibility of developing clinically relevant intranasal platforms for neurodegenerative disease.},
}

@article {pmid42527124,
year = {2026},
author = {Li, J and Wang, Y and Shi, L and Zheng, Z and Wu, Y and Jiang, N},
title = {Global Perspectives on Social Relationships and Cognitive Decline in Older Adults: Insights From Cohort Studies in the U.S., Mexico, England, and China.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648261470866},
doi = {10.1177/07334648261470866},
pmid = {42527124},
issn = {1552-4523},
abstract = {BackgroundThis research aimed to explore associations between social relationships and annual cognitive decline in older adults globally.MethodsHarmonized data from 4 longitudinal aging cohorts across the U.S., Mexico, England, and China were included. Participants (aged ≥55) with social relationship data and repeated cognitive assessments were analyzed, excluding dementia cases. Linear mixed models assessed associations between social relationship markers and annual rate of cognitive decline, with effects pooled via two-stage random-effects meta-analysis.ResultsAmong 29,805 participants, living with others was associated with slower decline in episodic memory (b = 0.086, 95%CI: 0.013 to 0.158) and global cognition (b = 0.025, 95%CI: 0.013 to 0.038). Felt loneliness was associated with faster decline in episodic memory (b = -0.087, 95%CI: -0.140 to -0.034) and global cognition (b = -0.023, 95%CI: -0.040 to -0.006).ConclusionsGood social relationships were associated with slower cognitive decline, while poor social relationships with faster decline.},
}

@article {pmid42527215,
year = {2026},
author = {Ahmad, M and Irshad, A and Ahmed, MA and Ahmed, FK and Noor, S and Irshad, H},
title = {Demographic, gender and ethnic disparities in COPD associated mortality trends among older adults (>55 years) with Alzheimer's disease in the United States, 1999-2020: a 20 year retrospective analysis using CDC WONDER database.},
journal = {Journal of the National Medical Association},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jnma.2026.06.021},
pmid = {42527215},
issn = {1943-4693},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the 3rd leading cause of global deaths. COPD and AD have a bi-directional positive relationship, increasing the interrelated mortality.

OBJECTIVES: To analyze the mortality trends associated with COPD in Alzheimer's disease among older adults (>55 years of age) in the United States, using CDC WONDER data from 1999 to 2020.

METHODS: A retrospective analysis using the CDC WONDER database was conducted to analyse the mortality trends due to COPD in Alzheimer's disease patients, stratified by sex, race/ethnicity, census region, states and urbanization status.

RESULTS: A total of 58,495 deaths due to COPD-associated Alzheimer's disease occurred among older adults (aged >55 years). Overall mortality increased from an AAMR of 2.04 per 100,000 in 1999 to 5.19 per 100,000 in 2020 (AAPC=4.31%, p < 0.05). Men exhibited higher mortality than women (AAMR 4.00 vs. 3.58 per 100,000). Non-Hispanic Whites had the highest mortality (AAMR 4.04), followed by Hispanics (AAMR; 2.58) and Non-Hispanic Blacks (AAMR; 2.39). The mortality was highest in the Western region (AAMR; 4.3), followed by Southern region (AAMR; 4.14), Midwestern region (AAMR; 3.94) and least in Northeastern region (AAMR; 2.26). Non-Metropolitan areas exhibit higher AAMR (4.62) than Metropolitan areas (AAMR; 3.52). Tennessee, Kentucky, and Washington were the top 3 states with the highest mortality. Significant increases in mortality were observed across most demographic groups (p < 0.05).

CONCLUSION: These findings highlight the increasing COPD-related mortality among Alzheimer's patients and reveal significant disparities by sex, race, and urbanization status. Systemic inflammation, oxidative stress, and COPD-induced hypoxia may contribute to cognitive impairment and dementia. These results underscore the urgent need for targeted healthcare strategies and further research to address these disparities.},
}

@article {pmid42527300,
year = {2026},
author = {Luppi, JJ and Koomen, AP and Stam, CJ and Scheltens, P and de Haan, W},
title = {Connectome-guided personalization of optimal tDCS intervention selection in Alzheimer's disease: A modeling study.},
journal = {eNeuro},
volume = {},
number = {},
pages = {},
doi = {10.1523/ENEURO.0407-25.2026},
pmid = {42527300},
issn = {2373-2822},
abstract = {Transcranial direct current stimulation (tDCS) could reduce the neurophysiological effects in Alzheimer's disease (AD), but progress is hampered by variable outcomes across studies, likely related to both methodological and individual differences. We recently described a virtual brain network simulation method for optimizing tDCS interventions and now propose a method for further personalizing this approach. We now personalized the model for 6 female and 4 male biomarker-confirmed AD patients based on their brain structure and functional connectivity, by using individual structural magnetic resonance imaging (MRI) data and amplitude envelope correlation (AEC)-based connectivity matrices extracted from magnetoencephalography (MEG) scans, respectively. We then assessed a set of previously established stimulation strategies based on their ability to improve relevant neurophysiological outcome parameters in each personalized model, while undergoing AD damage. Personalized tDCS strategies were able to delay neurophysiological deterioration, but while the general model favored posterior anodal stimulation targeting the precuneus region, the personalized models favored frontal anodal stimulation targeting the dorsolateral prefrontal cortex (dlPFC) region in 90% of the cases. This may be explained by higher connectivity levels of frontal regions in the personalized connectivity matrices, as anodal stimulation of highly connected regions produced more beneficial effects. In this methodological study we propose several ways to improve personalized computational tDCS stimulation prediction modeling. We conclude that connectome-guided personalization of tDCS effects lead to different strategies with potentially better intervention outcomes. For external validation of this model-guided tDCS approach, model predictions are being tested in an ongoing clinical tDCS-MEG trial in AD patients.Significance statement Our aim is to improve the efficacy of transcranial direct current stimulation (tDCS) in Alzheimer's disease (AD) through the use of a personalized modeling approach. This is beneficial since results of tDCS remain variable across groups, and therefore a systematic approach to choosing the stimulation parameters such as placement of electrodes is required. Modeling of tDCS allows us to do this while assessing multiple possible approaches without necessitating a considerable burden on patients across multiple trials. Furthermore, personalizing the model can enable more accurate selection of target regions for stimulation, for example by locating highly connected brain regions without too much damage in each patient, thus increasing the potential for recovery.},
}

@article {pmid42527361,
year = {2026},
author = {Persson, J and Geffre, G},
title = {Mind Matters: South Dakota's Public Health Response to Dementia.},
journal = {South Dakota medicine : the journal of the South Dakota State Medical Association},
volume = {79},
number = {6},
pages = {262-264},
pmid = {42527361},
issn = {0038-3317},
mesh = {Humans ; South Dakota/epidemiology ; *Dementia/diagnosis/therapy/epidemiology ; *Public Health ; Caregivers ; },
abstract = {Alzheimer's disease and related dementias pose a growing health and societal challenge in South Dakota, where dementia ranks as the fourth leading cause of death. The burden extends beyond patients to families and caregivers, many of whom report significant emotional, financial, and physical strain. In response, the South Dakota Department of Health introduced the South Dakota Healthy Brain Initiative. This statewide effort aims to improve brain health across the lifespan, promote earlier detection, strengthen caregiver support, and prepare the state's workforce to better respond to the needs of people living with dementia. The initiative promotes routine cognitive assessment, distributes clinical toolkits to assist with diagnosis and care planning, and expands access to community-based services. A core focus of the initiative is health equity, particularly for rural, tribal, and underserved communities that face significant barriers to care. Through strengthened partnerships among public health, healthcare systems, and aging services, the Healthy Brain Initiative seeks to reduce disparities, support caregivers, and improve outcomes for individuals and families affected by dementia across South Dakota.},
}

Humans
South Dakota/epidemiology
*Dementia/diagnosis/therapy/epidemiology
*Public Health
Caregivers